Synchrotron FTIR imaging of OH in quartz mylonites

NASA Astrophysics Data System (ADS)

Kronenberg, Andreas K.; Hasnan, Hasnor F. B.; Holyoke, Caleb W., III; Law, Richard D.; Liu, Zhenxian; Thomas, Jay B.

2017-10-01

Previous measurements of water in deformed quartzites using conventional Fourier transform infrared spectroscopy (FTIR) instruments have shown that water contents of larger grains vary from one grain to another. However, the non-equilibrium variations in water content between neighboring grains and within quartz grains cannot be interrogated further without greater measurement resolution, nor can water contents be measured in finely recrystallized grains without including absorption bands due to fluid inclusions, films, and secondary minerals at grain boundaries.Synchrotron infrared (IR) radiation coupled to a FTIR spectrometer has allowed us to distinguish and measure OH bands due to fluid inclusions, hydrogen point defects, and secondary hydrous mineral inclusions through an aperture of 10 µm for specimens > 40 µm thick. Doubly polished infrared (IR) plates can be prepared with thicknesses down to 4-8 µm, but measurement of small OH bands is currently limited by strong interference fringes for samples < 25 µm thick, precluding measurements of water within individual, finely recrystallized grains. By translating specimens under the 10 µm IR beam by steps of 10 to 50 µm, using a software-controlled x - y stage, spectra have been collected over specimen areas of nearly 4.5 mm2. This technique allowed us to separate and quantify broad OH bands due to fluid inclusions in quartz and OH bands due to micas and map their distributions in quartzites from the Moine Thrust (Scotland) and Main Central Thrust (Himalayas).Mylonitic quartzites deformed under greenschist facies conditions in the footwall to the Moine Thrust (MT) exhibit a large and variable 3400 cm-1 OH absorption band due to molecular water, and maps of water content corresponding to fluid inclusions show that inclusion densities correlate with deformation and recrystallization microstructures. Quartz grains of mylonitic orthogneisses and paragneisses deformed under amphibolite conditions in the hanging wall to the Main Central Thrust (MCT) exhibit smaller broad OH bands, and spectra are dominated by sharp bands at 3595 to 3379 cm-1 due to hydrogen point defects that appear to have uniform, equilibrium concentrations in the driest samples. The broad OH band at 3400 cm-1 in these rocks is much less common. The variable water concentrations of MT quartzites and lack of detectable water in highly sheared MCT mylonites challenge our understanding of quartz rheology. However, where water absorption bands can be detected and compared with deformation microstructures, OH concentration maps provide information on the histories of deformation and recovery, evidence for the introduction and loss of fluid inclusions, and water weakening processes.

Synchrotron FTIR imaging of OH in quartz mylonites

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kronenberg, Andreas K.; Hasnan, Hasnor F. B.; Holyoke III, Caleb W.

Previous measurements of water in deformed quartzites using conventional Fourier transform infrared spectroscopy (FTIR) instruments have shown that water contents of larger grains vary from one grain to another. However, the non-equilibrium variations in water content between neighboring grains and within quartz grains cannot be interrogated further without greater measurement resolution, nor can water contents be measured in finely recrystallized grains without including absorption bands due to fluid inclusions, films, and secondary minerals at grain boundaries.Synchrotron infrared (IR) radiation coupled to a FTIR spectrometer has allowed us to distinguish and measure OH bands due to fluid inclusions, hydrogen point defects,more » and secondary hydrous mineral inclusions through an aperture of 10 µm for specimens > 40 µm thick. Doubly polished infrared (IR) plates can be prepared with thicknesses down to 4–8 µm, but measurement of small OH bands is currently limited by strong interference fringes for samples < 25 µm thick, precluding measurements of water within individual, finely recrystallized grains. By translating specimens under the 10 µm IR beam by steps of 10 to 50 µm, using a software-controlled x- y stage, spectra have been collected over specimen areas of nearly 4.5 mm 2. This technique allowed us to separate and quantify broad OH bands due to fluid inclusions in quartz and OH bands due to micas and map their distributions in quartzites from the Moine Thrust (Scotland) and Main Central Thrust (Himalayas).Mylonitic quartzites deformed under greenschist facies conditions in the footwall to the Moine Thrust (MT) exhibit a large and variable 3400 cm -1 OH absorption band due to molecular water, and maps of water content corresponding to fluid inclusions show that inclusion densities correlate with deformation and recrystallization microstructures. Quartz grains of mylonitic orthogneisses and paragneisses deformed under amphibolite conditions in the hanging wall to the Main Central Thrust (MCT) exhibit smaller broad OH bands, and spectra are dominated by sharp bands at 3595 to 3379 cm -1 due to hydrogen point defects that appear to have uniform, equilibrium concentrations in the driest samples. The broad OH band at 3400 cm -1 in these rocks is much less common. The variable water concentrations of MT quartzites and lack of detectable water in highly sheared MCT mylonites challenge our understanding of quartz rheology. However, where water absorption bands can be detected and compared with deformation microstructures, OH concentration maps provide information on the histories of deformation and recovery, evidence for the introduction and loss of fluid inclusions, and water weakening processes.« less

A stream sediment geochemical survey of the Ganga River headwaters in the Garhwal Himalaya

USGS Publications Warehouse

Mukherjee, P.K.; Purohit, K.K.; Saini, N.K.; Khanna, P.P.; Rathi, M.S.; Grosz, A.E.

2007-01-01

This study models geochemical and adjunct geologic data to define provinces that are favorable for radioactive-mineral exploration. A multi-element bed-sediment geochemical survey of streams was carried out in the headwaters region of the Ganga River in northern India. Overall median values for uranium and thorium (3.6 and 13.8 ppm; maxima of 4.8 and 19.0 ppm and minima of 3.1 and 12.3 ppm respectively) exceed average upper crustal abundances (2.8 and 10.7 ppm) for these radioactive elements. Anomalously high values reach up to 8.3 and 30.1 ppm in thrust zone rocks, and 11.4 and 22.5 ppm in porphyroids. At their maxima, these abundances are nearly four- and three-fold (respectively) enriched in comparison to average crustal abundances for these rock types. Deformed, metamorphosed and sheared rocks are characteristic of the main central thrust zone (MCTZ). These intensively mylonitized rocks override and juxtapose porphyritic (PH) and proterozoic metasedimentary rock sequences (PMS) to the south. Granitoid rocks, the major protoliths for mylonites, as well as metamorphosed rocks in the MCT zone are naturally enriched in radioelements; high values associated with sheared and mylonitized zones are coincident with reports of radioelement mineralization and with anomalous radon concentrations in soils. The radioelement abundance as well as REE abundance shows a northward enrichment trend consistent with increasing grade of metamorphism indicating deformation-induced remobilization of these elements. U and Th illustrate good correlation with REEs but not with Zr. This implies that zircon is not a principal carrier of U and Th within the granitoid-dominant thrust zone and that other radioelement-rich secondary minerals are present in considerable amounts. Thus, the relatively flat, less fractionated, HREE trend is also not entirely controlled by zircon. The spatial correlation of geologic boundary zones (faults, sheared zones) with geochemical and with geophysical (Rn) anomalies infers ore mineralization by hydrothermal processes generated during multiple episodes of deformation and thrusting. The geologic setting of the anomalies also suggests that crystalline rocks (MCT Zone) along the nearly 2500 km length of the LesserHimalayan belt, where in the vicinity of thrust and fault zones, have potential for radioelement mineralization. Zones of higher concentrations of radioelements delineated by this study and locations of anomalous radon discharge determined by other investigations may indicate a potential health hazard over the long term. However, the low human population density precludes direct manifestation of health effects attributable to chronic exposure to these radioelements; however, the magnitude of natural concentrations suggests the need for more detailed studies and monitoring. Copyright ?? 2007 by The Geochemical Society of Japan.

Superior Effects of High-Intensity Interval Training vs. Moderate Continuous Training on Arterial Stiffness in Episodic Migraine: A Randomized Controlled Trial.

PubMed

Hanssen, Henner; Minghetti, Alice; Magon, Stefano; Rossmeissl, Anja; Papadopoulou, Athina; Klenk, Christopher; Schmidt-Trucksäss, Arno; Faude, Oliver; Zahner, Lukas; Sprenger, Till; Donath, Lars

2017-01-01

Background: Migraine is associated with increased cardiovascular risk and vascular dysfunction. Since aerobic exercise can reduce cardiovascular risk, the present randomized controlled trail aimed at investigating the effects of high-intensity interval training (HIT) vs. moderate continuous exercise training (MCT) on arterial stiffness in migraine patients. Methods: Forty-eight episodic migraineurs were initially enrolled in the study. 37 patients [female: 30; age: 37 ( SD : 10); BMI: 23.1 (5.2); Migraine days per month: 3.7 (2.5)] completed the intervention. Central blood pressure, pulse wave reflection, and aortic pulse wave velocity (PWV) were obtained by an oscillometric monitor. Incremental treadmill exercise testing yielded maximal and submaximal fitness parameters. Participants were randomly assigned to either HIT, MCT, or a control group (CON). The intervention groups trained twice a week over a 12-week intervention period. Results: After adjustment for between-group baseline differences, a moderate meaningful overall reduction of the augmentation index at 75 min -1 heart rate (AIx@75) was observed [partial eta squared ([Formula: see text]) = 0.16; p = 0.06]. With 91% likely beneficial effects, HIT was more effective in reducing AIx@75 than MCT [HIT: pre 22.0 (9.7), post 14.9 (13.0), standardized mean difference (SMD) = 0.62; MCT: pre 16.6 (8.5), post 21.3 (10.4), SMD -0.49]. HIT induced a relevant reduction in central systolic blood pressure [cSBP: pre 118 (23) mmHg, post 110 (16) mmHg, SMD = 0.42] with a 59% possibly beneficial effect compared to CON, while MCT showed larger effects in lowering central diastolic blood pressure [pre 78 (7) mmHg, post 74 (7) mmHg, SMD = 0.61], presenting 60% possibly beneficial effects compared to CON. Central aortic PWV showed no changes in any of the three groups. Migraine days were reduced more successfully by HIT than MCT (HIT: SMD = 1.05; MCT: SMD = 0.43). Conclusion: HIT but not MCT reduces AIx@75 as a measure of pulse wave reflection and indirect marker of systemic arterial stiffness. Both exercise modalities beneficially affect central blood pressure. HIT proved to be an effective complementary treatment option to reduce vascular dysfunction and blood pressure in migraineurs.

Burial of thermally perturbed Lesser Himalayan mid-crust: Evidence from petrochemistry and P-T estimation of the western Arunachal Himalaya, India

NASA Astrophysics Data System (ADS)

Goswami-Banerjee, Sriparna; Bhowmik, Santanu Kumar; Dasgupta, Somnath; Pant, Naresh Chandra

2014-11-01

In this work, we establish a dual prograde P-T path of the Lesser Himalayan Sequence (LHS) rocks from the western Arunachal Himalaya (WAH). The investigated metagranites, garnet- and kyanite-zone metapelites of the LHS are part of an inverted metamorphic sequence (IMS) that is exposed on the footwall side of the Main Central Thrust (MCT). Integrated petrographic, mineral chemistry, geothermobarometric (conventional and isopleth intersection methods) and P-T pseudosection modeling studies reveal a near isobaric (at P ~ 8-9 kbar) peak Barrovian metamorphism with increase in TMax from ~ 560 °C in the metagranite through ~ 590-600 °C in the lower and middle garnet-zone to ~ 600-630 °C in the upper garnet- and kyanite-zone rocks. The metamorphic sequence of the LHS additionally records a pre-Barrovian near isobaric thermal gradient in the mid crust (at ~ 6 kbar) from ~ 515 °C (in the middle garnet zone) to ~ 560-580 °C (in the upper garnet- and kyanite zone, adjoining the Main Central Thrust). Further burial (along steep dP/dT gradient) to a uniform depth corresponding to ~ 8-9 kbar and prograde heating of the differentially heated LHS rocks led to the formation of near isobaric metamorphic field gradient in the Barrovian metamorphic zones of the WAH. A combined critical taper and channel flow model is presented to explain the inverted metamorphic zonation of the rocks of the WAH.

­Oligo-Miocene Monazite Ages in the Lesser Himalaya Sequence, Arunachal Pradesh, India; Geological Content of Age Variations

NASA Astrophysics Data System (ADS)

Clarke, G. L.; Bhowmik, S. K.; Ireland, T. R.; Aitchison, J. C.; Chapman, S. L.; Kent, L.

2016-12-01

A telescoped and inverted greenschist-upper amphibolite facies sequence in the in the Siyom Valley of eastern Arunachal Pradesh is tectonically overlain by an upright (grade decreasing upward) granulite to lower amphibolite facies sequence. Such grade relationships would normally attribute the boundary to a Main Central Thrust (MCT) structure, and predict a change from underlying Lesser Himalaya Sequence (LHS) to Greater Himalaya Sequence rocks across the boundary. However, all pelitic and psammitic samples have similar detrital zircon age spectra, involving c. 2500, 1750-1500, 1200 and 1000 Ma Gondwanan populations correlated with the LHS. Isograds are broadly parallel to a penetrative NW-dipping S2 foliation, developed contemporaneously with the inversion. Garnet growth in garnet, staurolite and kyanite zone schists beneath the thrust commenced at P>8 kbar and T≈550°C, before syn- to post-S2 heating of staurolite and kyanite zone rocks to T≈640°C at P≈8.5 kbar, most probably at c. 18.5 Ma. Kyanite-rutile-garnet migmatite immediately above the thrust records peak conditions of P≈10 kbar and T≈750°C and c. 21.5 Ma monazite ages. Complexity in c. 21-1000 Ma monazite ages in overlying amphibolite facies schists reflects the patchy recrystallization of detrital grains, intra-grain complexity being dependent on whole rock composition, metamorphic grade and evolition. Slip on a SE-propagating thrust was likely contemporaneous with early Miocene metamorphism, based on the distribution of structure, metamorphic textures, and overlap of age relationships. It is inferred to have initially controlled the uplift of granulite to mid-crustal levels between 22 and 19 Ma, thermal relaxation within a disrupted LHS metamorphic profile inducing a post-S2 thermal peak in lower grade footwall rocks.

Tectonic and metamorphic discontinuities in the Greater Himalayan Sequence in Central Himalaya: in-sequence shearing by accretion from the Indian plate

NASA Astrophysics Data System (ADS)

Carosi, Rodolfo

2016-04-01

The Greater Himalayan Sequence (GHS) is the main metamorphic unit of the Himalayas, stretching for over 2400 km, bounded to the South by the Main Central Thrust (MCT) and to the North by the South Tibetan Detachment (STD) whose contemporanous activity controlled its exhumation between 23 and 17 Ma (Godin et al., 2006). Several shear zones and/or faults have been recognized within the GHS, usually regarded as out of sequence thrusts. Recent investigations, using a multitechnique approach, allowed to recognize a tectonic and metamorphic discontinuity, localized in the mid GHS, with a top-to-the SW sense of shear (Higher Himalayan Discontinuity: HHD) (Carosi et al., 2010; Montomoli et al., 2013). U-(Th)-Pb in situ monazite ages provide temporal constraint of the acitivity of the HHD from ~ 27-25 Ma to 18-17 Ma. Data on the P and T evolution testify that this shear zone affected the tectono-metamorphic evolution of the belt and different P and T conditions have been recorded in the hanging-wall and footwall of the HHD. The HHD is a regional tectonic feature running for more than 700 km, dividing the GHS in two different portions (Iaccarino et al., 2015; Montomoli et al., 2015). The occurrence of even more structurally higher contractional shear zone in the GHS (above the HHD): the Kalopani shear zone (Kali Gandaki valley, Central Nepal), active from ~ 41 to 30 Ma (U-Th-Pb on monazite) points out to a more complex deformation pattern in the GHS characterized by in sequence shearing. The actual proposed models of exhumation of the GHS, based exclusively on the MCT and STD activities, are not able to explain the occurrence of the HHD and other in-sequence shear zones. Any model of the tectonic and metamorphic evolution of the GHS should account for the occurrence of the tectonic and metamorphic discontinuities within the GHS and its consequences on the metamorphic paths and on the assembly of Himalayan belt. References Godin L., Grujic D., Law, R. D. & Searle, M. P. 2006. Geol. Soc. London Sp. Publ., 268, 1-23. Carosi R., Montomoli C., Rubatto D. & Visonà D. 2010. Tectonics, 29, TC4029. Iaccarino S., Montomoli C., Carosi R., Massonne H-J., Langone A., Visonà D. 2015. Lithos, 231, 103-121. Montomoli C., Iaccarino S., Carosi R., Langone A. & Visonà D. 2013. Tectonophysics 608, 1349-1370, doi:10.1016/j.tecto.2013.06.006. Montomoli C., Carosi R., Iaccarino S. 2015. Geol. Soc. London Sp. Publ., 412, 25-41.

Fluid-assisted Ductile Deformation in the Main Central Thrust, Sikkim Himalaya, India

NASA Astrophysics Data System (ADS)

Chakraborty, S.; Majumdar, A. S.; Mukul, M.

2016-12-01

The disparity in the definition and position of the Main Central Thrust (MCT), a major crustal scale fault-zone (FZ) in the Himalaya have hindered detailed studies on its geometry, kinematics, deformation mechanisms and role of fluid aiding in deformation within the MCTFZ. To resolve these ambiguities, we have mapped the MCT using a ductile fault-zone model, characterized by a fault core (FC) of maximum-grain size reduction flanked by relatively less deformed hanging-wall (HWDZ) and footwall damage zones (FWDZ). The mineralogical and compositional variations from protolith to FC are analysed by X-Ray Diffraction (XRD) and X-Ray Fluorescence (XRF). The study reveals in the structurally lowest exposure near Rongli, Sikkim, India the MCTFZ outcrops with 120m thick FC flanked by 1.2km HWDZ and 1.3km FWDZ. The modal proportion of quartz progressively increases from protolith ( 32%) to the FC ( 90%), coupled with decrease in proportion of feldspars ( 60% to 9%) and biotite ( 6% to 2%). Volume-conservative mass balance calculations show an increase in SiO2 concentration (in wt%), coupled with a decrease in other major and minor element concentrations like Al2O3, TiO2, Fe2O3, Na2O and CaO in the FC relative to the protolith composition. Similar trend was observed for Al2O3 and TiO2 conservative isocon analyses with volume gain of 138% and 55% respectively from the protolith to the FC. The extensive mineralogical and compositional changes from the protolith to the FC indicate fluid-induced element mobilization in the MCTFZ. Evidences of reaction softening, as observed by the transformation of mechanically stronger minerals like feldspar and hornblende to weaker sericite and biotite respectively, attest to deformation in the presence of fluid. The fluid enriches the FC with easily deformable quartz along with reduction in proportion of relatively less deformable feldspar. The presence of fluid facilitates deformation of quartz in MCTFZ at lower temperatures by hydrolytic weakening thus, supplementing deformation by grain-size sensitive dislocation-creep. These results from the present study indicate that fluids have played a significant role in the evolution of the MCTFZ, fluid induced mobility of perceived immobile elements like Al2O3 and TiO2 and probable cause of the ambiguous Ar-Ar ages in the region.

Tissue-Specific Expression of Monocarboxylate Transporters during Fasting in Mice

PubMed Central

Schutkowski, Alexandra; Wege, Nicole; Stangl, Gabriele I.; König, Bettina

2014-01-01

Monocarboxylates such as pyruvate, lactate and ketone bodies are crucial for energy supply of all tissues, especially during energy restriction. The transport of monocarboxylates across the plasma membrane of cells is mediated by monocarboxylate transporters (MCTs). Out of 14 known mammalian MCTs, six isoforms have been functionally characterized to transport monocarboxylates and short chain fatty acids (MCT1-4), thyroid hormones (MCT8, -10) and aromatic amino acids (MCT10). Knowledge on the regulation of the different MCT isoforms is rare. In an attempt to get more insights in regulation of MCT expression upon energy deprivation, we carried out a comprehensive analysis of tissue specific expression of five MCT isoforms upon 48 h of fasting in mice. Due to the crucial role of peroxisome proliferator-activated receptor (PPAR)-α as a central regulator of energy metabolism and as known regulator of MCT1 expression, we included both wildtype (WT) and PPARα knockout (KO) mice in our study. Liver, kidney, heart, small intestine, hypothalamus, pituitary gland and thyroid gland of the mice were analyzed. Here we show that the expression of all examined MCT isoforms was markedly altered by fasting compared to feeding. Expression of MCT1, MCT2 and MCT10 was either increased or decreased by fasting dependent on the analyzed tissue. MCT4 and MCT8 were down-regulated by fasting in all examined tissues. However, PPARα appeared to have a minor impact on MCT isoform regulation. Due to the fundamental role of MCTs in transport of energy providing metabolites and hormones involved in the regulation of energy homeostasis, we assumed that the observed fasting-induced adaptations of MCT expression seem to ensure an adequate energy supply of tissues during the fasting state. Since, MCT isoforms 1–4 are also necessary for the cellular uptake of drugs, the fasting-induced modifications of MCT expression have to be considered in future clinical care algorithms. PMID:25390336

Microseismicity, tectonics and seismic potential in the Western Himalayan segment, NW Himalaya, India

NASA Astrophysics Data System (ADS)

Parija, Mahesh Prasad; Kumar, Sushil; Tiwari, V. M.; Rao, N. Purnachandra; Kumar, Narendra; Biswal, Shubhasmita; Singh, Ishwar

2018-06-01

The tectonics and seismic potential of the western Himalayan segment (30-33°N; 76-80°E) of the NW Himalayan (India) region have been determined in this study. 423 earthquakes were located in the NW Himalaya between 2004 and 2013 using more than 4495 P and 4453 S differential travel times to determine the moment tensors for 8 (Mw ≥ 4.0) of these earthquakes using their broadband regional waveforms. The geometry of the Main Himalayan Thrust (MHT) plane which varies along the strike of the Himalaya in flat and ramp segments with a dip ranging between ∼2.5 to ∼4° to ∼19° below the Himalayan Frontal Thrust (HFT) in the south to the South Tibetan Detachment (STD) in the north has also been deduced in this study. Two crustal ramps were reported in this study with a depth variance below the Main Central Thrust (MCT) and to the South Tibetan Detachment (STD) between 12 to 22 km and 28 to 40 km depth respectively. The estimated earthquake potential prevailing in the western Himalayan seismic gap lying between the epicentral zone of the 1905 Kangra earthquake and the 1975 Kinnaur earthquake reveals that the total amount of energy released since the last great event is only a fraction (3-5%) of the accommodated energy i.e.1.1E+28 dyne-cm/yr. This suggests that if an earthquake hits this NW Himalayan segment in the future, its magnitude might be around Mw ≥ 8.0.

Involvement of monocarboxylate transporter 1 (SLC16A1) in the uptake of l-lactate in human astrocytes.

PubMed

Ideno, Masaya; Kobayashi, Masaki; Sasaki, Shotaro; Futagi, Yuya; Narumi, Katsuya; Furugen, Ayako; Iseki, Ken

2018-01-01

Astrocytes, the most abundant glial cells in the central nervous system (CNS), help neurons survive. Monocarboxylate transporters (MCTs) are reported to transport l-lactate, which is important for CNS physiology and cognitive function. However, it remains unclear which MCT isoform is functionally expressed by human astrocytes. The aim of this study was to establish the contribution of each MCT isoform to l-lactate transport in human astrocytes. The function of l-lactate transport was studied using NHA cells as a human astrocyte model and radiolabeled l-lactate. The expression of MCT in human astrocytes was detected by immunohistochemistry staining. The cellular uptake of l-lactate was found to be pH- and concentration-dependent with a Km value for l-lactate uptake of 0.64mM. This Km was similar to what has been previously established for MCT1-mediated l-lactate uptake. α-Cyano-4- hydroxycinnamate (CHC) and 5-oxoproline, which are both MCT1 inhibitors, were found to significantly inhibit the uptake of l-lactate, suggesting MCT1 is primarily responsible for l-lactate transport. Moreover, MCT1 protein was expressed in human astrocytes. pH-dependent l-lactate transport is mediated by MCT1 in human astrocytes. Copyright © 2017 Elsevier Inc. All rights reserved.

Thermal metamorphism of the Arunachal Himalaya, India: Raman thermometry and thermochronological constraints on the tectono-thermal evolution

NASA Astrophysics Data System (ADS)

Mathew, George; De Sarkar, Sharmistha; Pande, Kanchan; Dutta, Suryendu; Ali, Shakir; Rai, Apritam; Netrawali, Shilpa

2013-09-01

Determination of the peak thermal condition is vital in order to understand tectono-thermal evolution of the Himalayan belt. The Lesser Himalayan Sequence (LHS) in the Western Arunachal Pradesh, being rich in carbonaceous material (CM), facilitates the determination of peak metamorphic temperature based on Raman spectroscopy of carbonaceous material (RSCM). In this study, we have used RSCM method of Beyssac et al. (J Metamorph Geol 20:859-871, 2002a) and Rahl et al. (Earth Planet Sci Lett 240:339-354, 2005) to estimate the thermal history of LHS and Siwalik foreland from the western Arunachal Pradesh. The study indicates that the temperature of 700-800 °C in the Greater Himalayan Sequence (GHS) decreases to 650-700 °C in the main central thrust zone (MCTZ) and decreases further to <200 °C in the Mio-Pliocene sequence of Siwaliks. The work demonstrates greater reliability of Rahl et al.'s (Earth Planet Sci Lett 240:339-354, 2005) RSCM method for temperatures >600 and <340 °C. We show that the higher and lower zones of Bomdila Gneiss (BG) experienced temperature of ~600 °C and exhumed at different stages along the Bomdila Thrust (BT) and Upper Main Boundary Thrust (U.MBT). Pyrolysis analysis of the CM together with the Fission Track ages from upper Siwaliks corroborates the RSCM thermometry estimate of ~240 °C. The results indicate that the Permian sequence north of Lower MBT was deposited at greater depths (>12 km) than the upper Siwalik sediments to its south at depths <8 km before they were exhumed. The 40Ar/39Ar ages suggest that the upper zones of Se La evolved ~13-15 Ma. The middle zone exhumed at ~11 Ma and lower zone close to ~8 Ma indicating erosional unroofing of the MCT sheet. The footwall of MCTZ cooled between 6 and 8 Ma. Analyses of P-T path imply that LHS between MCT and U.MBT zone falls within the kyanite stability field with near isobaric condition. At higher structural level, the temperatures increase gradually with P-T conditions in the sillimanite stability field. The near isothermal (700-800 °C) condition in the GHS, isobaric condition in the MCTZ together with T-t path evidence of GHS that experienced relatively longer duration of near peak temperatures and rapid cooling towards MCTZ, compares the evolution of GHS and inverted metamorphic gradient closely to channel flow predictions.

Design of power electronics for TVC EMA systems

NASA Technical Reports Server (NTRS)

Nelms, R. Mark

1993-01-01

The Composite Development Division of the Propulsion Laboratory at Marshall Space Flight Center (MSFC) is currently developing a class of electromechanical actuators (EMA's) for use in space transportation applications such as thrust vector control (TVC) and propellant control valves (PCV). These high power servomechanisms will require rugged, reliable, and compact power electronic modules capable of modulating several hundred amperes of current at up to 270 volts. MSFC has selected the brushless dc motor for implementation in EMA's. This report presents the results of an investigation into the applicability of two new technologies, MOS-controlled thyristors (MCT's) and pulse density modulation (PDM), to the control of brushless dc motors in EMA systems. MCT's are new power semiconductor devices, which combine the high voltage and current capabilities of conventional thyristors and the low gate drive requirements of metal oxide semiconductor field effect transistors (MOSFET's). The commanded signals in a PDM system are synthesized using a series of sinusoidal pulses instead of a series of square pulses as in a pulse width modulation (PWM) system. A resonant dc link inverter is employed to generate the sinusoidal pulses in the PDM system. This inverter permits zero-voltage switching of all semiconductors which reduces switching losses and switching stresses. The objectives of this project are to develop and validate an analytical model of the MCT device when used in high power motor control applications and to design, fabricate, and test a prototype electronic circuit employing both MCT and PDM technology for controlling a brushless dc motor.

Upregulation of autophagy and glycolysis markers in keloid hypoxic-zone fibroblasts: Morphological characteristics and implications.

PubMed

Ryoko, Okuno; Ito, Yuko; Eid, Nabil; Otsuki, Yoshinori; Kondo, Yoichi; Ueda, Koichi

2018-05-29

Keloid is a fibro-proliferative skin disorder with tumor-like behavior and dependence on anaerobic glycolysis (the Warburg effect), but its exact pathogenesis is unknown. Although autophagy is widely accepted as a lysosomal pathway for cell survival and cellular homeostasis (specifically upon exposure to stressors such as hypoxia), very few studies have investigated the involvement of autophagy and related glycolytic effectors in keloidogenesis. Here the authors examined the expression and cellular localization of autophagy proteins (LC3, pan-cathepsin), glycolytic markers (LDH, MCT1, MCT4) and the transcription factor HIF isoforms in human keloid samples using immunohistochemical analysis and double-labeling immunofluorescence methods. Based on H&E staining and expression of CD31, keloids were compartmentalized into hypoxic central and normoxic marginal zones. Vimentin-expressing fibroblasts in the central zone exhibited greater autophagy than their marginal-zone counterparts, as evidenced by increased LC3 puncta formation and co-localization with lysosomal pan-cathepsin. LDH (a lactate stimulator), MCT4 (a lactate exporter) and HIF-1 α expression levels were also higher in central-zone fibroblasts. Conversely, HIF-2 α expression was upregulated in fibroblasts and endothelial cells of the peripheral zone, while MCT1 was expressed in both zones. Taken together, these observations suggest that upregulation of autophagy and glycolysis markers in keloid hypoxic-zone fibroblasts may indicate a prosurvival mechanism allowing the extrusion of lactate to marginal-zone fibroblasts via metabolic coupling. The authors believe this is the first report on differential expression of autophagic and glycolytic markers in keloid-zone fibroblasts. The study results indicate that autophagy inhibitors and MCT4 blockers may have therapeutic implications in keloid treatment.

Monocarboxylate transporter-dependent mechanism confers resistance to oxygen- and glucose-deprivation injury in astrocyte-neuron co-cultures.

PubMed

Gao, Chen; Zhou, Liya; Zhu, Wenxia; Wang, Hongyun; Wang, Ruijuan; He, Yunfei; Li, Zhiyun

2015-05-06

Hypoxic and low-glucose stressors contribute to neuronal death in many brain diseases. Astrocytes are anatomically well-positioned to shield neurons from hypoxic injury. During hypoxia/ischemia, lactate released from astrocytes is taken up by neurons and stored for energy. This process is mediated by monocarboxylate transporters (MCTs) in the central nervous system. In the present study, we investigated the ability of astrocytes to protect neurons from oxygen- and glucose-deprivation (OGD) injury via an MCT-dependent mechanism in vitro. Primary cultures of neurons, astrocytes, and astrocytes-neurons derived from rat hippocampus were subjected to OGD, MCT inhibition with small interfering (si)RNA. Cell survival and expression of MCT4, MCT2, glial fibrillary acidic protein, and neuronal nuclear antigen were evaluated. OGD significantly increased cell death in neuronal cultures and up-regulated MCT4 expression in astrocyte cultures, but no increased cell death was observed in neuron-astrocyte co-cultures or astrocyte cultures. However, neuronal cell death in co-cultures was increased by exposure to MCT4- or MCT2-specific siRNA, and this effect was attenuated by the addition of lactate into the extracellular medium of neuronal cultures prior to OGD. These findings demonstrate that resistance to OGD injury in astrocyte-neuron co-cultures occurs via an MCT-dependent mechanism. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Deficiency in Monocarboxylate Transporter 1 (MCT1) in Mice Delays Regeneration of Peripheral Nerves following Sciatic Nerve Crush

PubMed Central

Morrison, Brett M.; Tsingalia, Akivaga; Vidensky, Svetlana; Lee, Youngjin; Jin, Lin; Farah, Mohamed H.; Lengacher, Sylvain; Magistretti, Pierre J.; Pellerin, Luc; Rothstein, Jeffrey D.

2014-01-01

Peripheral nerve regeneration following injury occurs spontaneously, but many of the processes require metabolic energy. The mechanism of energy supply to axons has not previously been determined. In the central nervous system, monocarboxylate transporter 1 (MCT1), expressed in oligodendroglia, is critical for supplying lactate or other energy metabolites to axons. In the current study, MCT1 is shown to localize within the peripheral nervous system to perineurial cells, dorsal root ganglion neurons, and Schwann cells by MCT1 immunofluorescence and MCT1 tdTomato BAC reporter mice. To investigate whether MCT1 is necessary for peripheral nerve regeneration, sciatic nerves in MCT1 heterozygous null mice are crushed and peripheral nerve regeneration quantified electrophysiologically and anatomically. Compound muscle action potential (CMAP) recovery is delayed from a median of 21 days in wild-type mice to greater than 38 days in MCT1 heterozygote null mice. In fact, half of the MCT1 heterozygote null mice have no recovery of CMAP at 42 days, while all of the wild-type mice recovered. In addition, muscle fibers remain 40% more atrophic and neuromuscular junctions 40% more denervated at 42 days post-crush in the MCT1 heterozygote null mice than wild-type mice. The delay in nerve regeneration is not only in motor axons, as the number of regenerated axons in the sural sensory nerve of MCT1 heterozygote null mice at 4 weeks and tibial mixed sensory and motor nerve at 3 weeks is also significantly reduced compared to wild-type mice. This delay in regeneration may be partly through failed Schwann cell function, as there is reduced early phagocytosis of myelin debris and remyelination of axon segments. These data for the first time demonstrate that MCT1 is critical for regeneration of both sensory and motor axons in mice following sciatic nerve crush. PMID:25447940

Deficiency in monocarboxylate transporter 1 (MCT1) in mice delays regeneration of peripheral nerves following sciatic nerve crush.

PubMed

Morrison, Brett M; Tsingalia, Akivaga; Vidensky, Svetlana; Lee, Youngjin; Jin, Lin; Farah, Mohamed H; Lengacher, Sylvain; Magistretti, Pierre J; Pellerin, Luc; Rothstein, Jeffrey D

2015-01-01

Peripheral nerve regeneration following injury occurs spontaneously, but many of the processes require metabolic energy. The mechanism of energy supply to axons has not previously been determined. In the central nervous system, monocarboxylate transporter 1 (MCT1), expressed in oligodendroglia, is critical for supplying lactate or other energy metabolites to axons. In the current study, MCT1 is shown to localize within the peripheral nervous system to perineurial cells, dorsal root ganglion neurons, and Schwann cells by MCT1 immunofluorescence in wild-type mice and tdTomato fluorescence in MCT1 BAC reporter mice. To investigate whether MCT1 is necessary for peripheral nerve regeneration, sciatic nerves of MCT1 heterozygous null mice are crushed and peripheral nerve regeneration was quantified electrophysiologically and anatomically. Compound muscle action potential (CMAP) recovery is delayed from a median of 21 days in wild-type mice to greater than 38 days in MCT1 heterozygote null mice. In fact, half of the MCT1 heterozygote null mice have no recovery of CMAP at 42 days, while all of the wild-type mice recovered. In addition, muscle fibers remain 40% more atrophic and neuromuscular junctions 40% more denervated at 42 days post-crush in the MCT1 heterozygote null mice than wild-type mice. The delay in nerve regeneration is not only in motor axons, as the number of regenerated axons in the sural sensory nerve of MCT1 heterozygote null mice at 4 weeks and tibial mixed sensory and motor nerve at 3 weeks is also significantly reduced compared to wild-type mice. This delay in regeneration may be partly due to failed Schwann cell function, as there is reduced early phagocytosis of myelin debris and remyelination of axon segments. These data for the first time demonstrate that MCT1 is critical for regeneration of both sensory and motor axons in mice following sciatic nerve crush. Copyright © 2014 Elsevier Inc. All rights reserved.

1H magnetic resonance spectroscopy in monocarboxylate transporter 8 gene deficiency.

PubMed

Sijens, Paul E; Rödiger, Lars A; Meiners, Linda C; Lunsing, Roelineke J

2008-05-01

In monocarboxylate transporter 8 (MCT8) gene deficiency, a syndrome combining thyroid and neurological abnormalities, the central nervous system has not yet been characterized by magnetic resonance (MR) spectroscopy. We studied whether the degree of dysmyelinization in MCT8 gene deficiency according to MR imaging (MRI) is coupled with abnormalities in brain metabolism. MRI and MR spectroscopy of the brain were performed twice in two MCT8 gene deficiency patients, for the first time at age 8-10 months and for the second time at age 17-28 months. The results were compared with those obtained in controls of a similar age. Compared with controls, young children with MCT8 show choline and myoinositol level increases and N-acetyl aspartate decreases in supraventricular gray and white matter, phenomena associated with the degree of dysmyelinization according to MRI. MCT8 gene deficiency results in deviant myelinization and general atrophy, which is substantiated by the MR spectroscopy findings of increased choline and myoinositol levels and decreased N-acetyl aspartate. The observations suggest that different mutations in the MCT8 gene lead to differences in the severity of the clinical spectrum, dysmyelinization, and MR spectroscopy-detectable changes in brain metabolism.

MCT8 deficiency: extrapyramidal symptoms and delayed myelination as prominent features.

PubMed

Tonduti, Davide; Vanderver, Adeline; Berardinelli, Angela; Schmidt, Johanna L; Collins, Christin D; Novara, Francesca; Genni, Antonia Di; Mita, Alda; Triulzi, Fabio; Brunstrom-Hernandez, Janice E; Zuffardi, Orsetta; Balottin, Umberto; Orcesi, Simona

2013-06-01

Monocarboxylate transporter 8 (MCT8) deficiency is an X-linked disorder resulting from an impairment of the transcellular transportation of thyroid hormones. Within the central nervous system thyroid hormone transport is normally mediated by MCT8. Patients are described as affected by a static or slowly progressive clinical picture which consists of variable degrees of mental retardation, hypotonia, spasticity, ataxia and involuntary movements, occasionally paroxysmal. The authors describe the clinical and neuroradiological picture of 3 males patients with marked delayed brain myelination and in which the clinical picture was dominated by early onset nonparoxysmal extrapyramidal symptoms. In one subject a novel mutation is described.

Aftershock stress analysis of the April 2015 Mw 7.8 Gorkha earthquake from the NAMASTE project

NASA Astrophysics Data System (ADS)

Pant, M.; Velasco, A. A.; Karplus, M. S.; Patlan, E.; Ghosh, A.; Nabelek, J.; Kuna, V. M.; Sapkota, S. N.; Adhikari, L. B.; Klemperer, S. L.

2016-12-01

Continental collision between the Indian plate and the Eurasian plate, converging at 45 mm/yr, has uplifted the northern part of Nepal forming the Himalaya. Because of this convergence, the region has experienced large, devastating earthquakes, including the 1934 Mw 8.4 Nepal-Bihar earthquake and two recent earthquakes on April 25, 2015 Mw 7.8 (Gorkha earthquake) and May 12, 2015 Mw 7.2. These quakes killed thousands of people and caused billion dollars of property loss. Despite some recent geologic and geophysical studies of this area, many tectonic questions remain unanswered. Shortly after the Gorkha earthquake, we deployed a seismic network, NAMASTE (Nepal Array Measuring Aftershock Seismicity Trailing Earthquake), to study the aftershocks of these two large events. Our network included 45 different seismic stations (16 short period, 25 broadband, and 4 strong motion sensors) that spanned the Gorkha rupture area. The deployment extends from south of the Main Frontal Thrust (MFT) to the Main Central Thrust region (MCT), and it to recorded aftershocks for more than ten months from June 2015 to May 2016. We are leveraging high-precision earthquake locations by measuring and picking P-wave first-motion arrival polarity to develop a catalog of focal mechanisms for the larger aftershocks. We will use this catalog to correlate the seismicity and stress related of the Indo-Eurasian plate margin, hoping to address questions regarding the complex fault geometries and future earthquake hazards at this plate margin.

Age-Dependent Changes of Monocarboxylate Transporter 8 Availability in the Postnatal Murine Retina

PubMed Central

Henning, Yoshiyuki; Szafranski, Karol

2016-01-01

The thyroid hormones (TH) triiodothyronine (T3) and its prohormone thyroxine (T4) are crucial for retinal development and function, and increasing evidence points at TH dysregulation as a cause for retinal degenerative diseases. Thus, precise regulation of retinal TH supply is required for proper retinal function, but knowledge on these mechanisms is still fragmentary. Several transmembrane transporters have been described as key regulators of TH availability in target tissues of which the monocarboxylate transporter 8 (MCT8), a high affinity transporter for T4 and T3, plays an essential role in the central nervous system. Moreover, in the embryonic chicken retina, MCT8 is highly expressed, but the postnatal availability of MCT8 in the mammalian retina was not reported to date. In the present study, spatiotemporal retinal MCT8 availability was examined in mice of different age. For this purpose, we quantified expression levels of Mct8 via Real-Time Reverse-Transcriptase PCR in mouse eyecups (C57BL/6) of juvenile and adult age groups. Additionally, age-dependent MCT8 protein levels were quantified via Western blotting and localized via immunofluorescence confocal microscopy. While no difference in Mct8 expression levels could be detected between age groups, MCT8 protein levels in juvenile animals were about two times higher than in adult animals based on Western blot analyses. Immunohistochemical analyses showed that MCT8 immunoreactivity in the eyecup was restricted to the retina and the retinal pigment epithelium. In juvenile mice, MCT8 was broadly observed along the apical membrane of the retinal pigment epithelium, tightly surrounding photoreceptor outer segments. Distinct immunopositive staining was also detected in the inner nuclear layer and the ganglion cell layer. However, in adult specimens, immunoreactivity visibly declined in all layers, which was in line with Western blot analyses. Since MCT8 was abundantly present in juvenile and about twofold lower in adult retinae, our findings suggest a pivotal role of MCT8 especially during postnatal maturation. The present study provides novel insights into age-dependent retinal TH supply, which might help to understand different aspects regarding retinal development, function, and disorders. PMID:27616981

Pliocene episodic exhumation and the significance of the Munsiari thrust in the northwestern Himalaya

NASA Astrophysics Data System (ADS)

Stübner, Konstanze; Grujic, Djordje; Dunkl, István; Thiede, Rasmus; Eugster, Patricia

2018-01-01

The Himalayan thrust belt comprises three in-sequence foreland-propagating orogen-scale faults, the Main Central thrust, the Main Boundary thrust, and the Main Frontal thrust. Recently, the Munsiari-Ramgarh-Shumar thrust system has been recognized as an additional, potentially orogen-scale shear zone in the proximal footwall of the Main Central thrust. The timing of the Munsiari, Ramgarh, and Shumar thrusts and their role in Himalayan tectonics are disputed. We present 31 new zircon (U-Th)/He ages from a profile across the central Himachal Himalaya in the Beas River area. Within a ∼40 km wide belt northeast of the Kullu-Larji-Rampur window, ages ranging from 2.4 ± 0.4 Ma to 5.4 ± 0.9 Ma constrain a distinct episode of rapid Pliocene to Present exhumation; north and south of this belt, zircon (U-Th)/He ages are older (7.0 ± 0.7 Ma to 42.2 ± 2.1 Ma). We attribute the Pliocene rapid exhumation episode to basal accretion to the Himalayan thrust belt and duplex formation in the Lesser Himalayan sequence including initiation of the Munsiari thrust. Pecube thermokinematic modelling suggests exhumation rates of ∼2-3 mm/yr from 4-7 to 0 Ma above the duplex contrasting with lower (<0.3 mm/yr) middle-late Miocene exhumation rates. The Munsiari thrust terminates laterally in central Himachal Pradesh. In the NW Indian Himalaya, the Main Central thrust zone comprises the sheared basal sections of the Greater Himalayan sequence and the mylonitic 'Bajaura nappe' of Lesser Himalayan affinity. We correlate the Bajaura unit with the Ramgarh thrust sheet in Nepal based on similar lithologies and the middle Miocene age of deformation. The Munsiari thrust in the central Himachal Himalaya is several Myr younger than deformation in the Bajaura and Ramgarh thrust sheets. Our results illustrate the complex and segmented nature of the Munsiari-Ramgarh-Shumar thrust system.

Was Himalayan normal faulting triggered by initiation of the Ramgarh-Munsiari Thrust?

USGS Publications Warehouse

Robinson, Delores M.; Pearson, Ofori N.

2013-01-01

The Ramgarh–Munsiari thrust is a major orogen-scale fault that extends for more than 1,500 km along strike in the Himalayan fold-thrust belt. The fault can be traced along the Himalayan arc from Himachal Pradesh, India, in the west to eastern Bhutan. The fault is located within the Lesser Himalayan tectonostratigraphic zone, and it translated Paleoproterozoic Lesser Himalayan rocks more than 100 km toward the foreland. The Ramgarh–Munsiari thrust is always located in the proximal footwall of the Main Central thrust. Northern exposures (toward the hinterland) of the thrust sheet occur in the footwall of the Main Central thrust at the base of the high Himalaya, and southern exposures (toward the foreland) occur between the Main Boundary thrust and Greater Himalayan klippen. Although the metamorphic grade of rocks within the Ramgarh–Munsiari thrust sheet is not significantly different from that of Greater Himalayan rock in the hanging wall of the overlying Main Central thrust sheet, the tectonostratigraphic origin of the two different thrust sheets is markedly different. The Ramgarh–Munsiari thrust became active in early Miocene time and acted as the roof thrust for a duplex system within Lesser Himalayan rocks. The process of slip transfer from the Main Central thrust to the Ramgarh–Munsiari thrust in early Miocene time and subsequent development of the Lesser Himalayan duplex may have played a role in triggering normal faulting along the South Tibetan Detachment system.

Action of specific thyroid hormone receptor α(1) and β(1) antagonists in the central and peripheral regulation of thyroid hormone metabolism in the rat.

PubMed

van Beeren, Hermina C; Kwakkel, Joan; Ackermans, Mariëtte T; Wiersinga, Wilmar M; Fliers, Eric; Boelen, Anita

2012-12-01

The iodine-containing drug amiodarone (Amio) and its noniodine containing analogue dronedarone (Dron) are potent antiarrhythmic drugs. Previous in vivo and in vitro studies have shown that the major metabolite of Amio, desethylamiodarone, acts as a thyroid hormone receptor (TR) α(1) and β(1) antagonist, whereas the major metabolite of Dron debutyldronedarone acts as a selective TRα(1) antagonist. In the present study, Amio and Dron were used as tools to discriminate between TRα(1) or TRβ(1) regulated genes in central and peripheral thyroid hormone metabolism. Three groups of male rats received either Amio, Dron, or vehicle by daily intragastric administration for 2 weeks. We assessed the effects of treatment on triiodothyronine (T(3)) and thyroxine (T(4)) plasma and tissue concentrations, deiodinase type 1, 2, and 3 mRNA expressions and activities, and thyroid hormone transporters monocarboxylate transporter 8 (MCT8), monocarboxylate transporter 10 (MCT10), and organic anion transporter 1C1 (OATP1C1). Amio treatment decreased serum T(3), while serum T(4) and thyrotropin (TSH) increased compared to Dron-treated and control rats. At the central level of the hypothalamus-pituitary-thyroid axis, Amio treatment decreased hypothalamic thyrotropin releasing hormone (TRH) expression, while increasing pituitary TSHβ and MCT10 mRNA expression. Amio decreased the pituitary D2 activity. By contrast, Dron treatment resulted in decreased hypothalamic TRH mRNA expression only. Upon Amio treatment, liver T(3) concentration decreased substantially compared to Dron and control rats (50%, p<0.01), but liver T(4) concentration was unaffected. In addition, liver D1, mRNA, and activity decreased, while the D3 activity and mRNA increased. Liver MCT8, MCT10, and OATP1C1 mRNA expression were similar between groups. Our results suggest an important role for TRα1 in the regulation of hypothalamic TRH mRNA expression, whereas TRβ plays a dominant role in pituitary and liver thyroid hormone metabolism.

CD147 Required for Corneal Endothelial Lactate Transport

PubMed Central

Li, Shimin; Nguyen, Tracy T.; Bonanno, Joseph A.

2014-01-01

Purpose. CD147/basigin is a chaperone for lactate:H+ cotransporters (monocarboxylate transporters) MCT1 and MCT4. We tested the hypothesis that MCT1 and -4 in corneal endothelium contribute to lactate efflux from stroma to anterior chamber and that silencing CD147 expression would cause corneal edema. Methods. CD147 was silenced via small interfering ribonucleic acid (siRNA) transfection of rabbit corneas ex vivo and anterior chamber lenti-small hairpin RNA (shRNA) pseudovirus in vivo. CD147 and MCT expression was examined by Western blot, RT-PCR, and immunofluorescence. Functional effects were examined by measuring lactate-induced cell acidification, corneal lactate efflux, [lactate], central cornea thickness (CCT), and Azopt (a carbonic anhydrase inhibitor) sensitivity. Results. In ex vivo corneas, 100 nM CD147 siRNA reduced CD147, MCT1, and MCT4 expression by 85%, 79%, and 73%, respectively, while MCT2 expression was unaffected. CD147 siRNA decreased lactate efflux from 3.9 ± 0.81 to 1.5 ± 0.37 nmol/min, increased corneal [lactate] from 19.28 ± 7.15 to 56.73 ± 8.97 nmol/mg, acidified endothelial cells (pHi = 6.83 ± 0.07 vs. 7.19 ± 0.09 in control), and slowed basolateral lactate-induced acidification from 0.0034 ± 0.0005 to 0.0012 ± 0.0005 pH/s, whereas apical acidification was unchanged. In vivo, CD147 shRNA increased CCT by 28.1 ± 0.9 μm at 28 days; Azopt increased CCT to 24.4 ± 3.12 vs. 12.0 ± 0.48 μm in control, and corneal [lactate] was 47.63 ± 6.29 nmol/mg in shCD147 corneas and 17.82 ± 4.93 nmol/mg in paired controls. Conclusions. CD147 is required for the expression of MCT1 and MCT4 in the corneal endothelium. Silencing CD147 slows lactate efflux, resulting in stromal lactate accumulation and corneal edema, consistent with lactate efflux as a significant component of the corneal endothelial pump. PMID:24970254

CD147 required for corneal endothelial lactate transport.

PubMed

Li, Shimin; Nguyen, Tracy T; Bonanno, Joseph A

2014-06-26

CD147/basigin is a chaperone for lactate:H(+) cotransporters (monocarboxylate transporters) MCT1 and MCT4. We tested the hypothesis that MCT1 and -4 in corneal endothelium contribute to lactate efflux from stroma to anterior chamber and that silencing CD147 expression would cause corneal edema. CD147 was silenced via small interfering ribonucleic acid (siRNA) transfection of rabbit corneas ex vivo and anterior chamber lenti-small hairpin RNA (shRNA) pseudovirus in vivo. CD147 and MCT expression was examined by Western blot, RT-PCR, and immunofluorescence. Functional effects were examined by measuring lactate-induced cell acidification, corneal lactate efflux, [lactate], central cornea thickness (CCT), and Azopt (a carbonic anhydrase inhibitor) sensitivity. In ex vivo corneas, 100 nM CD147 siRNA reduced CD147, MCT1, and MCT4 expression by 85%, 79%, and 73%, respectively, while MCT2 expression was unaffected. CD147 siRNA decreased lactate efflux from 3.9 ± 0.81 to 1.5 ± 0.37 nmol/min, increased corneal [lactate] from 19.28 ± 7.15 to 56.73 ± 8.97 nmol/mg, acidified endothelial cells (pHi = 6.83 ± 0.07 vs. 7.19 ± 0.09 in control), and slowed basolateral lactate-induced acidification from 0.0034 ± 0.0005 to 0.0012 ± 0.0005 pH/s, whereas apical acidification was unchanged. In vivo, CD147 shRNA increased CCT by 28.1 ± 0.9 μm at 28 days; Azopt increased CCT to 24.4 ± 3.12 vs. 12.0 ± 0.48 μm in control, and corneal [lactate] was 47.63 ± 6.29 nmol/mg in shCD147 corneas and 17.82 ± 4.93 nmol/mg in paired controls. CD147 is required for the expression of MCT1 and MCT4 in the corneal endothelium. Silencing CD147 slows lactate efflux, resulting in stromal lactate accumulation and corneal edema, consistent with lactate efflux as a significant component of the corneal endothelial pump. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

Hybrid channel flow-type mechanisms in the Greater Himalayan Sequence (West Nepal): new constraints from vorticity of flow and quartz petrofabric analyses.

NASA Astrophysics Data System (ADS)

Frassi, Chiara

2016-04-01

Three main tectono-metamorphic units are classically recognized along the Himalayan belt: the Lesser Himalayan (LH), the Greater Himalayan sequence (GHS) and the Tibetan Sedimentary sequence (TSS). The GHS may be interpreted as a low-viscosity tabular body of mid-crustal rocks extruded southward in Miocene times beneath the Tibetan plateau between two parallel and opposite-sense crustal-scale shear zones: the Main Central thrust at the base, and the South Tibetan Detachment system at the top. The pre-/syn-shearing mineral assemblage documented within these crustal-scale shear zones indicates that the metamorphic grade increases toward the core of the GHS producing an inverted and a normal thermal gradient respectively on the top and on the bottom of the slab. In addition, thermal profiles estimated using both petrology- and microstructures/fabrics-based thermometers indicate that the metamorphic isograds are condensed. Although horizontal extension and vorticity estimates collected across the GHS could be strongly biased by the criteria used to define the map position of the MCT, published vorticity data document general shear flow (1>Wk>0) within the slab with a pure-shear component of flow slightly predominant within the core of the GHS whereas the simple-shear component seems to dominate at the top of the slab. The lower boundary of the GHS records a general shear flow with a comparable contribution of simple and pure shearing. The associated crustal extrusion is compatible with Couette - Poiseuille velocity flow profile as assumed in crustal-scale channel flow-type models In this study, the quartz c-axis petrofabrics, vorticity and deformation-temperature studies are integrated with microstructures and metamorphic studies to individuate the location of the MCT and to document the spatial distribution of ductile deformation patterns across the lower portion of the GHS exposed in the Chaudabise river valley in western Nepal. My results indicate that the Main Central Thrust is located ˜5 km structurally below the previous mapped locations. Deformation temperature increases up structural section from ˜450°C to ˜650°C and overlaps with peak metamorphic temperature indicating that penetrative shearing was responsible for the exhumation of the GHS occurred at "close" to peak metamorphic conditions. I interpreted the telescoping and the inversion of the paleo-isotherms at the base of the GHS as produced mainly by a sub-simple shearing (Wm = 0.88-1) pervasively distributed through the lower portion of the GHS. The results are consistent with hybrid channel flow-type models where the boundary between lower and upper portions of the GHS, broadly corresponding to the tectono-metamorphic discontinuity recently documented in west Nepal, represents the limit between buried material, affected by dominant simple shearing, and exhumed material affected by a general flow dominates by pure shearing. This interpretation is consistent with the recent models suggesting the simultaneous operation of channel flow- and critical wedge-type processes at different structural depth.

A study on the involvement of GABA-transaminase in MCT induced pulmonary hypertension.

PubMed

Lingeshwar, Poorella; Kaur, Gurpreet; Singh, Neetu; Singh, Seema; Mishra, Akanksha; Shukla, Shubha; Ramakrishna, Rachumallu; Laxman, Tulsankar Sachin; Bhatta, Rabi Sankar; Siddiqui, Hefazat H; Hanif, Kashif

2016-02-01

Increased sympathetic nervous system (SNS) activity is associated with cardiovascular diseases but its role has not been completely explored in pulmonary hypertension (PH). Increased SNS activity is distinguished by elevated level of norepinephrine (NE) and activity of γ-Amino butyric acid Transminase (GABA-T) which degrades GABA, an inhibitory neurotransmitter within the central and peripheral nervous system. Therefore, we hypothesized that GABA-T may contribute in pathophysiology of PH by modulating level of GABA and NE. The effect of daily oral administration of GABA-T inhibitor, Vigabatrin (GVG, 50 and 75 mg/kg/day, 35 days) was studied following a single subcutaneous administration of monocrotaline (MCT, 60 mg/kg) in male SD rats. The pressure and hypertrophy of right ventricle (RV), oxidative stress, inflammation, pulmonary vascular remodelling were assessed after 35 days in MCT treated rats. The expression of GABA-T and HIF-1α was studied in lung tissue. The levels of plasma NE (by High performance liquid chromatography coupled with electrochemical detector; HPLC-ECD) and lung GABA (by liquid chromatography-mass spectrometry) were also estimated. GVG at both doses significantly attenuated increased in pressure (35.82 ± 4.80 mm Hg, p < 0.001; 28.37 ± 3.32 mm Hg, p < 0.001 respectively) and hypertrophy of RV, pulmonary vascular remodelling, oxidative stress and inflammation in lungs of MCT exposed rats. GVG also reduced the expression of GABA-T and HIF-1α in MCT treated rats. Increased NE level and decreased GABA level was also reversed by GVG in MCT exposed rats. GABA-T plays an important role in PH by modulating SNS activity and may be considered as a therapeutic target in PH. Copyright © 2015 Elsevier Ltd. All rights reserved.

Monocarboxylate Transporters MCT1 and MCT4 Regulate Migration and Invasion of Pancreatic Ductal Adenocarcinoma Cells.

PubMed

Kong, Su Chii; Nøhr-Nielsen, Asbjørn; Zeeberg, Katrine; Reshkin, Stephan Joel; Hoffmann, Else Kay; Novak, Ivana; Pedersen, Stine Falsig

2016-08-01

Novel treatments for pancreatic ductal adenocarcinoma (PDAC) are severely needed. The aim of this work was to explore the roles of H-lactate monocarboxylate transporters 1 and 4 (MCT1 and MCT4) in PDAC cell migration and invasiveness. Monocarboxylate transporter expression, localization, activity, and function were explored in human PDAC cells (MIAPaCa-2, Panc-1, BxPC-3, AsPC-1) and normal human pancreatic ductal epithelial (HPDE) cells, by quantitative polymerase chain reaction, immunoblotting, immunocytochemistry, lactate flux, migration, and invasion assays. MCT1 and MCT4 (messenger RNA, protein) were robustly expressed in all PDAC lines, localizing to the plasma membrane. Lactate influx capacity was highest in AsPC-1 cells and lowest in HPDE cells and was inhibited by the MCT inhibitor α-cyano-4-hydroxycinnamate (4-CIN), MCT1/MCT2 inhibitor AR-C155858, or knockdown of MCT1 or MCT4. PDAC cell migration was largely unaffected by MCT1/MCT2 inhibition or MCT1 knockdown but was reduced by 4-CIN and by MCT4 knockdown (BxPC-3). Invasion measured in Boyden chamber (BxPC-3, Panc-1) and spheroid outgrowth (BxPC-3) assays was attenuated by 4-CIN and AR-C155858 and by MCT1 or MCT4 knockdown. Human PDAC cells exhibit robust MCT1 and MCT4 expression and partially MCT1- and MCT4-dependent lactate flux. PDAC cell migration is partially dependent on MCT4; and invasion, on MCT1 and MCT4. Inhibition of MCT1 and MCT4 may have clinical relevance in PDAC.

Dillon cutoff-Basement-involved tectonic link between the disturbed belt of west-central Montana and the overthrust belt of extreme southwestern Montana

NASA Astrophysics Data System (ADS)

O'Neill, J. Michael; Schmidt, Christopher J.; Genovese, Paul W.

1990-11-01

The front of the Cordilleran fold and thrust belt in western Montana follows the disturbed belt in the north, merges with the southwest Montana transverse zone in the west-central part of the region, and in southwestern Montana is marked by a broad zone characterized by complex interaction between thrust belt structures and basement uplifts. The front margin of the thrust belt in Montana reflects mainly thin-skinned tectonic features in the north, an east-trending lateral ramp that curves southwest in the central part into the Dillon cutoff, an oblique-slip, thick-skinned displacement transfer zone that cuts through basement rocks of the Lima recess, and a zone of overlap between thin- and thick-skinned thrusts in extreme southwestern Montana. The transverse ramp and basement-involved thrust faults are controlled by Proterozoic structures.

Stratigraphy and structure of the Sevier thrust belt and proximal foreland-basin system in central Utah: A transect from the Sevier Desert to the Wasatch Plateau

USGS Publications Warehouse

Lawton, T.F.; Sprinkel, D.A.; Decelles, P.G.; Mitra, G.; Sussman, A.J.; Weiss, M.P.

1997-01-01

The Sevier orogenic belt in central Utah comprises four north-northwest trending thrust plates and two structural culminations that record crustal shortening and uplift in late Mesozoic and early Tertiary time. Synorogenic clastic rocks, mostly conglomerate and sandstone, exposed within the thrust belt were deposited in wedge-top and foredeep depozones within the proximal part of the foreland-basin system. The geologic relations preserved between thrust structures and synorogenic deposits demonstrate a foreland-breaking sequence of thrust deformation that was modified by minor out-of-sequence thrust displacement. Structural culminations in the interior part of the thrust belt deformed and uplifted some of the thrust sheets following their emplacement. Strata in the foreland basin indicate that the thrust sheets of central Utah were emplaced between latest Jurassic and Eocene time. The oldest strata of the foredeep depozone (Cedar Mountain Formation) are Neocomian and were derived from the hanging wall of the Canyon Range thrust. The foredeep depozone subsided most rapidly during Albian through Santonian or early Campanian time and accumulated about 2.5 km of conglomeratic strata (Indianola Group). The overlying North Horn Formation accumulated in a wedge-top basin from the Campanian to the Eocene and records propagation of the Gunnison thrust beneath the former foredeep. The Canyon Range Conglomerate of the Canyon Mountains, equivalent to the Indianola Group and the North Horn Formation, was deposited exclusively in a wedge-top setting on the Canyon Range and Pavant thrust sheets. This field trip, a three day, west-to-east traverse of the Sevier orogenic belt in central Utah, visits localities where timing of thrust structures is demonstrated by geometry of cross-cutting relations, growth strata associated with faults and folds, or deformation of foredeep deposits. Stops in the Canyon Mountains emphasize geometry of late structural culminations and relationships of the Canyon Range thrust to growth strata deposited in the wedge-top depozone. Stops in the San Pitch Mountains illustrate deposits of the foredeep depozone and younger, superjacent wedge-top depozone. Stops in the Sanpete Valley and western part of the Wasatch Plateau examine the evolution of the foreland-basin system from foredeep to wedge-top during growth of a triangle zone near the front of the Gunnison thrust.

Structure and regional significance of the Late Permian(?) Sierra Nevada - Death Valley thrust system, east-central California

USGS Publications Warehouse

Stevens, C.H.; Stone, P.

2005-01-01

An imbricate system of north-trending, east-directed thrust faults of late Early Permian to middle Early Triassic (most likely Late Permian) age forms a belt in east-central California extending from the Mount Morrison roof pendant in the eastern Sierra Nevada to Death Valley. Six major thrust faults typically with a spacing of 15-20 km, original dips probably of 25-35??, and stratigraphic throws of 2-5 km compose this structural belt, which we call the Sierra Nevada-Death Valley thrust system. These thrusts presumably merge into a de??collement at depth, perhaps at the contact with crystalline basement, the position of which is unknown. We interpret the deformation that produced these thrusts to have been related to the initiation of convergent plate motion along a southeast-trending continental margin segment probably formed by Pennsylvanian transform truncation. This deformation apparently represents a period of tectonic transition to full-scale convergence and arc magmatism along the continental margin beginning in the Late Triassic in central California. ?? 2005 Elsevier B.V. All rights reserved.

MCT1 modulates cancer cell pyruvate export and growth of tumors that co-express MCT1 and MCT4

PubMed Central

Hong, Candice Sun; Graham, Nicholas A.; Gu, Wen; Camacho, Carolina Espindola; Mah, Vei; Maresh, Erin L.; Alavi, Mohammed; Bagryanova, Lora; Krotee, Pascal A. L.; Gardner, Brian K.; Behbahan, Iman Saramipoor; Horvath, Steve; Chia, David; Mellinghoff, Ingo K.; Hurvitz, Sara A.; Dubinett, Steven M.; Critchlow, Susan E.; Kurdistani, Siavash K.; Goodglick, Lee; Braas, Daniel; Graeber, Thomas G.; Christofk, Heather R.

2016-01-01

SUMMARY Monocarboxylate Transporter 1 (MCT1) inhibition is thought to block tumor growth through disruption of lactate transport and glycolysis. Here we show MCT1 inhibition impairs proliferation of glycolytic breast cancer cells co-expressing MCT1 and MCT4 via disruption of pyruvate rather than lactate export. MCT1 expression is elevated in glycolytic breast tumors, and high MCT1 expression predicts poor prognosis in breast and lung cancer patients. Acute MCT1 inhibition reduces pyruvate export but does not consistently alter lactate transport or glycolytic flux in breast cancer cells that co-express MCT1 and MCT4. Despite the lack of glycolysis impairment, MCT1 loss-of-function decreases breast cancer cell proliferation and blocks growth of mammary fat pad xenograft tumors. Our data suggest MCT1 expression is elevated in glycolytic cancers to promote pyruvate export, which when inhibited enhances oxidative metabolism and reduces proliferation. This study presents an alternative molecular consequence of MCT1 inhibitors further supporting their use as anti-cancer therapeutics. PMID:26876179

MCT1 Modulates Cancer Cell Pyruvate Export and Growth of Tumors that Co-express MCT1 and MCT4.

PubMed

Hong, Candice Sun; Graham, Nicholas A; Gu, Wen; Espindola Camacho, Carolina; Mah, Vei; Maresh, Erin L; Alavi, Mohammed; Bagryanova, Lora; Krotee, Pascal A L; Gardner, Brian K; Behbahan, Iman Saramipoor; Horvath, Steve; Chia, David; Mellinghoff, Ingo K; Hurvitz, Sara A; Dubinett, Steven M; Critchlow, Susan E; Kurdistani, Siavash K; Goodglick, Lee; Braas, Daniel; Graeber, Thomas G; Christofk, Heather R

2016-02-23

Monocarboxylate transporter 1 (MCT1) inhibition is thought to block tumor growth through disruption of lactate transport and glycolysis. Here, we show MCT1 inhibition impairs proliferation of glycolytic breast cancer cells co-expressing MCT1 and MCT4 via disruption of pyruvate rather than lactate export. MCT1 expression is elevated in glycolytic breast tumors, and high MCT1 expression predicts poor prognosis in breast and lung cancer patients. Acute MCT1 inhibition reduces pyruvate export but does not consistently alter lactate transport or glycolytic flux in breast cancer cells that co-express MCT1 and MCT4. Despite the lack of glycolysis impairment, MCT1 loss-of-function decreases breast cancer cell proliferation and blocks growth of mammary fat pad xenograft tumors. Our data suggest MCT1 expression is elevated in glycolytic cancers to promote pyruvate export that when inhibited, enhances oxidative metabolism and reduces proliferation. This study presents an alternative molecular consequence of MCT1 inhibitors, further supporting their use as anti-cancer therapeutics. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

CD147 regulates the expression of MCT1 and lactate export in multiple myeloma cells

PubMed Central

Walters, Denise K; Arendt, Bonnie K; Jelinek, Diane F

2013-01-01

Increased use of the glycolytic pathway, even in the presence of oxygen, has recently been recognized as a key characteristic of malignant cells. However, the glycolytic phenotype results in increased lactic acid production and, in order to prevent cellular acidosis, tumor cells must increase proton efflux via upregulation of pH regulators such as proton-pumps, sodium-proton exchangers, and/or monocarboxylate transporters (MCT) (e.g., MCT1, MCT4). Interestingly, expression of MCT1 and MCT4 has been previously shown to be dependent upon expression of the transmembrane glycoprotein CD147. Recently, we demonstrated that primary patient multiple myeloma (MM) cells and human MM cell lines (HMCLs) overexpress CD147. Therefore, the goal of the current study was to specifically determine if MCT1 and MCT4 were also overexpressed in MM cells. RT-PCR analysis demonstrated both primary patient MM cells and HMCLs overexpress MCT1 and MCT4 mRNA. Notably, primary MM cells or HMCLs were found to express variable levels of MCT1 and/or MCT4 at the protein level despite CD147 expression. In those HMCLs positive for MCT1 and/or MCT4 protein expression, MCT1 and/or MCT4 were found to be associated with CD147. Specific siRNA-mediated downregulation of MCT1 but not MCT4 resulted in decreased HMCL proliferation, decreased lactate export, and increased cellular media pH. However, western blot analysis revealed that downregulation of MCT1 also downregulated CD147 and vice versa despite no effect on mRNA levels. Taken together, these data demonstrate the association between MCT1 and CD147 proteins in MM cells and importance of their association for lactate export and proliferation in MM cells. PMID:24013424

CD147 regulates the expression of MCT1 and lactate export in multiple myeloma cells.

PubMed

Walters, Denise K; Arendt, Bonnie K; Jelinek, Diane F

2013-10-01

Increased use of the glycolytic pathway, even in the presence of oxygen, has recently been recognized as a key characteristic of malignant cells. However, the glycolytic phenotype results in increased lactic acid production and, in order to prevent cellular acidosis, tumor cells must increase proton efflux via upregulation of pH regulators such as proton-pumps, sodium-proton exchangers, and/or monocarboxylate transporters (MCT) (e.g., MCT1, MCT4). Interestingly, expression of MCT1 and MCT4 has been previously shown to be dependent upon expression of the transmembrane glycoprotein CD147. Recently, we demonstrated that primary patient multiple myeloma (MM) cells and human MM cell lines (HMCLs) overexpress CD147. Therefore, the goal of the current study was to specifically determine if MCT1 and MCT4 were also overexpressed in MM cells. RT-PCR analysis demonstrated both primary patient MM cells and HMCLs overexpress MCT1 and MCT4 mRNA. Notably, primary MM cells or HMCLs were found to express variable levels of MCT1 and/or MCT4 at the protein level despite CD147 expression. In those HMCLs positive for MCT1 and/or MCT4 protein expression, MCT1 and/or MCT4 were found to be associated with CD147. Specific siRNA-mediated downregulation of MCT1 but not MCT4 resulted in decreased HMCL proliferation, decreased lactate export, and increased cellular media pH. However, western blot analysis revealed that downregulation of MCT1 also downregulated CD147 and vice versa despite no effect on mRNA levels. Taken together, these data demonstrate the association between MCT1 and CD147 proteins in MM cells and importance of their association for lactate export and proliferation in MM cells.

The long N-terminus of the human monocarboxylate transporter 8 is a target of ubiquitin-dependent proteasomal degradation which regulates protein expression and oligomerization capacity.

PubMed

Zwanziger, Denise; Schmidt, Mathias; Fischer, Jana; Kleinau, Gunnar; Braun, Doreen; Schweizer, Ulrich; Moeller, Lars Christian; Biebermann, Heike; Fuehrer, Dagmar

2016-10-15

Monocarboxylate transporter 8 (MCT8) equilibrates thyroid hormones between the extra- and the intracellular sides. MCT8 exists either with a short or a long N-terminus, but potential functional differences between both variants are yet not known. We, therefore, generated MCT8 constructs which are different in N-terminal length: MCT8(1-613), MCT8(25-613), MCT8(49-613) and MCT8(75-613). The M75G substitution prevents translation of MCT8(75-613) and ensures expression of full-length MCT8 protein. The K56G substitution was made to prevent ubiquitinylation. Cell-surface expression, localization and proteasomal degradation were investigated using C-terminally GFP-tagged MCT8 constructs (HEK293 and MDCK1 cells) and oligomerization capacity was determined using N-terminally HA- and C-terminally FLAG-tagged MCT8 constructs (COS7 cells). MCT8(1-613)-GFP showed a lower protein expression than the shorter MCT8(75-613)-GFP protein. The proteasome inhibitor lactacystin increased MCT8(1-613)-GFP protein amount, suggesting proteasomal degradation of MCT8 with the long N-terminus. Ubiquitin conjugation of MCT8(1-613)-GFP was found by immuno-precipitation. A diminished ubiquitin conjugation caused by K56G substitution resulted in increased MCT8(1-613)-GFP protein expression. Sandwich ELISA was performed to investigate if the bands at higher molecular weight observed in Western blot analysis are due to MCT8 oligomerization, which was indeed shown. Our data imply a role of the long N-terminus of MCT8 as target of ubiquitin-dependent proteasomal degradation affecting MCT8 amount and subsequently oligomerization capacity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A simple topography-driven, calibration-free runoff generation model

NASA Astrophysics Data System (ADS)

Gao, H.; Birkel, C.; Hrachowitz, M.; Tetzlaff, D.; Soulsby, C.; Savenije, H. H. G.

2017-12-01

Determining the amount of runoff generation from rainfall occupies a central place in rainfall-runoff modelling. Moreover, reading landscapes and developing calibration-free runoff generation models that adequately reflect land surface heterogeneities remains the focus of much hydrological research. In this study, we created a new method to estimate runoff generation - HAND-based Storage Capacity curve (HSC) which uses a topographic index (HAND, Height Above the Nearest Drainage) to identify hydrological similarity and partially the saturated areas of catchments. We then coupled the HSC model with the Mass Curve Technique (MCT) method to estimate root zone storage capacity (SuMax), and obtained the calibration-free runoff generation model HSC-MCT. Both the two models (HSC and HSC-MCT) allow us to estimate runoff generation and simultaneously visualize the spatial dynamic of saturated area. We tested the two models in the data-rich Bruntland Burn (BB) experimental catchment in Scotland with an unusual time series of the field-mapped saturation area extent. The models were subsequently tested in 323 MOPEX (Model Parameter Estimation Experiment) catchments in the United States. HBV and TOPMODEL were used as benchmarks. We found that the HSC performed better in reproducing the spatio-temporal pattern of the observed saturated areas in the BB catchment compared with TOPMODEL which is based on the topographic wetness index (TWI). The HSC also outperformed HBV and TOPMODEL in the MOPEX catchments for both calibration and validation. Despite having no calibrated parameters, the HSC-MCT model also performed comparably well with the calibrated HBV and TOPMODEL, highlighting the robustness of the HSC model to both describe the spatial distribution of the root zone storage capacity and the efficiency of the MCT method to estimate the SuMax. Moreover, the HSC-MCT model facilitated effective visualization of the saturated area, which has the potential to be used for broader geoscience studies beyond hydrology.

Mutations of the Thyroid Hormone Transporter MCT8 Cause Prenatal Brain Damage and Persistent Hypomyelination

PubMed Central

López-Espíndola, Daniela; Morales-Bastos, Carmen; Grijota-Martínez, Carmen; Liao, Xiao-Hui; Lev, Dorit; Sugo, Ella; Verge, Charles F.; Refetoff, Samuel

2014-01-01

Context: Mutations in the MCT8 (SLC16A2) gene, encoding a specific thyroid hormone transporter, cause an X-linked disease with profound psychomotor retardation, neurological impairment, and abnormal serum thyroid hormone levels. The nature of the central nervous system damage is unknown. Objective: The objective of the study was to define the neuropathology of the syndrome by analyzing brain tissue sections from MCT8-deficient subjects. Design: We analyzed brain sections from a 30th gestational week male fetus and an 11-year-old boy and as controls, brain tissue from a 30th and 28th gestational week male and female fetuses, respectively, and a 10-year-old girl and a 12-year-old boy. Methods: Staining with hematoxylin-eosin and immunostaining for myelin basic protein, 70-kDa neurofilament, parvalbumin, calbindin-D28k, and synaptophysin were performed. Thyroid hormone determinations and quantitative PCR for deiodinases were also performed. Results: The MCT8-deficient fetus showed a delay in cortical and cerebellar development and myelination, loss of parvalbumin expression, abnormal calbindin-D28k content, impaired axonal maturation, and diminished biochemical differentiation of Purkinje cells. The 11-year-old boy showed altered cerebellar structure, deficient myelination, deficient synaptophysin and parvalbumin expression, and abnormal calbindin-D28k expression. The MCT8-deficient fetal cerebral cortex showed 50% reduction of thyroid hormones and increased type 2 deiodinase and decreased type 3 deiodinase mRNAs. Conclusions: The following conclusions were reached: 1) brain damage in MCT8 deficiency is diffuse, without evidence of focal lesions, and present from fetal stages despite apparent normality at birth; 2) deficient hypomyelination persists up to 11 years of age; and 3) the findings are compatible with the deficient action of thyroid hormones in the developing brain caused by impaired transport to the target neural cells. PMID:25222753

Inhibition of monocarboxylate transporter 2 in the retrotrapezoid nucleus in rats – a test of the astrocyte-neuron lactate-shuttle hypothesis

PubMed Central

Erlichman, J.S.; Hewitt, Amy; Damon, Tracey L.; Hart, Michael; Kurascz, Jennifer; Li, A.; Leiter, J.C.

2009-01-01

The astrocyte-neuronal lactate shuttle hypothesis (ANLSH) posits that lactate released from astrocytes into the extracellular space is metabolized by neurons. The lactate released should alter extracellular pH (pHe), and changes in pH in central chemosensory regions of the brainstem stimulate ventilation. Therefore, we assessed the impact of disrupting the lactate shuttle by administering 100 microM α-cyano-4-hydroxy-cinnamate (4-CIN), a dose that blocks the neuronal monocarboxylate transporter (MCT2), but not the astrocytic MCTs (MCT1 and MCT4). Administration of 4-CIN focally in the retrotrapezoid nucleus (RTN), a medullary central chemosensory nucleus, increased ventilation and decreased pHe in intact animals. In medullary brain slices, 4-CIN reduced astrocytic intracellular pH (pHi) slightly, but alkalinized neuronal pHi. Nonetheless, pHi fell significantly in both cell types when they were treated with exogenous lactate, although 100 microM 4-CIN significantly reduced the magnitude of the acidosis in neurons, but not astrocytes. Finally, 4-CIN treatment increased the uptake of a fluorescent 2-deoxy-d-glucose analogue in neurons, but did not alter the uptake rate of this 2-deoxy-d-glucose analogue in astrocytes. These data confirm the existence of an astrocyte to neuron lactate shuttle in intact animals in the RTN, and lactate derived from astrocytes forms part of the central chemosensory stimulus for ventilation in this nucleus. When the lactate shuttle was disrupted by treatment with 4-CIN, neurons increased the uptake of glucose. Thus, neurons seem to metabolize a combination of glucose and lactate (and other substances such as pyruvate) depending, in part, on the availability of each of these particular substrates. PMID:18463242

The Himalayas of Nepal, a natural laboratory for the search and measurement of CO2 discharge

NASA Astrophysics Data System (ADS)

Girault, Frédéric; Koirala, Bharat P.; Bhattarai, Mukunda; Rajaure, Sudhir; Richon, Patrick; Perrier, Frédéric

2010-05-01

Large CO2 flux has been found in the Trisuli Valley, North of Kathmandu, Central Nepal, in 2005. This leakage zone is located in the vicinity of the Syabru-Bensi hot springs, and is characterized by an average flux of CO2 of 6500±1100 g m-2 day-1 over an area of 15 m × 15 m (Perrier et al., Earth and Planetary Science Letters, 2009). The site is also located close to the Main Central Thrust Zone (MCT Zone), one of the large Himalayan thrust, connected at depth to the Main Himalayan Thrust, the main thrust currently accommodating the India-Tibet collision (Bollinger et al., Journal of Geophysical Research, 2004). Isotopic carbon ratios (δ13C) indicate that this CO2 may come from metamorphic reactions at about 15 km of depth (Becker et al., Earth and Planetary Science Letters, 2008; Evans et al., Geochemistry Geophysics Geosystems, 2008). Actually, this zone was originally found because of the large δ13C found in the water of the hot springs suggesting degassing (Evans et al., Geochemistry Geophysics Geosystems, 2008). In 2007, another zone of CO2 discharge was discovered 250 m away from the main Syabru-Bensi hot springs. This new zone, located next to the road and easy to access all over the year, was intensely studied, from the end of 2007 to the beginning of 2009. In this zone, an average value of CO2 flux of 1700±300 g m-2 d-1 was obtained over an area of about 40 m × 10 m. Using CO2 flux data from repeated measurements, similar flux values were observed during the dry winter season and the wet summer period (monsoon) (Girault et al., Journal of Environmental Radioactivity, 2009). Thus, in addition to fundamental issues related to global CO2 balance in orogenic belts and tectonically active zones, these small scale (100-meter) CO2 discharge sites emerge as a potentially useful laboratory for detailed methodological studies of diffusive and advective gas transport. Recently, the search for further gas discharge zones has been carried out using various clues: the presence of a hot spring with high δ13C, of H2S smell, of hot spots in thermal images, of a geological contact, of self-potential anomalies (Byrdina et al., Journal of Geophysical Research, 2009) or of large radon-222 flux. Preliminary results about the failures or successes of the various methods will be given in the Trisuli and Langtang valleys (Central Nepal), in the Kali Gandaki valley (Western Nepal) and in the Thuli Bheri valley (Lower Dolpo, Far Western Nepal). These various sites also offer an opportunity to test the optimal estimation of total CO2 flux, using the least amount of experimental measurements. Preliminary results complemented by simulations will also be given on the total CO2 flux. In parallel, monitoring methods are being studied in the Syabru-Bensi pilot site. First, CO2 flux has been studied as a function of time using repeated measurements. Furthermore, the high radon content of the geological CO2 allows cost-effective monitoring using BARASOL probes. More than two years of data are already available and give hints on the use of radon to follow CO2 discharge as a function of time. These first results show how experimental studies carried out in natural discharge zones provide a rich laboratory to test the methodological approaches useful for CO2 leakage and monitoring.

Cognition and Synaptic-Plasticity Related Changes in Aged Rats Supplemented with 8- and 10-Carbon Medium Chain Triglycerides.

PubMed

Wang, Dongmei; Mitchell, Ellen S

2016-01-01

Brain glucose hypometabolism is a common feature of Alzheimer's disease (AD). Previous studies have shown that cognition is improved by providing AD patients with an alternate energy source: ketones derived from either ketogenic diet or supplementation with medium chain triglycerides (MCT). Recently, data on the neuroprotective capacity of MCT-derived medium chain fatty acids (MCFA) suggest 8-carbon and 10-carbon MCFA may have cognition-enhancing properties which are not related to ketone production. We investigated the effect of 8 week treatment with MCT8, MCT10 or sunflower oil supplementation (5% by weight of chow diet) in 21 month old Wistar rats. Both MCT diets increased ketones plasma similarly compared to control diet, but MCT diets did not increase ketones in the brain. Treatment with MCT10, but not MCT8, significantly improved novel object recognition memory compared to control diet, while social recognition increased in both MCT groups. MCT8 and MCT10 diets decreased weight compared to control diet, where MCFA plasma levels were higher in MCT10 groups than in MCT8 groups. Both MCT diets increased IRS-1 (612) phosphorylation and decreased S6K phosphorylation (240/244) but only MCT10 increased Akt phosphorylation (473). MCT8 supplementation increased synaptophysin, but not PSD-95, in contrast MCT10 had no effect on either synaptic marker. Expression of Ube3a, which controls synaptic stability, was increased by both MCT diets. Cortex transcription via qPCR showed that immediate early genes related to synaptic plasticity (arc, plk3, junb, egr2, nr4a1) were downregulated by both MCT diets while MCT8 additionally down-regulated fosb and egr1 but upregulated grin1 and gba2. These results demonstrate that treatment of 8- and 10-carbon length MCTs in aged rats have slight differential effects on synaptic stability, protein synthesis and behavior that may be independent of brain ketone levels.

Cognition and Synaptic-Plasticity Related Changes in Aged Rats Supplemented with 8- and 10-Carbon Medium Chain Triglycerides

PubMed Central

Wang, Dongmei; Mitchell, Ellen S.

2016-01-01

Brain glucose hypometabolism is a common feature of Alzheimer’s disease (AD). Previous studies have shown that cognition is improved by providing AD patients with an alternate energy source: ketones derived from either ketogenic diet or supplementation with medium chain triglycerides (MCT). Recently, data on the neuroprotective capacity of MCT-derived medium chain fatty acids (MCFA) suggest 8-carbon and 10-carbon MCFA may have cognition-enhancing properties which are not related to ketone production. We investigated the effect of 8 week treatment with MCT8, MCT10 or sunflower oil supplementation (5% by weight of chow diet) in 21 month old Wistar rats. Both MCT diets increased ketones plasma similarly compared to control diet, but MCT diets did not increase ketones in the brain. Treatment with MCT10, but not MCT8, significantly improved novel object recognition memory compared to control diet, while social recognition increased in both MCT groups. MCT8 and MCT10 diets decreased weight compared to control diet, where MCFA plasma levels were higher in MCT10 groups than in MCT8 groups. Both MCT diets increased IRS-1 (612) phosphorylation and decreased S6K phosphorylation (240/244) but only MCT10 increased Akt phosphorylation (473). MCT8 supplementation increased synaptophysin, but not PSD-95, in contrast MCT10 had no effect on either synaptic marker. Expression of Ube3a, which controls synaptic stability, was increased by both MCT diets. Cortex transcription via qPCR showed that immediate early genes related to synaptic plasticity (arc, plk3, junb, egr2, nr4a1) were downregulated by both MCT diets while MCT8 additionally down-regulated fosb and egr1 but upregulated grin1 and gba2. These results demonstrate that treatment of 8- and 10-carbon length MCTs in aged rats have slight differential effects on synaptic stability, protein synthesis and behavior that may be independent of brain ketone levels. PMID:27517611

Optimisation of immunofluorescence methods to determine MCT1 and MCT4 expression in circulating tumour cells.

PubMed

Kershaw, Stephen; Cummings, Jeffrey; Morris, Karen; Tugwood, Jonathan; Dive, Caroline

2015-05-10

The monocarboxylate transporter-1 (MCT1) represents a novel target in rational anticancer drug design while AZD3965 was developed as an inhibitor of this transporter and is undergoing Phase I clinical trials ( http://www.clinicaltrials.gov/show/NCT01791595 ). We describe the optimisation of an immunofluorescence (IF) method for determination of MCT1 and MCT4 in circulating tumour cells (CTC) as potential prognostic and predictive biomarkers of AZD3965 in cancer patients. Antibody selectivity was investigated by western blotting (WB) in K562 and MDAMB231 cell lines acting as positive controls for MCT1 and MCT4 respectively and by flow cytometry also employing the control cell lines. Ability to detect MCT1 and MCT4 in CTC as a 4(th) channel marker utilising the Veridex™ CellSearch system was conducted in both human volunteer blood spiked with control cells and in samples collected from small cell lung cancer (SCLC) patients. Experimental conditions were established which yielded a 10-fold dynamic range (DR) for detection of MCT1 over MCT4 (antibody concentration 6.25 μg/mL; integration time 0.4 seconds) and a 5-fold DR of MCT4 over MCT 1 (8 μg/100 μL and 0.8 seconds). The IF method was sufficiently sensitive to detect both MCT1 and MCT4 in CTCs harvested from cancer patients. The first IF method has been developed and optimised for detection of MCT 1 and MCT4 in cancer patient CTC.

Effects of acute and chronic exercise on sarcolemmal MCT1 and MCT4 contents in human skeletal muscles: current status.

PubMed

Thomas, Claire; Bishop, David J; Lambert, Karen; Mercier, Jacques; Brooks, George A

2012-01-01

Two lactate/proton cotransporter isoforms (monocarboxylate transporters, MCT1 and MCT4) are present in the plasma (sarcolemmal) membranes of skeletal muscle. Both isoforms are symports and are involved in both muscle pH and lactate regulation. Accordingly, sarcolemmal MCT isoform expression may play an important role in exercise performance. Acute exercise alters human MCT content, within the first 24 h from the onset of exercise. The regulation of MCT protein expression is complex after acute exercise, since there is not a simple concordance between changes in mRNA abundance and protein levels. In general, exercise produces greater increases in MCT1 than in MCT4 content. Chronic exercise also affects MCT1 and MCT4 content, regardless of the initial fitness of subjects. On the basis of cross-sectional studies, intensity would appear to be the most important factor regulating exercise-induced changes in MCT content. Regulation of skeletal muscle MCT1 and MCT4 content by a variety of stimuli inducing an elevation of lactate level (exercise, hypoxia, nutrition, metabolic perturbations) has been demonstrated. Dissociation between the regulation of MCT content and lactate transport activity has been reported in a number of studies, and changes in MCT content are more common in response to contractile activity, whereas changes in lactate transport capacity typically occur in response to changes in metabolic pathways. Muscle MCT expression is involved in, but is not the sole determinant of, muscle H(+) and lactate anion exchange during physical activity.

Laramide structure of the central Sangre de Cristo Mountains and adjacent Raton Basin, southern Colorado

USGS Publications Warehouse

Lindsey, D.A.

1998-01-01

Laramide structure of the central Sangre de Cristo Mountains (Culebra Range) is interpreted as a system of west-dipping, basement-involved thrusts and reverse faults. The Culebra thrust is the dominant structure in the central part of the range; it dips 30 -55?? west and brings Precambrian metamorphic base-ment rocks over unmetamorphosed Paleozoic rocks. East of the Culebra thrust, thrusts and reverse faults break the basement and overlying cover rocks into north-trending fault blocks; these boundary faults probably dip 40-60?? westward. The orientation of fault slickensides indicates oblique (northeast) slip on the Culebra thrust and dip-slip (ranging from eastward to northward) movement on adjacent faults. In sedimentary cover rocks, east-vergent anticlines overlie and merge with thrusts and reverse faults; these anticlines are interpreted as fault-propagation folds. Minor east-dipping thrusts and reverse faults (backthrusts) occur in both the hanging walls and footwalls of thrusts. The easternmost faults and folds of the Culebra Range form a continuous structural boundary between the Laramide Sangre de Cristo highland and the Raton Basin. Boundary structures consist of west-dipping frontal thrusts flanked on the basinward side by poorly exposed, east-dipping backthrusts. The backthrusts are interpreted to overlie structural wedges that have been emplaced above blind thrusts in the basin margin. West-dipping frontal thrusts and blind thrusts are interpreted to involve basement, but backthrusts are rooted in basin-margin cover rocks. At shallow structural levels where erosion has not exposed a frontal thrust, the structural boundary of the basin is represented by an anticline or monocline. Based on both regional and local stratigraphic evidence, Laramide deformation in the Culebra Range and accompanying synorogenic sedimentation in the western Raton Basin probably took place from latest Cretaceous through early Eocene time. The earliest evidence of uplift and erosion of a highland is the appearance of abundant feldspar in the Late Cretaceous Vermejo Formation. Above the Vermejo, unconformities overlain by conglomerate indicate continued thrusting and erosion of highlands from late Cretaceous (Raton) through Eocene (Cuchara) time. Eocene alluvial-fan conglomerates in the Cuchara Formation may represent erosion of the Culebra thrust block. Deposition in the Raton Basin probably shifted north from New Mexico to southern Colorado from Paleocene to Eocene time as movement on individual thrusts depressed adjacent segments of the basin.

Seismic interpretation and thrust tectonics of the Amadeus Basin, central Australia, along the BMR regional seismic line

NASA Astrophysics Data System (ADS)

Shaw, Russell D.; Korsch, Russell J.; Wright, C.; Goleby, B. R.

At the northern margin of the Amadeus Basin the monoclinal upturn (the MacDonnell Homocline) is interpreted to be the result of rotation and limited back-thrusting of the sedimentary sequence in front of a southerly-directed, imbricate basement thrust-wedge. This thrust complex is linked at depth to the crust-cutting Redbank Thrust Zone. In the northern part of the basin immediately to the south, regional seismic reflection profiling across the Missionary Plain shows a sub-horizontal, north-dipping, parautochthonous sedimentary sequence between about 8.5 km and 12.0 km thick. This sedimentary sequence shows upturning only at the northern and southern extremities, and represents an unusual, relatively undeformed region between converging thrust systems. In this intervening region, the crust appears to have been tilted downwards and northwards in response to the upthrusting to the north. Still farther to the south, the vertical uplift of the southern hanging wall of the Gardiner Thrust is about 6 km. Seismic reflection profiling in the region immediately south of the Gardiner Thrust indicates repetition of the sedimentary sequence. At the far end of the profile, in the Kernot Range, an imbricate thrust system fans ahead of a ramp-flat thrust pair. This thrust system (the Kernot Range Thrust System) occurs immediately north of an aeromagnetic domain boundary which marks the southern limit of a central ridge region characterized by thin Palaeozoic sedimentary cover and shallow depths to magnetic basement. A planar seismic event, imaged to a depth of at least 18 km, may correspond to the same boundary and is interpreted as a pre-basin Proterozoic thrust. Overall, the structure in the shallow sedimentary section in the central-southern region of the Amadeus Basin indicates that north-directed thrusting during the Dovonian-Carboniferous Alice Springs Orogeny was thin-skinned. During this orogeny an earlier thrust system, formed during the Petermann Ranges Orogeny and precursor orogenies in the Late Proterozoic, was reactivated with Proterozoic salt deposits localising the decollement zone. The Alice Springs Orogeny also reactivated a major mid Proterozoic province boundary in the basement to the north of the basin, resulting in major thrust movement at the northern basin margin.

Regulation of monocarboxylate transporter MCT1 expression by p53 mediates inward and outward lactate fluxes in tumors.

PubMed

Boidot, Romain; Végran, Frédérique; Meulle, Aline; Le Breton, Aude; Dessy, Chantal; Sonveaux, Pierre; Lizard-Nacol, Sarab; Feron, Olivier

2012-02-15

The monocarboxylate transporter (MCT) family member MCT1 can transport lactate into and out of tumor cells. Whereas most oxidative cancer cells import lactate through MCT1 to fuel mitochondrial respiration, the role of MCT1 in glycolysis-derived lactate efflux remains less clear. In this study, we identified a direct link between p53 function and MCT1 expression. Under hypoxic conditions, p53 loss promoted MCT1 expression and lactate export produced by elevated glycolytic flux, both in vitro and in vivo. p53 interacted directly with the MCT1 gene promoter and altered MCT1 mRNA stabilization. In hypoxic p53(-/-) tumor cells, NF-κB further supported expression of MCT1 to elevate its levels. Following glucose deprivation, upregulated MCT1 in p53(-/-) cells promoted lactate import and favored cell proliferation by fuelling mitochondrial respiration. We also found that MCT1 expression was increased in human breast tumors harboring p53 mutations and coincident features of hypoxia, with higher MCT1 levels associated with poorer clinical outcomes. Together, our findings identify MCT1 as a target for p53 repression and they suggest that MCT1 elevation in p53-deficient tumors allows them to adapt to metabolic needs by facilitating lactate export or import depending on the glucose availability.

Vitamin E and selenium treatment of monocrotaline induced hepatotoxicity in rats.

PubMed

Cuce, G; Canbaz, H T; Sozen, M E; Yerlikaya, F H; Kalkan, S

2017-01-01

Monocrotaline (MCT) is a hepatotoxic pyrrolizidine alkaloid that is derived from plants; exposure may occur by consumption of contaminated grains, herbal teas and medicines. MCT can cause liver damage. We investigated the antioxidant effects of selenium (Se) and vitamin E against the toxic effects of MCT. Female Wistar albino rats were divided into four groups: a control group, an MCT group, an MCT + Se group, and an MCT + vitamin E group. Liver tissues were harvested, fixed, processed to paraffin and sections were cut. Anti-von Willebrand factor (vWF) immunohistochemistry, terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL), and hematoxylin and eosin staining were performed. Serum and liver tissue glutathione (GSH), catalase (CAT), and glutathione peroxidase (GPx) levels were measured. Histopathological and TUNEL data showed significantly increased liver damage in the MCT group compared to controls. Histopathological and TUNEL staining indicated significant improvements in the MCT + vitamin E and MCT + Se groups compared to the MCT group. MCT significantly reduced the serum GSH level and GPx activity, and liver GPx activity. Biochemical data indicated a significant improvement in serum GSH level in the MCT + vitamin E group compared to the MCT group. We suggest that vitamin E and Se afford limited protection against MCT hepatotoxicity.

MCT1, MCT4 and CD147 gene polymorphisms in healthy horses and horses with myopathy.

PubMed

Mykkänen, A K; Koho, N M; Reeben, M; McGowan, C M; Pösö, A R

2011-12-01

Polymorphisms in human lactate transporter proteins (monocarboxylate transporters; MCTs), especially the MCT1 isoform, can affect lactate transport activity and cause signs of exercise-induced myopathy. Muscles express MCT1, MCT4 and CD147, an ancillary protein, indispensable for the activity of MCT1 and MCT4. We sequenced the coding sequence (cDNA) of horse MCT4 for the first time and examined polymorphisms in the cDNA of MCT1, MCT4 and CD147 of 16 healthy horses. To study whether signs of myopathy are linked to the polymorphisms, biopsy samples were taken from 26 horses with exercise-induced recurrent myopathy. Two polymorphisms that cause a change in amino acid sequence were found in MCT1 (Val(432)Ile and Lys(457)Gln) and one in CD147 (Met(125)Val). All polymorphisms in MCT4 were silent. Mutations in MCT1 or CD147 in equine muscle were not associated with myopathy. In the future, a functional study design is needed to evaluate the physiological role of the polymorphisms found. Copyright © 2010 Elsevier Ltd. All rights reserved.

Geomorphic indices indicated differential active tectonics of the Longmen Shan

NASA Astrophysics Data System (ADS)

Gao, M.; Xu, X.; Tan, X.

2012-12-01

The Longmen Shan thrust belt is located at the eastern margin of the Tibetan Plateau. It is a region of rapid active tectonics with high erosion rates and dense vegetation. The structure of the Longmen Shan region is dominated by northeast-trending thrusts and overturned folds that verge to the east and southeast (Burchfiel et al. 1995, Chen and Wilson 1996). The Longmen Shan thrust belt consists of three major faults from west to east: back-range fault, central fault, and frontal-range fault. The Mw 7.9 Wenchuan earthquake ruptured two large thrust faults along the Longmen Shan thrust belt (Xiwei et al., 2009). In this paper, we focus on investigating the spatial variance of tectonic activeness from the back-range fault to the frontal-range fault, particular emphasis on the differential recent tectonic activeness reflected by the hypsometry and the asymmetric factor of the drainage. Results from asymmetric factor indicate the back-rannge thrust fault on the south of the Maoxian caused drainage basins tilted on the hanging wall. For the north of the Maoxian, the strike-slip fault controlled the shapes of the drainage basins. Constantly river capture caused the expansion of the drainage basins which traversed by the fault. The drainages on the central fault and the frontal-range fault are also controlled by the fault slip. The drainage asymmetric factor suggested the central and southern segments of the Longmen Shan are more active than the northern segment, which is coherence with results of Huiping et al. (2010). The results from hypsometry show the back-range fault is the most active fault among the three major faults. Central fault is less active than the back-range fault but more active than the frontal-range fault. Beichuan is identified as the most active area along the central fault. Our geomorphic indices reflect an overall eastward decreasing of tectonic activeness of the Longmen Shan thrust belt.

Dietary medium-chain triglycerides attenuate hepatic lipid deposition in growing rats with protein malnutrition.

PubMed

Kuwahata, Masashi; Kubota, Hiroyo; Amano, Saki; Yokoyama, Meiko; Shimamura, Yasuhiro; Ito, Shunsuke; Ogawa, Aki; Kobayashi, Yukiko; Miyamoto, Ken-ichi; Kido, Yasuhiro

2011-01-01

The objective of this study was to investigate the effects of dietary medium-chain triglycerides (MCT) on hepatic lipid accumulation in growing rats with protein malnutrition. Weaning rats were fed either a low-protein diet (3%, LP) or control protein diet (20%, CP), in combination with or without MCT. The four groups were as follows: CP-MCT, CP+MCT, LP-MCT, and LP+MCT. Rats in the CP-MCT, CP+MCT and LP+MCT groups were pair-fed their respective diets based on the amount of diet consumed by the LP-MCT group. Rats were fed each experimental diet for 30 d. Four weeks later, the respiratory quotient was higher in the LP-MCT group than those in the other groups during the fasting period. Hepatic triglyceride content increased in the LP groups compared with the CP groups. Hepatic triglyceride content in the LP+MCT group, however, was significantly decreased compared with that in the LP-MCT group. Levels of carnitine palmitoyltransferase (CPT) 1a mRNA and CPT2 mRNA were significantly decreased in the livers of the LP-MCT group, as compared with corresponding mRNA levels of the other groups. These results suggest that ingestion of a low-protein diet caused fatty liver in growing rats. However, when rats were fed the low-protein diet with MCT, hepatic triglyceride deposition was attenuated, and mRNA levels encoding CPT1a and CPT2 were preserved at the levels of rats fed control protein diets.

Transport mechanism for L-lactic acid in human myocytes using human prototypic embryonal rhabdomyosarcoma cell line (RD cells).

PubMed

Kobayashi, Masaki; Fujita, Itaru; Itagaki, Shirou; Hirano, Takeshi; Iseki, Ken

2005-07-01

Monocarboxylate transporter (MCT), which cotransport L-lactic acid and protons across cell membranes, are important for regulation of muscle pH. However, it has not been demonstrated in detail whether MCT isoform contribute to the transport of L-lactic acid in skeletal muscle. The aim of this study was to characterize L-lactic acid transport using an human rhabdomyosarcoma (RD) cell line as a model of human skeletal muscle. mRNAs of MCT 1, 2 and 4 were found to be expressed in RD cells. The [14C] L-lactic acid uptake was concentration-dependent with a Km of 1.19 mM. This Km value was comparable to its Km values for MCT1 or MCT2. MCT1 mRNA was found to be present markedly greater than that MCT2. Therefore, MCT1 most probably acts on L-lactic acid uptake at RD cells. [14C] L-Lactic acid efflux in RD cells was inhibited by alpha-cyano-4-hydroxycinnamate (CHC) but not by butyric acid, a substrate of MCT1. Accordingly, MCT2 or MCT4 is responsible for L-lactic acid efflux by RD cells. MCT4 mRNA was found to be present significantly greater than that MCT2. We conclude that MCT1 is responsible for L-lactic acid uptake and L-lactic acid efflux is mediated by MCT4 in RD cells.

PGC-1alpha increases skeletal muscle lactate uptake by increasing the expression of MCT1 but not MCT2 or MCT4.

PubMed

Benton, Carley R; Yoshida, Yuko; Lally, James; Han, Xiao-Xia; Hatta, Hideo; Bonen, Arend

2008-09-17

We examined the relationship between PGC-1alpha protein; the monocarboxylate transporters MCT1, 2, and 4; and CD147 1) among six metabolically heterogeneous rat muscles, 2) in chronically stimulated red (RTA) and white tibialis (WTA) muscles (7 days), and 3) in RTA and WTA muscles transfected with PGC-1alpha-pcDNA plasmid in vivo. Among rat hindlimb muscles, there was a strong positive association between PGC-1alpha and MCT1 and CD147, and between MCT1 and CD147. A negative association was found between PGC-1alpha and MCT4, and CD147 and MCT4, while there was no relationship between PGC-1alpha or CD147 and MCT2. Transfecting PGC-1alpha-pcDNA plasmid into muscle increased PGC-1alpha protein (RTA +23%; WTA +25%) and induced the expression of MCT1 (RTA +16%; WTA +28%), but not MCT2 and MCT4. As a result of the PGC-1alpha-induced upregulation of MCT1 and its chaperone CD147 (+29%), there was a concomitant increase in the rate of lactate uptake (+20%). In chronically stimulated muscles, the following proteins were upregulated, PGC-1alpha in RTA (+26%) and WTA (+86%), MCT1 in RTA (+61%) and WTA (+180%), and CD147 in WTA (+106%). In contrast, MCT4 protein expression was not altered in either RTA or WTA muscles, while MCT2 protein expression was reduced in both RTA (-14%) and WTA (-10%). In these studies, whether comparing oxidative capacities among muscles or increasing their oxidative capacities by PGC-1alpha transfection and chronic muscle stimulation, there was a strong relationship between the expression of PGC-1alpha and MCT1, and PGC-1alpha and CD147 proteins. Thus, MCT1 and CD147 belong to the family of metabolic genes whose expression is regulated by PGC-1alpha in skeletal muscle.

CD147 subunit of lactate/H+ symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors.

PubMed

Le Floch, Renaud; Chiche, Johanna; Marchiq, Ibtissam; Naiken, Tanesha; Naïken, Tanesha; Ilc, Karine; Ilk, Karine; Murray, Clare M; Critchlow, Susan E; Roux, Danièle; Simon, Marie-Pierre; Pouysségur, Jacques

2011-10-04

Malignant tumors exhibit increased dependence on glycolysis, resulting in abundant export of lactic acid, a hypothesized key step in tumorigenesis. Lactic acid is mainly transported by two H(+)/lactate symporters, MCT1/MCT4, that require the ancillary protein CD147/Basigin for their functionality. First, we showed that blocking MCT1/2 in Ras-transformed fibroblasts with AR-C155858 suppressed lactate export, glycolysis, and tumor growth, whereas ectopic expression of MCT4 in these cells conferred resistance to MCT1/2 inhibition and reestablished tumorigenicty. A mutant-derivative, deficient in respiration (res(-)) and exclusively relying on glycolysis for energy, displayed low tumorigenicity. These res(-) cells could develop resistance to MCT1/2 inhibition and became highly tumorigenic by reactivating their endogenous mct4 gene, highlighting that MCT4, the hypoxia-inducible and tumor-associated lactate/H(+) symporter, drives tumorigenicity. Second, in the human colon adenocarcinoma cell line (LS174T), we showed that combined silencing of MCT1/MCT4 via inducible shRNA, or silencing of CD147/Basigin alone, significantly reduced glycolytic flux and tumor growth. However, both silencing approaches, which reduced tumor growth, displayed a low level of CD147/Basigin, a multifunctional protumoral protein. To gain insight into CD147/Basigin function, we designed experiments, via zinc finger nuclease-mediated mct4 and basigin knockouts, to uncouple MCTs from Basigin expression. Inhibition of MCT1 in MCT4-null, Basigin(high) cells suppressed tumor growth. Conversely, in Basigin-null cells, in which MCT activity had been maintained, tumorigenicity was not affected. Collectively, these findings highlight that the major protumoral action of CD147/Basigin is to control the energetics of glycolytic tumors via MCT1/MCT4 activity and that blocking lactic acid export provides an efficient anticancer strategy.

CD147 subunit of lactate/H+ symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors

PubMed Central

Le Floch, Renaud; Chiche, Johanna; Marchiq, Ibtissam; Naiken, Tanesha; Ilc, Karine; Murray, Clare M.; Critchlow, Susan E.; Roux, Danièle; Simon, Marie-Pierre; Pouysségur, Jacques

2011-01-01

Malignant tumors exhibit increased dependence on glycolysis, resulting in abundant export of lactic acid, a hypothesized key step in tumorigenesis. Lactic acid is mainly transported by two H+/lactate symporters, MCT1/MCT4, that require the ancillary protein CD147/Basigin for their functionality. First, we showed that blocking MCT1/2 in Ras-transformed fibroblasts with AR-C155858 suppressed lactate export, glycolysis, and tumor growth, whereas ectopic expression of MCT4 in these cells conferred resistance to MCT1/2 inhibition and reestablished tumorigenicty. A mutant-derivative, deficient in respiration (res−) and exclusively relying on glycolysis for energy, displayed low tumorigenicity. These res− cells could develop resistance to MCT1/2 inhibition and became highly tumorigenic by reactivating their endogenous mct4 gene, highlighting that MCT4, the hypoxia-inducible and tumor-associated lactate/H+ symporter, drives tumorigenicity. Second, in the human colon adenocarcinoma cell line (LS174T), we showed that combined silencing of MCT1/MCT4 via inducible shRNA, or silencing of CD147/Basigin alone, significantly reduced glycolytic flux and tumor growth. However, both silencing approaches, which reduced tumor growth, displayed a low level of CD147/Basigin, a multifunctional protumoral protein. To gain insight into CD147/Basigin function, we designed experiments, via zinc finger nuclease-mediated mct4 and basigin knockouts, to uncouple MCTs from Basigin expression. Inhibition of MCT1 in MCT4-null, Basiginhigh cells suppressed tumor growth. Conversely, in Basigin-null cells, in which MCT activity had been maintained, tumorigenicity was not affected. Collectively, these findings highlight that the major protumoral action of CD147/Basigin is to control the energetics of glycolytic tumors via MCT1/MCT4 activity and that blocking lactic acid export provides an efficient anticancer strategy. PMID:21930917

Downregulation of MCT1 inhibits tumor growth, metastasis and enhances chemotherapeutic efficacy in osteosarcoma through regulation of the NF-κB pathway.

PubMed

Zhao, Zhiqiang; Wu, Man-Si; Zou, Changye; Tang, Qinglian; Lu, Jinchang; Liu, Dawei; Wu, Yuanzhong; Yin, Junqiang; Xie, Xianbiao; Shen, Jingnan; Kang, Tiebang; Wang, Jin

2014-01-01

Monocarboxylate transporter isoform 1 (MCT1) is an important member of the proton-linked MCT family and has been reported in an array of human cancer cell lines and primary human tumors. MCT1 expression is associated with developing a new therapeutic approach for cancer. In this study, we initially showed that MCT1 is expressed in a variety of human osteosarcoma cell lines. Moreover, we evaluated the therapeutic response of targeting MCT1 using shRNA or MCT1 inhibitor. Inhibiting MCT1 delayed tumor growth in vitro and in vivo, including in an orthotopic model of osteosarcoma. Targeting MCT1 greatly enhanced the sensitivity of human osteosarcoma cells to the chemotherapeutic drugs adriamycin (ADM). In addition, we observed that MCT1 knockdown significantly suppressed the metastatic activity of osteosarcoma, including wound healing, invasion and migration. Further mechanistic studies revealed that the antitumor effects of targeting MCT1 might be related to the NF-κB pathway. Immunochemistry assay showed that MCT1 was an independent positive prognostic marker in osteosarcoma patients. In conclusion, our data, for the first time, demonstrate that MCT1 inhibition has antitumor potential which is associated with the NF-κB pathway, and high MCT1 expression predicates poor overall survival in patients with osteosarcoma. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Enhanced cerebral expression of MCT1 and MCT2 in a rat ischemia model occurs in activated microglial cells.

PubMed

Moreira, Tiago J T P; Pierre, Karin; Maekawa, Fumihiko; Repond, Cendrine; Cebere, Aleta; Liljequist, Sture; Pellerin, Luc

2009-07-01

Monocarboxylate transporters (MCTs) are essential for the use of lactate, an energy substrate known to be overproduced in brain during an ischemic episode. The expression of MCT1 and MCT2 was investigated at 48 h of reperfusion from focal ischemia induced by unilateral extradural compression in Wistar rats. Increased MCT1 mRNA expression was detected in the injured cortex and hippocampus of compressed animals compared to sham controls. In the contralateral, uncompressed hemisphere, increases in MCT1 mRNA level in the cortex and MCT2 mRNA level in the hippocampus were noted. Interestingly, strong MCT1 and MCT2 protein expression was found in peri-lesional macrophages/microglia and in an isolectin B4+/S100beta+ cell population in the corpus callosum. In vitro, MCT1 and MCT2 protein expression was observed in the N11 microglial cell line, whereas an enhancement of MCT1 expression by tumor necrosis factor-alpha (TNF-alpha) was shown in these cells. Modulation of MCT expression in microglia suggests that these transporters may help sustain microglial functions during recovery from focal brain ischemia. Overall, our study indicates that changes in MCT expression around and also away from the ischemic area, both at the mRNA and protein levels, are a part of the metabolic adaptations taking place in the brain after ischemia.

Mosaic Expression of Thyroid Hormone Regulatory Genes Defines Cell Type-Specific Dependency in the Developing Chicken Cerebellum.

PubMed

Delbaere, Joke; Van Herck, Stijn L J; Bourgeois, Nele M A; Vancamp, Pieter; Yang, Shuo; Wingate, Richard J T; Darras, Veerle M

2016-12-01

The cerebellum is a morphologically unique brain structure that requires thyroid hormones (THs) for the correct coordination of key cellular events driving its development. Unravelling the interplay between the multiple factors that can regulate intracellular TH levels is a key step to understanding their role in the regulation of these cellular processes. We therefore investigated the regional/cell-specific expression pattern of TH transporters and deiodinases in the cerebellum using the chicken embryo as a model. In situ hybridisation revealed expression of the TH transporters monocarboxylate transporter 8 (MCT8) and 10 (MCT10), L-type amino acid transporter 1 (LAT1) and organic anion transporting polypeptide 1C1 (OATP1C1) as well as the inactivating type 3 deiodinase (D3) in the fourth ventricle choroid plexus, suggesting a possible contribution of the resulting proteins to TH exchange and subsequent inactivation of excess hormone at the blood-cerebrospinal fluid barrier. Exclusive expression of LAT1 and the activating type 2 deiodinase (D2) mRNA was found at the level of the blood-brain barrier, suggesting a concerted function for LAT1 and D2 in the direct access of active T 3 to the developing cerebellum via the capillary endothelial cells. The presence of MCT8 mRNA in Purkinje cells and cerebellar nuclei during the first 2 weeks of embryonic development points to a potential role of this transporter in the uptake of T 3 in central neurons. At later stages, together with MCT10, detection of MCT8 signal in close association with the Purkinje cell dendritic tree suggests a role of both transporters in TH signalling during Purkinje cell synaptogenesis. MCT10 was also expressed in late-born cells in the rhombic lip lineage with a clear hybridisation signal in the outer external granular layer, indicating a potential role for MCT10 in the proliferation of granule cell precursors. By contrast, expression of D3 in the first-born rhombic lip-derived population may serve as a buffering mechanism against high T 3 levels during early embryonic development, a hypothesis supported by the pattern of expression of a fluorescent TH reporter in this lineage. Overall, this study builds a picture of the TH dependency in multiple cerebellar cell types starting from early embryonic development.

Monocarboxylate transporters MCT1 and MCT4 are independent prognostic biomarkers for the survival of patients with clear cell renal cell carcinoma and those receiving therapy targeting angiogenesis.

PubMed

Cao, Yan-Wei; Liu, Yong; Dong, Zhen; Guo, Lei; Kang, En-Hao; Wang, Yong-Hua; Zhang, Wei; Niu, Hai-Tao

2018-04-12

Prognostic biomarkers for patients with clear cell renal cell carcinoma (ccRCC), particularly those receiving therapy targeting angiogenesis, are not well established. In this study, we examined the correlations of monocarboxylate transporter 1 (MCT1) and MCT4, 2 critical transporters for glycolytic metabolism, with various clinicopathological parameters as well as survival of patients with ccRCC and those treated with vascular endothelial growth factor receptor (VEGFR) inhibitors. A cohort of 150 ccRCC patients were recruited into this study. All patients underwent radical or partial nephrectomy as the first-line treatment, and 38 received targeted therapy (sorafenib or sunitinib) after the surgery. Expression levels of MCT1, MCT4, and CD34 were examined by immunohistochemistry. Correlations between MCT1 or MCT4 expression and different clinicopathological parameters or patient survival were analyzed among all as well as patients receiving targeted therapy. MCT1 or MCT4 expression did not significantly correlate with sex, age, tumor diameter, microvascular density, tumor staging, pathological Furmann grade, or MSKCC (P>0.05). High expression of either MCT1 or MCT4 significantly correlated with reduced overall survival (OS) and progression-free survival (PFS) among the total cohort of ccRCC patients. For patients receiving targeted therapy, high expression of either MCT1 or MCT4 significantly correlated with reduced PFS, but not OS. Both conditions were independent prognostic biomarkers for reduced PFS among all patients or those receiving targeted therapy. MCT1 and MCT4 are prognostic biomarkers for patients with ccRCC or those receiving targeted therapy. High expression of these 2 proteins predicts reduced PFS in these patients. Copyright © 2018 Elsevier Inc. All rights reserved.

Prognostic significance of lactate/proton symporters MCT1, MCT4, and their chaperone CD147 expressions in urothelial carcinoma of the bladder.

PubMed

Choi, Jung-Woo; Kim, Younghye; Lee, Ju-Han; Kim, Young-Sik

2014-07-01

To investigate the prognostic significance of lactate/proton monocarboxylate transporters MCT1, MCT4, and their chaperone CD147 expressions in urothelial carcinoma of the bladder (UCB). We examined the expressions of MCT1, MCT4, and CD147 proteins in a total of 360 cases of UCB by immunohistochemistry. The immunohistochemical expressions were quantified using an ImageJ-based analysis program. MCT1, MCT4, and CD147 expressions were increased in 130 (36.1%), 168 (46.7%), and 228 (63.3%) UCB cases, respectively. Most tumor cells showed diffuse membranous staining, whereas normal urothelial cells showed negative or weak staining. High levels of MCT1 expression correlated with high World Health Organization grade (P<.001), advanced tumor node metastasis (TNM) stage (P<.001), nonpapillary growth type (P<.001), and lymphatic tumor invasion (P=.010), whereas high levels of MCT4 expression did not significantly correlate with any of these variables. High CD147 expression was associated with high World Health Organization grade (P<.001), advanced tumor node metastatis stage (P<.001), and nonpapillary growth type (P=.003). Univariate analyses revealed that high MCT1 (P<.001) and CD147 (P=.029) expressions were associated with poor overall survival and that high MCT4 expression was correlated with poor recurrence-free survival (P=.036). Multivariate analyses revealed that high MCT1 and MCT4 expressions were independent prognostic factors for poor overall survival and poor recurrence-free survival, respectively, in UCB patients. Our results indicate that increased MCT1, MCT4, and CD147 expressions have prognostic implications in UCB and suggest their roles in urothelial cancer metabolism. Copyright © 2014 Elsevier Inc. All rights reserved.

Analysis of the Binding Moiety Mediating the Interaction between Monocarboxylate Transporters and Carbonic Anhydrase II*

PubMed Central

Noor, Sina Ibne; Dietz, Steffen; Heidtmann, Hella; Boone, Christopher D.; McKenna, Robert; Deitmer, Joachim W.; Becker, Holger M.

2015-01-01

Proton-coupled monocarboxylate transporters (MCTs) mediate the exchange of high energy metabolites like lactate between different cells and tissues. We have reported previously that carbonic anhydrase II augments transport activity of MCT1 and MCT4 by a noncatalytic mechanism, while leaving transport activity of MCT2 unaltered. In the present study, we combined electrophysiological measurements in Xenopus oocytes and pulldown experiments to analyze the direct interaction between carbonic anhydrase II (CAII) and MCT1, MCT2, and MCT4, respectively. Transport activity of MCT2-WT, which lacks a putative CAII-binding site, is not augmented by CAII. However, introduction of a CAII-binding site into the C terminus of MCT2 resulted in CAII-mediated facilitation of MCT2 transport activity. Interestingly, introduction of three glutamic acid residues alone was not sufficient to establish a direct interaction between MCT2 and CAII, but the cluster had to be arranged in a fashion that allowed access to the binding moiety in CAII. We further demonstrate that functional interaction between MCT4 and CAII requires direct binding of the enzyme to the acidic cluster 431EEE in the C terminus of MCT4 in a similar fashion as previously shown for binding of CAII to the cluster 489EEE in the C terminus of MCT1. In CAII, binding to MCT1 and MCT4 is mediated by a histidine residue at position 64. Taken together, our results suggest that facilitation of MCT transport activity by CAII requires direct binding between histidine 64 in CAII and a cluster of glutamic acid residues in the C terminus of the transporter that has to be positioned in surroundings that allow access to CAII. PMID:25561737

Association of exercise-induced hyperinsulinaemic hypoglycaemia with MCT1-expressing insulinoma.

PubMed

Marquard, J; Welters, A; Buschmann, T; Barthlen, W; Vogelgesang, S; Klee, D; Krausch, M; Raffel, A; Otter, S; Piemonti, L; Mayatepek, E; Otonkoski, T; Lammert, E; Meissner, T

2013-01-01

Exercise-induced hyperinsulinism (EIHI) is a hypoglycaemic disorder characterised by inappropriate insulin secretion following anaerobic exercise or pyruvate load. Activating promoter mutations in the MCT1 gene (also known as SCLA16A1), coding for monocarboxylate transporter 1 (MCT1), were shown to associate with EIHI. Recently, transgenic Mct1 expression in pancreatic beta cells was shown to introduce EIHI symptoms in mice. To date, MCT1 has not been demonstrated in insulin-producing cells from an EIHI patient. In vivo insulin secretion was studied during an exercise test before and after the resection of an insulinoma. The presence of MCT1 was analysed using immunohistochemistry followed by laser scanning microscopy, western blot analysis and real-time RT-PCR of MCT1. The presence of MCT1 protein was analysed in four additional insulinoma patients. Clinical testing revealed massive insulin secretion induced by anaerobic exercise preoperatively, but not postoperatively. MCT1 protein was not detected in the patient's normal islets. In contrast, immunoreactivity was clearly observed in the insulinoma tissue. Western blot analysis and real-time RT-PCR showed a four- to fivefold increase in MCT1 in the insulinoma tissue of the EIHI patient compared with human pancreatic islets. MCT1 protein was detected in three of four additional insulinomas. We show for the first time that an MCT1-expressing insulinoma was associated with EIHI and that MCT1 might be present in most insulinomas. Our data suggest that MCT1 expression in human insulin-producing cells can lead to EIHI and warrant further studies on the role of MCT1 in human insulinoma patients.

An Essential Physiological Role for MCT8 in Bone in Male Mice

PubMed Central

Leitch, Victoria D.; Di Cosmo, Caterina; Liao, Xiao-Hui; O’Boy, Sam; Galliford, Thomas M.; Evans, Holly; Croucher, Peter I.; Boyde, Alan; Dumitrescu, Alexandra; Weiss, Roy E.; Refetoff, Samuel; Williams, Graham R.

2017-01-01

T3 is an important regulator of skeletal development and adult bone maintenance. Thyroid hormone action requires efficient transport of T4 and T3 into target cells. We hypothesized that monocarboxylate transporter (MCT) 8, encoded by Mct8 on the X-chromosome, is an essential thyroid hormone transporter in bone. To test this hypothesis, we determined the juvenile and adult skeletal phenotypes of male Mct8 knockout mice (Mct8KO) and Mct8D1D2KO compound mutants, which additionally lack the ability to convert the prohormone T4 to the active hormone T3. Prenatal skeletal development was normal in both Mct8KO and Mct8D1D2KO mice, whereas postnatal endochondral ossification and linear growth were delayed in both Mct8KO and Mct8D1D2KO mice. Furthermore, bone mass and mineralization were decreased in adult Mct8KO and Mct8D1D2KO mice, and compound mutants also had reduced bone strength. Delayed bone development and maturation in Mct8KO and Mct8D1D2KO mice is consistent with decreased thyroid hormone action in growth plate chondrocytes despite elevated serum T3 concentrations, whereas low bone mass and osteoporosis reflects increased thyroid hormone action in adult bone due to elevated systemic T3 levels. These studies identify an essential physiological requirement for MCT8 in chondrocytes, and demonstrate a role for additional transporters in other skeletal cells during adult bone maintenance. PMID:28637283

The antagonism between MCT-1 and p53 affects the tumorigenic outcomes

PubMed Central

2010-01-01

Background MCT-1 oncoprotein accelerates p53 protein degradation via a proteosome pathway. Synergistic promotion of the xenograft tumorigenicity has been demonstrated in circumstance of p53 loss alongside MCT-1 overexpression. However, the molecular regulation between MCT-1 and p53 in tumor development remains ambiguous. We speculate that MCT-1 may counteract p53 through the diverse mechanisms that determine the tumorigenic outcomes. Results MCT-1 has now identified as a novel target gene of p53 transcriptional regulation. MCT-1 promoter region contains the response elements reactive with wild-type p53 but not mutant p53. Functional p53 suppresses MCT-1 promoter activity and MCT-1 mRNA stability. In a negative feedback regulation, constitutively expressed MCT-1 decreases p53 promoter function and p53 mRNA stability. The apoptotic events are also significantly prevented by oncogenic MCT-1 in a p53-dependent or a p53-independent fashion, according to the genotoxic mechanism. Moreover, oncogenic MCT-1 promotes the tumorigenicity in mice xenografts of p53-null and p53-positive lung cancer cells. In support of the tumor growth are irrepressible by p53 reactivation in vivo, the inhibitors of p53 (MDM2, Pirh2, and Cop1) are constantly stimulated by MCT-1 oncoprotein. Conclusions The oppositions between MCT-1 and p53 are firstly confirmed at multistage processes that include transcription control, mRNA metabolism, and protein expression. MCT-1 oncogenicity can overcome p53 function that persistently advances the tumor development. PMID:21138557

Impact of MCT1 Haploinsufficiency on the Mouse Retina.

PubMed

Peachey, Neal S; Yu, Minzhong; Han, John Y S; Lengacher, Sylvain; Magistretti, Pierre J; Pellerin, Luc; Philp, Nancy J

2018-01-01

The monocarboxylate transporter 1 (MCT1) is highly expressed in the outer retina, suggesting that it plays a critical role in photoreceptors. We examined MCT1 +/- heterozygotes, which express half of the normal complement of MCT1. The MCT1 +/- retina developed normally and retained normal function, indicating that MCT1 is expressed at sufficient levels to support outer retinal metabolism.

Co-expression of monocarboxylate transporter 1 (MCT1) and its chaperone (CD147) is associated with low survival in patients with gastrointestinal stromal tumors (GISTs).

PubMed

de Oliveira, Antônio Talvane Torres; Pinheiro, Céline; Longatto-Filho, Adhemar; Brito, Maria Jose; Martinho, Olga; Matos, Delcio; Carvalho, André Lopes; Vazquez, Vinícius Lima; Silva, Thiago Buosi; Scapulatempo, Cristovam; Saad, Sarhan Sydney; Reis, Rui Manuel; Baltazar, Fátima

2012-02-01

Monocarboxylate transporters (MCTs) have been described to play an important role in cancer, but to date there are no reports on the significance of MCT expression in gastrointestinal stromal tumors (GISTs). The aim of the present work was to assess the value of MCT expression, as well as co-expression with the MCT chaperone CD147 in GISTs and evaluate their clinical-pathological significance. We analyzed the immunohistochemical expression of MCT1, MCT2, MCT4 and CD147 in a series of 64 GISTs molecularly characterized for KIT, PDGFRA and BRAF mutations. MCT1, MCT2 and MCT4 were highly expressed in GISTs. CD147 expression was associated with mutated KIT (p = 0.039), as well as a progressive increase in Fletcher's Risk of Malignancy (p = 0.020). Importantly, co-expression of MCT1 with CD147 was associated with low patient's overall survival (p = 0.037). These findings suggest that co-expression of MCT1 with its chaperone CD147 is involved in GISTs aggressiveness, pointing to a contribution of cancer cell metabolic adaptations in GIST development and/or progression.

Localisation of Lactate Transporters in Rat and Rabbit Placentae

PubMed Central

Picut, Catherine A.; Charlap, Jeffrey H.

2016-01-01

The distribution of monocarboxylate transporter (MCT) isoforms 1 and 4, which mediate the plasmalemmal transport of l-lactic and pyruvic acids, has been identified in the placentae of rats and rabbits at different ages of gestation. Groups of three pregnant Sprague-Dawley rats and New Zealand White rabbits were sacrificed on gestation days (GD) 11, 14, 18, or 20 and on GD 13, 18, or 28, respectively. Placentae were removed and processed for immunohistochemical detection of MCT1 and MCT4. In the rat, staining for MCT1 was associated with lakes and blood vessels containing enucleated red blood cells (maternal vessels) while staining for MCT4 was associated with vessels containing nucleated red blood cells (embryofoetal vessels). In the rabbit, staining for MCT1 was associated with blood vessels containing nucleated red blood cells while staining for MCT4 was associated with vessels containing enucleated red blood cells. Strength of staining for MCT1 decreased during gestation in both species, but that for MCT4 was stronger than that for MCT1 and was consistent between gestation days. The results imply an opposite polarity of MCT1 and MCT4 across the trophoblast between rat and rabbit. PMID:27843454

Tertiary deformation history of southeastern and southwestern Tibet during the Indo-Asian collision

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yin, A.; Harrison, T.M.; Murphy, M.A.

1999-11-01

Geologic mapping and geochronological analysis in southwest (Kailas area) and southeast (Zedong area) Tibet reveal two major episodes of Tertiary crustal shortening along the classic Indus-Tsangpo suture in the Yalu River valley. The older event occurred between ca. 30 and 24 Ma during movement along the north-dipping Gangdese thrust. The development of this thrust caused extensive denudation of the Gangdese batholith in its hanging wall and underthrusting of the Xigase forearc strata in its footwall. Examination of timing of major tectonic events in central Asia suggests that the initiation of the Gangdese thrust was approximately coeval with the late Oligocenemore » initiation and development of north-south shortening in the eastern Kunlun Shan of northern Tibet, the Nan Shan at the northeastern end of the Altyn Tagh fault, the western Kunlun Shan at the southwestern end of the Altyn Tagh fault, and finally the Tian Shan (north of the tarim basin). Such regionally synchronous initiation of crustal shortening in and around the plateau may have been related to changes in convergence rate and direction between the Eurasian plate and the Indian and Pacific plates. The younger thrusting event along the Yalu River valley occurred between 19 and 10 Ma along the south-dipping Great Counter thrust system, equivalent to the locally named Renbu-Zedong thrust in southeastern Tibet, the Backthrust system in south-central Tibet, and the South Kailas thrust in southwest Tibet. The coeval development of the Great Counter thrust and the North Himalayan granite-gneiss dome belt is consistent with their development being related to thermal weakening of the north Himalayan and south Tibetan crust, due perhaps to thermal relaxation of an already thickened crust created by the early phase of collision between India and Asia or frictional heating along major thrusts, such as the Main Central thrust, beneath the Himalaya.« less

MCT1 and MCT4 kinetic of mRNA expression in different tissues after aerobic exercise at maximal lactate steady state workload.

PubMed

de Araujo, G G; Gobatto, C A; de Barros Manchado-Gobatto, F; Teixeira, L Fm; Dos Reis, I Gm; Caperuto, L C; Papoti, M; Bordin, S; Cavaglieri, C R; Verlengia, R

2015-01-01

We evaluate the mRNA expression of monocarboxylate transporters 1 and 4 (MCT1 and MCT4) in skeletal muscle (soleus, red and white gastrocnemius), heart and liver tissues in mice submitted to a single bout of swimming exercise at the maximal lactate steady state workload (MLSSw). After 72 h of MLSS test, the animals were submitted to a swimming exercise session for 25 min at individual MLSSw. Tissues and muscle samples were obtained at rest (control, n=5), immediately (n=5), 5 h (n=5) and 10 h (n=5) after exercise for determination of the MCT1 and MCT4 mRNA expression (RT-PCR). The MCT1 mRNA expression in liver increased after 10 h in relation to the control, immediate and 5 h groups, but the MCT4 remained unchanged. The MCT1 mRNA expression in heart increased by 31 % after 10 h when compared to immediate, but no differences were observed in relation to the control group. No significant differences were observed for red gastrocnemius in MCT1 and MCT4 mRNA expression. However, white gastrocnemius increased MCT1 mRNA expression immediately when compared to rest, 5 and 10 h test groups. In soleus muscle, the MCT1 mRNA expression increased immediately, 5 and 10 h after exercise when compared to the control. In relation to MCT4 mRNA expression, the soleus increased immediately and 10 h after acute exercise when compared to the control group. The soleus, liver and heart were the main tissues that showed improved the MCT1 mRNA expression, indicating its important role in controlling MLSS concentration in mice.

Acute exercise increases brain region-specific expression of MCT1, MCT2, MCT4, GLUT1, and COX IV proteins.

PubMed

Takimoto, Masaki; Hamada, Taku

2014-05-01

The brain is capable of oxidizing lactate and ketone bodies through monocarboxylate transporters (MCTs). We examined the protein expression of MCT1, MCT2, MCT4, glucose transporter 1 (GLUT1), and cytochrome-c oxidase subunit IV (COX IV) in the rat brain within 24 h after a single exercise session. Brain samples were obtained from sedentary controls and treadmill-exercised rats (20 m/min, 8% grade). Acute exercise resulted in an increase in lactate in the cortex, hippocampus, and hypothalamus, but not the brainstem, and an increase in β-hydroxybutyrate in the cortex alone. After a 2-h exercise session MCT1 increased in the cortex and hippocampus 5 h postexercise, and the effect lasted in the cortex for 24 h postexercise. MCT2 increased in the cortex and hypothalamus 5-24 h postexercise, whereas MCT2 increased in the hippocampus immediately after exercise, and remained elevated for 10 h postexercise. Regional upregulation of MCT2 after exercise was associated with increases in brain-derived neurotrophic factor and tyrosine-related kinase B proteins, but not insulin-like growth factor 1. MCT4 increased 5-10 h postexercise only in the hypothalamus, and was associated with increased hypoxia-inducible factor-1α expression. However, none of the MCT isoforms in the brainstem was affected by exercise. Whereas GLUT 1 in the cortex increased only at 18 h postexercise, COX IV in the hippocampus increased 10 h after exercise and remained elevated for 24 h postexercise. These results suggest that acute prolonged exercise induces the brain region-specific upregulation of MCT1, MCT2, MCT4, GLUT1, and COX IV proteins.

Genetic disruption of lactate/H+ symporters (MCTs) and their subunit CD147/BASIGIN sensitizes glycolytic tumor cells to phenformin.

PubMed

Marchiq, Ibtissam; Le Floch, Renaud; Roux, Danièle; Simon, Marie-Pierre; Pouyssegur, Jacques

2015-01-01

Rapidly growing glycolytic tumors require energy and intracellular pH (pHi) homeostasis through the activity of two major monocarboxylate transporters, MCT1 and the hypoxia-inducible MCT4, in intimate association with the glycoprotein CD147/BASIGIN (BSG). To further explore and validate the blockade of lactic acid export as an anticancer strategy, we disrupted, via zinc finger nucleases, MCT4 and BASIGIN genes in colon adenocarcinoma (LS174T) and glioblastoma (U87) human cell lines. First, we showed that homozygous loss of MCT4 dramatically sensitized cells to the MCT1 inhibitor AZD3965. Second, we demonstrated that knockout of BSG leads to a decrease in lactate transport activity of MCT1 and MCT4 by 10- and 6-fold, respectively. Consequently, cells accumulated an intracellular pool of lactic and pyruvic acids, magnified by the MCT1 inhibitor decreasing further pHi and glycolysis. As a result, we found that these glycolytic/MCT-deficient cells resumed growth by redirecting their metabolism toward OXPHOS. Third, we showed that in contrast with parental cells, BSG-null cells became highly sensitive to phenformin, an inhibitor of mitochondrial complex I. Phenformin addition to these MCT-disrupted cells in normoxic and hypoxic conditions induced a rapid drop in cellular ATP-inducing cell death by "metabolic catastrophe." Finally, xenograft analysis confirmed the deleterious tumor growth effect of MCT1/MCT4 ablation, an action enhanced by phenformin treatment. Collectively, these findings highlight that inhibition of the MCT/BSG complexes alone or in combination with phenformin provides an acute anticancer strategy to target highly glycolytic tumors. This genetic approach validates the anticancer potential of the MCT1 and MCT4 inhibitors in current development. ©2014 American Association for Cancer Research.

Expression of monocarboxylate transporter 1 (MCT1) in the dog intestine.

PubMed

Shimoyama, Yumiko; Kirat, Doaa; Akihara, Yuko; Kawasako, Kazufumi; Komine, Misa; Hirayama, Kazuko; Matsuda, Kazuya; Okamoto, Minoru; Iwano, Hidetomo; Kato, Seiyu; Taniyama, Hiroyuki

2007-06-01

In this study, the expression and distribution of monocarboxyolate transporter 1 (MCT1) along the intestines (duodenum, jejunum, ileum, cecum, colon and rectum) of dogs were investigated at both the mRNA and protein levels. The expression of MCT1 protein and its distribution were confirmed by Western blotting and immunohistochemical staining using the antibody for MCT1. We identified mRNA coding for MCT1 and a 43-kDa band of MCT1 protein in all regions from the duodenum to the rectum. Immunoreactive staining for MCT1 was also observed in epithelial cells throughout the intestines. MCT1 immunoreactivity was greater in the large intestine than in the small intestine. MCT1 protein was predominantly expressed on the basolateral membranes along intestinal epithelial cells, suggesting that MCT1 may play an important role in lactate efflux and transport of short-chain fatty acids (SCFAs) to the bloodstream across the basolateral membranes of the dog intestine.

Interaction between basigin and monocarboxylate transporter 2 in the mouse testes and spermatozoa

PubMed Central

Chen, Cheng; Maekawa, Mamiko; Yamatoya, Kenji; Nozaki, Masami; Ito, Chizuru; Iwanaga, Toshihiko; Toshimori, Kiyotaka

2016-01-01

Basigin is a member of the immunoglobulin superfamily and plays various important roles in biological events including spermatogenesis. To examine the basigin molecular variants during spermatogenesis and sperm maturation in the mouse, immunoprecipitated basigin samples from testis and epididymal spermatozoa were analyzed by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). The results demonstrated that basigin molecules from the testis and spermatozoa were separable into two major bands and that the differences in the molecular sizes were possibly because of an endoproteolytic cleavage. Since basigin is known to be a chaperone for the monocarboxylate transporter 1 (MCT1), the localization of basigin, MCT1 and MCT2 was examined during postnatal testicular development. Immunohistochemical studies showed different expression patterns of MCT1 and MCT2. MCT1 was localized on the surface of spermatogonia, spermatocytes, and spermatids. In contrast, MCT2 appeared on the principal piece of spermatozoa in the testis, where basigin was also observed. In mature epididymal spermatozoa, MCT2 was located on the midpiece, where basigin co-localized with MCT2 but not with MCT1. Furthermore, MCT2 was immunoprecipitated with basigin in mouse testes and sperm. These results suggest that basigin has a functional role as a binding partner with MCT2 in testicular and epididymal spermatozoa. PMID:26208397

Hypoxia-mediated upregulation of MCT1 expression supports the glycolytic phenotype of glioblastomas.

PubMed

Miranda-Gonçalves, Vera; Granja, Sara; Martinho, Olga; Honavar, Mrinalini; Pojo, Marta; Costa, Bruno M; Pires, Manuel M; Pinheiro, Célia; Cordeiro, Michelle; Bebiano, Gil; Costa, Paulo; Reis, Rui M; Baltazar, Fátima

2016-07-19

Glioblastomas (GBM) present a high cellular heterogeneity with conspicuous necrotic regions associated with hypoxia, which is related to tumor aggressiveness. GBM tumors exhibit high glycolytic metabolism with increased lactate production that is extruded to the tumor microenvironment through monocarboxylate transporters (MCTs). While hypoxia-mediated regulation of MCT4 has been characterized, the role of MCT1 is still controversial. Thus, we aimed to understand the role of hypoxia in the regulation of MCT expression and function in GBM, MCT1 in particular. Expression of hypoxia- and glycolytic-related markers, as well as MCT1 and MCT4 isoforms was assessed in in vitro and in vivo orthotopic glioma models, and also in human GBM tissues by immunofluorescence/immunohistochemistry and Western blot. Following MCT1 inhibition, either pharmacologically with CHC (α-cyano-4-hydroxynnamic acid) or genetically with siRNAs, we assessed GBM cell viability, proliferation, metabolism, migration and invasion, under normoxia and hypoxia conditions. Hypoxia induced an increase in MCT1 plasma membrane expression in glioma cells, both in in vitro and in vivo models. Additionally, treatment with CHC and downregulation of MCT1 in glioma cells decreased lactate production, cell proliferation and invasion under hypoxia. Moreover, in the in vivo orthotopic model and in human GBM tissues, there was extensive co-expression of MCT1, but not MCT4, with the GBM hypoxia marker CAIX. Hypoxia-induced MCT1 supports GBM glycolytic phenotype, being responsible for lactate efflux and an important mediator of cell survival and aggressiveness. Therefore, MCT1 constitutes a promising therapeutic target in GBM.

Characterization of monocarboxylate transporters (MCTs) expression in soft tissue sarcomas: distinct prognostic impact of MCT1 sub-cellular localization

PubMed Central

2014-01-01

Background Soft tissue sarcomas (STSs) are a group of neoplasms, which, despite current therapeutic advances, still confer a poor outcome to half of the patients. As other solid tumors, STSs exhibit high glucose consumption rates, associated with worse prognosis and therapeutic response. As highly glycolytic tumors, we hypothesized that sarcomas should present an increased expression of lactate transporters (MCTs). Methods Immunohistochemical expression of MCT1, MCT2, MCT4 and CD147 was assessed in a series of 86 STSs and the expression profiles were associated with patients’ clinical-pathological parameters. Results MCT1, MCT4 and CD147 were mainly observed in the plasma membrane of cancer cells (around 60% for MCTs and 40% for CD147), while MCT2 was conspicuously found in the cytoplasm (94.2%). Importantly, we observed MCT1 nuclear expression (32.6%). MCT1 and MCT4, alone or co-expressed with CD147 in the plasma membrane, were associated with poor prognostic variables including high tumor grade, disease progression and shorter overall survival. Conversely, we found MCT1 nuclear expression to be associated with low grade tumors and longer overall survival. Conclusions The present work represents the first report of MCTs characterization in STSs. We showed the original finding of MCT1 expression in the nucleus. Importantly, opposite biological roles should be behind the dual sub-cellular localization of MCT1, as plasma membrane expression of MCT1 is associated with worse patients’ prognosis, while nuclear expression is associated with better prognosis. PMID:24885736

Hypoxia-mediated upregulation of MCT1 expression supports the glycolytic phenotype of glioblastomas

PubMed Central

Miranda-Gonçalves, Vera; Granja, Sara; Martinho, Olga; Honavar, Mrinalini; Pojo, Marta; Costa, Bruno M.; Pires, Manuel M.; Pinheiro, Célia; Cordeiro, Michelle; Bebiano, Gil; Costa, Paulo; Reis, Rui M.; Baltazar, Fátima

2016-01-01

Background Glioblastomas (GBM) present a high cellular heterogeneity with conspicuous necrotic regions associated with hypoxia, which is related to tumor aggressiveness. GBM tumors exhibit high glycolytic metabolism with increased lactate production that is extruded to the tumor microenvironment through monocarboxylate transporters (MCTs). While hypoxia-mediated regulation of MCT4 has been characterized, the role of MCT1 is still controversial. Thus, we aimed to understand the role of hypoxia in the regulation of MCT expression and function in GBM, MCT1 in particular. Methods Expression of hypoxia- and glycolytic-related markers, as well as MCT1 and MCT4 isoforms was assessed in in vitro and in vivo orthotopic glioma models, and also in human GBM tissues by immunofluorescence/immunohistochemistry and Western blot. Following MCT1 inhibition, either pharmacologically with CHC (α-cyano-4-hydroxynnamic acid) or genetically with siRNAs, we assessed GBM cell viability, proliferation, metabolism, migration and invasion, under normoxia and hypoxia conditions. Results Hypoxia induced an increase in MCT1 plasma membrane expression in glioma cells, both in in vitro and in vivo models. Additionally, treatment with CHC and downregulation of MCT1 in glioma cells decreased lactate production, cell proliferation and invasion under hypoxia. Moreover, in the in vivo orthotopic model and in human GBM tissues, there was extensive co-expression of MCT1, but not MCT4, with the GBM hypoxia marker CAIX. Conclusion Hypoxia-induced MCT1 supports GBM glycolytic phenotype, being responsible for lactate efflux and an important mediator of cell survival and aggressiveness. Therefore, MCT1 constitutes a promising therapeutic target in GBM. PMID:27331625

Characterization of monocarboxylate transporters (MCTs) expression in soft tissue sarcomas: distinct prognostic impact of MCT1 sub-cellular localization.

PubMed

Pinheiro, Céline; Penna, Valter; Morais-Santos, Filipa; Abrahão-Machado, Lucas F; Ribeiro, Guilherme; Curcelli, Emílio C; Olivieri, Marcus V; Morini, Sandra; Valença, Isabel; Ribeiro, Daniela; Schmitt, Fernando C; Reis, Rui M; Baltazar, Fátima

2014-05-09

Soft tissue sarcomas (STSs) are a group of neoplasms, which, despite current therapeutic advances, still confer a poor outcome to half of the patients. As other solid tumors, STSs exhibit high glucose consumption rates, associated with worse prognosis and therapeutic response. As highly glycolytic tumors, we hypothesized that sarcomas should present an increased expression of lactate transporters (MCTs). Immunohistochemical expression of MCT1, MCT2, MCT4 and CD147 was assessed in a series of 86 STSs and the expression profiles were associated with patients' clinical-pathological parameters. MCT1, MCT4 and CD147 were mainly observed in the plasma membrane of cancer cells (around 60% for MCTs and 40% for CD147), while MCT2 was conspicuously found in the cytoplasm (94.2%). Importantly, we observed MCT1 nuclear expression (32.6%). MCT1 and MCT4, alone or co-expressed with CD147 in the plasma membrane, were associated with poor prognostic variables including high tumor grade, disease progression and shorter overall survival. Conversely, we found MCT1 nuclear expression to be associated with low grade tumors and longer overall survival. The present work represents the first report of MCTs characterization in STSs. We showed the original finding of MCT1 expression in the nucleus. Importantly, opposite biological roles should be behind the dual sub-cellular localization of MCT1, as plasma membrane expression of MCT1 is associated with worse patients' prognosis, while nuclear expression is associated with better prognosis.

Latest Cretaceous-Paleogene basin development and resultant sedimentation patterns in the thrust belt and broken foreland of central Utah

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lawton, T.F.; Franczyk, K.J.; Pitman, J.K.

1990-05-01

Latest Cretaceous tectonism in central and east-central Utah formed several intermontane basins both atop thrust sheets and between the thrust front and basement-involved uplifts in the former foreland basin. The upper Campanian Castlegate Sandstone and its inferred western equivalents were the last strata deposited prior to segmentation of the foreland basin. Thereafter, eastward transport of the thrust allochthon uplifted the most proximal part of the Castlegate depositional wedge. West of the thrust front, small intermontane basins formed on the allochthon. Sediment was transported into these basins from both eastern and western sources. In each basin, facies grade from basin-margin conglomeraticmore » alluvial fan deposits to basin-interior flood-plain and lacustrine deposits within a few kilometers. These intermontane basins existed from latest Campanian through the late Paleocene, and may have been transported a short distance eastward as they formed. East of the thrust front in the latest Campanian and contemporaneous with basin formation on the allochthon, a northward-northeastward-flowing big river system transported sediment into the foreland basin from feldspar-rich source areas southwest of the study area. Subsequently, major movement of the San Rafael uplift in the very late Campanian or early Maastrichtian gave rise to an intermontane basin between the thrust front and the San Rafael uplift. Northwestward-flowing, pebble-bearing braided rivers deposited the oldest sediments in this basin prior to an influx from the south and southwest of sediment that formed a thick Maastrichtian clastic sequence. In contrast to deposition in basins on the allochthon, deposition east of the thrust front in the Paleocene was intermittent and restricted to rapidly shifting centers of basin subsidence.« less

Immunohistochemical localization of GLUT3, MCT1, and MCT2 in the testes of mice and rats: the use of different energy sources in spermatogenesis.

PubMed

Kishimoto, Ayuko; Ishiguro-Oonuma, Toshina; Takahashi, Ritei; Maekawa, Mamiko; Toshimori, Kiyotaka; Watanabe, Masahiko; Iwanaga, Toshihiko

2015-01-01

Lactate represents a preferential energy substrate of germ cells rather than glucose. Testicular Sertoli cells are believed to produce lactate and pyruvate and to supply these to germ cells, particularly spermatocytes and spermatids. Monocarboxylate transporter (MCT), responsible for the transport of lactate and other monocarboxylates via the cell membrane, is abundant in the testes and sperm (MCT1, MCT2, and MCT4). For the uptake of glucose, germ cells within the seminiferous tubules and sperm have been known to intensely express GLUT3. The present study investigated expression profiles of MCTs and GLUTs and revealed their cellular and subcellular localization in the mouse and rat testis. An in situ hybridization analysis showed significant expressions of MCT1, MCT2, and GLUT3 mRNA in the testis. Immunohistochemically, spermatogonia, spermatocytes, and spermatids expressed MCT1 on their cell surfaces in a stage-dependent manner: in some seminiferous tubules, an intense expression of MCT1 was unique to the spermatogonia. MCT2 was restricted to the tails of elongated spermatids and sperm. An intense immunoreactivity for GLUT3 was shared by spermatocytes, spermatids, and sperm. Sertoli cells were devoid of any immunoreactivities for MCT1, MCT2, and GLUT3. The predominant energy source of germ cells may be lactate and other monocarboxylates--especially for spermatogonia, but glucose and other hexoses may be responsible for an energy supply to spermatocytes and spermatids.

Monocarboxylate transporters 1-4 in NSCLC: MCT1 is an independent prognostic marker for survival.

PubMed

Eilertsen, Marte; Andersen, Sigve; Al-Saad, Samer; Kiselev, Yury; Donnem, Tom; Stenvold, Helge; Pettersen, Ingvild; Al-Shibli, Khalid; Richardsen, Elin; Busund, Lill-Tove; Bremnes, Roy M

2014-01-01

Monocarboxylate transporters (MCTs) 1-4 are lactate transporters crucial for cancers cells adaption to upregulated glycolysis. Herein, we aimed to explore their prognostic impact on disease-specific survival (DSS) in both cancer and tumor stromal cells in NSCLC. Tissue micro arrays (TMAs) were constructed, representing both cancer and stromal tumor tissue from 335 unselected patients diagnosed with stage I-IIIA NSCLC. Immunohistochemistry was used to evaluate the expression of MCT1-4. In univariate analyses; ↓ MCT1 (P = 0.021) and ↑ MCT4 (P = 0.027) expression in cancer cells, and ↑ MCT1 (P = 0.003), ↓ MCT2 (P = 0.006), ↓ MCT3 (P = 0.020) expression in stromal cells correlated significantly with a poor DSS. In multivariate analyses; ↓ MCT1 expression in cancer cells (HR: 1.9, CI 95%: 1.3-2.8, P = 0.001), ↓ MCT2 (HR: 2.4, CI 95%: 1.5-3.9, P<0.001), ↓ MCT3 (HR: 1.9, CI 95%: 1.1-3.5, P = 0.031) and ↑ MCT1 expression in stromal cells (HR: 1.7, CI 95%: 1.1-2.7, P = 0.016) were significant independent poor prognostic markers for DSS. We provide novel information of MCT1 as a candidate marker for prognostic stratification in NSCLC. Interestingly, MCT1 shows diverging, independent prognostic impact in the cancer cell and stromal cell compartments.

Basement thrust sheets in the Clearwater orogenic zone, central Idaho and western Montana

NASA Astrophysics Data System (ADS)

Skipp, Betty

1987-03-01

The Clearwater orogenic zone in central Idaho and western Montana contains at least two major northeast-directed Cordilleran thrust plates of Early Proterozoic metasedimentary and metaigneous rocks that overrode previously folded Middle Proterozoic rocks of the Belt basin in Cretaceous time. The northeastward migration of the resultant thickened wedge of crustal material combined with Cretaceous subduction along the western continental margin produced a younger northern Bitterroot lobe of the Idaho batholith relative to an older southern Atlanta lobe. Eocene extensional unroofing and erosion of the Bitterroot lobe has exposed the roots of the thick Cordilleran thrust sheets.

Expression of lactate/H⁺ symporters MCT1 and MCT4 and their chaperone CD147 predicts tumor progression in clear cell renal cell carcinoma: immunohistochemical and The Cancer Genome Atlas data analyses.

PubMed

Kim, Younghye; Choi, Jung-Woo; Lee, Ju-Han; Kim, Young-Sik

2015-01-01

Clear cell renal cell carcinomas (ccRCCs) have inactivation of the von Hippel-Lindau protein, leading to the accumulation of hypoxia-inducible factor-α (HIF-α). HIF-1α induces aerobic glycolysis, the Warburg effect, whereas HIF-2α functions as an oncoprotein. Lactate transport through monocarboxylate transporters (MCTs) and the chaperone CD147 is essential for high glycolytic cancer cell survival. To elucidate the clinical significance of MCT1, MCT4, and CD147 expression, we investigated their expressions by immunohistochemistry in ccRCC specimens and validated the results by an open-access The Cancer Genome Atlas data analysis. Overexpression of MCT1, MCT4, and CD147 was observed in 49.4% (89/180), 39.4% (71/180), and 79.4% (143/180) of ccRCC patients, respectively. High MCT1 expression was associated with older age (P = .017), larger tumor size (P = .015), and advanced TNM stage (P = .012). However, MCT4 overexpression was not related to any variables. CD147 overexpression correlated with high grade (P = .005), tumor necrosis (P = .016), and larger tumor size (P = .038). In univariate analysis, high expression of MCT1 (P < .001), MCT4 (P = .016), and CD147 (P = .02) was linked to short progression-free survival. In multivariate analysis, high MCT1 expression was associated with worse progression-free survival (P = .001). In conclusion, high expression of MCT1 and CD147 is associated with poor prognostic factors. Overexpression of MCT1, MCT4, and CD147 predicts tumor progression. Reversing the Warburg effect by targeting the lactate transporters may be a useful strategy to prevent ccRCC progression. Copyright © 2014 Elsevier Inc. All rights reserved.

Monocarboxylate Transporter 1 (MCT1) is an independent prognostic biomarker in endometrial cancer.

PubMed

Latif, Ayşe; Chadwick, Amy L; Kitson, Sarah J; Gregson, Hannah J; Sivalingam, Vanitha N; Bolton, James; McVey, Rhona J; Roberts, Stephen A; Marshall, Kay M; Williams, Kaye J; Stratford, Ian J; Crosbie, Emma J

2017-01-01

Endometrial cancer (EC) is a major health concern due to its rising incidence. Whilst early stage disease is generally cured by surgery, advanced EC has a poor prognosis with limited treatment options. Altered energy metabolism is a hallmark of malignancy. Cancer cells drive tumour growth through aerobic glycolysis and must export lactate to maintain intracellular pH. The aim of this study was to evaluate the expression of the lactate/proton monocarboxylate transporters MCT1 and MCT4 and their chaperone CD147 in EC, with the ultimate aim of directing future drug development. MCT1, MCT4 and CD147 expression was examined using immunohistochemical analysis in 90 endometrial tumours and correlated with clinico-pathological characteristics and survival outcomes. MCT1 and MCT4 expression was observed in the cytoplasm, the plasma membrane or both locations. CD147 was detected in the plasma membrane and associated with MCT1 ( p  = 0.003) but not with MCT4 ( p  = 0.207) expression. High MCT1 expression was associated with reduced overall survival ( p  = 0.029) and remained statistically significant after adjustment for survival covariates ( p  = 0.017). Our data suggest that MCT1 expression is an important marker of poor prognosis in EC. MCT1 inhibition may have potential as a treatment for advanced or recurrent EC.

The history of N-methanocarbathymidine: the investigation of a conformational concept leads to the discovery of a potent and selective nucleoside antiviral agent.

PubMed

Marquez, Victor E; Hughes, Stephen H; Sei, Shizuko; Agbaria, Riad

2006-09-01

Conformationally locked (North)-methanocarbathymidine (N-MCT) and (South)-methanocarbathymidine (S-MCT) have been used to investigate the conformational preferences of kinases and polymerases. The herpes kinases show a distinct bias for S-MCT, while DNA polymerases almost exclusively incorporate the North 5'-triphosphate (N-MCT-TP). Only N-MCT demonstrated potent antiviral activity against herpes simplex viruses (HSV-1 and 2) and Kaposi's sarcoma-associated herpesvirus (KSHV). The activity of N-MCT depends on its metabolic transformation to N-MCT-TP by the herpes kinases (HSV-tk or KSHV-tk), which catalyze the mono and diphosphorylation steps; cellular kinases generate the triphosphate. N-MCT at a dose of 5.6 mg/kg was totally protective for mice inoculated intranasally with HSV-1. Tumor cells that are not responsive to antiviral therapy became sensitive to N-MCT if the cells expressed HSV-tk. N-MCT given twice daily (100 mg/kg) for 7 days completely inhibited the growth of MC38 tumors derived from cells that express HSV-tk in mice while exhibiting no effect on tumors derived from non-transduced cells. After i.p. administration, N-MCT was rapidly absorbed and distributed in all organs examined with slow penetration into brain and testes. N-MCT-TP was also a potent inhibitor of HIV replication in human osteosarcoma (HOS) cells expressing HSV-tk.

Integration of a 'proton antenna' facilitates transport activity of the monocarboxylate transporter MCT4.

PubMed

Noor, Sina Ibne; Pouyssegur, Jacques; Deitmer, Joachim W; Becker, Holger M

2017-01-01

Monocarboxylate transporters (MCTs) mediate the proton-coupled transport of high-energy metabolites like lactate and pyruvate and are expressed in nearly every mammalian tissue. We have shown previously that transport activity of MCT4 is enhanced by carbonic anhydrase II (CAII), which has been suggested to function as a 'proton antenna' for the transporter. In the present study, we tested whether creation of an endogenous proton antenna by introduction of a cluster of histidine residues into the C-terminal tail of MCT4 (MCT4-6xHis) could facilitate MCT4 transport activity when heterologously expressed in Xenopus oocytes. Our results show that integration of six histidines into the C-terminal tail does indeed increase transport activity of MCT4 to the same extent as did coexpression of MCT4-WT with CAII. Transport activity of MCT4-6xHis could be further enhanced by coexpression with extracellular CAIV, but not with intracellular CAII. Injection of an antibody against the histidine cluster into MCT4-expressing oocytes decreased transport activity of MCT4-6xHis, while leaving activity of MCT4-WT unaltered. Taken together, these findings suggest that transport activity of the proton-coupled monocarboxylate transporter MCT4 can be facilitated by integration of an endogenous proton antenna into the transporter's C-terminal tail. © 2016 Federation of European Biochemical Societies.

Zebrafish as a model for monocarboxyl transporter 8-deficiency.

PubMed

Vatine, Gad David; Zada, David; Lerer-Goldshtein, Tali; Tovin, Adi; Malkinson, Guy; Yaniv, Karina; Appelbaum, Lior

2013-01-04

Allan-Herndon-Dudley syndrome (AHDS) is a severe psychomotor retardation characterized by neurological impairment and abnormal thyroid hormone (TH) levels. Mutations in the TH transporter, monocarboxylate transporter 8 (MCT8), are associated with AHDS. MCT8 knock-out mice exhibit impaired TH levels; however, they lack neurological defects. Here, the zebrafish mct8 gene and promoter were isolated, and mct8 promoter-driven transgenic lines were used to show that, similar to humans, mct8 is primarily expressed in the nervous and vascular systems. Morpholino-based knockdown and rescue experiments revealed that MCT8 is strictly required for neural development in the brain and spinal cord. This study shows that MCT8 is a crucial regulator during embryonic development and establishes the first vertebrate model for MCT8 deficiency that exhibits a neurological phenotype.

Expression of lactate transporters MCT1, MCT2 and CD147 in the red blood cells of three horse breeds: Finnhorse, Standardbred and Thoroughbred.

PubMed

Mykkänen, A K; Pösö, A R; McGowan, C M; McKane, S A

2010-11-01

In exercising horses, up to 50% of blood lactate is taken up into red blood cells (RBCs). Lactate transporter proteins MCT1, MCT2 and CD147 (an ancillary protein for MCT1) are expressed in the equine RBC membrane. In Standardbreds (SB), lactate transport activity is bimodally distributed and correlates with the amount of MCT1 and CD147. About 75% of SB studied have high lactate transport activity in RBCs. In other breeds, the distribution of lactate transport activity is unknown. To study whether similar bimodal distribution of MCT1 and CD147 is present also in the racing Finnhorse (FH) and Thoroughbred (TB) as in the SB and to study the distribution of MCT2 in all 3 breeds and to determine if there is a connection between MCT expression and performance markers in TB racehorses. Venous blood samples were taken from 118 FHs, 98 TBs and 44 SBs. Red blood cell membranes were purified and MCT1, MCT2 and CD147 measured by western blot. The amount of transporters was compared with TB performance markers. In TBs, the distribution of MCT1 was bimodal and in all breeds distribution of MCT2 unimodal. The amount of CD147 was clearly bimodal in FH and SB, with 85 and 82% expressing high amounts of CD147. In TBs, 88% had high expression of CD147 and 11% low expression, but one horse showed intermediate expression not apparent in FH or SB. Performance markers did not correlate with the amount of MCT1, MCT2 or CD147. High lactate transport activity was present in all 3 racing breeds, with the greatest proportion in the TB, followed by the racing FH, then SB. There was no significant statistical correlation found between lactate transporters in RBC membrane and markers of racing performance in the TB. © 2010 EVJ Ltd.

AR-C155858 is a potent inhibitor of monocarboxylate transporters MCT1 and MCT2 that binds to an intracellular site involving transmembrane helices 7-10.

PubMed

Ovens, Matthew J; Davies, Andrew J; Wilson, Marieangela C; Murray, Clare M; Halestrap, Andrew P

2010-01-15

In the present study we characterize the properties of the potent MCT1 (monocarboxylate transporter 1) inhibitor AR-C155858. Inhibitor titrations of L-lactate transport by MCT1 in rat erythrocytes were used to determine the Ki value and number of AR-C155858-binding sites (Et) on MCT1 and the turnover number of the transporter (kcat). Derived values were 2.3+/-1.4 nM, 1.29+/-0.09 nmol per ml of packed cells and 12.2+/-1.1 s-1 respectively. When expressed in Xenopus laevis oocytes, MCT1 and MCT2 were potently inhibited by AR-C155858, whereas MCT4 was not. Inhibition of MCT1 was shown to be time-dependent, and the compound was also active when microinjected, suggesting that AR-C155858 probably enters the cell before binding to an intracellular site on MCT1. Measurement of the inhibitor sensitivity of several chimaeric transporters combining different domains of MCT1 and MCT4 revealed that the binding site for AR-C155858 is contained within the C-terminal half of MCT1, and involves TM (transmembrane) domains 7-10. This is consistent with previous data identifying Phe360 (in TM10) and Asp302 plus Arg306 (TM8) as key residues in substrate binding and translocation by MCT1. Measurement of the Km values of the chimaeras for L-lactate and pyruvate demonstrate that both the C- and N-terminal halves of the molecule influence transport kinetics consistent with our proposed molecular model of MCT1 and its translocation mechanism that requires Lys38 in TM1 in addition to Asp302 and Arg306 in TM8 [Wilson, Meredith, Bunnun, Sessions and Halestrap (2009) J. Biol. Chem. 284, 20011-20021].

Dai-kenchu-to attenuates rat sinusoidal obstruction syndrome by inhibiting the accumulation of neutrophils in the liver.

PubMed

Narita, Masato; Hatano, Etsuro; Tamaki, Nobuyuki; Yamanaka, Kenya; Yanagida, Atsuko; Nagata, Hiromitsu; Asechi, Hiroyuki; Takada, Yasutsugu; Ikai, Iwao; Uemoto, Shinji

2009-06-01

Sinusoidal obstruction syndrome (SOS) is drug-induced liver injury that occurs in patients who receive hematopoietic cell transplantation and oxaliplatin-contained chemotherapy. The aim of study was to investigate the pharmacological treatment of SOS using a traditional Japanese medicine, Dai-kenchu-to (DKT). Male Sprague-Dawley rats were treated with monocrotaline (MCT) to induce SOS. The rats were divided into three groups: control, MCT and MCT+DKT groups. In the MCT+DKT group, DKT was gavaged at 12 h after MCT treatment and given every 12 h until the end of the protocol. The rats of MCT group were treated with water instead of DKT. At 48 h after MCT treatment, blood and liver samples were collected. In the MCT+DKT group, the macroscopic and histological findings revealed liver congestion, sinusoidal alteration and the destruction of sinusoidal lining, which were comparable with those of the MCT group. However, the area of hepatic necrosis and serum AST levels significantly decreased in the MCT+DKT group compared with those of the MCT group. Treatment with DKT resulted in the reduction of neutrophil accumulation, myeloperoxidase activity and the expression of cytokine-induced neutrophil chemoattractant (CINC) and intracellular adhesion molecule-1 (ICAM-1) mRNA in the liver compared with those of the MCT group. Treatment with processed ginger, one of the ingredients in DKT, resulted in similar effects to those shown by DKT. Dai-kenchu-to attenuates MCT-induced liver injury by preventing neutrophil-induced liver injury through blockage of upregulation of CINC and ICAM-1 mRNA level.

Monocarboxylate transporter 1 contributes to growth factor-induced tumor cell migration independent of transporter activity

PubMed Central

Gray, Alana L.; Coleman, David T.; Shi, Runhua; Cardelli, James A.

2016-01-01

Tumor progression to metastatic disease contributes to the vast majority of incurable cancer. Understanding the processes leading to advanced stage cancer is important for the development of future therapeutic strategies. Here, we establish a connection between tumor cell migration, a prerequisite to metastasis, and monocarboxylate transporter 1 (MCT1). MCT1 transporter activity is known to regulate aspects of tumor progression and, as such, is a clinically relevant target for treating cancer. Knockdown of MCT1 expression caused decreased hepatocyte growth factor (HGF)-induced as well as epidermal growth factor (EGF)-induced tumor cell scattering and wound healing. Western blot analysis suggested that MCT1 knockdown (KD) hinders signaling through the HGF receptor (c-Met) but not the EGF receptor. Exogenous, membrane-permeable MCT1 substrates were not able to rescue motility in MCT1 KD cells, nor was pharmacologic inhibition of MCT1 able to recapitulate decreased cell motility as seen with MCT1 KD cells, indicating transporter activity of MCT1 was dispensable for EGF- and HGF-induced motility. These results indicate MCT1 expression, independent of transporter activity, is required for growth factor-induced tumor cell motility. The findings presented herein suggest a novel function for MCT1 in tumor progression independent of its role as a monocarboxylate transporter. PMID:27127175

Expression of the monocarboxylate transporter 1 (MCT1) in cells of the porcine intestine.

PubMed

Welter, Harald; Claus, Rolf

2008-06-01

Uptake of energy into cells and its allocation to individual cellular compartments by transporters are essential for tissue homeostasis. The present study gives an analysis of MCT1 expression and its cellular occurrence in the porcine intestine. Tissue portions from duodenum, jejunum, ileum, colon ascendens, colon transversum and colon descendens were collected and prepared for immunohistochemistry, Western blot and real time RT-PCR. A 169bp porcine MCT1 cDNA fragment was amplified and published. MCT1 mRNA expression in the large intestine was 20 fold higher compared to the small intestine. Western blot detected a single protein band of 41kDa at a much higher amount of MCT1 protein in the large intestine vs. the small intestine. MCT1 protein was detected in mitochondrial fractions of the large but not the small intestine. Immunohistochemistry in the small intestine showed that immune cells in the lamina propria and in the lymphoid follicles primarily expressed MCT1 while in the colon epithelial cells were the main source of MCT1. In summary, cellular expression of MCT1 differs between epithelial cells in the colon and small intestine. A possible role of MCT1 for uptake of butyrate into immune cells and the overall role of MCT1 for intestinal immune cell function remains elusive.

Preventive effect of sildenafil on right ventricular function in rats with monocrotaline-induced pulmonary arterial hypertension

PubMed Central

Yoshiyuki, Rieko; Tanaka, Ryo; Fukushima, Ryuji; Machida, Noboru

2016-01-01

The present study aimed to evaluate the preventive effect of sildenafil treatment on pulmonary hypertension (PH) induced by monocrotaline (MCT) in rats. Fifty-four 12-week-old male Sprague–Dawley rats were injected with MCT or saline solution (MCT-injected rats: n=36; saline: n=18). Serial echocardiography and right ventricular systolic pressure (RVSP) measurements via a cardiac catheter were performed at 2, 4 and 6 weeks after the injection. After injection of MCT, rats received oral sildenafil (MCT/sildenafil group: n=18) or no treatment (MCT group: n=18) until undergoing echocardiography and cardiac catheterization. RVSP in the MCT/sildenafil group was lower than that in the MCT group at 4 (P<0.001) and 6 weeks (P<0.001). The septal curvature was improved in the MCT/sildenafil group compared with the MCT group. This finding showed that sildenafil prevented flattening of the interventricular septum because of right ventricular pressure overload. The ratio of peak trans-tricuspid early diastolic wave velocity to active filling with atrial systolic velocity showed that sildenafil improved diastolic function. Tricuspid annular plane systolic excursion and tricuspid annular systolic velocity in the MCT/sildenafil group did not show preserved myocardial contraction after administration of sildenafil. Administration of sildenafil leads to a reduction in RVSP and improvement in cardiac function in rats with PH induced by MCT. The vasodilatory action of sildenafil improves right ventricular diastolic function, but the intrinsic, positive, inotropic effect of sildenafil is minimal. PMID:26876436

Activity of the Monocarboxylate Transporter 1 inhibitor AZD3965 in Small Cell Lung Cancer

PubMed Central

Polański, Radosław; Hodgkinson, Cassandra L.; Fusi, Alberto; Nonaka, Daisuke; Priest, Lynsey; Kelly, Paul; Trapani, Francesca; Bishop, Paul W.; White, Anne; Critchlow, Susan E.; Smith, Paul D.; Blackhall, Fiona

2013-01-01

Purpose The monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 is undergoing Phase I evaluation in the UK. AZD3965 is proposed, via lactate transport modulation, to kill tumor cells reliant on glycolysis. We investigated the therapeutic potential of AZD3965 in small cell lung cancer (SCLC) seeking rationale for clinical testing in this disease and putative predictive biomarkers for trial use. Experimental Design AZD3965 sensitivity was determined for 7 SCLC cell lines, in normoxia and hypoxia, and for a tumor xenograft model. Proof of mechanism was sought via changes in intracellular/tumor lactate. Expression of MCT1 and related transporter MCT4 were assessed by western blot. Drug resistance was investigated via MCT4 siRNAi and overexpression. The expression and clinical significance of MCT1 and MCT4 were explored in a tissue microarray from 78 SCLC patients. Results AZD3965 sensitivity varied in vitro and was highest in hypoxia. Resistance in hypoxia was associated with increased MCT4 expression. In vivo, AZD3965 reduced tumor growth and increased intra-tumor lactate. In the tissue microarray, high MCT1 expression was associated with worse prognosis (p=0.014). MCT1 and hypoxia marker CA IX expression in the absence of MCT4 was observed in 21% of SCLC tumors. Conclusions This study provides a rationale to test AZD3965 in SCLC patients. Our results suggest that patients with tumors expressing MCT1 and lacking in MCT4 are most likely to respond. PMID:24277449

Coseismic fault-related fold model, growth structure, and the historic multisegment blind thrust earthquake on the basement-involved Yoro thrust, central Japan

NASA Astrophysics Data System (ADS)

Ishiyama, Tatsuya; Mueller, Karl; Sato, Hiroshi; Togo, Masami

2007-03-01

We use high-resolution seismic reflection profiles, boring transects, and mapping of fold scarps that deform late Quaternary and Holocene sediments to define the kinematic evolution, subsurface geometry, coseismic behavior, and fault slip rates for an active, basement-involved blind thrust system in central Japan. Coseismic fold scarps on the Yoro basement-involved fold are defined by narrow fold limbs and angular hinges on seismic profiles, suggesting that at least 3.9 km of fault slip is consumed by wedge thrust folding in the upper 10 km of the crust. The close coincidence and kinematic link between folded horizons and the underlying thrust geometry indicate that the Yoro basement-involved fold has accommodated slip at an average rate of 3.2 ± 0.1 mm/yr on a shallowly west dipping thrust fault since early Pleistocene time. Past large-magnitude earthquakes, including an historic M˜7.7 event in A.D. 1586 that occurred on the Yoro blind thrust, are shown to have produced discrete folding by curved hinge kink band migration above the eastward propagating tip of the wedge thrust. Coseismic fold scarps formed during the A.D. 1586 earthquake can be traced along the en echelon active folds that extend for at least 60 km, in spite of different styles of folding along the apparently hard-linked Nobi-Ise blind thrust system. We thus emphasize the importance of this multisegment earthquake rupture across these structures and the potential risk for similar future events in en echelon active fold and thrust belts.

The thrust belt in Southwest Montana and east-central Idaho

USGS Publications Warehouse

Ruppel, Edward T.; Lopez, David A.

1984-01-01

The leading edge of the Cordilleran fold and thrust in southwest Montana appears to be a continuation of the edge of the Wyoming thrust belt, projected northward beneath the Snake River Plain. Trces of the thrust faults that form the leading edge of the thrust belts are mostly concealed, but stratigraphic and structural evidence suggests that the belt enters Montana near the middle of the Centennial Mountains, continues west along the Red Rock River valley, and swings north into the Highland Mountains near Butte. The thrust belt in southwest Montana and east-central Idaho includes at least two major plates -- the Medicine Lodge and Grasshopper thrust plates -- each of which contains a distinctive sequence of rocks, different in facies and structural style from those of the cratonic region east of the thrust belt. The thrust plates are characterized by persuasive, open to tight and locally overturned folds, and imbricate thrust faults, structural styles unusual in Phanerozoic cratonic rocks. The basal decollement zones of the plates are composed of intensely sheared, crushed, brecciated, and mylonitized rocks, the decollement at the base of the Medicine Lodge plate is as much as 300 meters thick. The Medicine Lodge and Grasshopper thrust plates are fringed on the east by a 10- to 50-kilometer-wide zone of tightly folded rocks cut by imbricate thrust fauls, a zone that forms the eastern margin of the thrust belt in southwest Montana. The frontal fold and thrust zone includes rocks that are similar to those of the craton, even though they differ in details of thickness, composition, or stratigraphic sequence. The zone is interpreted to be one of terminal folding and thrusting in cratonic rocks overridden by the major thrust plates from farther west. The cratonic rocks were drape-folded over rising basement blocks that formed a foreland bulge in front of the thrust belt. The basement blocks are bounded by steep faults of Proterozoic ancestry, which also moved as tear faults during thrusting, and seem to have controlled the curving patterns of salients and reentrants at the leading edge of the thrust belt. Radiometric and stratiographic evidence shows that the thrust belt was in its present position by about 75 million year go.

Role of MCT1 and CAII in skeletal muscle pH homeostasis, energetics, and function: in vivo insights from MCT1 haploinsufficient mice.

PubMed

Chatel, Benjamin; Bendahan, David; Hourdé, Christophe; Pellerin, Luc; Lengacher, Sylvain; Magistretti, Pierre; Le Fur, Yann; Vilmen, Christophe; Bernard, Monique; Messonnier, Laurent A

2017-06-01

The purpose of this study was to investigate the effects of a partial suppression of monocarboxylate transporter (MCT)-1 on skeletal muscle pH, energetics, and function (MCT1 +/- mice). Twenty-four MCT1 +/- and 13 wild-type (WT) mice were subjected to a rest-exercise-recovery protocol, allowing assessment of muscle energetics (by magnetic resonance spectroscopy) and function. The study included analysis of enzyme activities and content of protein involved in pH regulation. Skeletal muscle of MCT1 +/- mice had lower MCT1 (-61%; P < 0.05) and carbonic anhydrase (CA)-II (-54%; P < 0.05) contents. Although intramuscular pH was higher in MCT1 +/- mice at rest ( P < 0.001), the mice showed higher acidosis during the first minute of exercise ( P < 0.01). Then, the pH time course was similar among groups until exercise completion. MCT1 +/- mice had higher specific peak ( P < 0.05) and maximum tetanic ( P < 0.01) forces and lower fatigability ( P < 0.001) when compared to WT mice. We conclude that both MCT1 and CAII are involved in the homeostatic control of pH in skeletal muscle, both at rest and at the onset of exercise. The improved muscle function and resistance to fatigue in MCT1 +/- mice remain unexplained.-Chatel, B., Bendahan, D., Hourdé, C., Pellerin, L., Lengacher, S., Magistretti, P., Fur, Y. L., Vilmen, C., Bernard, M., Messonnier, L. A. Role of MCT1 and CAII in skeletal muscle pH homeostasis, energetics, and function: in vivo insights from MCT1 haploinsufficient mice. © FASEB.

Prevalence and risk factors for mast cell tumours in dogs in England.

PubMed

Shoop, Stephanie Jw; Marlow, Stephanie; Church, David B; English, Kate; McGreevy, Paul D; Stell, Anneliese J; Thomson, Peter C; O'Neill, Dan G; Brodbelt, David C

2015-01-01

Mast cell tumour (MCT) appears to be a frequent tumour type in dogs, though there is little published in relation to its frequency in dogs in the UK. The current study aimed to investigate prevalence and risk factors for MCTs in dogs attending English primary-care veterinary practices. Electronic patient records from practices participating in the VetCompass animal surveillance project between July 2007 and June 2013 were searched for MCT diagnosis. Various search terms and standard diagnostic terms (VeNom codes) identified records containing MCT diagnoses, which were evaluated against clinical criteria for inclusion to the study. MCT prevalence for the entire dataset and specific breed types were calculated. Descriptive statistics characterised MCT cases and multivariable logistic regression methods evaluated risk factors for association with MCT (P < 0.05). Within a population of 168,636 dogs, 453 had MCT, yielding a prevalence of 0.27% (95% confidence interval (CI) 0.24% - 0.29%). The highest breed type specific prevalences were for the Boxer at 1.95% (95% CI 1.40% - 2.51%), Golden Retriever at 1.39% (0.98% - 1.81%) and Weimaraner at 0.85% (95% CI 0.17% to 1.53%). Age, insurance status, neuter status, weight and breed type were associated with MCT diagnosis. Of dogs of specific breed type, the Boxer, Pug and Staffordshire Bull Terrier showed greater odds of MCT diagnosis compared with crossbred dogs. Conversely, the German Shepherd Dog, Border Collie, West Highland White Terrier, Springer Spaniel and Cocker Spaniel had reduced odds of MCT diagnosis compared with crossbred dogs. No association was found between MCT diagnosis and sex. This study highlights a clinically significant prevalence of MCT and identifies specific breed types with predisposition to MCT, potentially aiding veterinarian awareness and facilitating diagnosis.

A rich medium-chain triacylglycerol diet benefits adiposity but has adverse effects on the markers of hepatic lipogenesis and beta-oxidation.

PubMed

Chamma, Carolina Maria de Oliveira; Bargut, Thereza Cristina Lonzetti; Mandarim-de-Lacerda, Carlos Alberto; Aguila, Marcia Barbosa

2017-02-22

We investigated the increasing amounts of medium-chain triacylglycerol (MCT) in the diet on hepatic lipid metabolism. Mature C57BL/6 male mice were randomly divided into five groups (n = 10/group). The animals received their diet for 12 weeks, as a control (C group, 10% of energy from lipids); high-fat lard (HF group, isoenergetic diet, 50% of energy from lipids with lard); a mixture of lard and MCT oil (with a gradual replacement of lard by MCT: HF-MCT25%, HF-MCT75%, and HF-MCT100% groups). At euthanasia, we collected blood and dissected the liver for analyses (glucose, insulin, HOMA-IR, QUICK index, and triacylglycerol, light microscopy, western blotting, and RT-qPCR). The HF diet groups showed a greater body mass gain compared to the C group, but the HF-MCT100% group showed diminished adiposity and amelioration of insulin resistance. All the HF groups also showed a clear increase in hepatic lipid accumulation, increased lipogenesis and decreased PPAR-alpha expression, although HF-MCT groups showed improved local insulin signaling. Lastly, the HF-MCT100% group had raised markers of beta-oxidation (UCP3 and MCAD) and mitochondrial biogenesis (PGC1-alpha and NRF1). In conclusion, the findings demonstrated that a high amount of MCT (HF-MCT100% group) added to an HF diet reduces the body fat accumulation and insulin resistance. However, the lipid accumulation as well as the lipid metabolism is altered in the liver of animals fed with a very high MCT diet, indicating that higher doses of MCT may be harmful in a long-term.

The MCT4 Gene: A Novel, Potential Target for Therapy of Advanced Prostate Cancer.

PubMed

Choi, Stephen Yiu Chuen; Xue, Hui; Wu, Rebecca; Fazli, Ladan; Lin, Dong; Collins, Colin C; Gleave, Martin E; Gout, Peter W; Wang, Yuzhuo

2016-06-01

The management of castration-resistant prostate cancer (CRPC) is a major challenge in the clinic. Androgen receptor signaling-directed strategies are not curative in CRPC therapy, and new strategies targeting alternative, key cancer properties are needed. Using reprogrammed glucose metabolism (aerobic glycolysis), cancer cells typically secrete excessive amounts of lactic acid into their microenvironment, promoting cancer development, survival, and progression. Cellular lactic acid secretion is thought to be predominantly mediated by MCT4, a plasma membrane transporter protein. As such, the MCT4 gene provides a unique, potential therapeutic target for cancer. A tissue microarray of various Gleason grade human prostate cancers was stained for MCT4 protein. Specific, MCT4-targeting antisense oligonucleotides (MCT4 ASO) were designed and candidate MCT4 ASOs checked for effects on (i) MCT4 expression, lactic acid secretion/content, glucose consumption, glycolytic gene expression, and proliferation of human CRPC cells and (ii) growth of PC-3 tumors in nude mice. Elevated MCT4 expression was associated with human CRPC and an earlier time to relapse. The treatment of PC-3, DU145, and C4-2 CRPC cultures with candidate MCT4 ASOs led to marked inhibition of MCT4 expression, lactic acid secretion, to increased intracellular lactic acid levels, and markedly reduced aerobic glycolysis and cell proliferation. Treatment of PC-3 tumor-bearing nude mice with the MCT4 ASOs markedly inhibited tumor growth without inducing major host toxicity. MCT4-targeting ASOs that inhibit lactic acid secretion may be useful for therapy of CRPC and other cancers, as they can interfere with reprogrammed energy metabolism of cancers, an emerging hallmark of cancer. Clin Cancer Res; 22(11); 2721-33. ©2016 AACR. ©2016 American Association for Cancer Research.

Basement thrust sheets in the Clearwater orogenic zone, central Idaho and western Montana ( USA).

USGS Publications Warehouse

Skipp, B.

1987-01-01

The Clearwater orogenic zone in central Idaho and W Montana contains at least 2 major NE-directed Cordilleran thrust plates of Early Proterozoic metasedimentary and metaigneous rocks that overrode previously folded Middle Proterozoic rocks of the Belt basin in Cretaceous time. The northeastward migration of the resultant thickened wedge of crustal material combined with Cretaceous subduction along the W continental margin produced a younger N Bitterroot lobe of the Idaho batholith relative to an older S Atlanta lobe. Eocene extensional unroofing and erosion of the Bitterroot lobe has exposed the roots of the thick Cordilleran thrust sheets.-Author

MCT1 in Invasive Ductal Carcinoma: Monocarboxylate Metabolism and Aggressive Breast Cancer.

PubMed

Johnson, Jennifer M; Cotzia, Paolo; Fratamico, Roberto; Mikkilineni, Lekha; Chen, Jason; Colombo, Daniele; Mollaee, Mehri; Whitaker-Menezes, Diana; Domingo-Vidal, Marina; Lin, Zhao; Zhan, Tingting; Tuluc, Madalina; Palazzo, Juan; Birbe, Ruth C; Martinez-Outschoorn, Ubaldo E

2017-01-01

Introduction: Monocarboxylate transporter 1 (MCT1) is an importer of monocarboxylates such as lactate and pyruvate and a marker of mitochondrial metabolism. MCT1 is highly expressed in a subgroup of cancer cells to allow for catabolite uptake from the tumor microenvironment to support mitochondrial metabolism. We studied the protein expression of MCT1 in a broad group of breast invasive ductal carcinoma specimens to determine its association with breast cancer subtypes and outcomes. Methods: MCT1 expression was evaluated by immunohistochemistry on tissue micro-arrays (TMA) obtained through our tumor bank. Two hundred and fifty-seven cases were analyzed: 180 cases were estrogen receptor and/or progesterone receptor positive (ER+ and/or PR+), 62 cases were human epidermal growth factor receptor 2 positive (HER2+), and 56 cases were triple negative breast cancers (TNBC). MCT1 expression was quantified by digital pathology with Aperio software. The intensity of the staining was measured on a continuous scale (0-black to 255-bright white) using a co-localization algorithm. Statistical analysis was performed using a linear mixed model. Results: High MCT1 expression was more commonly found in TNBC compared to ER+ and/or PR+ and compared to HER-2+ ( p < 0.001). Tumors with an in-situ component were less likely to stain strongly for MCT1 ( p < 0.05). High nuclear grade was associated with higher MCT1 staining ( p < 0.01). Higher T stage tumors were noted to have a higher expression of MCT1 ( p < 0.05). High MCT1 staining in cancer cells was associated with shorter progression free survival, increased risk of recurrence, and larger size independent of TNBC status ( p < 0.05). Conclusion: MCT1 expression, which is a marker of high catabolite uptake and mitochondrial metabolism, is associated with recurrence in breast invasive ductal carcinoma. MCT1 expression as quantified with digital image analysis may be useful as a prognostic biomarker and to design clinical trials using MCT1 inhibitors.

Possible involvement of AMPK in acute exercise-induced expression of monocarboxylate transporters MCT1 and MCT4 mRNA in fast-twitch skeletal muscle.

PubMed

Takimoto, Masaki; Takeyama, Mirei; Hamada, Taku

2013-11-01

The regulatory mechanisms responsible for acute exercise-induced expression of monocarboxylate transporters MCT1 and MCT4 mRNA in skeletal muscle remain unclear. 5'-adenosine-activated protein kinase (AMPK) is a key signaling molecule that regulates gene expression at the mRNA level. We examined whether AMPK activation is involved in acute exercise-induced expression of MCT1 and MCT4 mRNA in fast-twitch muscle. Male Sprague-Dawley rats were subjected to an acute bout of either 5min high-intensity intermittent swimming (HIS) or 6-h low-intensity prolonged swimming (LIS). The effects of acute exercise on the phosphorylation of AMPK (p-AMPK), calcium/calmodulin pendent kinase II (p-CaMKII), p38 mitogen-activated protein kinase (p-p38MAPK), and MCTs mRNA were analyzed in vivo. To observe the direct effects of AMPK activation on MCTs mRNA, the effects of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), caffeine, and dantrolene were analyzed in vitro using an isolated muscle incubation model. The p-AMPK increased in response to both HIS and LIS, although the p-CaMKII and p-p38MAPK were increased only following HIS. Irrespective of exercise intensity, MCT1 and MCT4 mRNA was also transiently upregulated by both HIS and LIS. Direct exposure of the epitrochlearis muscle to 0.5mmol/L AICAR or 1mmol/L caffeine, which activated p-AMPK increased both MCT1 and MCT4 mRNA levels. When pAMPK was inhibited by dantrolene, neither MCT1 nor MCT4 mRNA was increased. These results suggest that acute exercise-induced increases in MCT1 and MCT4 mRNA expression may be possibly mediated by AMPK activation, at least in part in fast-twitch muscle. © 2013.

Organized metabolic crime in prostate cancer: The coexpression of MCT1 in tumor and MCT4 in stroma is an independent prognosticator for biochemical failure.

PubMed

Andersen, Sigve; Solstad, Ørjan; Moi, Line; Donnem, Tom; Eilertsen, Marte; Nordby, Yngve; Ness, Nora; Richardsen, Elin; Busund, Lill-Tove; Bremnes, Roy M

2015-08-01

Lactate import or export over cell membranes is facilitated by monocarboxylate transporters (MCTs) 1 and 4. Expression profiles can be markers of an oxidative or glycolytic phenotype. Descriptive studies and functional studies in neoplastic cells and fibroblasts in prostate cancer (PC) have suggested a distinct phenotype. We aimed to explore expression of MCT1 and MCT4 in PC cells and surrounding stroma in a large cohort. Additionally, we wanted to find out if distinct expression profiles were associated with biochemical failure-free survival (BFFS). Tissue microarrays were constructed from 535 patients with radical prostatectomies between January 1, 1995, and December 31, 2005. Immunohistochemistry was used to detect expression, and degrees of expression were evaluated semiquantitatively by 2 pathologists using light microscopy. For MCT1, there was only epithelial expression, whereas there was a low level of expression of MCT4 in tumor and stroma. A total of 172 patients had a low expression of MCT1 in tumor and MCT4 in stroma. There were 232 patients who had a high expression of MCT1 and a low expression of MCT4 in stroma. Only 11 patients had a low tumoral MCT1 expression and a high stromal MCT4 expression, and 26 patients (5%) had a high expression of both. Patients with a high-high combination had a significantly reduced BFFS (P = 0.011), and when adjusting for other factors, its effect was significant and independent (HR = 1.99, CI 95%: 1.09-3.62; P = 0.024). This study adds to the current understanding of the reversed Warburg effect to be a significant phenotype in PC. High coexpression of MCT1 in tumor and MCT4 in stroma is independently associated to a worse BFFS, and the strength of this association is as strong as having a Gleason score of ≥9. Copyright © 2015 Elsevier Inc. All rights reserved.

MCT1 in Invasive Ductal Carcinoma: Monocarboxylate Metabolism and Aggressive Breast Cancer

PubMed Central

Johnson, Jennifer M.; Cotzia, Paolo; Fratamico, Roberto; Mikkilineni, Lekha; Chen, Jason; Colombo, Daniele; Mollaee, Mehri; Whitaker-Menezes, Diana; Domingo-Vidal, Marina; Lin, Zhao; Zhan, Tingting; Tuluc, Madalina; Palazzo, Juan; Birbe, Ruth C.; Martinez-Outschoorn, Ubaldo E.

2017-01-01

Introduction: Monocarboxylate transporter 1 (MCT1) is an importer of monocarboxylates such as lactate and pyruvate and a marker of mitochondrial metabolism. MCT1 is highly expressed in a subgroup of cancer cells to allow for catabolite uptake from the tumor microenvironment to support mitochondrial metabolism. We studied the protein expression of MCT1 in a broad group of breast invasive ductal carcinoma specimens to determine its association with breast cancer subtypes and outcomes. Methods: MCT1 expression was evaluated by immunohistochemistry on tissue micro-arrays (TMA) obtained through our tumor bank. Two hundred and fifty-seven cases were analyzed: 180 cases were estrogen receptor and/or progesterone receptor positive (ER+ and/or PR+), 62 cases were human epidermal growth factor receptor 2 positive (HER2+), and 56 cases were triple negative breast cancers (TNBC). MCT1 expression was quantified by digital pathology with Aperio software. The intensity of the staining was measured on a continuous scale (0-black to 255-bright white) using a co-localization algorithm. Statistical analysis was performed using a linear mixed model. Results: High MCT1 expression was more commonly found in TNBC compared to ER+ and/or PR+ and compared to HER-2+ (p < 0.001). Tumors with an in-situ component were less likely to stain strongly for MCT1 (p < 0.05). High nuclear grade was associated with higher MCT1 staining (p < 0.01). Higher T stage tumors were noted to have a higher expression of MCT1 (p < 0.05). High MCT1 staining in cancer cells was associated with shorter progression free survival, increased risk of recurrence, and larger size independent of TNBC status (p < 0.05). Conclusion: MCT1 expression, which is a marker of high catabolite uptake and mitochondrial metabolism, is associated with recurrence in breast invasive ductal carcinoma. MCT1 expression as quantified with digital image analysis may be useful as a prognostic biomarker and to design clinical trials using MCT1 inhibitors. PMID:28421181

Bevacizumab exacerbates sinusoidal obstruction syndrome (SOS) in the animal model and increases MMP 9 production.

PubMed

Jafari, Azin; Matthaei, Hanno; Wehner, Sven; Tonguc, Tolga; Kalff, Jörg C; Manekeller, Steffen

2018-04-24

Thanks to modern multimodal treatment the ouctome of patients with colorectal cancer has experienced significant improvements. As a downside, agent specific side effects have been observed such as sinusoidal obstruction syndrome (SOS) after oxaliplatin chemotherapy (OX). Bevazicumab targeting VEGF is nowadays comprehensively used in combination protocols with OX but its impact on hepatotoxicity is thus far elusive and focus of the present study. After MCT administration 67% of animals developed SOS. GOT serum concentration significantly increased in animals developing SOS ( p < 0.001). Subsequent to MCT administration 100% of animals treated with Anti-VEGF developed SOS. In contrast, animals receiving VEGF developed SOS merely in 40% while increasing the VEGF dose led to a further decrease in SOS development to 25%. MMP 9 concentration in animals developing SOS was significantly higher compared to controls ( p < 0,001). Additional treatment with Anti-VEGF increased the MMP 9 concentration significantly ( p < 0,05). Preservation of liver function is a central goal in both curative and palliative treatment phases of patients with CRC. Thus, knowledge about hepatotoxic side effects of chemotherapeutic and biological agents is crucial. From the results it can be concluded that Anti-VEGF exacerbates SOS paralleled by MMP 9 production. Therefore, OX-Bevacizumab combination therapies should be administered with caution, especially if liver parenchyma damage is apparent. Male Sprague-Dawley rats were gavaged Monocrotaline (MCT) to induce SOS. Recombinant VEGF or an Anti-VEGF antibody was administered to MCT-treated rats and the hepatotoxic effect monitored in defined time intervals. MMP 9 expression in the liver was measured by ELISA.

Monocarboxylate transporters in temporal lobe epilepsy: roles of lactate and ketogenic diet.

PubMed

Lauritzen, Fredrik; Eid, Tore; Bergersen, Linda H

2015-01-01

Epilepsy is a serious neurological disorder that affects approximately 1 % of the general population, making it one of the most common disorders of the central nervous system. Furthermore, up to 40 % of all patients with epilepsy cannot control their seizures with current medications. More efficacious treatments for medication refractory epilepsy are therefore needed. A better understanding of the mechanisms that cause this disorder is likely to facilitate the discovery of such treatments. Impairment in cerebral energy metabolism has been proposed as a possible causative factor in the pathogenesis of temporal lobe epilepsy (TLE), which is one of the most common types of medication-refractory epilepsies in adults. In this review, we will discuss some of the current hypotheses regarding the possible causal relationship between brain energy metabolism and TLE. Emphasis will be placed on the role of energy substrates (lactate and ketone bodies) and their transporter molecules, particularly monocarboxylate transporters 1 and 2 (MCT1 and MCT2). We recently reported that the cellular distribution of MCT1 and MCT2 is perturbed in the hippocampus in patients with TLE. The changes may be an adaptive response aimed at keeping high levels of lactate in the epileptic tissue, which may serve to counteract epileptic activity by downregulating cAMP levels through the lactate receptor GPR81, newly discovered in hippocampus. We propose that the perturbation of MCTs may be further involved in the pathophysiology of TLE by influencing brain energy homeostasis, mitochondrial function, GABA-ergic and glutamatergic neurotransmission, and flux of lactate through the brain.

P-T data from central Bhutan imply distributed extensional shear at the Black Mountain "klippe"

NASA Astrophysics Data System (ADS)

Corrie, S. L.; Kohn, M. J.; Long, S. P.; McQuarrie, N.; Tobgay, T.

2011-12-01

The Southern Tibetan Detachment system (STDS) occurs along the entire length of the Himalayan orogen, and extensionally emplaces low-grade to unmetamorphosed Tethyan Himalayan (TH) rocks over highly metamorphosed Greater Himalayan sequence (GH) rocks. The base of TH remnants preserved in northern Bhutan all have top-to-the-north shear sense indicators (C'-type shear bands, asymmetric folds, and boudinaged leucogranite dikes) that are interpreted to reflect a discrete shear zone. In contrast, the GH-TH contact in the southernmost TH remnant (the Black Mountain region, central Bhutan) has been interpreted as depositional. A depositional contact limits the magnitude of displacement along the early STDS to 10's of km. If the GH-TH contact in the Black Mountain region is instead a discrete shear zone, as observed farther north, displacement on the STDS could be as high as 100's of km. To discriminate between these two interpretations, we determined peak metamorphic P-T conditions through the GH and TH sections, reasoning that a discrete shear zone would produce a distinct jump in metamorphic temperature, pressure or both. Thin section-scale kinematic indicators reveal pervasive top-to-the-north shear from 2-3 km structurally above the Main Central thrust (MCT) through the rest of the 11 km thick GH and TH sections. P-T conditions were determined from immediately above the MCT to 4 km above the GH-TH contact, with 19 samples from the GH, 6 from the overlying Chekha Fm (TH), and 9 from the overlying Maneting Fm (TH). We applied standard Fe-Mg exchange thermometers and Ca net-transfer barometers involving garnet. P-T conditions range from 700 °C and 11 kbar in migmatitic GHS to 600 °C and 8 kbar at the GH-Chekha contact, and 500 °C and 5 kbar at the top of the Maneting. We found no jumps in either temperature or pressure at any level, but a steeper than lithostatic pressure gradient, which we interpret to result from distributed extensional shear. The average thermal field gradient is surprisingly cool - only 20-25 °C/km. The baric field gradient is approximately 2 times steeper than lithostatic - 0.6 to 0.7 kbar/km, rather than 0.3 - so approximately 10 km of section has been excised. We argue that instead of a discrete structure, the Black Mountain "klippe," is part of a broad (≥8 km thick), low displacement shear zone and that the relationship between the GH and TH rocks in this region is depositional. These results support relatively minor displacement (a few tens of km) on the STDS remnants in northern Bhutan. Thus while channel- like behavior is present within the GHS and TH sections, its role in controlling Himalayan architecture is minor.

Medium-chain triglycerides are advantageous in promoting weight loss although not beneficial to exercise performance.

PubMed

Clegg, Miriam E

2010-11-01

Medium-chain triglycerides (MCT) are triglycerides with a fatty acid chain length varying between 6 and 10 carbon atoms. MCT differ from long-chain triglycerides as they are relatively soluble in water and, hence, rapidly hydrolysed and absorbed. MCT are transported in the blood through the portal system, consequently they bypass adipose tissue that makes them less susceptible to hormone-sensitive lipase and deposition into adipose tissue stores. Due to these properties, MCT have been researched for both benefits to exercise performance and health. The present review aims to assess whether MCT are beneficial in either of these situations. MCT have been proposed as a means to maximizing an athlete's ability to maintain their glycogen stores so they can be more competitive. However, only two studies to date have shown an improvement in exercise performance. From a health perspective, MCT increase fat oxidation and energy expenditure as well as reduce food intake and beneficially alter body composition. Results indicate that MCT feeding is ineffective in improving exercise performance and future work should focus on the health benefits and applications of MCT.

Exhumation of Greater Himalayan rock along the main central thrust in Nepal: Implications for channel flow

USGS Publications Warehouse

Robinson, D.M.; Pearson, O.N.; ,

2006-01-01

South-vergent channel flow from beneath the Tibetan Plateau may have played an important role in forming the Himalaya. The possibility that Greater Himalayan rocks currently exposed in the Himalayan Fold-Thrust Belt flowed at mid-crustal depths before being exhumed is intriguing, and may suggest a natural link between orogenic processes operating under the Tibetan Plateau and in the fold-thrust belt. Conceptual and numeric models for the Himalayan-Tibetan Orogen currently reported in the literature do an admirable job of replicating many of the observable primary geological features and relationships. However, detailed observations from Greater Himalayan rocks exposed in the fold-thrust belt's external klippen, and from Lesser Himalayan rocks in the proximal footwall of the Main Central Thrust, suggest that since Early Miocene time, it may be more appropriate to model the evolution of the fold-thrust belt using the critical taper paradigm. This does not exclude the possibility that channel flow and linked extrusion of Greater Himalayan rocks may have occurred, but it places important boundaries on a permissible time frame during which these processes may have operated. ?? The Geological Society of London 2006.

Intracellular and Extracellular Carbonic Anhydrases Cooperate Non-enzymatically to Enhance Activity of Monocarboxylate Transporters*

PubMed Central

Klier, Michael; Andes, Fabian T.; Deitmer, Joachim W.; Becker, Holger M.

2014-01-01

Proton-coupled monocarboxylate transporters (MCTs) are carriers of high-energy metabolites such as lactate, pyruvate, and ketone bodies and are expressed in most tissues. It has previously been shown that transport activity of MCT1 and MCT4 is enhanced by the cytosolic carbonic anhydrase II (CAII) independent of its catalytic activity. We have now studied the influence of the extracellular, membrane-bound CAIV on transport activity of MCT1/4, heterologously expressed in Xenopus oocytes. Coexpression of CAIV with MCT1 and MCT4 resulted in a significant increase in MCT transport activity, even in the nominal absence of CO2/HCO3−. CAIV-mediated augmentation of MCT activity was independent of the CAIV catalytic function, since application of the CA-inhibitor ethoxyzolamide or coexpression of the catalytically inactive mutant CAIV-V165Y did not suppress CAIV-mediated augmentation of MCT transport activity. The interaction required CAIV at the extracellular surface, since injection of CAIV protein into the oocyte cytosol did not augment MCT transport function. The effects of cytosolic CAII (injected as protein) and extracellular CAIV (expressed) on MCT transport activity, were additive. Our results suggest that intra- and extracellular carbonic anhydrases can work in concert to ensure rapid shuttling of metabolites across the cell membrane. PMID:24338019

Monocarboxylate transporters (MCTs) in gliomas: expression and exploitation as therapeutic targets

PubMed Central

Miranda-Gonçalves, Vera; Honavar, Mrinalini; Pinheiro, Céline; Martinho, Olga; Pires, Manuel M.; Pinheiro, Célia; Cordeiro, Michelle; Bebiano, Gil; Costa, Paulo; Palmeirim, Isabel; Reis, Rui M.; Baltazar, Fátima

2013-01-01

Background Gliomas exhibit high glycolytic rates, and monocarboxylate transporters (MCTs) play a major role in the maintenance of the glycolytic metabolism through the proton-linked transmembrane transport of lactate. However, their role in gliomas is poorly studied. Thus, we aimed to characterize the expression of MCT1, MCT4, and their chaperone CD147 and to assess the therapeutic impact of MCT inhibition in gliomas. Methods MCTs and CD147 expressions were characterized by immunohistochemistry in nonneoplastic brain and glioma samples. The effect of CHC (MCT inhibitor) and MCT1 silencing was assessed in in vitro and in vivo glioblastoma models. Results MCT1, MCT4, and CD147 were overexpressed in the plasma membrane of glioblastomas, compared with diffuse astrocytomas and nonneoplastic brain. CHC decreased glycolytic metabolism, migration, and invasion and induced cell death in U251 cells (more glycolytic) but only affected proliferation in SW1088 (more oxidative). The effectiveness of CHC in glioma cells appears to be dependent on MCT membrane expression. MCT1 downregulation showed similar effects on different glioma cells, supporting CHC as an MCT1 inhibitor. There was a synergistic effect when combining CHC with temozolomide treatment in U251 cells. In the CAM in vivo model, CHC decreased the size of tumors and the number of blood vessels formed. Conclusions This is the most comprehensive study reporting the expression of MCTs and CD147 in gliomas. The MCT1 inhibitor CHC exhibited anti-tumoral and anti-angiogenic activity in gliomas and, of importance, enhanced the effect of temozolomide. Thus, our results suggest that development of therapeutic approaches targeting MCT1 may be a promising strategy in glioblastoma treatment. PMID:23258846

Characterization of fibroblasts from hypertrophied right ventricle of pulmonary hypertensive rats.

PubMed

Imoto, Keisuke; Okada, Muneyoshi; Yamawaki, Hideyuki

2018-06-02

Pulmonary arterial hypertension (PAH), which is characterized by an elevation of pulmonary arterial resistance, leads to a lethal right heart failure. It is an urgent issue to clarify the pathogenesis of PAH-induced right heart failure. The present study aimed to elucidate the characteristics of cardiac fibroblasts (CFs) isolated from hypertrophied right ventricles of monocrotaline (MCT)-induced PAH model rats. CFs were isolated from the right ventricles of MCT-injected rats (MCT-CFs) and saline-injected control rats (CONT-CFs). Expression of α-smooth muscle actin and collagen type I in MCT-CFs was lower than that in CONT-CFs. On the other hand, proliferation, migration, and matrix metalloproteinase (MMP)-9 production were significantly enhanced in MCT-CFs. In MCT-CFs, phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase (JNK), and Ca 2+ /calmodulin-dependent protein kinase (CaMK) II was significantly enhanced. In addition to mRNA expression of Orai1, a Ca 2+ release-activated Ca 2+ channel, and stromal interaction molecules (STIM) 1, an endoplasmic reticulum Ca 2+ sensor, the associated store-operated Ca 2+ entry (SOCE) was significantly higher in MCT-CFs than CONT-CFs. Pharmacological inhibition of ERK1/2 pathway prevented the enhanced proliferation of MCT-CFs. The enhanced migration of MCT-CFs was prevented by a pharmacological inhibition of ERK1/2, JNK, CaMKII, or SOCE pathway. The enhanced MMP-9 production in MCT-CFs was prevented by a pharmacological inhibition of ERK1/2, CaMKII, or SOCE pathway but not JNK. The present results suggested that MCT-CFs exhibit proliferative and migratory phenotypes perhaps through multiple signaling pathways. This study for the first time determined the characteristics of CFs isolated from hypertrophied right ventricles of MCT-induced PAH model rats.

Regulation of monocarboxylate transporter 1 (MCT1) promoter by butyrate in human intestinal epithelial cells: involvement of NF-kappaB pathway.

PubMed

Borthakur, Alip; Saksena, Seema; Gill, Ravinder K; Alrefai, Waddah A; Ramaswamy, Krishnamurthy; Dudeja, Pradeep K

2008-04-01

Butyrate, a short chain fatty acid (SCFA) produced by bacterial fermentation of undigested carbohydrates in the colon, constitutes the major fuel for colonocytes. We have earlier shown the role of apically localized monocarboxylate transporter isoform 1 (MCT1) in transport of butyrate into human colonic Caco-2 cells. In an effort to study the regulation of MCT1 gene, we and others have cloned the promoter region of the MCT1 gene and identified cis elements for key transcription factors. A previous study has shown up-regulation of MCT1 expression, and activity by butyrate in AA/C1 human colonic epithelial cells, however, the detailed mechanisms of this up-regulation are not known. In this study, we demonstrate that butyrate, a substrate for MCT1, stimulates MCT1 promoter activity in Caco-2 cells. This effect was dose dependent and specific to butyrate as other predominant SCFAs, acetate, and propionate, were ineffective. Utilizing progressive deletion constructs of the MCT1 promoter, we showed that the putative butyrate responsive elements are in the -229/+91 region of the promoter. Butyrate stimulation of the MCT1 promoter was found to be independent of PKC, PKA, and tyrosine kinases. However, specific inhibitors of the NF-kappaB pathway, lactacystein (LC), and caffeic acid phenyl ester (CAPE) significantly reduced the MCT1 promoter stimulation by butyrate. Also, butyrate directly stimulated NF-kappaB-dependent luciferase reporter activity. Histone deacetylase (HDAC) inhibitor trichostatin A (TSA) also stimulated MCT1 promoter activity, however, unlike butyrate, this stimulation was unaltered by the NF-kappaB inhibitors. Further, the combined effect of butyrate, and TSA on MCT1 promoter activity was additive, indicating that their mechanisms of action were independent. Our results demonstrate the involvement of NF-kappaB pathway in the regulation of MCT1 promoter activity by butyrate. 2007 Wiley-Liss, Inc.

Immunohistochemical analysis of MCT1 and CD147 in equine skeletal muscle fibres.

PubMed

Mykkänen, A K; Hyyppä, S; Pösö, A R; Ronéus, N; Essén-Gustavsson, B

2010-12-01

Monocarboxylate transporter 1 (MCT1) and its ancillary protein CD147 facilitate efflux of lactate from the muscle. Expression of MCT1 and CD147 were studied with immunohistochemistry in type I, IIA, IIAB and IIB fibres of equine gluteal muscle. Staining intensity of MCT1 in the cytoplasm as well as in the membranes of fibre types decreased in the order I=IIA>IIAB>IIB and correlated with the oxidative capacity. Capillaries were pronounced in the MCT1 staining. CD147 antibody stained plasma membranes of all fibre types evenly, whereas the staining in the cytoplasm followed that of MCT1. In the middle gluteal muscle the expression of MCT1 follows the oxidative capacity of muscle fibres, but the expression of CD147 in sarcolemma does not vary among fibre types. The use of horse specific MCT1 and CD147 antibodies can in future studies help to evaluate lactate efflux from different muscle fibre types. Copyright © 2010 Elsevier Ltd. All rights reserved.

MCT1 promotes the cisplatin-resistance by antagonizing Fas in epithelial ovarian cancer.

PubMed

Yan, Chunxiao; Yang, Fan; Zhou, Chunxia; Chen, Xuejun; Han, Xuechuan; Liu, Xueqin; Ma, Hongyun; Zheng, Wei

2015-01-01

This study was designed to investigate the role of MCT1 in the development of cisplatin-resistant ovarian cancer and its possible relationship with Fas. We found the expression of MCT1 was obviously increased both in cisplatin-resistant ovarian cancer tissue and A2780/CP cells compared with sensitive ovarian cancer tissue and cell lines A2780. And in A2780 cells treated with Cisplatin, the expression of MCT1 increased in a concentration-dependent manner, MCT1 knockdown attenuates cisplatin-induced cell viability. In A2780 and A2780/CP cells transfected with MCT1 siRNA, the activation of several downstream targets of Fas, including FasL and FAP-1 were largely prevented, whereas the expression of Caspase-3 was increased, accompanying with increased abundance of Fas. Coimmunoprecipitation and immunofluorescence showed that there is interaction between endogenous MCT1 with Fas in vivo and in vitro. In vivo, depletion of MCT1 by shRNA reverses cisplatin-resistance and the expression of Fas. This study showed that down regulation of MCT1 promote the sensibility to Cisplatin in ovarian cancer cell line. And this effect appeared to be mediated via antagonizing the effect of Fas.

Monocarboxylate transporter 1 (MCT1) in the liver of pre-ruminant and adult bovines.

PubMed

Kirat, D; Inoue, H; Iwano, H; Yokota, H; Taniyama, H; Kato, S

2007-01-01

This study investigated the distribution and expression of monocarboxylate transporter 1 (MCT1) in the livers of pre-ruminant calves and adult bovines (bulls and cows), using different molecular biological techniques. Reverse transcription-polymerase chain reaction (RT-PCR) verified the presence of mRNA encoding for MCT1 in both pre-ruminant and adult bovine livers. Immunohistochemically, MCT1 was clearly demonstrated on the sinusoidal surfaces of bovine hepatocytes but its expression varied widely between pre-ruminants and adult bovines. In pre-ruminants, a faint hepatocellular expression of MCT1 was observed in a few hepatocytes, whereas an intense immunoreactive staining for MCT1 was shown in the majority of adult bovine hepatocytes. Western blot analysis also confirmed the results of the immunohistochemistry. Quantitative immunoblotting, as estimated by densitometric analysis, showed that the level of MCT1 in the liver of adult bovines was 8-9-fold greater (P<0.01) than that in pre-ruminant calf livers although no significant differences were detected between bulls and cows. The results demonstrated that MCT1 may play a crucial role in the transport of propionate in bovine liver, suggesting that MCT1 expression may be influenced by developmental and metabolic regulations.

Monocarboxylate Transporter MCT1 Promotes Tumor Metastasis Independently of Its Activity as a Lactate Transporter.

PubMed

Payen, Valéry L; Hsu, Myriam Y; Rädecke, Kristin S; Wyart, Elisabeth; Vazeille, Thibaut; Bouzin, Caroline; Porporato, Paolo E; Sonveaux, Pierre

2017-10-15

Extracellular acidosis resulting from intense metabolic activities in tumors promotes cancer cell migration, invasion, and metastasis. Although host cells die at low extracellular pH, cancer cells resist, as they are well equipped with transporters and enzymes to regulate intracellular pH homeostasis. A low extracellular pH further activates proteolytic enzymes that remodel the extracellular matrix to facilitate cell migration and invasion. Monocarboxylate transporter MCT1 is a passive transporter of lactic acid that has attracted interest as a target for small-molecule drugs to prevent metastasis. In this study, we present evidence of a function for MCT1 in metastasis beyond its role as a transporter of lactic acid. MCT1 activates transcription factor NF-κB to promote cancer cell migration independently of MCT1 transporter activity. Although pharmacologic MCT1 inhibition did not modulate MCT1-dependent cancer cell migration, silencing or genetic deletion of MCT1 in vivo inhibited migration, invasion, and spontaneous metastasis. Our findings raise the possibility that pharmacologic inhibitors of MCT1-mediated lactic acid transport may not effectively prevent metastatic dissemination of cancer cells. Cancer Res; 77(20); 5591-601. ©2017 AACR . ©2017 American Association for Cancer Research.

MCT1 promotes the cisplatin-resistance by antagonizing Fas in epithelial ovarian cancer

PubMed Central

Yan, Chunxiao; Yang, Fan; Zhou, Chunxia; Chen, Xuejun; Han, Xuechuan; Liu, Xueqin; Ma, Hongyun; Zheng, Wei

2015-01-01

This study was designed to investigate the role of MCT1 in the development of cisplatin-resistant ovarian cancer and its possible relationship with Fas. We found the expression of MCT1 was obviously increased both in cisplatin-resistant ovarian cancer tissue and A2780/CP cells compared with sensitive ovarian cancer tissue and cell lines A2780. And in A2780 cells treated with Cisplatin, the expression of MCT1 increased in a concentration-dependent manner, MCT1 knockdown attenuates cisplatin-induced cell viability. In A2780 and A2780/CP cells transfected with MCT1 siRNA, the activation of several downstream targets of Fas, including FasL and FAP-1 were largely prevented, whereas the expression of Caspase-3 was increased, accompanying with increased abundance of Fas. Coimmunoprecipitation and immunofluorescence showed that there is interaction between endogenous MCT1 with Fas in vivo and in vitro. In vivo, depletion of MCT1 by shRNA reverses cisplatin-resistance and the expression of Fas. This study showed that down regulation of MCT1 promote the sensibility to Cisplatin in ovarian cancer cell line. And this effect appeared to be mediated via antagonizing the effect of Fas. PMID:26045776

Monocarboxylate Transporters Mediate Fluorescein Uptake in Corneal Epithelial Cells.

PubMed

Sun, Yi-Chen; Liou, Hau-Min; Yeh, Po-Ting; Chen, Wei-Li; Hu, Fung-Rong

2017-07-01

To determine the presence of monocarboxylate transporter (MCT) in human and rabbit corneal epithelium and its role in transcellular fluorescein transportation in the cornea. The presence of MCTs in human and rabbit corneal epithelium was determined by RT-PCR and immunohistochemistry. Intracellular fluorescein uptake experiment was performed using cultured human corneal epithelial cells (HCECs). The involvement of MCT in fluorescein uptake was determined by addition of MCT inhibitors to HCECs and acute dry eye model on New Zealand albino rabbits by spectrophotometry, corneal impression cytology, and external eye photographs. MCT-1 and MCT-4 were identified in both human and rabbit corneal epithelia. A longer treatment period and a lower pH value in culture medium increased fluorescein uptake in HCECs. Fluorescein uptake in HCECs was decreased following addition of MCT inhibitors in a concentration-dependent manner. Impression cytology under fluorescent microscopy showed intracellular fluorescein staining in the rabbit cornea with acute dry eye treatment that was decreased following topical treatment of MCT inhibitors. Fluorescein ingress in corneal epithelial cells is mediated by the MCT family. Further study of MCT-mediated transport on HCECs may potentially benefit differential diagnosis and contribute better understandings of ocular surface disorders.

Flight trajectories with maximum tangential thrust in a central Newtonian field

NASA Astrophysics Data System (ADS)

Azizov, A. G.; Korshunova, N. A.

1983-07-01

The paper examines the two-dimensional problem of determining the optimal trajectories of a point moving with a limited per-second mass consumption in a central Newtonian field. It is shown that one of the cases in which the variational equations in the Meier formulation can be integrated in quadratures is motion with maximum tangential thrust. Trajectories corresponding to this motion are determined. By way of application, attention is given to the problem of determining the thrust which assures maximum kinetic energy for the point at the moment t = t1, corresponding to the mass consumption M0 - M1, where M0 and M1 are, respectively, the initial and final mass.

Oligodendroglial MCT1 and Metabolic Support of Axons in Multiple Sclerosis

DTIC Science & Technology

2015-10-01

AWARD NUMBER: W81XWH-14-1-0524 TITLE:Oligodendroglial MCT1 and Metabolic Support of Axons in Multiple Sclerosis PRINCIPAL INVESTIGATOR: Jeffrey D...29 Sep 2015 4. TITLE AND SUBTITLE Oligodendroglial MCT1 and Metabolic Support of Axons in Multiple Sclerosis 5a. CONTRACT NUMBER W81XWH-14-1-0524...MCT1 in injured oligodendroglia of multiple sclerosis patients contributes to axon neurodegeneration and that increasing MCT1 will be protective in the

MCT1 and MCT4 Expression and Lactate Flux Activity Increase During White and Brown Adipogenesis and Impact Adipocyte Metabolism.

PubMed

Petersen, Charlotte; Nielsen, Mette D; Andersen, Elise S; Basse, Astrid L; Isidor, Marie S; Markussen, Lasse K; Viuff, Birgitte M; Lambert, Ian H; Hansen, Jacob B; Pedersen, Stine F

2017-10-12

Adipose tissue takes up glucose and releases lactate, thereby contributing significantly to systemic glucose and lactate homeostasis. This implies the necessity of upregulation of net acid and lactate flux capacity during adipocyte differentiation and function. However, the regulation of lactate- and acid/base transporters in adipocytes is poorly understood. Here, we tested the hypothesis that adipocyte thermogenesis, browning and differentiation are associated with an upregulation of plasma membrane lactate and acid/base transport capacity that in turn is important for adipocyte metabolism. The mRNA and protein levels of the lactate-H + transporter MCT1 and the Na + ,HCO 3 - cotransporter NBCe1 were upregulated in mouse interscapular brown and inguinal white adipose tissue upon cold induction of thermogenesis and browning. MCT1, MCT4, and NBCe1 were furthermore strongly upregulated at the mRNA and protein level upon differentiation of cultured pre-adipocytes. Adipocyte differentiation was accompanied by increased plasma membrane lactate flux capacity, which was reduced by MCT inhibition and by MCT1 knockdown. Finally, in differentiated brown adipocytes, glycolysis (assessed as ECAR), and after noradrenergic stimulation also oxidative metabolism (OCR), was decreased by MCT inhibition. We suggest that upregulation of MCT1- and MCT4-mediated lactate flux capacity and NBCe1-mediated HCO 3 - /pH homeostasis are important for the physiological function of mature adipocytes.

MCT Expression and Lactate Influx/Efflux in Tanycytes Involved in Glia-Neuron Metabolic Interaction

PubMed Central

Cortés-Campos, Christian; Elizondo, Roberto; Llanos, Paula; Uranga, Romina María; Nualart, Francisco; García, María Angeles

2011-01-01

Metabolic interaction via lactate between glial cells and neurons has been proposed as one of the mechanisms involved in hypothalamic glucosensing. We have postulated that hypothalamic glial cells, also known as tanycytes, produce lactate by glycolytic metabolism of glucose. Transfer of lactate to neighboring neurons stimulates ATP synthesis and thus contributes to their activation. Because destruction of third ventricle (III-V) tanycytes is sufficient to alter blood glucose levels and food intake in rats, it is hypothesized that tanycytes are involved in the hypothalamic glucose sensing mechanism. Here, we demonstrate the presence and function of monocarboxylate transporters (MCTs) in tanycytes. Specifically, MCT1 and MCT4 expression as well as their distribution were analyzed in Sprague Dawley rat brain, and we demonstrate that both transporters are expressed in tanycytes. Using primary tanycyte cultures, kinetic analyses and sensitivity to inhibitors were undertaken to confirm that MCT1 and MCT4 were functional for lactate influx. Additionally, physiological concentrations of glucose induced lactate efflux in cultured tanycytes, which was inhibited by classical MCT inhibitors. Because the expression of both MCT1 and MCT4 has been linked to lactate efflux, we propose that tanycytes participate in glucose sensing based on a metabolic interaction with neurons of the arcuate nucleus, which are stimulated by lactate released from MCT1 and MCT4-expressing tanycytes. PMID:21297988

The kinematic evolution of the Serra Central Salient, Eastern Brazil: A Neoproterozoic progressive arc in northern Espinhaço fold-thrust belt

NASA Astrophysics Data System (ADS)

Bersan, Samuel Moreira; Danderfer, André; Lagoeiro, Leonardo; Costa, Alice Fernanda de Oliveira

2017-12-01

Convex-to-the-foreland map-view curves are common features in fold-thrust belts around cratonic areas. These features are easily identifiable in belts composed of supracrustal rocks but have been rarely described in rocks from relatively deeper crustal levels where plastic deformation mechanisms stand out. Several local salients have been described in Neoproterozoic marginal fold-thrust belts around the São Francisco craton. In the northern part of the Espinhaço fold-thrust belt, which borders the eastern portion of the São Francisco craton, both Archean-Paleoproterozoic basement rocks and Proterozoic cover rocks are involved in the so-called Serra Central salient. A combination of conventional structural analysis and microstructural and paleostress studies were conducted to characterize the kinematic and the overall architecture and processes involved in the generation of this salient. The results allowed us to determine that the deformation along the Serra Central salient occur under low-grade metamorphic conditions and was related to a gently oblique convergence with westward mass transport that developed in a confined flow, controlled by two transverse bounding shear zones. We propose that the Serra Central salient nucleates as a basin-controlled primary arc that evolves to a progressive arc with secondary vertical axis rotation. This secondary rotation, well-illustrated by the presence of two almost orthogonal families of folds, was dominantly controlled by buttress effect exert by a basement high located in the foreland of the Serra Central salient.

Cytologic diagnosis of medullary carcinoma of the thyroid gland.

PubMed

Papaparaskeva, K; Nagel, H; Droese, M

2000-06-01

The cytomorphologic features in fine-needle aspiration (FNA) biopsies from 91 histologiacally verified medullary carcinomas of the thyroid (MCT) were investigated. FNA was able to diagnose neoplasms with indications of surgical removal in 98.9% of cases and moreover, was accurate in specific tumor typing in 89% of cases. The most important cytologic criteria of MCT with FNA are: dispersed cell-pattern of polygonal or triangular cells, azurophilic cytoplasmic granules, and extremely eccentrically placed nuclei with coarse granular chromatin and amyloid. These and other cytologic features of MCT are discussed in detail. Fourteen cases of thyroid tumors originally diagnosed as MCT by cytology are illustrated to discuss the differential diagnosis of MCT and its potential pitfalls. If MCT is cytologically presumed but amyloid and azurophilic cytoplasmic granules are not demonstrated, the use of immunostaining is necessary for a correct tumor typing. The application of immunocytochemistry in MCT is discussed. Copyright 2000 Wiley-Liss, Inc.

Variable shortening on the Main Frontal Thrust in Nepal

NASA Astrophysics Data System (ADS)

Almeida, R. V.; Hubbard, J.; Lee, Y. S.; Liberty, L. M.; Paudel, L.; Shrestha, A.; Sapkota, S. N.; Joshi, G.

2017-12-01

The Main Frontal Thrust (MFT) is the youngest, most active, and southernmost thrust system in the Himalaya. It is located in the footwall of the Main Boundary thrust (MBT), deforming Miocene to Pliocene age Siwalik Group rocks. Although often considered a single, continuous fault, in reality as many as four subparallel faults, spaced 5-30 km apart, make up this fault system. Estimates of total shortening across the MFT for eastern and central Nepal vary from 15 to 40 km, based on cross-sections and surface measurements. However, when the same methods are applied, shortening does not vary significantly along strike (Hirschmiller et al., 2014), suggesting contrasting methodologies rather than a difference in interpreted along strike structural history. Based on high resolution seismic reflection imaging, we present new interpretations of total shortening recorded by the MFT system in central vs. eastern Nepal (200 km apart), together with a detailed transect of field observations in central Nepal. Our structural interpretations demonstrate that the geological shortening recorded on the MFT ranges from >20 km in central Nepal to <1 km in far eastern Nepal. Geodetic measurements show only a slight decrease in interseismic convergence from central (15±1 mm/yr) to eastern Nepal (14±1 mm/yr) and therefore cannot explain this dramatic difference (Lindsey et al., in prep). Taken at face value, these results imply that the MBT must have been much more recently active in eastern Nepal ( 70 ka) than central Nepal ( 1.4 Ma). We propose an alternative model that does not require this dramatic difference in the age of the MFT. As one end-member, it is indeed possible that the MFT may have broken forward much more recently in the east. However, it is also possible that older MFT thrust sheets have formed, and then have been consumed as the MBT passively slid south in the hanging wall of the MFT. Distinguishing between these models is important not only for understanding the evolution of the MBT and MFT, but also plays a critical role in assessing the current geometry and earthquake hazard associated with the Main Himalayan Thrust, the décollement that underlies the entire system (e.g., Hubbard et al., 2016). We explore the implications of these two end-member models and identify ways in which each model could be tested.

Results of early thyroidectomy for medullary thyroid carcinoma in children with multiple endocrine neoplasia type 2.

PubMed

Telander, R L; Zimmerman, D; van Heerden, J A; Sizemore, G W

1986-12-01

Children with multiple endocrine neoplasia type 2 (MEN2) often develop medullary carcinoma of the thyroid (MCT) or its precursor, C-cell hyperplasia. Survival results are improved if malignancy is diagnosed early from the results of plasma immunoreactive calcitonin (iCT) measurement. The effect of early detection and thyroidectomy in children with MEN2 syndrome was determined by reviewing the experience between 1975 and 1985. Seventeen children with MEN2 who were 12 years old or younger underwent a total thyroidectomy for MCT or C-cell hyperplasia. iCT was measured in all patients preoperatively and postoperatively. Of the 17 children, 14 (82%) had MEN2a and 3 (18%) had MEN2b. There were 14 (82%) female and three (18%) male patients; their mean age was 6.97 years (range 1.5 to 12 years). In all patients, the diagnosis of MCT was made from initial elevated levels of iCT after stimulation with pentagastrin. Three patients had clinical evidence of disease preoperatively. All patients underwent a total thyroidectomy and lymph nodes were removed from the central zone; a neck dissection was performed in the three with clinically obvious disease. MCT with C-cell hyperplasia was found in 11 children and C-cell hyperplasia alone in six. Of the 11 with carcinoma, eight had bilateral disease and three unilateral. Six children had bilateral C-cell hyperplasia. All 17 children were alive and feeling well at the time of this report; however, three had evidence of metastatic disease according to iCT measurements. None of the children had recurrent nerve injuries; one had evidence of hypoparathyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of short-term and long-term treatment with medium- and long-chain triglycerides ketogenic diet on cortical spreading depression in young rats.

PubMed

de Almeida Rabello Oliveira, Marcela; da Rocha Ataíde, Terezinha; de Oliveira, Suzana Lima; de Melo Lucena, Ana Luíza; de Lira, Carla Emmanuela Pereira Rodrigues; Soares, Anderson Acioli; de Almeida, Clarissa Beatriz Santos; Ximenes-da-Silva, Adriana

2008-03-21

The ketogenic diet (KD) is a high fat and low carbohydrate and protein diet. It is used in the clinical treatment of epilepsy, in order to decrease cerebral excitability. KD is usually composed by long-chain triglycerides (LCT) while medium-chain triglycerides (MCT) diet is beginning to be used in some clinical treatment of disorders of pyruvate carboxylase enzyme and long-chain fatty acid oxidation. Our study aimed to analyze the effects of medium- and long-chain KD on cerebral electrical activity, analyzing the propagation of the phenomenon of cortical spreading depression (CSD). Three groups of weaned rats (21 days old) received, for 7 weeks, either a control (AIN-93G diet), or a MCT-KD (rich in triheptanoin oil), or a LCT-KD (rich in soybean oil). They were compared to another three groups (21 days old) receiving the same diets for just 10 days. CSD propagation was evaluated just after ending the dietary treatments. Results showed that short-term KD treatment resulted in a significant reduction of the CSD velocity of propagation (control group: 4.02+/-1.04mm/min; MCT-KD: 0.81+/-1.46mm/min and LCT-KD: 2.26+/-0.41mm/min) compared to the control group. However, long-term treatment with both KDs had no effect on the CSD velocity (control group: 3.10+/-0.41mm/min, MCT-KD: 2.91+/-1.62mm/min, LCT-KD: 3.02+/-2.26mm/min) suggesting that both short-term KDs have a positive effect in decreasing brain cerebral excitability in young animals. These data show for the first time that triheptanoin has an effect on central nervous system.

Bevacizumab exacerbates sinusoidal obstruction syndrome (SOS) in the animal model and increases MMP 9 production

PubMed Central

Jafari, Azin; Matthaei, Hanno; Wehner, Sven; Tonguc, Tolga; Kalff, Jörg C.; Manekeller, Steffen

2018-01-01

Background Thanks to modern multimodal treatment the ouctome of patients with colorectal cancer has experienced significant improvements. As a downside, agent specific side effects have been observed such as sinusoidal obstruction syndrome (SOS) after oxaliplatin chemotherapy (OX). Bevazicumab targeting VEGF is nowadays comprehensively used in combination protocols with OX but its impact on hepatotoxicity is thus far elusive and focus of the present study. Results After MCT administration 67% of animals developed SOS. GOT serum concentration significantly increased in animals developing SOS (p < 0.001). Subsequent to MCT administration 100% of animals treated with Anti-VEGF developed SOS. In contrast, animals receiving VEGF developed SOS merely in 40% while increasing the VEGF dose led to a further decrease in SOS development to 25%. MMP 9 concentration in animals developing SOS was significantly higher compared to controls (p < 0,001). Additional treatment with Anti-VEGF increased the MMP 9 concentration significantly (p < 0,05). Conclusions Preservation of liver function is a central goal in both curative and palliative treatment phases of patients with CRC. Thus, knowledge about hepatotoxic side effects of chemotherapeutic and biological agents is crucial. From the results it can be concluded that Anti-VEGF exacerbates SOS paralleled by MMP 9 production. Therefore, OX-Bevacizumab combination therapies should be administered with caution, especially if liver parenchyma damage is apparent. Methods Male Sprague-Dawley rats were gavaged Monocrotaline (MCT) to induce SOS. Recombinant VEGF or an Anti-VEGF antibody was administered to MCT-treated rats and the hepatotoxic effect monitored in defined time intervals. MMP 9 expression in the liver was measured by ELISA. PMID:29774103

Strength training alters MCT1-protein expression and exercise-induced translocation in erythrocytes of men with non-insulin-dependent type-2 diabetes.

PubMed

Opitz, David; Kreutz, Thorsten; Lenzen, Edward; Dillkofer, Benedict; Wahl, Patrick; Montiel-Garcia, Gracia; Graf, Christine; Bloch, Wilhelm; Brixius, Klara

2014-03-01

We investigated the cellular distribution of lactate transporter (MCT1) and its chaperone CD147 (using immunohistochemistry and fluorescence-activated cell sorting) in the erythrocytes of men with non-insulin-dependent type-2 diabetes (NIDDM, n = 11, 61 ± 8 years of age) under acute exercise (ergometer cycling test, World Health Organisation scheme) performed before and after a 3-month strength training program. Cytosolic MCT1 distribution and membraneous CD147 density did not change after acute exercise (ergometer). After the 3-month strength training, MCT1-density was increased and the reaction of MCT1 (but not that of CD147) towards acute exercise (ergometer) was altered. MCT1 localisation was shifted from the centre to the cellular membrane. This resulted in a decrease in the immunohistochemically measured cytosolic MCT1-density. We conclude that strength training alters the acute exercise reaction of MCT1 but not that of CD147 in erythrocytes in patients with NIDDM. This reaction may contribute to long-term normalisation and stabilisation of the regulation of lactate plasma concentration in NIDDM.

Decreased astroglial monocarboxylate transporter 4 expression in temporal lobe epilepsy.

PubMed

Liu, Bei; Niu, Le; Shen, Ming-Zhi; Gao, Lei; Wang, Chao; Li, Jie; Song, Li-Jia; Tao, Ye; Meng, Qiang; Yang, Qian-Li; Gao, Guo-Dong; Zhang, Hua

2014-10-01

Efflux of monocaroxylates like lactate, pyruvate, and ketone bodies from astrocytes through monocarboxylate transporter 4 (MCT4) supplies the local neuron population with metabolic intermediates to meet energy requirements under conditions of increased demand. Disruption of this astroglial-neuron metabolic coupling pathway may contribute to epileptogenesis. We measured MCT4 expression in temporal lobe epileptic foci excised from patients with intractable epilepsy and in rats injected with pilocarpine, an animal model of temporal lobe epilepsy (TLE). Cortical MCT4 expression levels were significantly lower in TLE patients compared with controls, due at least partially to MCT4 promoter methylation. Expression of MCT4 also decreased progressively in pilocarpine-treated rats from 12 h to 14 days post-administration. Underexpression of MCT4 in cultured astrocytes induced by a short hairpin RNA promoted apoptosis. Knockdown of astrocyte MCT4 also suppressed excitatory amino acid transporter 1 (EAAT1) expression. Reduced MCT4 and EAAT1 expression by astrocytes may lead to neuronal hyperexcitability and epileptogenesis in the temporal lobe by reducing the supply of metabolic intermediates and by allowing accumulation of extracellular glutamate.

The metabolic microenvironment of melanomas: Prognostic value of MCT1 and MCT4.

PubMed

Pinheiro, Céline; Miranda-Gonçalves, Vera; Longatto-Filho, Adhemar; Vicente, Anna L S A; Berardinelli, Gustavo N; Scapulatempo-Neto, Cristovam; Costa, Ricardo F A; Viana, Cristiano R; Reis, Rui M; Baltazar, Fátima; Vazquez, Vinicius L

2016-06-02

BRAF mutations are known drivers of melanoma development and, recently, were also described as players in the Warburg effect, while this reprogramming of energy metabolism has been identified as a possible strategy for treating melanoma patients. Therefore, the aim of this work was to evaluate the expression and prognostic value of a panel of glycolytic metabolism-related proteins in a series of melanomas. The immunohistochemical expression of MCT1, MCT4, GLUT1, and CAIX was evaluated in 356 patients presenting melanoma and 20 patients presenting benign nevi. Samples included 20 benign nevi, 282 primary melanomas, 117 lymph node and 54 distant metastases samples. BRAF mutation was observed in 29/92 (31.5%) melanoma patients and 17/20 (85%) benign nevi samples. NRAS mutation was observed in 4/36 (11.1%) melanoma patients and 1/19 (5.3%) benign nevi samples. MCT4 and GLUT1 expression was significantly increased in metastatic samples, and MCT1, MCT4 and GLUT1 were significantly associated with poor prognostic variables. Importantly, MCT1 and MCT4 were associated with shorter overall survival. In conclusion, the present study brings new insights on metabolic aspects of melanoma, paving the way for the development of new-targeted therapies.

MCT2 Expression and Lactate Influx in Anorexigenic and Orexigenic Neurons of the Arcuate Nucleus

PubMed Central

Cortes-Campos, Christian; Elizondo, Roberto; Carril, Claudio; Martínez, Fernando; Boric, Katica; Nualart, Francisco; Garcia-Robles, Maria Angeles

2013-01-01

Hypothalamic neurons of the arcuate nucleus control food intake, releasing orexigenic and anorexigenic neuropeptides in response to changes in glucose concentration. Several studies have suggested that the glucosensing mechanism is governed by a metabolic interaction between neurons and glial cells via lactate flux through monocarboxylate transporters (MCTs). Hypothalamic glial cells (tanycytes) release lactate through MCT1 and MCT4; however, similar analyses in neuroendocrine neurons have yet to be undertaken. Using primary rat hypothalamic cell cultures and fluorimetric assays, lactate incorporation was detected. Furthermore, the expression and function of MCT2 was demonstrated in the hypothalamic neuronal cell line, GT1-7, using kinetic and inhibition assays. Moreover, MCT2 expression and localization in the Sprague Dawley rat hypothalamus was analyzed using RT-PCR, in situ hybridization and Western blot analyses. Confocal immunohistochemistry analyses revealed MCT2 localization in neuronal but not glial cells. Moreover, MCT2 was localized to ∼90% of orexigenic and ∼60% of anorexigenic neurons as determined by immunolocalization analysis of AgRP and POMC with MCT2-positives neurons. Thus, MCT2 distribution coupled with lactate uptake by hypothalamic neurons suggests that hypothalamic neurons control food intake using lactate to reflect changes in glucose levels. PMID:23638108

Prognostic Indications of Elevated MCT4 and CD147 across Cancer Types: A Meta-Analysis

PubMed Central

Bovenzi, Cory D.; Hamilton, James; Tassone, Patrick; Johnson, Jennifer; Cognetti, David M.; Luginbuhl, Adam; Keane, William M.; Zhan, Tingting; Tuluc, Madalina; Bar-Ad, Voichita; Martinez-Outschoorn, Ubaldo; Curry, Joseph M.

2015-01-01

Background. Metabolism in the tumor microenvironment can play a critical role in tumorigenesis and tumor aggression. Metabolic coupling may occur between tumor compartments; this phenomenon can be prognostically significant and may be conserved across tumor types. Monocarboxylate transporters (MCTs) play an integral role in cellular metabolism via lactate transport and have been implicated in metabolic synergy in tumors. The transporters MCT1 and MCT4 are regulated via expression of their chaperone, CD147. Methods. We conducted a meta-analysis of existing publications on the relationship between MCT1, MCT4, and CD147 expression and overall survival and disease-free survival in cancer, using hazard ratios derived via multivariate Cox regression analyses. Results. Increased MCT4 expressions in the tumor microenvironment, cancer cells, or stromal cells were all associated with decreased overall survival and decreased disease-free survival (p < 0.001 for all analyses). Increased CD147 expression in cancer cells was associated with decreased overall survival and disease-free survival (p < 0.0001 for both analyses). Few studies were available on MCT1 expression; MCT1 expression was not clearly associated with overall or disease-free survival. Conclusion. MCT4 and CD147 expression correlate with worse prognosis across many cancer types. These results warrant further investigation of these associations. PMID:26779534

Medium-chain triglycerides impair lipid metabolism and induce hepatic steatosis in very long-chain acyl-CoA dehydrogenase (VLCAD)-deficient mice.

PubMed

Tucci, Sara; Primassin, Sonja; Ter Veld, Frank; Spiekerkoetter, Ute

2010-09-01

A medium-chain-triglyceride (MCT)-based diet is mainstay of treatment in very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD), a long-chain fatty acid beta-oxidation defect. Beneficial effects have been reported with an MCT-bolus prior to exercise. Little is known about the impact of a long-term MCT diet on hepatic lipid metabolism. Here we investigate the effects of MCT-supplementation on liver and blood lipids in the murine model of VLCADD. Wild-type (WT) and VLCAD-knock-out (KO) mice were fed (1) a long-chain triglyceride (LCT)-diet over 5weeks, (2) an MCT diet over 5 weeks and (3) an LCT diet plus MCT-bolus. Blood and liver lipid content were determined. Expression of genes regulating lipogenesis was analyzed by RT-PCR. Under the LCT diet, VLCAD-KO mice accumulated significantly higher blood cholesterol concentrations compared to WT mice. The MCT-diet induced severe hepatic steatosis, significantly higher serum free fatty acids and impaired hepatic lipid mobilization in VLCAD-KO mice. Expression at mRNA level of hepatic lipogenic genes was up-regulated. The long-term MCT diet stimulates lipogenesis and impairs hepatic lipid metabolism in VLCAD-KO mice. These results suggest a critical reconsideration of a long-term MCT-modified diet in human VLCADD. In contrast, MCT in situations of increased energy demand appears to be a safer treatment alternative.

Exercise-induced changes of MCT1 in cardiac and skeletal muscles of diabetic rats induced by high-fat diet and STZ.

PubMed

Nikooie, Rohollah; Rajabi, Hamid; Gharakhanlu, Reza; Atabi, Fereshteh; Omidfar, Kobra; Aveseh, Malihe; Larijani, Bagher

2013-12-01

We hypothesized that a part of therapeutic effects of endurance training on insulin resistance is mediated by increase in cardiac and skeletal muscle mitochondrial lactate transporter, monocarboxylate transporter 1 (MCT1). Therefore, we examined the effect of 7 weeks endurance training on the mRNA and protein expression of MCT1 and MCT4 and their chaperon, CD147, on both sarcolemmal and mitochondrial membrane, separately, in healthy and type 2 diabetic rats. Diabetes was induced by injection of low dose of streptozotocin and feeding with high-fat diet. Insulin resistance was confirmed by homeostasis model assessment-estimated insulin resistance index and accuracy of two membranes separation was confirmed by negative control markers (glucose transporter 1 and cytochrome c oxidase. Real-time PCR and western blotting were used for mRNA and protein expression, respectively. Diabetes dramatically reduced MCT1 and MCT4 mRNA and their expression on sarcolemmal membrane whereas the reduction in MCT1 expression was less in mitochondrial membrane. Training increased the MCT1 mRNA and protein expression in both membranes and decreased insulin resistance as an adaptive consequence. In both tissues increase in CD147 mRNA was only parallel to MCT1 expression. The response of MCT1 on sarcolemmal and mitochondrial membranes was different between cardiac and skeletal muscles which indicate that intracellular lactate kinetic is tissue specific that allows a tissue to coordinate whole organism metabolism.

Polarized lactate transporter activity and expression in the syncytiotrophoblast of the term human placenta.

PubMed

Settle, P; Mynett, K; Speake, P; Champion, E; Doughty, I M; Sibley, C P; D'Souza, S W; Glazier, J

2004-07-01

We investigated the polarization of l-lactate transport in human syncytiotrophoblast by measuring uptake of [(14)C] l-lactate by both microvillous (maternal-facing; MVM) and basal (fetal-facing; BM) plasma membranes. [(14)C] l-lactate uptake by MVM and BM was stimulated in the presence of an inwardly directed H(+)gradient, with a significantly higher uptake in MVM than in BM at initial rate (15.4+/-2.3 vs 5.6+/-0.6 pmol/mg protein/20 sec). Stereospecific inhibition was observed in MVM, with a higher affinity for l-lactate compared with d-lactate. In BM, there was no difference in the inhibition by these two stereoisomers. Inhibition of lactate uptake in both MVM and BM by 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), an inhibitor of monocarboxylate transporter (MCT) activity, indicated MCT-mediated mechanisms across both membranes. Kinetic modelling supported a two-transporter model as the best fit for both MVM and BM, the K(m)of the major component being 6.21 mm and 25.01 mm in MVM and BM respectively. Western blotting and immunolocalization examining the distribution of MCT1 and MCT4, showed that MCT expression was polarized, MCT1 being predominantly localized to BM and MCT4 showing greater abundance on MVM. CD147, a chaperone protein for MCT1 and MCT4, was equally expressed by both membranes. These studies demonstrate that the opposing plasma membranes of human syncytiotrophoblast are polarized with respect to both MCT activity and expression.

Synchronous diagnosis of metastatic cancer to the thyroid is associated with poor prognosis.

PubMed

Chen, Jeng-Yeou; Chen, I-Wen; Hsueh, Chuen; Chao, Tzu-Chieh; Gao, Bing-Ru; Lin, Jen-Der

2015-03-01

The incidence and histopathological characteristics of metastatic cancers to the thyroid (MCT) are different in various geographic areas. The aim of this study was to elucidate the clinical features of MCT, including histocytological diagnosis and therapeutic outcomes. A retrospective analysis of patients with thyroid cancer treated and followed up at the Chang Gung Medical Center in Linkou was performed. Among 3957 patients with thyroid cancer, a total of 56 patients with MCT were evaluated. Of them, 47 patients (83.9 %) were diagnosed with malignancy or suspected malignancy via fine needle aspiration cytology of the thyroid. Synchronous primary cancers were diagnosed in 44 of the patients with MCT. Of the MCT, metastasis of lung cancer to the thyroid was the leading category. Other primary sites of MCT were the head and neck, gastrointestinal tract, kidneys, breast, cervix, and unknown primary site. The mean 5-, 10-, 20-, and 60-month survival rates were 46.4, 32.1, 21.4, and 7.9 % for the patients. Patients with metachronous thyroid carcinoma had significantly better survival than patients with synchronous cancer. In conclusions, the incidence of MCT in patients with thyroid cancer is low; however, the prognosis of patients with MCT is poor, especially in patients diagnosed with synchronous primary tumors. In this study, MCT commonly originated in organs located near the thyroid, such as the lungs, head, and neck. Close monitoring of these malignancies may improve the prognosis of patients with MCT in the future.

Pharmacological treatment and BBB-targeted genetic therapy for MCT8-dependent hypomyelination in zebrafish

PubMed Central

2016-01-01

ABSTRACT Hypomyelination is a key symptom of Allan-Herndon-Dudley syndrome (AHDS), a psychomotor retardation associated with mutations in the thyroid-hormone (TH) transporter MCT8 (monocarboxylate transporter 8). AHDS is characterized by severe intellectual deficiency, neuromuscular impairment and brain hypothyroidism. In order to understand the mechanism for TH-dependent hypomyelination, we developed an mct8 mutant (mct8−/−) zebrafish model. The quantification of genetic markers for oligodendrocyte progenitor cells (OPCs) and mature oligodendrocytes revealed reduced differentiation of OPCs into oligodendrocytes in mct8−/− larvae and adults. Live imaging of single glial cells showed that the number of oligodendrocytes and the length of their extensions are reduced, and the number of peripheral Schwann cells is increased, in mct8−/− larvae compared with wild type. Pharmacological analysis showed that TH analogs and clemastine partially rescued the hypomyelination in the CNS of mct8−/− larvae. Intriguingly, triiodothyronine (T3) treatment rescued hypomyelination in mct8−/− embryos before the maturation of the blood–brain barrier (BBB), but did not affect hypomyelination in older larvae. Thus, we expressed Mct8-tagRFP in the endothelial cells of the vascular system and showed that even relatively weak mosaic expression completely rescued hypomyelination in mct8−/− larvae. These results suggest potential pharmacological treatments and BBB-targeted gene therapy that can enhance myelination in AHDS and possibly in other TH-dependent brain disorders. PMID:27664134

Pharmacological treatment and BBB-targeted genetic therapy for MCT8-dependent hypomyelination in zebrafish.

PubMed

Zada, David; Tovin, Adi; Lerer-Goldshtein, Tali; Appelbaum, Lior

2016-11-01

Hypomyelination is a key symptom of Allan-Herndon-Dudley syndrome (AHDS), a psychomotor retardation associated with mutations in the thyroid-hormone (TH) transporter MCT8 (monocarboxylate transporter 8). AHDS is characterized by severe intellectual deficiency, neuromuscular impairment and brain hypothyroidism. In order to understand the mechanism for TH-dependent hypomyelination, we developed an mct8 mutant (mct8 -/- ) zebrafish model. The quantification of genetic markers for oligodendrocyte progenitor cells (OPCs) and mature oligodendrocytes revealed reduced differentiation of OPCs into oligodendrocytes in mct8 -/- larvae and adults. Live imaging of single glial cells showed that the number of oligodendrocytes and the length of their extensions are reduced, and the number of peripheral Schwann cells is increased, in mct8 -/- larvae compared with wild type. Pharmacological analysis showed that TH analogs and clemastine partially rescued the hypomyelination in the CNS of mct8 -/- larvae. Intriguingly, triiodothyronine (T3) treatment rescued hypomyelination in mct8 -/- embryos before the maturation of the blood-brain barrier (BBB), but did not affect hypomyelination in older larvae. Thus, we expressed Mct8-tagRFP in the endothelial cells of the vascular system and showed that even relatively weak mosaic expression completely rescued hypomyelination in mct8 -/- larvae. These results suggest potential pharmacological treatments and BBB-targeted gene therapy that can enhance myelination in AHDS and possibly in other TH-dependent brain disorders. © 2016. Published by The Company of Biologists Ltd.

An RRM-containing mei2-like MCT1 plays a negative role in the seed germination and seedling growth of Arabidopsis thaliana in the presence of ABA.

PubMed

Gu, Lili; Jung, Hyun Ju; Kwak, Kyung Jin; Dinh, Sy Nguyen; Kim, Yeon-Ok; Kang, Hunseung

2016-12-01

Despite an increasing understanding of the essential role of the Mei2 gene encoding an RNA-binding protein (RBP) in premeiotic DNA synthesis and meiosis in yeasts and animals, the functional roles of the mei2-like genes in plant growth and development are largely unknown. Contrary to other mei2-like RBPs that contain three RNA-recognition motifs (RRMs), the mei2 C-terminal RRM only (MCT) is unique in that it harbors only the last C-terminal RRM. Although MCTs have been implicated to play important roles in plants, their functional roles in stress responses as well as plant growth and development are still unknown. Here, we investigated the expression and functional role of MCT1 (At1g37140) in plant response to abscisic acid (ABA). Confocal analysis of MCT1-GFP-expressing plants revealed that MCT1 is localized to the nucleus. The transcript level of MCT1 was markedly increased upon ABA treatment. Analysis of MCT1-overexpressing transgenic Arabidopsis plants and artificial miRNA-mediated mct1 knockdown mutants demonstrated that MCT1 inhibited seed germination and cotyledon greening of Arabidopsis plants under ABA. The transcript levels of ABA signaling-related genes, such as ABI3, ABI4, and ABI5, were markedly increased in the MCT1-overexpressing transgenic plant. Collectively, these results suggest that ABA-upregulated MCT1 plays a negative role in Arabidopsis seed germination and seedling growth under ABA by modulating the expression of ABA signaling-related genes. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration.

PubMed

De Saedeleer, C J; Porporato, P E; Copetti, T; Pérez-Escuredo, J; Payen, V L; Brisson, L; Feron, O; Sonveaux, P

2014-07-31

The glycolytic end-product lactate is a pleiotropic tumor growth-promoting factor. Its activities primarily depend on its uptake, a process facilitated by the lactate-proton symporter monocarboxylate transporter 1 (MCT1). Therefore, targeting the transporter or its chaperon protein CD147/basigin, itself involved in the aggressive malignant phenotype, is an attractive therapeutic option for cancer, but basic information is still lacking regarding the regulation of the expression, interaction and activities of both proteins. In this study, we found that glucose deprivation dose-dependently upregulates MCT1 and CD147 protein expression and their interaction in oxidative tumor cells. While this posttranslational induction could be recapitulated using glycolysis inhibition, hypoxia, oxidative phosphorylation (OXPHOS) inhibitor rotenone or hydrogen peroxide, it was blocked with alternative oxidative substrates and specific antioxidants, pointing out at a mitochondrial control. Indeed, we found that the stabilization of MCT1 and CD147 proteins upon glucose removal depends on mitochondrial impairment and the associated generation of reactive oxygen species. When glucose was a limited resource (a situation occurring naturally or during the treatment of many tumors), MCT1-CD147 heterocomplexes accumulated, including in cell protrusions of the plasma membrane. It endowed oxidative tumor cells with increased migratory capacities towards glucose. Migration increased in cells overexpressing MCT1 and CD147, but it was inhibited in glucose-starved cells provided with an alternative oxidative fuel, treated with an antioxidant, lacking MCT1 expression, or submitted to pharmacological MCT1 inhibition. While our study identifies the mitochondrion as a glucose sensor promoting tumor cell migration, MCT1 is also revealed as a transducer of this response, providing a new rationale for the use of MCT1 inhibitors in cancer.

PKC-dependent stimulation of the human MCT1 promoter involves transcription factor AP2.

PubMed

Saksena, Seema; Dwivedi, Alka; Gill, Ravinder K; Singla, Amika; Alrefai, Waddah A; Malakooti, Jaleh; Ramaswamy, Krishnamurthy; Dudeja, Pradeep K

2009-02-01

Monocarboxylate transporter (MCT1) plays an important role in the absorption of short-chain fatty acids (SCFA) such as butyrate in the human colon. Previous studies from our laboratory have demonstrated that phorbol ester, PMA (1 microM, 24 h), upregulates butyrate transport and MCT1 protein expression in human intestinal Caco-2 cells. However, the molecular mechanisms involved in the transcriptional regulation of MCT1 gene expression by PMA in the intestine are not known. In the present study, we showed that PMA (0.1 microM, 24 h) increased the MCT1 promoter activity (-871/+91) by approximately fourfold. A corresponding increase in MCT1 mRNA abundance in response to PMA was also observed. PMA-induced stimulation of MCT1 promoter activity was observed as early as 1 h and persisted until 24 h, suggesting that the effects of PMA are attributable to initial PKC activation. Kinase inhibitor and phosphorylation studies indicated that these effects may be mediated through activation of the atypical PKC-zeta isoform. 5'-deletion studies demonstrated that the MCT1 core promoter region (-229/+91) is the PMA-responsive region. Site-directed mutagenesis studies showed the predominant involvement of potential activator protein 2 (AP2) binding site in the activation of MCT1 promoter activity by PMA. In addition, overexpression of AP2 in Caco-2 cells significantly increased MCT1 promoter activity in a dose-dependent manner. These findings showing the regulation of MCT1 promoter by PKC and AP2 are of significant importance for an understanding of the molecular regulation of SCFA absorption in the human intestine.

Functional analysis of human aromatic amino acid transporter MCT10/TAT1 using the yeast Saccharomyces cerevisiae.

PubMed

Uemura, Satoshi; Mochizuki, Takahiro; Kurosaka, Goyu; Hashimoto, Takanori; Masukawa, Yuki; Abe, Fumiyoshi

2017-10-01

Tryptophan is an essential amino acid in humans and an important serotonin and melatonin precursor. Monocarboxylate transporter MCT10 is a member of the SLC16A family proteins that mediates low-affinity tryptophan transport across basolateral membranes of kidney, small intestine, and liver epithelial cells, although the precise transport mechanism remains unclear. Here we developed a simple functional assay to analyze tryptophan transport by human MCT10 using a deletion mutant for the high-affinity tryptophan permease Tat2 in Saccharomyces cerevisiae. tat2Δtrp1 cells are defective in growth in YPD medium because tyrosine present in the medium competes for the low-affinity tryptophan permease Tat1 with tryptophan. MCT10 appeared to allow growth of tat2Δtrp1 cells in YPD medium, and accumulate in cells deficient for Rsp5 ubiquitin ligase. These results suggest that MCT10 is functional in yeast, and is subject to ubiquitin-dependent quality control. Whereas growth of Tat2-expressing cells was significantly impaired by neutral pH, that of MCT10-expressing cells was nearly unaffected. This property is consistent with the transport mechanism of MCT10 via facilitated diffusion without a need for pH gradient across the plasma membrane. Single-nucleotide polymorphisms (SNPs) are known to occur in the human MCT10 coding region. Among eight SNP amino acid changes in MCT10, the N81K mutation completely abrogated tryptophan import without any abnormalities in the expression or localization. In the MCT10 modeled structure, N81 appeared to protrude into the putative trajectory of tryptophan. Plasma membrane localization of MCT10 and the variant proteins was also verified in human embryonic kidney 293T cells. Copyright © 2017 Elsevier B.V. All rights reserved.

Dietary medium-chain triglycerides promote oral allergic sensitization and orally induced anaphylaxis to peanut protein in mice

PubMed Central

Li, Jianing; Wang, Yu; Tang, Lihua; de Villiers, Willem JS; Cohen, Donald; Woodward, Jerold; Finkelman, Fred D; Eckhardt, Erik RM

2012-01-01

BACKGROUND The prevalence of peanut allergies is rising. Peanuts and many other allergen sources contain significant amounts of triglycerides, which affect absorption of antigens but have unknown effects on sensitization and anaphylaxis. We recently reported that dietary medium-chain triglycerides (MCT), which bypass mesenteric lymph and directly enter portal blood, reduce intestinal antigen absorption into blood compared to long-chain triglycerides (LCT), which stimulate mesenteric lymph flow and are absorbed in chylomicrons via mesenteric lymph. OBJECTIVE Test how dietary MCT affect food allergy. METHODS C3H/HeJ mice were fed peanut butter protein in MCT, LCT (peanut oil), or LCT plus an inhibitor of chylomicron formation (Pluronic L81; “PL81”). Peanut-specific antibodies in plasma, responses of the mice to antigen challenges, and intestinal epithelial cytokine expression were subsequently measured. RESULTS MCT suppressed antigen absorption into blood, but stimulated absorption into Peyer's patches. A single gavage of peanut protein with MCT as well as prolonged feeding in MCT-based diets caused spontaneous allergic sensitization. MCT-sensitized mice experienced IgG-dependent anaphylaxis upon systemic challenge and IgE-dependent anaphylaxis upon oral challenge. MCT feeding stimulated jejunal-epithelial TSLP, IL-25 and IL-33 expression compared to LCT, and promoted Th2 cytokine responses in splenocytes. Moreover, oral challenges of sensitized mice with antigen in MCT significantly aggravated anaphylaxis compared to challenges with LCT. Importantly, effects of MCT could be mimicked by adding PL81 to LCT, and in vitro assays indicated that chylomicrons prevent basophil activation. CONCLUSION Dietary MCT promote allergic sensitization and anaphylaxis by affecting antigen absorption and availability and by stimulating Th2 responses. PMID:23182172

Inclusion complexes of cypermethrin and permethrin with monochlorotriazinyl-beta-cyclodextrin: A combined spectroscopy, TG/DSC and DFT study

NASA Astrophysics Data System (ADS)

Yao, Qi; You, Bin; Zhou, Shuli; Chen, Meng; Wang, Yujiao; Li, Wei

2014-01-01

The suitable size hydrophobic cavity and monochlorotriazinyl group as a reactive anchor make MCT-β-CD to be widely used in fabric finishing. In this paper, the inclusion complexes of monochlorotriazinyl-beta-cyclodextrin (MCT-β-CD) with cypermethrin (CYPERM) and permethrin (PERM) are synthesized and analyzed by TG/DSC, FT-IR and Raman spectroscopy. TG/DSC reveals that the decomposed temperatures of inclusion complexes are lower by 25-30 °C than that of physical mixtures. DFT calculations in conjunction with FT-IR and Raman spectral analyses are used to study the structures of MCT-β-CD and their inclusion complexes. Four isomers of trisubstituted MCT-β-CD are designed and DFT calculations reveal that 1,3,5-trisubstituted MCT-β-CD has the lowest energy and can be considered as main component of MCT-β-CD. The ground-state geometries, vibrational wavenumbers, IR and Raman intensities of MCT-β-CD and their inclusion complexes were calculated at B3LYP/6-31G (d) level of theory. Upon examining the optimized geometry of inclusion complex, we find that the CYPERM and PERM are inserted into the toroid of MCT-β-CD from the larger opening. The band at 1646 cm-1 in IR and at 1668 cm-1 in Raman spectrum reveals that monochloroazinyl group of MCT-β-CD exists in ketone form but not in anion form. The noticeable IR and Raman shift of phenyl reveals that these two benzene rings of CYPERM and PERM stays inside the cavity of MCT-β-CD and has weak interaction with MCT-β-CD. This spectroscopy conclusion is consistent with theoretical predicted structure.

Protective Effects of Medium-Chain Triglycerides on the Liver and Gut in Rats Administered Endotoxin

PubMed Central

Kono, Hiroshi; Fujii, Hideki; Asakawa, Masami; Yamamoto, Masayuki; Matsuda, Masanori; Maki, Akira; Matsumoto, Yoshiro

2003-01-01

Objective To determine if medium-chain triglycerides (MCTs) prevent organ injuries and mortality in rats administered endotoxin and to investigate effects of MCT on the gut. Summary Background Data Since dietary MCTs prevent alcohol-induced liver injury by inhibiting activation of Kupffer cells in the enteral feeding model, the authors hypothesized that MCT could prevent deleterious conditions in endotoxemia. Methods After a preliminary experiment determined the optimal dose of MCT, rats were given MCT (5 g/kg per day) or the same dose of corn oil by gavage daily for 1 week. Then, lipopolysaccharide (LPS) was administered intravenously and survival was assessed for the next 24 hours. For analysis of mechanisms, rats were killed 9 hours after LPS injection and serum and liver sections were collected. To investigate effects of MCT on the gut, pathologic change, permeability, and microflora were assessed. Kupffer cells isolated by collagenase digestion and differential centrifugation were used for endotoxin receptor CD14 immunoblotting, phagocytic index, and TNF-α production assay. Results All rats given corn oil died after LPS administration; however, this mortality was prevented by MCT in a dose-dependent manner. Rats given corn oil showed liver injury after LPS administration. In contrast, MCT prevented this pathologic change nearly completely. MCT blunted CD14 expression on the Kupffer cells and TNF-α production by isolated Kupffer cells; however, there were no differences in phagocytic index between the two groups. The length of the intestinal epithelium was increased in the MCT group compared to the corn oil group. Further, after LPS administration, increases in gut permeability and injury were prevented by MCT. Importantly, MCT also prevented hepatic energy charge and gut injuries in this condition. Conclusions Enteral feeding using MCT could be a practical way of protecting the liver and intestine during endotoxemia. PMID:12560783

Clinically relevant HIF-1α-dependent metabolic reprogramming in oropharyngeal squamous cell carcinomas includes coordinated activation of CAIX and the miR-210/ISCU signaling axis, but not MCT1 and MCT4 upregulation

PubMed Central

Sáenz-de-Santa-María, Inés; Bernardo-Castiñeira, Cristóbal; Secades, Pablo; Bernaldo-de-Quirós, Sandra; Rodrigo, Juan Pablo; Astudillo, Aurora; Chiara, María-Dolores

2017-01-01

Metabolic reprogramming is a very heterogeneous phenomenon in cancer. It mostly consists on increased glycolysis, lactic acid formation and extracellular acidification. These events have been associated to increased activity of the hypoxia inducible factor, HIF-1α. This study aimed at defining the metabolic program activated by HIF-1α in oropharyngeal squamous cell carcinomas (SCC) and assessing its clinical impact. Global gene/miRNA expression was analyzed in SCC-derived cells exposed to hypoxia. Expression of HIF-1α, the carbonic anhydrase CAIX, and the lactate/H+ transporters MCT1 and MCT4 were analyzed by immunohistochemistry in 246 SCCs. Cell-based analysis revealed that HIF-1α-driven metabolic program includes over-expression of glycolytic enzymes and the microRNA miR-210 coupled to down-regulation of its target, the iron-sulfur cluster assembly protein, ISCU. pH-regulator program entailed over-expression of CAIX, but not MCT1 or MCT4. Accordingly, significant overlapping exists between over-expression of HIF-1α and CAIX, but not HIF-1α and MCT1 or MCT4, in tumor cells. Increased miR-210 and concomitant decreased ISCU RNA levels were found in ~40% of tumors and this was significantly associated with HIF-1α and CAIX, but not MCT1 or MCT4, over-expression. HIF-1α and/or CAIX over-expression was associated with high recurrence rate and low overall survival of surgically treated patients. By contrast, clinically significant correlations were not found in tumors with MCT1 or MCT4 over-expression. This is the first study that provides in vivo evidences of coordinated activation of HIF-1α, CAIX, miR-210 and ISCU in carcinoma and association with poor prognosis, a finding with important implications for the development of metabolic-targeting therapies against hypoxia. PMID:28099149

Identification of key binding site residues of MCT1 for AR-C155858 reveals the molecular basis of its isoform selectivity.

PubMed

Nancolas, Bethany; Sessions, Richard B; Halestrap, Andrew P

2015-02-15

The proton-linked monocarboxylate transporters (MCTs) are required for lactic acid transport into and out of all mammalian cells. Thus, they play an essential role in tumour cells that are usually highly glycolytic and are promising targets for anti-cancer drugs. AR-C155858 is a potent MCT1 inhibitor (Ki ~2 nM) that also inhibits MCT2 when associated with basigin but not MCT4. Previous work [Ovens, M.J. et al. (2010) Biochem. J. 425, 523-530] revealed that AR-C155858 binding to MCT1 occurs from the intracellular side and involves transmembrane helices (TMs) 7-10. In the present paper, we generate a molecular model of MCT4 based on our previous models of MCT1 and identify residues in the intracellular substrate-binding cavity that differ significantly between MCT4 and MCT1/MCT2 and so might account for differences in inhibitor binding. We tested their involvement using site-directed mutagenesis (SDM) of MCT1 to change residues individually or in combination with their MCT4 equivalent and determined inhibitor sensitivity following expression in Xenopus oocytes. Phe360 and Ser364 were identified as important for AR-C155858 binding with the F360Y/S364G mutant exhibiting >100-fold reduction in inhibitor sensitivity. To refine the binding site further, we used molecular dynamics (MD) simulations and additional SDM. This approach implicated six more residues whose involvement was confirmed by both transport studies and [3H]-AR-C155858 binding to oocyte membranes. Taken together, our data imply that Asn147, Arg306 and Ser364 are important for directing AR-C155858 to its final binding site which involves interaction of the inhibitor with Lys38, Asp302 and Phe360 (residues that also play key roles in the translocation cycle) and also Leu274 and Ser278.

Sequence variations and two levels of MCT1 and CD147 expression in red blood cells and gluteus muscle of horses.

PubMed

Koho, N M; Mykkänen, A K; Reeben, M; Raekallio, M R; Ilves, M; Pösö, A R

2012-01-01

MCT1-CD147 complex is the prime lactate transporter in mammalian plasma membranes. In equine red blood cells (RBCs), activity of the complex and expression of MCT1 and CD147 is bimodal; high in 70% and low in 30%. We studied whether sequence variations contribute to the bimodal expression of MCT1 and CD147. Samples of blood and cremaster muscle were collected in connection of castration from 24 horses. Additional gluteus muscle samples were collected from 15 Standardbreds of which seven were known to express low amounts of CD147 in RBCs. The cDNA of MCT1 and CD147 together with a promoter region of CD147 was sequenced. The amounts of MCT1 and CD147 expressed in RBC and muscle membranes were measured by Western blot and mRNA levels in muscles by qPCR. MCT1 and CD147 were expressed in 20 castrates, and in four only were traces found. Sequence variations found in MCT1 were not linked to MCT1 expression. In CD147 linked heterozygous single nucleotide polymorphisms (SNPs) 389A>G (Met(125)Val) and 990C>T (3'-UTR) were associated to low expression of CD147. Also a mutation 168A>G (Ile(51)Val) in CD147 was associated to low MCT1 and CD147 expression. Low MCT1 and CD147 mRNA levels in gluteus were found in Standardbreds with low CD147 expression in RBCs. The results suggest that sequence variations affect the expression level of CD147, but do not explain its bimodality. The levels of MCT1 and CD147 mRNA correlated with the expression of CD147 and suggest that bimodality of their expression is regulated at transcriptional level. Copyright © 2011 Elsevier B.V. All rights reserved.

Clinically relevant HIF-1α-dependent metabolic reprogramming in oropharyngeal squamous cell carcinomas includes coordinated activation of CAIX and the miR-210/ISCU signaling axis, but not MCT1 and MCT4 upregulation.

PubMed

Sáenz-de-Santa-María, Inés; Bernardo-Castiñeira, Cristóbal; Secades, Pablo; Bernaldo-de-Quirós, Sandra; Rodrigo, Juan Pablo; Astudillo, Aurora; Chiara, María-Dolores

2017-02-21

Metabolic reprogramming is a very heterogeneous phenomenon in cancer. It mostly consists on increased glycolysis, lactic acid formation and extracellular acidification. These events have been associated to increased activity of the hypoxia inducible factor, HIF-1α. This study aimed at defining the metabolic program activated by HIF-1α in oropharyngeal squamous cell carcinomas (SCC) and assessing its clinical impact. Global gene/miRNA expression was analyzed in SCC-derived cells exposed to hypoxia. Expression of HIF-1α, the carbonic anhydrase CAIX, and the lactate/H+ transporters MCT1 and MCT4 were analyzed by immunohistochemistry in 246 SCCs. Cell-based analysis revealed that HIF-1α-driven metabolic program includes over-expression of glycolytic enzymes and the microRNA miR-210 coupled to down-regulation of its target, the iron-sulfur cluster assembly protein, ISCU. pH-regulator program entailed over-expression of CAIX, but not MCT1 or MCT4. Accordingly, significant overlapping exists between over-expression of HIF-1α and CAIX, but not HIF-1α and MCT1 or MCT4, in tumor cells. Increased miR-210 and concomitant decreased ISCU RNA levels were found in ~40% of tumors and this was significantly associated with HIF-1α and CAIX, but not MCT1 or MCT4, over-expression. HIF-1α and/or CAIX over-expression was associated with high recurrence rate and low overall survival of surgically treated patients. By contrast, clinically significant correlations were not found in tumors with MCT1 or MCT4 over-expression. This is the first study that provides in vivo evidences of coordinated activation of HIF-1α, CAIX, miR-210 and ISCU in carcinoma and association with poor prognosis, a finding with important implications for the development of metabolic-targeting therapies against hypoxia.

Identification of key binding site residues of MCT1 for AR-C155858 reveals the molecular basis of its isoform selectivity

PubMed Central

Nancolas, Bethany; Sessions, Richard B.; Halestrap, Andrew P.

2014-01-01

The proton-linked monocarboxylate transporters (MCTs) are required for lactic acid transport into and out of all mammalian cells. Thus, they play an essential role in tumour cells that are usually highly glycolytic and are promising targets for anti-cancer drugs. AR-C155858 is a potent MCT1 inhibitor (Ki ~2 nM) that also inhibits MCT2 when associated with basigin but not MCT4. Previous work [Ovens, M.J. et al. (2010) Biochem. J. 425, 523–530] revealed that AR-C155858 binding to MCT1 occurs from the intracellular side and involves transmembrane helices (TMs) 7–10. In the present paper, we generate a molecular model of MCT4 based on our previous models of MCT1 and identify residues in the intracellular substrate-binding cavity that differ significantly between MCT4 and MCT1/MCT2 and so might account for differences in inhibitor binding. We tested their involvement using site-directed mutagenesis (SDM) of MCT1 to change residues individually or in combination with their MCT4 equivalent and determined inhibitor sensitivity following expression in Xenopus oocytes. Phe360 and Ser364 were identified as important for AR-C155858 binding with the F360Y/S364G mutant exhibiting >100-fold reduction in inhibitor sensitivity. To refine the binding site further, we used molecular dynamics (MD) simulations and additional SDM. This approach implicated six more residues whose involvement was confirmed by both transport studies and [3H]-AR-C155858 binding to oocyte membranes. Taken together, our data imply that Asn147, Arg306 and Ser364 are important for directing AR-C155858 to its final binding site which involves interaction of the inhibitor with Lys38, Asp302 and Phe360 (residues that also play key roles in the translocation cycle) and also Leu274 and Ser278. PMID:25437897

Cerebral Cortex Hyperthyroidism of Newborn Mct8-Deficient Mice Transiently Suppressed by Lat2 Inactivation

PubMed Central

Núñez, Bárbara; Martínez de Mena, Raquel; Obregon, Maria Jesus; Font-Llitjós, Mariona; Nunes, Virginia; Palacín, Manuel; Dumitrescu, Alexandra M.; Morte, Beatriz; Bernal, Juan

2014-01-01

Thyroid hormone entry into cells is facilitated by transmembrane transporters. Mutations of the specific thyroid hormone transporter, MCT8 (Monocarboxylate Transporter 8, SLC16A2) cause an X-linked syndrome of profound neurological impairment and altered thyroid function known as the Allan-Herndon-Dudley syndrome. MCT8 deficiency presumably results in failure of thyroid hormone to reach the neural target cells in adequate amounts to sustain normal brain development. However during the perinatal period the absence of Mct8 in mice induces a state of cerebral cortex hyperthyroidism, indicating increased brain access and/or retention of thyroid hormone. The contribution of other transporters to thyroid hormone metabolism and action, especially in the context of MCT8 deficiency is not clear. We have analyzed the role of the heterodimeric aminoacid transporter Lat2 (Slc7a8), in the presence or absence of Mct8, on thyroid hormone concentrations and on expression of thyroid hormone-dependent cerebral cortex genes. To this end we generated Lat2-/-, and Mct8-/yLat2 -/- mice, to compare with wild type and Mct8-/y mice during postnatal development. As described previously the single Mct8 KO neonates had a transient increase of 3,5,3′-triiodothyronine concentration and expression of thyroid hormone target genes in the cerebral cortex. Strikingly the absence of Lat2 in the double Mct8Lat2 KO prevented the effect of Mct8 inactivation in newborns. The Lat2 effect was not observed from postnatal day 5 onwards. On postnatal day 21 the Mct8 KO displayed the typical pattern of thyroid hormone concentrations in plasma, decreased cortex 3,5,3′-triiodothyronine concentration and Hr expression, and concomitant Lat2 inactivation produced little to no modifications. As Lat2 is expressed in neurons and in the choroid plexus, the results support a role for Lat2 in the supply of thyroid hormone to the cerebral cortex during early postnatal development. PMID:24819605

Cerebral cortex hyperthyroidism of newborn mct8-deficient mice transiently suppressed by lat2 inactivation.

PubMed

Núñez, Bárbara; Martínez de Mena, Raquel; Obregon, Maria Jesus; Font-Llitjós, Mariona; Nunes, Virginia; Palacín, Manuel; Dumitrescu, Alexandra M; Morte, Beatriz; Bernal, Juan

2014-01-01

Thyroid hormone entry into cells is facilitated by transmembrane transporters. Mutations of the specific thyroid hormone transporter, MCT8 (Monocarboxylate Transporter 8, SLC16A2) cause an X-linked syndrome of profound neurological impairment and altered thyroid function known as the Allan-Herndon-Dudley syndrome. MCT8 deficiency presumably results in failure of thyroid hormone to reach the neural target cells in adequate amounts to sustain normal brain development. However during the perinatal period the absence of Mct8 in mice induces a state of cerebral cortex hyperthyroidism, indicating increased brain access and/or retention of thyroid hormone. The contribution of other transporters to thyroid hormone metabolism and action, especially in the context of MCT8 deficiency is not clear. We have analyzed the role of the heterodimeric aminoacid transporter Lat2 (Slc7a8), in the presence or absence of Mct8, on thyroid hormone concentrations and on expression of thyroid hormone-dependent cerebral cortex genes. To this end we generated Lat2-/-, and Mct8-/yLat2-/- mice, to compare with wild type and Mct8-/y mice during postnatal development. As described previously the single Mct8 KO neonates had a transient increase of 3,5,3'-triiodothyronine concentration and expression of thyroid hormone target genes in the cerebral cortex. Strikingly the absence of Lat2 in the double Mct8Lat2 KO prevented the effect of Mct8 inactivation in newborns. The Lat2 effect was not observed from postnatal day 5 onwards. On postnatal day 21 the Mct8 KO displayed the typical pattern of thyroid hormone concentrations in plasma, decreased cortex 3,5,3'-triiodothyronine concentration and Hr expression, and concomitant Lat2 inactivation produced little to no modifications. As Lat2 is expressed in neurons and in the choroid plexus, the results support a role for Lat2 in the supply of thyroid hormone to the cerebral cortex during early postnatal development.

Emulsification Increases the Acute Ketogenic Effect and Bioavailability of Medium-Chain Triglycerides in Humans

PubMed Central

Courchesne-Loyer, Alexandre; Lowry, Carolyn-Mary; St-Pierre, Valérie; Vandenberghe, Camille; Fortier, Mélanie; Castellano, Christian-Alexandre; Wagner, J Richard; Cunnane, Stephen C

2017-01-01

Abstract Background: Lower-brain glucose uptake is commonly present before the onset of cognitive deterioration associated with aging and may increase the risk of Alzheimer disease. Ketones are the brain's main alternative energy substrate to glucose. Medium-chain triglycerides (MCTs) are rapidly β-oxidized and are ketogenic but also have gastrointestinal side effects. We assessed whether MCT emulsification into a lactose-free skim-milk matrix [emulsified MCTs (MCT-Es)] would improve ketogenesis, reduce side effects, or both compared with the same oral dose of MCTs consumed without emulsification [nonemulsified MCTs (MCT-NEs)]. Objectives: Our aims were to show that, in healthy adults, MCT-Es will induce higher ketonemia and have fewer side effects than MCT-NEs and the effects of MCT-NEs and MCT-Es on ketogenesis and plasma medium-chain fatty acids (MCFAs) will be dose-dependent. Methods: Using a metabolic study day protocol, 10 healthy adults were each given 3 separate doses (10, 20, or 30 g) of MCT-NEs or MCT-Es with a standard breakfast or no treatment [control (CTL)]. Blood samples were taken every 30 min for 4 h to measure plasma ketones (β-hydroxybutyrate and acetoacetate), octanoate, decanoate, and other metabolites. Participants completed a side-effects questionnaire at the end of each study day. Results: Compared with CTL, MCT-NEs increased ketogenesis by 2-fold with no significant differences between doses. MCT-Es increased total plasma ketones by 2- to 4-fold in a dose-dependent manner. Compared with MCT-NEs, MCT-Es increased plasma MCFA bioavailability (F) by 2- to 3-fold and decreased the number of side effects by ∼50%. Conclusions: Emulsification increased the ketogenic effect and decreased side effects in a dose-dependent manner for single doses of MCTs ≤30 g under matching conditions. Further investigation is needed to establish whether emulsification could sustain ketogenesis and minimize side effects and therefore be used as a treatment to change brain ketone availability over a prolonged period of time. This trial was registered at clinicaltrials.gov as NCT02409927.

Role of medium-chain triglycerides in the alcohol-mediated cytochrome P450 2E1 induction of mitochondria.

PubMed

Lieber, Charles S; Cao, Qi; DeCarli, Leonore M; Leo, Maria A; Mak, Ki M; Ponomarenko, Anatoly; Ren, Chaoling; Wang, Xiaolei

2007-10-01

Chronic alcohol consumption is known to induce cytochrome P450 2E1 (CYP2E1) leading to lipid peroxidation, mitochondrial dysfunction and hepatotoxicity. We showed that replacement of dietary long-chain triglycerides (LCT) by medium-chain triglycerides (MCT) could be protective. We now wondered whether the induction of mitochondrial CYP2E1 plays a role and whether liver injury could be avoided through mitochondrial intervention. Rats were fed 4 different isocaloric liquid diets. The control group received our standard dextrin-maltose diet with intake limited to the average consumption of the 3 alcohol groups fed ad libitum the alcohol containing Lieber-DeCarli liquid diet. The fat was either 32% of calories as LCT (alcohol), or 16% as LCT + 16% as MCT (alcohol-MCT 16%), or 32% as MCT only (alcohol-MCT 32%). After 21 days, compared to the controls, the alcohol and both alcohol-MCT groups had a significant increase in mitochondrial CYP2E1 (p < 0.05 for both). As shown before, the same was found for the microsomal CYP2E1. When MCT replaced all the fat, like in the alcohol-MCT 32% group, CYP2E1 was significantly reduced by 40% in mitochondria (p < 0.05) and 30% in microsomes (p < 0.01). In mitochondria, 4-hydroxynonenal (4-HNE), a parameter of oxidative stress, paralleled CYP2E1. Compared to controls, alcohol and alcohol-MCT 16% significantly raised mitochondrial 4-HNE (p < 0.001), whereas the alcohol-MCT 32% diet brought it down to control levels (p < 0.001). Mitochondrial reduced glutathione (GSH) was also significantly lowered by alcohol consumption (p < 0.05), and it increased to almost normal levels with alcohol-MCT 32% (p = 0.006). These changes in the mitochondria reflected the reduction observed in total liver in which alcohol-MCT 32% decreased the alcohol-induced steatosis with a diminution of triglycerides (p < 0.001) and of the pro-inflammatory cytokine tumor necrosis factor-alpha (p < 0.001). Mitochondria participate in the induction of CYP2E1 by alcohol and contribute to lipid peroxidation and GSH depletion. Thus, lipid composition of the diet is an important determinant for the beneficial effect of MCT, with a diet containing a mixture of LCT/MCT being ineffective.

Growth stratal records of instantaneous and progressive limb rotation in the Precordillera thrust belt and Bermejo basin, Argentina

NASA Astrophysics Data System (ADS)

Zapata, TomáS. R.; Allmendinger, Richard W.

1996-10-01

Analysis of synorogenic deposits preserved near the thrust front zone of the Precordillera fold and thrust belt and in the Bermejo foreland basin in central Argentina documents the evolution of deformation during the last 5 Myr as well as the thrust system kinematics. Seismic lines across the area display examples of progressive and instantaneous limb rotations. The easternmost thrust plate of the Central Precordillera, the Niquivil thrust, experienced episodic motion in two main stages: a first thrust movement as a fault-propagation fold and a second movement as a high-angle anticlinal breakthrough fault after a period of quiescence. Growth strata deposited in the La Pareja intermontane basin and the Las Salinas and Bermejo anticline recorded continuous growth of Eastern Precordilleran structures beginning at ˜2.7 Ma, with uplift rates of ˜0.3 mm/yr for the Niquivil anticline, 1.08 mm/yr for the Las Salinas anticline, and between ˜0.6 and 0.38 mm/yr during the last ˜2 Myr for the Bermejo anticline. Once the Eastern Precordillera began to grow, the propagation of the Niquivil thrust stopped, restricting the deformation to the young Vallecito out-of sequence thrust. The complex geometry of growth strata deposited on the back limb of the Las Salinas anticline can be explained by using a model of a two-step fault propagation fold with constant layer thickness. The Bermejo anticline of the Eastern Precordillera is formed by the simultaneous propagation of a shallow fault, responsible for the fold shape, and a deep fault that produced vertical uplift. A growth triangle that documents instantaneous forelimb rotation for a fault-propagation fold is recorded for the first time in a published seismic line.

Cancer metabolism, stemness and tumor recurrence: MCT1 and MCT4 are functional biomarkers of metabolic symbiosis in head and neck cancer.

PubMed

Curry, Joseph M; Tuluc, Madalina; Whitaker-Menezes, Diana; Ames, Julie A; Anantharaman, Archana; Butera, Aileen; Leiby, Benjamin; Cognetti, David M; Sotgia, Federica; Lisanti, Michael P; Martinez-Outschoorn, Ubaldo E

2013-05-01

Here, we interrogated head and neck cancer (HNSCC) specimens (n = 12) to examine if different metabolic compartments (oxidative vs. glycolytic) co-exist in human tumors. A large panel of well-established biomarkers was employed to determine the metabolic state of proliferative cancer cells. Interestingly, cell proliferation in cancer cells, as marked by Ki-67 immunostaining, was strictly correlated with oxidative mitochondrial metabolism (OXPHOS) and the uptake of mitochondrial fuels, as detected via MCT1 expression (p < 0.001). More specifically, three metabolic tumor compartments were delineated: (1) proliferative and mitochondrial-rich cancer cells (Ki-67+/TOMM20+/COX+/MCT1+); (2) non-proliferative and mitochondrial-poor cancer cells (Ki-67-/TOMM20-/COX-/MCT1-); and (3) non-proliferative and mitochondrial-poor stromal cells (Ki-67-/TOMM20-/COX-/MCT1-). In addition, high oxidative stress (MCT4+) was very specific for cancer tissues. Thus, we next evaluated the prognostic value of MCT4 in a second independent patient cohort (n = 40). Most importantly, oxidative stress (MCT4+) in non-proliferating epithelial cancer cells predicted poor clinical outcome (tumor recurrence; p < 0.0001; log-rank test), and was functionally associated with FDG-PET avidity (p < 0.04). Similarly, oxidative stress (MCT4+) in tumor stromal cells was specifically associated with higher tumor stage (p < 0.03), and was a highly specific marker for cancer-associated fibroblasts (p < 0.001). We propose that oxidative stress is a key hallmark of tumor tissues that drives high-energy metabolism in adjacent proliferating mitochondrial-rich cancer cells, via the paracrine transfer of mitochondrial fuels (such as L-lactate and ketone bodies). New antioxidants and MCT4 inhibitors should be developed to metabolically target "three-compartment tumor metabolism" in head and neck cancers. It is remarkable that two "non-proliferating" populations of cells (Ki-67-/MCT4+) within the tumor can actually determine clinical outcome, likely by providing high-energy mitochondrial "fuels" for proliferative cancer cells to burn. Finally, we also show that in normal mucosal tissue, the basal epithelial "stem cell" layer is hyper-proliferative (Ki-67+), mitochondrial-rich (TOMM20+/COX+) and is metabolically programmed to use mitochondrial fuels (MCT1+), such as ketone bodies and L-lactate. Thus, oxidative mitochondrial metabolism (OXPHOS) is a common feature of both (1) normal stem cells and (2) proliferating cancer cells. As such, we should consider metabolically treating cancer patients with mitochondrial inhibitors (such as Metformin), and/or with a combination of MCT1 and MCT4 inhibitors, to target "metabolic symbiosis."

A Study of Minimum Competency Testing Programs. Final Program Development Resource Document.

ERIC Educational Resources Information Center

Gorth, William Phillip; Perkins, Marcy R.

This resource document represents the integration of both practice and theory related to minimum competency testing (MCT), and is largely based on information collected in a nationwide survey of MCT programs. Chapter 1, To Implement or Not to Implement MCT, by Marcy R. Perkins, presents a definition of MCT and a discussion of the perceived…

Characterization of monocarboxylate transporter 1 (MCT1) binding affinity for Basigin gene products and L1cam.

PubMed

Howard, John; Finch, Nicole A; Ochrietor, Judith D

2010-07-01

The purpose of this study was to determine the binding affinities of Basigin gene products and neural cell adhesion molecule L1cam for monocarboxylate transporter-1 (MCT1). ELISA binding assays were performed in which recombinant proteins of the transmembrane domains of Basigin gene products and L1cam were incubated with MCT1 captured from mouse brain. It was determined that Basigin gene products bind MCT1 with moderate affinity, but L1cam does not bind MCT1. Despite a high degree of sequence conservation between Basigin gene products and L1cam, the sequences are different enough to prevent L1cam from interacting with MCT1.

Geomorphology, kinematic history, and earthquake behavior of the active Kuwana wedge thrust anticline, central Japan

NASA Astrophysics Data System (ADS)

Ishiyama, Tatsuya; Mueller, Karl; Togo, Masami; Okada, Atsumasa; Takemura, Keiji

2004-12-01

We combine surface mapping of fault and fold scarps that deform late Quaternary alluvial strata with interpretation of a high-resolution seismic reflection profile to develop a kinematic model and determine fault slip rates for an active blind wedge thrust system that underlies Kuwana anticline in central Japan. Surface fold scarps on Kuwana anticline are closely correlated with narrow fold limbs and angular hinges on the seismic profile that suggest at least ˜1.3 km of fault slip completely consumed by folding in the upper 4 km of the crust. The close coincidence and kinematic link between folded terraces and the underlying thrust geometry indicate that Kuwana anticline has accommodated slip at an average rate of 2.2 ± 0.5 mm/yr on a 27°, west dipping thrust fault since early-middle Pleistocene time. In contrast to classical fault bend folds the fault slip budget in the stacked wedge thrusts also indicates that (1) the fault tip propagated upward at a low rate relative to the accrual of fault slip and (2) fault slip is partly absorbed by numerous bedding plane flexural-slip faults above the tips of wedge thrusts. An historic earthquake that occurred on the Kuwana blind thrust system possibly in A.D. 1586 is shown to have produced coseismic surface deformation above the doubly vergent wedge tip. Structural analyses of Kuwana anticline coupled with tectonic geomorphology at 103-105 years timescales illustrate the significance of active folds as indicators of slip on underlying blind thrust faults and thus their otherwise inaccessible seismic hazards.

Large-scale glacitectonic deformation in response to active ice sheet retreat across Dogger Bank (southern central North Sea) during the Last Glacial Maximum

NASA Astrophysics Data System (ADS)

Phillips, Emrys; Cotterill, Carol; Johnson, Kirstin; Crombie, Kirstin; James, Leo; Carr, Simon; Ruiter, Astrid

2018-01-01

High resolution seismic data from the Dogger Bank in the central southern North Sea has revealed that the Dogger Bank Formation records a complex history of sedimentation and penecontemporaneous, large-scale, ice-marginal to proglacial glacitectonic deformation. These processes led to the development of a large thrust-block moraine complex which is buried beneath a thin sequence of Holocene sediments. This buried glacitectonic landsystem comprises a series of elongate, arcuate moraine ridges (200 m up to > 15 km across; over 40-50 km long) separated by low-lying ice marginal to proglacial sedimentary basins and/or meltwater channels, preserving the shape of the margin of this former ice sheet. The moraines are composed of highly deformed (folded and thrust) Dogger Bank Formation with the lower boundary of the deformed sequence (up to 40-50 m thick) being marked by a laterally extensive décollement. The ice-distal parts of the thrust moraine complex are interpreted as a "forward" propagating imbricate thrust stack developed in response to S/SE-directed ice-push. The more complex folding and thrusting within the more ice-proximal parts of the thrust-block moraines record the accretion of thrust slices of highly deformed sediment as the ice repeatedly reoccupied this ice marginal position. Consequently, the internal structure of the Dogger Bank thrust-moraine complexes can be directly related to ice sheet dynamics, recording the former positions of a highly dynamic, oscillating Weichselian ice sheet margin as it retreated northwards at the end of the Last Glacial Maximum.

Fluid lubricated bearing assembly

DOEpatents

Boorse, Henry A.; Boeker, Gilbert F.; Menke, John R.

1976-01-01

1. A support for a loaded rotatable shaft comprising in combination on a housing having a fluid-tight cavity encasing an end portion of said shaft, a thrust bearing near the open end of said cavity for supporting the axial thrust of said shaft, said thrust bearing comprising a thrust plate mounted in said housing and a thrust collar mounted on said shaft, said thrust plate having a central opening the peripheral portion of which is hermetically sealed to said housing at the open end of said cavity, and means for supplying a fluid lubricant to said thrust bearing, said thrust bearing having a lubricant-conducting path connecting said lubricant supplying means with the space between said thrust plate and collar intermediate the peripheries thereof, the surfaces of said plate and collar being constructed and arranged to inhibit radial flow of lubricant and, on rotation of said thrust collar, to draw lubricant through said path between the bearing surfaces and to increase the pressure therebetween and in said cavity and thereby exert a supporting force on said end portion of said shaft.

Effect of medium-chain triglycerides on the release behavior of Endostar encapsulated PLGA microspheres.

PubMed

Meng, Boyu; Li, Ling; Hua, Su; Wang, Qingsong; Liu, Chunhui; Xu, Xiangyang; Yin, Xiaojin

2010-09-15

The incomplete release of Endostar from PLGA microspheres was observed in our previous study. In the present study, we focused on the effect of medium-chain triglycerides (MCT) on the in vitro/in vivo release behavior of Endostar encapsulated PLGA microspheres, which were prepared by a water-in-oil-in-water (W/O/W) double-emulsion method with or without MCT. The in vitro accumulated release of Endostar from microspheres co-encapsulated with 30% MCT was found to be 79.04% after a 30-day incubation period in PBS (pH 7.4) at 37 degrees C. However, the accumulated release of Endostar from MCT-free microspheres was found to be only 32.22%. Pouches containing Endostar encapsulated PLGA microspheres were implanted subcutaneously in rats. The effect of MCT on the in vivo release showed a similar trend to the in vitro release. After 30 days, only 9.87% of the total encapsulated Endostar was retained in microspheres co-encapsulated with 30% MCT, while 42.25% of Endostar was retained in MCT-free microspheres. The co-encapsulation of MCT provided the microspheres with a porous surface, which significantly improved the in vitro/in vivo release of Endostar from PLGA microspheres. In addition, in vitro experiments showed that MCT co-encapsulated PLGA microspheres had more inter-connected pores, faster degradation of PLGA, and faster swelling of microspheres, which helped to explain the mechanism of the effect of MCT on improving the release of Endostar from PLGA microspheres. Copyright 2010 Elsevier B.V. All rights reserved.

A novel nutrient sensing mechanism underlies substrate-induced regulation of monocarboxylate transporter-1

PubMed Central

Priyamvada, Shubha; Kumar, Anoop; Natarajan, Arivarasu A.; Gill, Ravinder K.; Alrefai, Waddah A.; Dudeja, Pradeep K.

2012-01-01

Monocarboxylate transporter isoform-1 (MCT1) plays an important role in the absorption of short-chain fatty acids (SCFAs) in the colon. Butyrate, a major SCFA, serves as the primary energy source for the colonic mucosa, maintains epithelial integrity, and ameliorates intestinal inflammation. Previous studies have shown substrate (butyrate)-induced upregulation of MCT1 expression and function via transcriptional mechanisms. The present studies provide evidence that short-term MCT1 regulation by substrates could be mediated via a novel nutrient sensing mechanism. Short-term regulation of MCT1 by butyrate was examined in vitro in human intestinal C2BBe1 and rat intestinal IEC-6 cells and ex vivo in rat intestinal mucosa. Effects of pectin feeding on MCT1, in vivo, were determined in rat model. Butyrate treatment (30–120 min) of C2BBe1 cells increased MCT1 function {p-(chloromercuri) benzene sulfonate (PCMBS)-sensitive [14C]butyrate uptake} in a pertussis toxin-sensitive manner. The effects were associated with decreased intracellular cAMP levels, increased Vmax of butyrate uptake, and GPR109A-dependent increase in apical membrane MCT1 level. Nicotinic acid, an agonist for the SCFA receptor GPR109A, also increased MCT1 function and decreased intracellular cAMP. Pectin feeding increased apical membrane MCT1 levels and nicotinate-induced transepithelial butyrate flux in rat colon. Our data provide strong evidence for substrate-induced enhancement of MCT1 surface expression and function via a novel nutrient sensing mechanism involving GPR109A as a SCFA sensor. PMID:22982338

Quercetin, Morin, Luteolin, and Phloretin Are Dietary Flavonoid Inhibitors of Monocarboxylate Transporter 6.

PubMed

Jones, Robert S; Parker, Mark D; Morris, Marilyn E

2017-09-05

Monocarboxylate transporter 6 (MCT6; SLC16A5) has been recognized for its role as a xenobiotic transporter, with characterized substrates probenecid, bumetanide, and nateglinide. To date, the impact of commonly ingested dietary compounds on MCT6 function has not been investigated, and therefore, the objective of this study was to evaluate a variety of flavonoids for their potential MCT6-specific interactions. Flavonoids are a large group of polyphenolic phytochemicals found in commonly consumed plant-based products that have been recognized for their dietary health benefits. The uptake of bumetanide in human MCT6 gene-transfected Xenopus laevis oocytes was significantly decreased in the presence of a variety of flavonoids (e.g., quercetin, luteolin, phloretin, and morin), but was not significantly affected by flavonoid glycosides (e.g., naringin, rutin, phlorizin). The IC 50 values of quercetin, phloretin, and morin were determined to be 25.3 ± 3.36, 17.3 ± 2.37, and 33.1 ± 3.29 μM, respectively. The mechanism of inhibition of phloretin was reversible and competitive, with a K i value of 22.8 μM. Furthermore, typical MCT substrates were also investigated for their potential interactions with MCT6. Substrates of MCTs 1, 2, 4, 8, and 10 did not cause any significant decrease in MCT6-mediated bumetanide uptake, suggesting that MCT6 has distinct compound selectivity. In summary, these results suggest that dietary aglycon flavonoids may significantly alter the pharmacokinetics and pharmacodynamics of bumetanide and other MCT6-specific substrates, and may represent potential substrates for MCT6.

Coconut oil has less satiating properties than medium chain triglyceride oil.

PubMed

Kinsella, R; Maher, T; Clegg, M E

2017-10-01

It is well established that the consumption of medium-chain triglycerides (MCT) can increase satiety and reduce food intake. Many media articles promote the use of coconut oil for weight loss advocating similar health benefits to that of MCT. The aim of this study was to examine the effect of MCT oil compared to coconut oil and control oil on food intake and satiety. Following an overnight fast, participants consumed a test breakfast smoothie containing 205kcal of either (i) MCT oil (ii) coconut oil or (iii) vegetable oil (control) on three separate test days. Participants recorded appetite ratings on visual analogue scales and were presented with an ad libitum lunch meal of preselected sandwiches 180min after consumption of the breakfast. The results showed a significant difference in energy and macronutrient intakes at the ad libitum meal between the three oils with the MCT oil reducing food intake compared to the coconut and control oil. Differences in food intake throughout the day were found for energy and fat, with the control having increased food intake compared to the MCT and coconut. The MCT also increased fullness over the three hours after breakfast compared to the control and coconut oils. The coconut oil was also reported as being less palatable than the MCT oil. The results of this study confirm the differences that exist between MCT and coconut oil such that coconut oil cannot be promoted as having similar effects to MCT oil on food intake and satiety. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

Holistic Overview of the Contribution of Tectonic, Geomorphic, and Geologic Factors to the Seismic Hazard of the Kathmandu Valley, Nepal

NASA Astrophysics Data System (ADS)

Banda, S.; Chang, A.; Sanquini, A.; Hilley, G. E.

2013-12-01

Nepal has been a seismically active region since the mid-Eocene collision of the Indian and Eurasian plates. It can be divided into four major tectonostratigraphic units. The Lesser Himalayan Zone, where Kathmandu Valley is located, is bounded to the south by the Main Boundary Thrust (MBT) and to the north by the Main Central Thrust (MCT). These faults, and the Main Frontal Thrust (MFT) traverse the NW-SE length of Nepal and sole into the Main Himalayan Thrust (MHT). Slip along these structures during the Plio-Quaternary has ponded sediment in the interior of the orogen, producing the nearly circular Kathmandu Basin, which hosts a series of radially converging rivers that exit the basin to the south. The sediment that is ponded within the basin consists of alluvial, lacustrine and debris flow deposits that are ~500 m thick. The faults in the vicinity of the Kathmandu Valley currently serve as potential earthquake sources. Sources that might plausibly be generated by these faults are constrained by structural, paleoseismic, and geodetic observations. The continued collision between India and Tibet is reflected in a convergence rate of about 20 mm/yr, as measured by Global Positioning System (GPS) geodetic networks. Strain accumulates on the MHT, and is released during large earthquakes. The epicenter of the 1934 (M8.2) earthquake, about 175 km to the east of Kathmandu, resulted in MMI VIII- IX shaking intensity in the Kathmandu Valley. Seismic waves generated from faults in proximity to Kathmandu may be amplified or attenuated at particular locations due to specific site responses that reflect the geologic framework of the Kathmandu Valley. The ponded sediments within the Kathmandu Basin may contribute to basin effects, trapping seismic waves and prolonging ground motion, as well as increasing the amplitude of the waves as they travel from crystalline outer rocks into the soft lake-bed sediments. A hazard analysis suggests that a M8.0 earthquake originating in the currently seismically-locked area to the west of Kathmandu would produce MMI VIII intensity in Kathmandu Valley, and a M5.8 earthquake on an active fault in the valley itself would result in MMI IX intensity close to the fault, and MMI VII - VIII elsewhere in the valley. The government of Nepal initiated a seismic hazard analysis and scenario-based estimation of the impact of a major earthquake in Kathmandu Valley in support of the development of a National Building Code. Earthquake awareness, preparation and mitigation initiatives have been undertaken, including implementation of the School Earthquake Safety Program, a preparedness and risk mitigation program for raising awareness and strengthening vulnerable buildings. The effectiveness of this program has been well-demonstrated, and it is a candidate for acceleration of adoption.

Differential protein abundance of a basolateral MCT1 transporter in the human gastrointestinal tract.

PubMed

Al-Mosauwi, Hashemeya; Ryan, Elizabeth; McGrane, Alison; Riveros-Beltran, Stefanie; Walpole, Caragh; Dempsey, Eugene; Courtney, Danielle; Fearon, Naomi; Winter, Desmond; Baird, Alan; Stewart, Gavin

2016-12-01

Bacterially derived short chain fatty acids (SCFAs), such as butyrate, are vital in maintaining the symbiotic relationship that exists between humans and their gastrointestinal microbial populations. A key step in this process is the transport of SCFAs across colonic epithelial cells via MCT1 transporters. This study investigated MCT1 protein abundance in various human intestinal tissues. Initial RT-PCR analysis confirmed the expected MCT1 RNA expression pattern of colon > small intestine > stomach. Using surgical resection samples, immunoblot analysis detected higher abundance of a 45 kDa MCT1 protein in colonic tissue compared to ileum tissue (P < 0.001, N = 4, unpaired t-test). Importantly, MCT1 abundance was found to be significantly lower in sigmoid colon compared to ascending colon (P < 0.01, N = 8-11, ANOVA). Finally, immunolocalization studies confirmed MCT1 to be abundant in the basolateral membranes of surface epithelial cells of the ascending, transverse, and descending colon, but significantly less prevalent in the sigmoid colon (P < 0.05, N = 5-21, ANOVA). In conclusion, these data confirm that basolateral MCT1 protein abundance is correlated to levels of bacterially derived SCFAs along the human gastrointestinal tract. These findings highlight the importance of precise tissue location in studies comparing colonic MCT1 abundance between normal and diseased states. © 2016 International Federation for Cell Biology.

H3K9ac and HDAC2 Activity Are Involved in the Expression of Monocarboxylate Transporter 1 in Oligodendrocyte

PubMed Central

Lai, Qingwei; Du, Wantong; Wu, Jian; Wang, Xiao; Li, Xinyu; Qu, Xuebin; Wu, Xiuxiang; Dong, Fuxing; Yao, Ruiqin; Fan, Hongbin

2017-01-01

Recently, it is reported that monocarboxylate transporter 1 (MCT1) plays crucial role in oligodendrocyte differentiation and myelination. We found that MCT1 is strongly expressed in oligodendrocyte but weakly expressed in oligodendrocyte precursors (OPCs), and the underlying mechanisms remain elusive. Histone deacetylases (HDACs) activity is required for induction of oligodendrocyte differentiation and maturation. We asked whether HDACs are involved in the regulation of MCT1 expression. This work revealed that the acetylation level of histone H3K9 (H3K9ac) was much higher in mct1 gene (Slc16a1) promoter in OPCs than that in oligodendrocyte. H3K9ac regulates MCT1 expression was confirmed by HDAC acetyltransferase inhibitors trichostatin A and curcumin. Of note, there was a negative correlation between H3K9ac and MCT1 expression in oligodendrocyte. Further, we found that the levels of HDAC1, 2, and 3 protein in oligodendrocyte were obviously higher than those in OPCs. However, specific knockdown of HDAC2 but not HDAC1 and HDAC3 significantly decreased the expression of MCT1 in oligodendrocyte. Conversely, overexpression of HDAC2 remarkably enhanced the expression of MCT1. The results imply that HDAC2 is involved in H3K9ac modification which regulates the expression of MCT1 during the development of oligodendrocyte. PMID:29184483

Lipid Emulsion Attenuates Acetylcholine-Induced Relaxation in Isolated Rat Aorta

PubMed Central

Ok, Seong-Ho; Lee, Soo Hee; Yu, Jongsun; Park, Jungchul; Shin, Il-Woo; Lee, Youngju; Cho, Hyunhoo; Choi, Mun-Jeoung; Baik, Jiseok; Hong, Jeong-Min; Han, Jeong Yeol; Lee, Heon Keun; Chung, Young-Kyun; Sohn, Ju-Tae

2015-01-01

We investigated the effect of Lipofundin MCT/LCT and Intralipid on acetylcholine-induced nitric oxide- (NO-) mediated relaxation in rat aorta to determine which lipid emulsion (LE) is more potent in terms of inhibition of NO-induced relaxation. Dose-response curves of responses induced by acetylcholine, the calcium ionophore A23187, and sodium nitroprusside were generated using isolated rat aorta with or without LE. The effect of Lipofundin MCT/LCT on acetylcholine-induced endothelial nitric oxide synthase (eNOS) phosphorylation in human umbilical vein endothelial cells (HUVECs) was investigated using western blotting. Lipofundin MCT/LCT (0.1 and 0.2%) attenuated acetylcholine-induced relaxation in endothelium-intact aorta with or without tiron, whereas 0.2% Intralipid only inhibited relaxation. Lipofundin MCT/LCT inhibited relaxation induced by the calcium ionophore A23187 and sodium nitroprusside in endothelium-intact aorta, but Lipofundin MCT/LCT had no effect on sodium nitroprusside-induced relaxation in the endothelium-denuded aorta. Combined pretreatment with l-arginine plus Lipofundin MCT/LCT increased acetylcholine-induced maximal relaxation in endothelium-intact aorta compared with Lipofundin MCT/LCT alone. l-Arginine attenuated Lipofundin MCT/LCT-mediated inhibition of acetylcholine-induced eNOS phosphorylation in HUVECs. Taken together, Lipofundin MCT/LCT attenuated acetylcholine-induced NO-mediated relaxation via an inhibitory effect on the endothelium including eNOS, which is proximal to activation of guanylyl cyclase. PMID:26273653

Lipid Emulsion Attenuates Acetylcholine-Induced Relaxation in Isolated Rat Aorta.

PubMed

Ok, Seong-Ho; Lee, Soo Hee; Yu, Jongsun; Park, Jungchul; Shin, Il-Woo; Lee, Youngju; Cho, Hyunhoo; Choi, Mun-Jeoung; Baik, Jiseok; Hong, Jeong-Min; Han, Jeong Yeol; Lee, Heon Keun; Chung, Young-Kyun; Sohn, Ju-Tae

2015-01-01

We investigated the effect of Lipofundin MCT/LCT and Intralipid on acetylcholine-induced nitric oxide- (NO-) mediated relaxation in rat aorta to determine which lipid emulsion (LE) is more potent in terms of inhibition of NO-induced relaxation. Dose-response curves of responses induced by acetylcholine, the calcium ionophore A23187, and sodium nitroprusside were generated using isolated rat aorta with or without LE. The effect of Lipofundin MCT/LCT on acetylcholine-induced endothelial nitric oxide synthase (eNOS) phosphorylation in human umbilical vein endothelial cells (HUVECs) was investigated using western blotting. Lipofundin MCT/LCT (0.1 and 0.2%) attenuated acetylcholine-induced relaxation in endothelium-intact aorta with or without tiron, whereas 0.2% Intralipid only inhibited relaxation. Lipofundin MCT/LCT inhibited relaxation induced by the calcium ionophore A23187 and sodium nitroprusside in endothelium-intact aorta, but Lipofundin MCT/LCT had no effect on sodium nitroprusside-induced relaxation in the endothelium-denuded aorta. Combined pretreatment with l-arginine plus Lipofundin MCT/LCT increased acetylcholine-induced maximal relaxation in endothelium-intact aorta compared with Lipofundin MCT/LCT alone. L-Arginine attenuated Lipofundin MCT/LCT-mediated inhibition of acetylcholine-induced eNOS phosphorylation in HUVECs. Taken together, Lipofundin MCT/LCT attenuated acetylcholine-induced NO-mediated relaxation via an inhibitory effect on the endothelium including eNOS, which is proximal to activation of guanylyl cyclase.

Fifty years of successful MCT research and production in France

NASA Astrophysics Data System (ADS)

Bensussan, Philippe; Tribolet, Philippe; Destéfanis, Gérard; Sirieix, Michel

2009-05-01

France has a long and fruitful history regarding Mercury Cadmium Telluride (MCT) research and production and is still one of the leading countries for the production of MCT IR detectors. To give a historical account of its development and progress, SAGEM Défense Sécurité will describe the early days of MCT developments in France. CEA-Leti (the French Atomic Energy Commission and a leading applied research center in electronics) will then present the research carried out on second- and third-generation MCT technologies, followed by Sofradir who will discuss the production of these new detector types.

Effect of Medium-chain Triglyceride (MCT) on Growth Performance, Nutrient Digestibility, Blood Characteristics in Weanling Pigs

PubMed Central

Hong, S. M.; Hwang, J. H.; Kim, I. H.

2012-01-01

One hundred and twenty weanling pigs in experiment 1 (Exp. 1) (6.91±0.99 kg; 21 d of age) and Exp. 2 (10.20±1.09 kg; 28 d of age) were used in two 42-d and 35-d experiments to evaluate the effect of medium-chain-triglyceride (MCT) on growth performance, apparent total tract digestibility (ATTD) of nutrients and blood profile. In both of Exp. 1 and Exp. 2, the same dietary treatments were utilized as follows : i) negative control (NC), ii) positive control (PC), NC+antibiotics (40 mg/kg Tiamulin, 110 mg/kg Tylosin, and 10 mg/kg Enramycin, iii) MCT3, NC+0.32% (phase 1, 2 and 3) MCT, and iv) MCT5, NC+0.55% (phase 1), 0.32% (phase 2 and 3) MCT. In Exp. 1, the pigs fed MCT5 diets had higher (p<0.05) ADG compared to NC treatment during the first 2 wk. From d 15 to 28, the ATTD of energy was improved (p<0.05) by MCT3 compared to the PC treatment. No effect has been observed on the blood profiles [red blood cell (RBC), white blood cell (WBC), immunoglobulin-G (IgG), lymphocyte concentration] measured in this study. In Exp. 2, the ADG were increased (p<0.05) by the MCT5 treatment than the PC treatment from d 0 to 14. Pigs fed PC treatment diet had lower ADFI (p<0.05) and better FCR (p<0.05) than NC treatment, whereas no differences were shown between MCT treatments and NC or PC treatment from d 15 to 35 and overall phase. The ATTD of DM and nitrogen were improved (p<0.05) by the effect of MCT5 related to the NC and PC treatment at the end of 2nd and 5th wk. The pigs fed MCT3 had higher (p<0.05) energy digestibility than PC treatment. No effects were seen in the blood profiles we measured (WBC, RBC, lymphocyte and immunoglobulin-G). In conclusion, the addition of MCT in the weanling pigs diet can improve the ADG and digestibility during the earlier period (first 2 wks), but had little effect on the blood characteristics. PMID:25049656

Glucose Transporter 1 and Monocarboxylate Transporters 1, 2, and 4 Localization within the Glial Cells of Shark Blood-Brain-Barriers

PubMed Central

Balmaceda-Aguilera, Carolina; Cortés-Campos, Christian; Cifuentes, Manuel; Peruzzo, Bruno; Mack, Lauren; Tapia, Juan Carlos; Oyarce, Karina; García, María Angeles; Nualart, Francisco

2012-01-01

Although previous studies showed that glucose is used to support the metabolic activity of the cartilaginous fish brain, the distribution and expression levels of glucose transporter (GLUT) isoforms remained undetermined. Optic/ultrastructural immunohistochemistry approaches were used to determine the expression of GLUT1 in the glial blood-brain barrier (gBBB). GLUT1 was observed solely in glial cells; it was primarily located in end-feet processes of the gBBB. Western blot analysis showed a protein with a molecular mass of 50 kDa, and partial sequencing confirmed GLUT1 identity. Similar approaches were used to demonstrate increased GLUT1 polarization to both apical and basolateral membranes in choroid plexus epithelial cells. To explore monocarboxylate transporter (MCT) involvement in shark brain metabolism, the expression of MCTs was analyzed. MCT1, 2 and 4 were expressed in endothelial cells; however, only MCT1 and MCT4 were present in glial cells. In neurons, MCT2 was localized at the cell membrane whereas MCT1 was detected within mitochondria. Previous studies demonstrated that hypoxia modified GLUT and MCT expression in mammalian brain cells, which was mediated by the transcription factor, hypoxia inducible factor-1. Similarly, we observed that hypoxia modified MCT1 cellular distribution and MCT4 expression in shark telencephalic area and brain stem, confirming the role of these transporters in hypoxia adaptation. Finally, using three-dimensional ultrastructural microscopy, the interaction between glial end-feet and leaky blood vessels of shark brain was assessed in the present study. These data suggested that the brains of shark may take up glucose from blood using a different mechanism than that used by mammalian brains, which may induce astrocyte-neuron lactate shuttling and metabolic coupling as observed in mammalian brain. Our data suggested that the structural conditions and expression patterns of GLUT1, MCT1, MCT2 and MCT4 in shark brain may establish the molecular foundation of metabolic coupling between glia and neurons. PMID:22389700

Monocarboxylate transporters, blood lactate removal after supramaximal exercise, and fatigue indexes in humans.

PubMed

Thomas, C; Perrey, S; Lambert, K; Hugon, G; Mornet, D; Mercier, J

2005-03-01

The present study investigated whether muscular monocarboxylate transporter (MCT) 1 and 4 contents are related to the blood lactate removal after supramaximal exercise, fatigue indexes measured during different supramaximal exercises, and muscle oxidative parameters in 15 humans with different training status. Lactate recovery curves were obtained after a 1-min all-out exercise. A biexponential time function was then used to determine the velocity constant of the slow phase (gamma(2)), which denoted the blood lactate removal ability. Fatigue indexes were calculated during 1-min all-out (FI(AO)) and repeated 10-s (FI(Sprint)) cycling sprints. Biopsies were taken from the vastus lateralis muscle. MCT1 and MCT4 contents were quantified by Western blots, and maximal muscle oxidative capacity (V(max)) was evaluated with pyruvate + malate and glutamate + malate as substrates. The results showed that the blood lactate removal ability (i.e., gamma(2)) after a 1-min all-out test was significantly related to MCT1 content (r = 0.70, P < 0.01) but not to MCT4 (r = 0.50, P > 0.05). However, greater MCT1 and MCT4 contents were negatively related with a reduction of blood lactate concentration at the end of 1-min all-out exercise (r = -0.56, and r = -0.61, P < 0.05, respectively). Among skeletal muscle oxidative indexes, we only found a relationship between MCT1 and glutamate + malate V(max) (r = 0.63, P < 0.05). Furthermore, MCT1 content, but not MCT4, was inversely related to FI(AO) (r = -0.54, P < 0.05) and FI(Sprint) (r = -0.58, P < 0.05). We concluded that skeletal muscle MCT1 expression was associated with the velocity constant of net blood lactate removal after a 1-min all-out test and with the fatigue indexes. It is proposed that MCT1 expression may be important for blood lactate removal after supramaximal exercise based on the existence of lactate shuttles and, in turn, in favor of a better tolerance to muscle fatigue.

Effects of medium-chain triglycerides, long-chain triglycerides, or 2-monododecanoin on fatty acid composition in the portal vein, intestinal lymph, and systemic circulation in rats.

PubMed

You, Yi-Qian Nancy; Ling, Pei-Ra; Qu, Jason Zhensheng; Bistrian, Bruce R

2008-01-01

Fatty acid absorption patterns can have a major impact on the fatty acid composition in the portal, intestinal lymph, and systemic circulation. This study sought to determine the effects of long-chain triglycerides (LCT), medium-chain triglycerides (MCT), and 2-monododecanoin (2mono) on intestinal fatty acid composition during continuous feeding over a brief period. The lipid sources were 100% LCT, 100% MCT, a 50:50 mixture of LCT and MCT (LCT/MCT), and a 50:50 mixture of LCT and 2mono (LCT/2mono). A total of 27 rats were randomly given 1 of the 4 diets at 200 kcal/kg/d, with 30% of total calories from lipids over 3 hours. MCT significantly increased each of the medium-chain fatty acids (C6:0, C8:0, and C10:0) as free fatty acids in the portal vein and about 10%/mol of C10:0 as triglycerides in the lymph compared with the other groups. There was significantly less C10:0 in lymphatic triglycerides with LCT/MCT than with MCT, but more than in the LCT and LCT/2mono diets. MCT also significantly increased the contents of C16:0, C18:0, C18:1, and C20:4 in the lymphatic triglycerides compared with all other groups including LCT/MCT. The amount of linoleic acid (C18:2) in lymphatic triglycerides followed the relative amounts of this fatty acid in the diet, with the greatest in LCT followed by LCT/MCT and LCT/2mono and least in MCT. A so-called structured lipid composed of the medium-chain fatty acid dodecanoic acid on the 2 position and long-chain fatty acids on the 1 and 3 positions appeared to be endogenously synthesized in response to the LCT/2mono diet. The original differences in MCT and LCT content in the diets were preserved in the fatty acid composition in the intestinal free fatty acids and triglycerides during feeding. In addition, the duration of lipid administration can play a role in altering fatty acid composition in the intestine.

Resistance to Diet-Induced Obesity and Associated Metabolic Perturbations in Haploinsufficient Monocarboxylate Transporter 1 Mice

PubMed Central

Steiner, Nadia; Carneiro, Lionel; Favrod, Céline; Preitner, Frédéric; Thorens, Bernard; Stehle, Jean-Christophe; Dix, Laure; Pralong, François; Magistretti, Pierre J.; Pellerin, Luc

2013-01-01

The monocarboxylate transporter 1 (MCT1 or SLC16A1) is a carrier of short-chain fatty acids, ketone bodies, and lactate in several tissues. Genetically modified C57BL/6J mice were produced by targeted disruption of the mct1 gene in order to understand the role of this transporter in energy homeostasis. Null mutation was embryonically lethal, but MCT1 +/− mice developed normally. However, when fed high fat diet (HFD), MCT1 +/− mice displayed resistance to development of diet-induced obesity (24.8% lower body weight after 16 weeks of HFD), as well as less insulin resistance and no hepatic steatosis as compared to littermate MCT1 +/+ mice used as controls. Body composition analysis revealed that reduced weight gain in MCT1 +/− mice was due to decreased fat accumulation (50.0% less after 9 months of HFD) notably in liver and white adipose tissue. This phenotype was associated with reduced food intake under HFD (12.3% less over 10 weeks) and decreased intestinal energy absorption (9.6% higher stool energy content). Indirect calorimetry measurements showed ∼ 15% increase in O2 consumption and CO2 production during the resting phase, without any changes in physical activity. Determination of plasma concentrations for various metabolites and hormones did not reveal significant changes in lactate and ketone bodies levels between the two genotypes, but both insulin and leptin levels, which were elevated in MCT1 +/+ mice when fed HFD, were reduced in MCT1 +/− mice under HFD. Interestingly, the enhancement in expression of several genes involved in lipid metabolism in the liver of MCT1 +/+ mice under high fat diet was prevented in the liver of MCT1 +/− mice under the same diet, thus likely contributing to the observed phenotype. These findings uncover the critical role of MCT1 in the regulation of energy balance when animals are exposed to an obesogenic diet. PMID:24367518

The Chemical Chaperone Phenylbutyrate Rescues MCT8 Mutations Associated With Milder Phenotypes in Patients With Allan-Herndon-Dudley Syndrome.

PubMed

Braun, Doreen; Schweizer, Ulrich

2017-03-01

Mutations in the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) prevent appropriate entry of thyroid hormones into brain cells during development and cause severe mental retardation in affected patients. The current treatment options are thyromimetic compounds that enter the brain independently of MCT8. Some MCT8-deficient patients (e.g., those carrying MCT8delF501) will not be as severely affected as most others. We have shown that the MCT8delF501 protein has decreased protein stability but important residual function once it reaches the plasma membrane. We were able to rescue protein expression and the function of MCT8delF501 in a Madin-Darby canine kidney cell model by application of the chemical chaperone sodium phenylbutyrate (NaPB), a drug that has been used to treat patients with cystic fibrosis and urea cycle defects for extended periods of time. In the present study, we have extended our previous study and report on the NaPB-dependent rescue of a series of other pathogenic MCT8 mutants associated with milder patient phenotypes. We show that NaPB can functionally rescue the expression and activities of Ser194Phe, Ser290Phe, Leu434Trp, Arg445Cys, Leu492Pro, and Leu568Pro mutations in MCT8 in a dose-dependent manner. The soy isoflavone genistein, a dietary supplement, which was effective in MCT8delF501, was also effective in increasing the expression and transport of these MCT8 mutants; however, the effect size differed among mutants. Kinetic analyses revealed that the Michaelis constants of the mutants toward the primary substrate 3,3',5-triiodothyronine were not much different from the wild-type value, suggesting that these mutants are not impaired in their interaction with substrate but rather destabilized by the mutation and degraded. Copyright © 2017 by the Endocrine Society.

STAT3:FOXM1 and MCT1 drive uterine cervix carcinoma fitness to a lactate-rich microenvironment.

PubMed

Silva, Lidia Santos; Goncalves, Luis Gafeira; Silva, Fernanda; Domingues, Germana; Maximo, Valdemar; Ferreira, Joana; Lam, Eric W-F; Dias, Sergio; Felix, Ana; Serpa, Jacinta

2016-04-01

Uterine cervix cancer is the second most common malignancy in women worldwide with human papillomavirus (HPV) as the etiologic factor. The two main histological variants, squamous cell carcinomas (SCC) and adenocarcinomas (AC), resemble the cell morphology of exocervix and endocervix, respectively. Cancer metabolism is a cancer hallmark conditioned by the microenvironment. As uterine cervix homeostasis is dependent on lactate, we hypothesized lactate plays a role in uterine cervix cancer progression. Using in vitro (SiHa-SCC and HeLa-AC) and BALB-c/SCID models, we demonstrated that lactate metabolism is linked to histological types, with SCC predominantly consuming and AC producing lactate. MCT1 is a key factor, allowing lactate consumption and being regulated in vitro by lactate through the FOXM1:STAT3 pathway. In vivo models showed that SCC (SiHa) expresses MCT1 and is dependent on lactate to grow, whereas AC (HeLa) expresses MCT1 and MCT4, with higher growth capacities. Immunohistochemical analysis of tissue microarrays (TMA) from human cervical tumors showed that MCT1 expression associates with the SCC type and metastatic behavior of AC, whereas MCT4 expression concomitantly increases from in situ SCC to invasive SCC and is significantly associated with the AC type. Consistently, FOXM1 expression is statistically associated with MCT1 positivity in SCC, whereas the expression of FOXO3a, a FOXM1 functional antagonist, is linked to MCT1 negativity in AC. Our study reinforces the role of the microenvironment in the metabolic adaptation of cancer cells, showing that cells that retain metabolic features of their normal counterparts are positively selected by the organ's microenvironment and will survive. In particular, MCT1 was shown to be a key element in uterine cervix cancer development; however, further studies are needed to validate MCT1 as a suitable therapeutic target in uterine cervix cancer.

The effect of extracellular alkalinization on lactate metabolism of breast cancer stem cells: Overview of LDH-A, LDH-B, MCT1 and MCT4 gene expression

NASA Astrophysics Data System (ADS)

Neolaka, G. M. G.; Yustisia, I.; Sadikin, M.; Wanandi, S. I.

2017-08-01

Changes in the metabolic status of cancer cells are presumed to be correlated with the adjustment of these cells to extracellular changes. Cell glycolysis increases the production of intracellular lactate catalyzed by the lactate dehydrogenases, both LDH-A and LDH-B. An increase in intracellular lactate can affect extracellular pH balance through monocarboxylate transporters, particularly MCT1 and MCT4. This study aimed to analyze the effects of extracellular alkalinization on the lactate metabolism of human breast cancer stem cells (BCSCs). In this study, human primary BCSCs (CD24-/CD44+ cells) were treated with 100 mM sodium bicarbonate for 0.5, 24, and 48 h in DMEM F12/HEPES. After incubation, extracellular pH was measured and cells were harvested to extract the total RNA and protein. The expression of LDH-A, LDH-B, MCT1, and MCT4 mRNA genes were analyzed using qRT-PCR method. Our study shows that administration of sodium bicarbonate in the BCSC culture medium could increase extracellular pH. To balance the increase of extracellular pH, BCSCs regulated the expression of LDH-A, LDH-B, MCT1, and MCT4 genes. As the extracellular pH increases, the expression of LDH-A that converts pyruvate to lactate increased along with the increase of MCT 4 and MCT 1 expression, which act as lactate transporters. As the incubation time increases, the pH decreases, leading to the suppression of LDH-A and increase of LDH-B expression that converts lactate into pyruvate. Therefore, we suggest that the extracellular alkalinization by sodium bicarbonate in BCSCs affected the genes that regulate lactate metabolism.

Regulation of Acetate Utilization by Monocarboxylate Transporter 1 (MCT1) in Hepatocellular Carcinoma (HCC).

PubMed

Jeon, Jeong Yong; Lee, Misu; Whang, Sang Hyun; Kim, Jung-Whan; Cho, Arthur; Yun, Mijin

2018-01-19

Altered energy metabolism is a biochemical fingerprint of cancer cells. Hepatocellular carcinoma (HCC) shows reciprocal [18F]fluorodeoxyglucose (FDG) and [11C]acetate uptake, as revealed by positron emission tomography/computed tomography (PET/CT). Previous studies have focused on the role of FDG uptake in cancer cells. In this study, we evaluated the mechanism and roles of [11C]acetate uptake in human HCCs and cell lines. The expression of monocarboxylate transporters (MCTs) was assessed to determine the transporters of [11C]acetate uptake in HCC cell lines and human HCCs with different [11C]acetate uptake. Using two representative cell lines with widely different [11C]acetate uptake (HepG2 for high uptake and Hep3B for low uptake), changes in [11C]acetate uptake were measured after treatment with an MCT1 inhibitor or MCT1-targeted siRNA. To verify the roles of MCT1 in cells, oxygen consumption rate and the amount of lipid synthesis were measured. HepG2 cells with high [11C]acetate uptake showed higher MCT1 expression than other HCC cell lines with low [11C]acetate uptake. MCT1 expression was elevated in human HCCs with high [11C]acetate uptake compared to those with low [11C]acetate uptake. After blocking MCT1 with AR-C155858 or MCT1 knockdown, [11C]acetate uptake in HepG2 cells was significantly reduced. Additionally, inhibition of MCT1 suppressed mitochondrial oxidative phosphorylation, lipid synthesis, and cellular proliferation in HCC cells with high [11C]acetate uptake. MCT1 may be a new therapeutic target for acetate-dependent HCCs with high [11C]acetate uptake, which can be selected by [11C]acetate PET/CT imaging in clinical practice.

Increased densities of monocarboxylate transport protein MCT1 after chronic administration of nicotine in rat brain.

PubMed

Canis, Martin; Mack, Brigitte; Gires, Olivier; Maurer, Martin H; Kuschinsky, Wolfgang; Duembgen, Lutz; Duelli, Roman

2009-08-01

Chronic administration of nicotine is followed by a general stimulation of brain metabolism that results in a distinct increase of glucose transport protein densities for Glut1 and Glu3, and local cerebral glucose utilization (LCGU). This increase of LCGU might be paralleled by an enhanced production of lactate. Therefore, the question arose as to whether chronic nicotine infusion is accompanied by increased local densities of monocarboxylate transporter MCT1 in the brain. Secondly, we inquired whether LCGU might be correlated with local densities of MCT1 during normal conditions and after chronic nicotine infusion. Nicotine was given subcutaneously for 1 week by osmotic mini-pumps and local densities of MCT1 were measured by immunoautoradiographic methods in cryosections of rat brains. MCT1 density was significantly increased in 21 of 32 brain structures investigated (median increase 15.0+/-3.6%). Immunohistochemical stainings of these substructures revealed an over-expression of MCT1 within endothelial cells and astrocytes of treated animals. A comparison of 23 MCT1 densities with LCGU measured in the same structures in a previous study revealed a partial correlation between both parameters under control conditions and after chronic nicotine infusion. 10 out of 23 brain areas, which showed a significant increase of MCT1 density due to chronic nicotine infusion, also showed a significant increase of LCGU. In summary, our data show that chronic nicotine infusion induces a moderate increase of local and global density of MCT1 in defined brain structures. However, in terms of brain topologies and substructures this phenomenon did partially match with increased LCGU. It is concluded that MCT1 transporters were upregulated during chronic nicotine infusion at the level of brain substructures and, at least partially, independently of LCGU.

CD25 is expressed by canine cutaneous mast cell tumors but not by cutaneous connective tissue mast cells.

PubMed

Meyer, A; Gruber, A D; Klopfleisch, R

2012-11-01

Canine cutaneous mast cell tumors (MCT) of different histological grades have distinct biological behaviors. However, little is known about underlying molecular mechanisms that lead to tumor development and increasing malignancy with higher tumor grade. Recent studies have identified the interleukin-2 receptor (IL-2R) subunits CD25 and CD2 as markers that distinguish nonneoplastic from neoplastic mast cells in human systemic mastocytosis. In this study, their potential as a marker for canine MCT and their possible impact on MCT carcinogenesis were evaluated. mRNA expression levels of both genes were compared between grade 1 (n = 12) and grade 3 (n = 8) MCT, and protein expression levels of CD25 were compared in 90 MCT of different tumor grades. mRNA expression levels of both CD25 and CD2 were upregulated in grade 3 MCT. In contrast, CD25 protein was expressed by fewer tumor cells and at decreased levels in grade 3 tumors, while most grade 1 MCT had strong CD25 protein expression. Moreover, CD25 was not expressed by nonneoplastic, resting cutaneous mast cells, while few presumably activated mast cells in tissue samples from dogs with allergic dermatitis had weak CD25 expression. Taken together, these findings suggest that CD25 may play a critical role in early MCT development and may be a stimulatory factor in grade 1 MCT, while grade 3 MCT seem to be less dependent on CD25. Because of the low number of CD25-positive tumor cells in high-grade tumors, the usefulness of CD25 as a tumor marker is, however, questionable.

Mutation in the Monocarboxylate Transporter 12 Gene Affects Guanidinoacetate Excretion but Does Not Cause Glucosuria.

PubMed

Dhayat, Nasser; Simonin, Alexandre; Anderegg, Manuel; Pathare, Ganesh; Lüscher, Benjamin P; Deisl, Christine; Albano, Giuseppe; Mordasini, David; Hediger, Matthias A; Surbek, Daniel V; Vogt, Bruno; Sass, Jörn Oliver; Kloeckener-Gruissem, Barbara; Fuster, Daniel G

2016-05-01

A heterozygous mutation (c.643C>A; p.Q215X) in the monocarboxylate transporter 12-encoding gene MCT12 (also known as SLC16A12) that mediates creatine transport was recently identified as the cause of a syndrome with juvenile cataracts, microcornea, and glucosuria in a single family. Whereas the MCT12 mutation cosegregated with the eye phenotype, poor correlation with the glucosuria phenotype did not support a pathogenic role of the mutation in the kidney. Here, we examined MCT12 in the kidney and found that it resides on basolateral membranes of proximal tubules. Patients with MCT12 mutation exhibited reduced plasma levels and increased fractional excretion of guanidinoacetate, but normal creatine levels, suggesting that MCT12 may function as a guanidinoacetate transporter in vivo However, functional studies in Xenopus oocytes revealed that MCT12 transports creatine but not its precursor, guanidinoacetate. Genetic analysis revealed a separate, undescribed heterozygous mutation (c.265G>A; p.A89T) in the sodium/glucose cotransporter 2-encoding gene SGLT2 (also known as SLC5A2) in the family that segregated with the renal glucosuria phenotype. When overexpressed in HEK293 cells, the mutant SGLT2 transporter did not efficiently translocate to the plasma membrane, and displayed greatly reduced transport activity. In summary, our data indicate that MCT12 functions as a basolateral exit pathway for creatine in the proximal tubule. Heterozygous mutation of MCT12 affects systemic levels and renal handling of guanidinoacetate, possibly through an indirect mechanism. Furthermore, our data reveal a digenic syndrome in the index family, with simultaneous MCT12 and SGLT2 mutation. Thus, glucosuria is not part of the MCT12 mutation syndrome. Copyright © 2016 by the American Society of Nephrology.

Tier-2 studies on monocrotaline immunotoxicity in C57BL/6 mice.

PubMed

Deyo, J A; Kerkvliet, N I

1991-01-01

Monocrotaline (MCT) is a member of a class of naturally occurring phytotoxins known as pyrrolizidine alkaloids, and is a toxicological concern to both man and his livestock. The purpose of these studies was to evaluate the effect of a 14-day oral MCT (0-100 mg/kg per day) exposure on the functional integrity of various immunocyte effector systems in C57BL/6 mice, as well as to investigate potential mechanisms for its immunotoxicity. Decreases in lymphoid organ weights and cellularity, and resident peritoneal exudate cell (PEC) number were only observed after exposure to the highest dose of 100 mg/kg MCT. This dose also inhibited NK cell cytotoxicity, while the total number of NK lytic units per spleen was decreased (-53%) after exposure to 50 mg/kg MCT. Following i.p. injection of SRBC, the percentage of PEC macrophages containing engulfed SRBC was significantly increased in MCT-exposed mice, while the percentage of large vacuolated (activated) macrophages was decreased in a dose-dependent manner. Exposure to MCT significantly decreased the total number of Ig+ cells without altering the number of CD4+ and CD8+ cells. The antibody responses (PFC/10(6) spleen cells) to two T cell-independent antigens, TNP-LPS and DNP-Ficoll, were significantly decreased at all MCT doses, and the degree of suppression of both responses was identical at coincident doses. MCT exposure (25 mg/kg) significantly suppressed the blastogenic response to the T cell mitogen concanavalin A (-38%), and to the B cell mitogen lipopolysaccharide (-58%). These results indicate that exposure to MCT can alter the functional integrity of various immune effector responses in a dose-dependent manner, and suggest that the B cell may be a relatively more sensitive target of MCT immunotoxicity compared to T cells, macrophages and NK cells.

Neuronal 3',3,5-triiodothyronine (T3) uptake and behavioral phenotype of mice deficient in Mct8, the neuronal T3 transporter mutated in Allan-Herndon-Dudley syndrome.

PubMed

Wirth, Eva K; Roth, Stephan; Blechschmidt, Cristiane; Hölter, Sabine M; Becker, Lore; Racz, Ildiko; Zimmer, Andreas; Klopstock, Thomas; Gailus-Durner, Valerie; Fuchs, Helmut; Wurst, Wolfgang; Naumann, Thomas; Bräuer, Anja; de Angelis, Martin Hrabé; Köhrle, Josef; Grüters, Annette; Schweizer, Ulrich

2009-07-29

Thyroid hormone transport into cells requires plasma membrane transport proteins. Mutations in one of these, monocarboxylate transporter 8 (MCT8), have been identified as underlying cause for the Allan-Herndon-Dudley syndrome, an X-linked mental retardation in which the patients also present with abnormally high 3',3,5-triiodothyronine (T(3)) plasma levels. Mice deficient in Mct8 replicate the thyroid hormone abnormalities observed in the human condition. However, no neurological deficits have been described in mice lacking Mct8. Therefore, we subjected Mct8-deficient mice to a comprehensive immunohistochemical, neurological, and behavioral screen. Several behavioral abnormalities were found in the mutants. Interestingly, some of these behavioral changes are compatible with hypothyroidism, whereas others rather indicate hyperthyroidism. We thus hypothesized that neurons exclusively dependent on Mct8 are in a hypothyroid state, whereas neurons expressing other T(3) transporters become hyperthyroid, if they are exposed directly to the high plasma T(3). The majority of T(3) uptake in primary cortical neurons is mediated by Mct8, but pharmacological inhibition suggested functional expression of additional T(3) transporter classes. mRNAs encoding six T(3) transporters, including L-type amino acid transporters (LATs), were coexpressed with Mct8 in isolated neurons. We then demonstrated Lat2 expression in cultured neurons and throughout murine brain development. In contrast, LAT2 is expressed in microglia in the developing human brain during gestation, but not in neurons. We suggest that lack of functional complementation by alternative thyroid hormone transporters in developing human neurons precipitates the devastating neurodevelopmental phenotype in MCT8-deficient patients, whereas Mct8-deficient mouse neurons are functionally complemented by other transporters, for possibly Lat2.

Causes of reduced survival of neonatal pigs by medium-chain triglycerides: blood metabolite and behavioral activity approaches.

PubMed

Lin, C L; Chiang, S H; Lee, H F

1995-07-01

Two experiments were conducted to investigate the causes of the failure of orally dosed medium-chain triglycerides (MCT) in improving the survival of neonatal pigs. In Exp. 1, four litters consisting of 24 unsuckled neonatal pigs were either dosed with 6 mL/kg BW.75 of MCT or the dosing process was mimicked by inserting and withdrawing the feeding tube at 10 and 18 h after birth. Blood beta-hydroxybutyrate concentration was increased (P < .06) and the depletion of liver glycogen was reduced (P < .05) by MCT. Plasma octanoate (C8) concentration peaked at 1 h and was minimized at 4 to 8 h after each MCT dosage; decanoate (C10) concentration increased (P < .001) gradually after each dosage. Activity of pigs was decreased (P < .01) by MCT. In Exp. 2, 94 litters consisting of 887 neonatal pigs were dosed with either 6 mL/kg BW.75 of MCT, coconut oil (CO), or saline at 10 to 14 and 20 to 28 h after birth. Milk intake (P < .05) and weight gain were reduced (P < .01) in 1- to 2-d-old pigs dosed with MCT compared with intake and gain of pigs dosed with saline. Mortality of large pigs (> 1 kg) was increased (P < .05) but mortality of small pigs (< 1 kg) was not affected by MCT. Mortality of small pigs was reduced (P < .05) but mortality of large pigs (> 1 kg) was not affected by CO. Standing, walking, and suckling behaviors of pigs were not affected by MCT or CO. Coma was evident in 9.7% of pigs dosed with MCT.(ABSTRACT TRUNCATED AT 250 WORDS)

Medium Chain Triglycerides enhances exercise endurance through the increased mitochondrial biogenesis and metabolism.

PubMed

Wang, Ying; Liu, Zhenzhen; Han, Yi; Xu, Jiping; Huang, Wen; Li, Zhaoshen

2018-01-01

Medium Chain Triglycerides (MCT) is a dietary supplement and usually used along with medications for treating food absorption disorders including diarrhea, steatorrhea and liver disease. It has been shown that MCT plays a role in lowering weight, and decreasing metabolic syndrome, abdominal obesity and inflammation. However, it is still unknown whether MCT enhances exercise endurance. Here, we demonstrated that MCT containing diet improves high temperature induced exercise performance impairment. We found that MCT up-regulates the expression and protein levels of genes involved in mitochondrial biogenesis and metabolism. Further investigation demonstrated that the increased mitochondrial biogenesis and metabolism is mediated through the activation of Akt and AMPK signaling pathways and inhibition of TGF-β signaling pathway. Collectively, our findings indicate a beneficial effect of dietary MCT in exercise performance through the increase of mitochondrial biogenesis and metabolism.

Medium-chain triglyceride feeding in premature infants: effects on fat and nitrogen absorption.

PubMed

Tantibhedhyangkul, P; Hashim, S A

1975-03-01

The effect of medium-chain triglycerides (MCT) on the "physiological" steatorrhea of prematurity was studied in 34 infants with birthweights below 2,000 gm. The infants were divided into three groups and fed three formulas identical in nutrient content except for the type of fat, as follows: group 1 (control): corn oil, oleo, and coconut oil (39:41:20); group 2: MCT, corn oil, and coconut oil (40:40:20); group 3: MCT and corn oil (80:20). The infants fed MCT-containing formulas had striking diminution in stool volume and frequency. Their total fat absorption was significantly improved when compared with controls; nitrogen absorption was slightly but significantly improved in the 80% MCT group. The results also suggest that nitrogen sparing may be enhanced in premature infants fed MCT-containing formulas.

Targeting of MCT1 and PFKFB3 influences cell proliferation and apoptosis in bladder cancer by altering the tumor microenvironment.

PubMed

Hu, Ke Yao; Wang, De Gui; Liu, Peng Fei; Cao, Yan Wei; Wang, Yong Hua; Yang, Xue Cheng; Hu, Cheng Xia; Sun, Li Jiang; Niu, Hai Tao

2016-08-01

Phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) and monocarboxylate transporter 1 (MCT1) play important roles in tumor endothelial cells (ECs) and several biological processes. The present study was conducted to study the effects of PFKFB3 and MCT1 on cell proliferation and apoptosis in the tumor microenvironment by co-culture of HUVECs and T24, a bladder cancer (BC) cell line, using a microfluidic device. Immunofluorescence assay showed that HUVEC activity was significantly enhanced under co-culture with T24 cells, according to the stronger fluorescence intensity of CD31 and CD105 than that in the signal‑cultured cells. Quercetin treatment inhibited MCT1 expression but did not affect PFKFB3 expression. Knockdown of MCT1 or/and PFKFB3 increased the apoptosis rate of the HUVECs under single-culture and co-culture situations by staining with calcein and propidium iodide. Meanwhile, cell proliferation and lactic concentration were significantly decreased after the blocking of MCT1 or/and PFKFB3, as compared with that in the control group. No obvious differences in the effects on apoptosis, proliferation and lactic concentration were found between cells treated with quercetin and siMCT1. Thus, we concluded that the targeting of MCT1 and PFKFB3 regulated cell proliferation and apoptosis in BC cells by altering the tumor microenvironment, and quercetin exhibited a potential antitumor effect by targeting MCT1.

Mitochondrial and glycolytic metabolic compartmentalization in diffuse large B-cell lymphoma.

PubMed

Gooptu, Mahasweta; Whitaker-Menezes, Diana; Sprandio, John; Domingo-Vidal, Marina; Lin, Zhao; Uppal, Guldeep; Gong, Jerald; Fratamico, Roberto; Leiby, Benjamin; Dulau-Florea, Alina; Caro, Jaime; Martinez-Outschoorn, Ubaldo

2017-06-01

Metabolic heterogeneity between neoplastic cells and surrounding stroma has been described in several epithelial malignancies; however, the metabolic phenotypes of neoplastic lymphocytes and neighboring stroma in diffuse large B-cell lymphoma (DLBCL) is unknown. We investigated the metabolic phenotypes of human DLBCL tumors by using immunohistochemical markers of glycolytic and mitochondrial oxidative phosphorylation (OXPHOS) metabolism. The lactate importer MCT4 is a marker of glycolysis, whereas the lactate importer MCT1 and TOMM20 are markers of OXPHOS metabolism. Staining patterns were assessed in 33 DLBCL samples as well as 18 control samples (non-neoplastic lymph nodes). TOMM20 and MCT1 were highly expressed in neoplastic lymphocytes, indicating an OXPHOS phenotype, whereas non-neoplastic lymphocytes in the control samples did not express these markers. Stromal cells in DLBCL samples strongly expressed MCT4, displaying a glycolytic phenotype, a feature not seen in stromal elements of non-neoplastic lymphatic tissue. Furthermore, the differential expression of lactate exporters (MCT4) on tumor-associated stroma and lactate importers (MCT1) on neoplastic lymphocytes support the hypothesis that neoplastic cells are metabolically linked to the stroma likely via mutually beneficial reprogramming. MCT4 is a marker of tumor-associated stroma in neoplastic tissue. Our findings suggest that disruption of neoplastic-stromal cell metabolic heterogeneity including MCT1 and MCT4 blockade should be studied to determine if it could represent a novel treatment target in DLBCL. Copyright © 2017 Elsevier Inc. All rights reserved.

Butyric acid increases transepithelial transport of ferulic acid through upregulation of the monocarboxylate transporters SLC16A1 (MCT1) and SLC16A3 (MCT4).

PubMed

Ziegler, Kerstin; Kerimi, Asimina; Poquet, Laure; Williamson, Gary

2016-06-01

Ferulic acid is released by microbial hydrolysis in the colon, where butyric acid, a major by-product of fermentation, constitutes the main energy source for colonic enterocytes. We investigated how varying concentrations of this short chain fatty acid may influence the absorption of the phenolic acid. Chronic treatment of Caco-2 cells with butyric acid resulted in increased mRNA and protein abundance of the monocarboxylate transporters SLC16A1 (MCT1) and SLC16A3 (MCT4), previously proposed to facilitate ferulic acid absorption in addition to passive diffusion. Short term incubation with butyric acid only led to upregulation of MCT4 while both conditions increased transepithelial transport of ferulic acid in the apical to basolateral, but not basolateral to apical, direction. Chronic treatment also elevated intracellular concentrations of ferulic acid, which in turn gave rise to increased concentrations of ferulic acid metabolites. Immunofluorescence staining of cells revealed uniform distribution of MCT1 protein in the cell membrane, whereas MCT4 was only detected in the lateral plasma membrane sections of Caco-2 cells. We therefore propose that MCT1 may be acting as an uptake transporter and MCT4 as an efflux system across the basolateral membrane for ferulic acid, and that this process is stimulated by butyric acid. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Geometry of a large-scale, low-angle, midcrustal thrust (Woodroffe Thrust, central Australia)

NASA Astrophysics Data System (ADS)

Wex, S.; Mancktelow, N. S.; Hawemann, F.; Camacho, A.; Pennacchioni, G.

2017-11-01

The Musgrave Block in central Australia exposes numerous large-scale mylonitic shear zones developed during the intracontinental Petermann Orogeny around 560-520 Ma. The most prominent structure is the crustal-scale, over 600 km long, E-W trending Woodroffe Thrust, which is broadly undulate but generally dips shallowly to moderately to the south and shows an approximately top-to-north sense of movement. The estimated metamorphic conditions of mylonitization indicate a regional variation from predominantly midcrustal (circa 520-620°C and 0.8-1.1 GPa) to lower crustal ( 650°C and 1.0-1.3 GPa) levels in the direction of thrusting, which is also reflected in the distribution of preserved deformation microstructures. This variation in metamorphic conditions is consistent with a south dipping thrust plane but is only small, implying that a ≥60 km long N-S segment of the Woodroffe Thrust was originally shallowly dipping at an average estimated angle of ≤6°. The reconstructed geometry suggests that basement-cored, thick-skinned, midcrustal thrusts can be very shallowly dipping on a scale of many tens of kilometers in the direction of movement. Such a geometry would require the rocks along the thrust to be weak, but field observations (e.g., large volumes of syntectonic pseudotachylyte) argue for a strong behavior, at least transiently. Localization on a low-angle, near-planar structure that crosscuts lithological layers requires a weak precursor, such as a seismic rupture in the middle to lower crust. If this was a single event, the intracontinental earthquake must have been large, with the rupture extending laterally over hundreds of kilometers.

Application of MCT Failure Criterion using EFM

DTIC Science & Technology

2010-03-26

because HELIUS:MCT™ does not facilitate this. Attempts have been made to use ABAQUS native thermal expansion model combined in addition to Helius-MCT... ABAQUS using a user defined element subroutine EFM. Comparisons have been made between the analysis results using EFM-MCT code and HELIUS:MCT™ code...using the Element-Failure Method (EFM) in ABAQUS . The EFM-MCT has been implemented in ABAQUS using a user defined element subroutine EFM. Comparisons

Inhibition effect of flavonoids on monocarboxylate transporter 1 (MCT1) in Caco-2 cells.

PubMed

Shim, Chang-Koo; Cheon, Eun-Pa; Kang, Keon Wook; Seo, Ki-Soo; Han, Hyo-Kyung

2007-11-01

This study aimed to investigate the inhibition effect of flavonoids on monocarboxylate transporter 1 (MCT1) in Caco-2 cells. The cellular uptake of benzoic acid was examined in the presence and the absence of naringin, naringenin, morin, silybin and quercetin in Caco-2 cells. All the tested flavonoids except naringin significantly inhibited (P<0.05) the cellular uptake of [(14)C]-benzoic acid. Particularly, naringenin and silybin exhibited strong inhibition effects with IC50 values of 23.4 and 30.2 microM, respectively. Kinetic analysis indicated that the inhibition mode of naringenin and silybin on MCT1 activity was competitive with a Ki of 15-20 microM. The effect of flavonoids on the gene expression of MCT1 was also examined by using RT-PCR and western blot analysis. Results indicated that the expression level of MCT1 was not affected by the treatment with naringenin or silybin. The cellular accumulation of naringenin in Caco-2 cells was not changed in the presence of benzoic acid or L-lactic acid, implying that naringenin might not be a substrate of MCT1. In conclusion, some flavonoids appeared to be competitive inhibitors of MCT1, suggesting the potential for diet-drug interactions between flavonoids and MCT1 substrates.

Metacognitive therapy versus cognitive behavioural therapy for depression: a randomized pilot study.

PubMed

Jordan, Jennifer; Carter, Janet D; McIntosh, Virginia V W; Fernando, Kumari; Frampton, Christopher M A; Porter, Richard J; Mulder, Roger T; Lacey, Cameron; Joyce, Peter R

2014-10-01

Metacognitive therapy (MCT) is one of the newer developments within cognitive therapy. This randomized controlled pilot study compared independently applied MCT with cognitive behavioural therapy (CBT) in outpatients with depression to explore the relative speed and efficacy of MCT, ahead of a planned randomized controlled trial. A total of 48 participants referred for outpatient therapy were randomized to up to 12 weeks of MCT or CBT. Key outcomes were reduction in depressive symptoms at week 4 and week 12, measured using the independent-clinician-rated Quick Inventory of Depressive Symptomatology16. Intention-to-treat and completer analyses as well as additional methods of reporting outcome of depression are presented. Both therapies were effective in producing clinically significant change in depressive symptoms, with moderate-to-large effect sizes obtained. No differences were detected between therapies in overall outcome or early change on clinician-rated or self-reported measures. Post-hoc analyses suggest that MCT may have been adversely affected by greater comorbidity. In this large pilot study conducted independently of MCT's developers, MCT was an effective treatment for outpatients with depression, with similar results overall to CBT. Insufficient power and imbalanced comorbidity limit conclusions regarding comparative efficacy so further studies of MCT and CBT are required. © The Royal Australian and New Zealand College of Psychiatrists 2014.

Molecular dynamics simulation and TDDFT study of the structures and UV-vis absorption spectra of MCT-β-CD and its inclusion complexes.

PubMed

Lu, Huijuan; Wang, Yujiao; Xie, Xiaomei; Chen, Feifei; Li, Wei

2015-01-01

In this research, the inclusion ratios and inclusion constants of MCT-β-CD/PERM and MCT-β-CD/CYPERM inclusion complexes were measured by UV-vis and fluorescence spectroscopy. The inclusion ratios are both 1:1, and the inclusion constants are 60 and 342.5 for MCT-β-CD/PERM and MCT-β-CD/CYPERM, respectively. The stabilities of inclusion complexes were investigated by MD simulation. MD shows that VDW energy plays a vital role in the stability of inclusion complex, and the destruction of inclusion complex is due to the increasing temperature. The UV-vis absorption spectra of MCT-β-CD and its inclusion complexes were studied by time-dependent density functional theory (TDDFT) method employing BLYP-D3, B3LYP-D3 and M06-2X-D3 functionals. BLYP-D3 well reproduces the UV-vis absorption spectrum and reveals that the absorption bands of MCT-β-CD mainly arise from n→π(∗) and n→σ(∗) transition, and those of inclusion complexes mainly arise from intramolecular charge transfer (ICT). ICT results in the shift of main absorption bands of MCT-β-CD. Copyright © 2015 Elsevier B.V. All rights reserved.

Crustal Structure Beneath India and Tibet: New Constraints From Inversion of Receiver Functions

NASA Astrophysics Data System (ADS)

Singh, Arun; Ravi Kumar, M.; Mohanty, Debasis D.; Singh, Chandrani; Biswas, Rahul; Srinagesh, D.

2017-10-01

The Indian subcontinent comprises geological terranes of varied age and structural character. In this study, we provide new constraints to existing crustal models by inverting the P-to-s receiver functions (RFs) at 317 broadband seismic stations. Inversion results fill crucial gaps in existing velocity models (CRUST1.0 and SEAPS) by capturing regions which are less represented. The final model produced is much more heterogeneous and is able to capture the structural variations between closely spaced seismic stations. In comparison to the global models, major differences are seen for seismic stations located over various rift zones (e.g., Godavari, Narmada, and Cambay) and those close to the coastal regions where transition from oceanic to continental crust is expected to create drastic changes in the crustal configuration. Seismic images are produced along various profiles using 49,682 individual RFs recorded at 442 seismic stations. Lateral variations captured using migrated images across the Himalayan collisional front revealed the hitherto elusive southern extent of the Moho and intracrustal features south of the Main Central Thrust (MCT). Poisson's ratio and crustal thickness estimates obtained using H-k stacking technique and inversion of RFs are grossly similar lending credence to the robustness of inversions. An updated crustal thickness map produced using 1,525 individual data points from controlled source seismics and RFs reveals a (a) thickened crust (>55 km) at the boundary of Dharwar Craton and Southern Granulite Terrain, (b) clear difference in crustal thickness estimates between Eastern Dharwar Craton and Western Dharwar Craton, (c) thinner crust beneath Cambay Basin between southwest Deccan Volcanic Province and Delhi-Aravalli Fold Belt, (d) thinner crust (<35 km) beneath Bengal Basin, (e) thicker crust (>40 km) beneath paleorift zones like Narmada Son Lineament and Godavari Graben, and (f) very thick crust beneath central Tibet (>65 km) with maximum lateral variations along the Himalayan collision front.

Ketogenic Medium Chain Triglycerides Increase Brain Energy Metabolism in Alzheimer's Disease.

PubMed

Croteau, Etienne; Castellano, Christian-Alexandre; Richard, Marie Anne; Fortier, Mélanie; Nugent, Scott; Lepage, Martin; Duchesne, Simon; Whittingstall, Kevin; Turcotte, Éric E; Bocti, Christian; Fülöp, Tamàs; Cunnane, Stephen C

2018-06-09

In Alzheimer's disease (AD), it is unknown whether the brain can utilize additional ketones as fuel when they are derived from a medium chain triglyceride (MCT) supplement. To assess whether brain ketone uptake in AD increases in response to MCT as it would in young healthy adults. Mild-moderate AD patients sequentially consumed 30 g/d of two different MCT supplements, both for one month: a mixture of caprylic (55%) and capric acids (35%) (n = 11), followed by a wash-out and then tricaprylin (95%; n = 6). Brain ketone (11C-acetoacetate) and glucose (FDG) uptake were quantified by PET before and after each MCT intervention. Brain ketone consumption doubled on both types of MCT supplement. The slope of the relationship between plasma ketones and brain ketone uptake was the same as in healthy young adults. Both types of MCT increased total brain energy metabolism by increasing ketone supply without affecting brain glucose utilization. Ketones from MCT compensate for the brain glucose deficit in AD in direct proportion to the level of plasma ketones achieved.

Expression of a monocarboxylate transporter in reticular cells of the mouse lymph node and its involvement in the uptake of exogenous particles.

PubMed

Zheng, Miao; Ishiguro-Oonuma, Toshina; Iwanaga, Toshihiko

2014-01-01

The monocarboxylate transporter (MCT)-1 plays an important role in the transfer of monocarboxylate metabolites such as lactate, ketone bodies, and acetic acid. The present study revealed the selective localization of MCT1 in reticular cells of the murine lymph node. An intense MCT1 immunoreactivity was found in the reticular cells forming a cellular network together with sinus-lining cells in the medullary sinuses and in cells covering the inside of subcapsular sinuses.Electron-microscopically, MCT1 was localized along the plasma membrane of the reticular cells.The medullary reticular cells vigorously ingested carboxylate-modified latex particles, but any reticular cells within the cortical lymphoid follicles and medullary cords neither expressed MCT1 nor incorporated latex particles. MCT1-immunoreactive reticular cells also expressed LYVE-1,which is a hyaluronan receptor abundant in both the lymphatic endothelium and hepatic sinusoidal epithelium. The selective localization of MCT1 and LYVE-1 suggests a high level of activity for lymphoid reticular cells in the uptake of carboxylate-modified and hyaluronate waste substances circulating in the body.

Seismic images of a tectonic subdivision of the Greenville Orogen beneath lakes Ontario and Erie

USGS Publications Warehouse

Forsyth, D. A.; Milkereit, B.; Davidson, A.; Hanmer, S.; Hutchinson, Deborah R.; Hinze, W. J.; Mereu, R.F.

1994-01-01

New seismic data from marine air-gun and Vibroseis profiles in Lake Ontario and Lake Erie provide images of subhorizontal Phanerozoic sediments underlain by a remarkable series of easterly dipping reflections that extends from the crystalline basement to the lower crust. These reflections are interpreted as structural features of crustal-scale subdivisions within the Grenville Orogen. Broadly deformed, imbricated, and overlapping thrust sheets within the western Central Metasedimentary Belt are succeeded to the west by a complex zone of easterly dipping, apparent thrust faults that are interpreted as a southwest subsurface extension of the boundary zone between the Central Metasedimentary Belt and the Central Gneiss Belt. The interpreted Central Metasedimentary Belt boundary zone has a characteristic magnetic anomaly that provides a link from the adjacent ends of lakes Ontario and Erie to structures exposed 150 km to the north. Less reflective, west-dipping events are interpreted as structures within the eastern Central Gneiss Belt. The seismic interpretation augments current tectonic models that suggest the exposed ductile structures formed at depth as a result of crustal shortening along northwest-verging thrust faults. Relatively shallow reflections across the boundary region suggest local, Late Proterozoic extensional troughs containing post-Grenville sediments, preserved possibly as a result of pre-Paleozoic reactivation of basement structures.

Geomorphology and Kinematics of the Nobi-Ise Active Fault Zone, Central Japan: Implications for the kinematic growth of tectonic landforms within an active thrust belt

NASA Astrophysics Data System (ADS)

Ishiyama, T.; Mueller, K. J.; Togo, M.; Takemura, K.; Okada, A.

2002-12-01

We present structural models constrained by tectonic geomorphology, surface geologic mapping and high-resolution seismic reflection profiles to define the kinematic evolution and geometry of active fault-related folds along the Nobi-Ise active fault zone (NAFZ). The NAFZ is an active intraplate fault system in central Japan, and consists of a 110-km-long array of active, east-verging reverse faults. We focus on the northern half of the NAFZ, where we use the kinematic evolution of active fault-related folds to constrain rates of slip on underlying blind thrusts and the rate of contraction across the belt since early Quaternary time. Fluvial terraces folded across the east-dipping forelimb, and west-dipping backlimb of the frontal Kuwana anticline suggest that it grows above a stacked sequence of thin-skinned wedge thrusts. Numerous secondary, bedding-parallel thrusts also deform the terraces and are interpreted to form by flexural slip folding that acts to consume slip on the primary blind thrusts across synclinal axial surfaces. Late Holocene fold scarps formed in the floodplain of the Ibi River east of Kuwana anticline coincide with the projected surface trace of the east-vergent wedge thrust tip and indicate the structure has accommodated coseismic (?) kink-band migration of a fault-bend fold during a historic blind thrust earthquake in 1586. A topographic cross-section based on a detailed photogrammetric map suggests 111 m of uplift of ca. 50-80 ka fluvial terraces deposited across the forelimb. For a 35° thrust, this yields the minimum slip rate of 2.7-4.8 mm/yr on the deepest wedge thrust beneath Kuwana anticline. Kinematic analysis for the much larger thrust defined to the west (the Fumotomura fault) suggests that folding of fluvial terraces occurred by trishear fault-propagation folding above a more steeply-dipping (54°), basement-involved blind thrust that propagated upward from the base of the seismogenic crust (about 12 km). Pleistocene growth strata defined by tephra (ca. 1.6 Ma) suggest the Fumotomura fault slips at a rate of 0.7-0.9 mm/yr.

Blocking Lactate Export by Inhibiting the Myc Target MCT1 Disables Glycolysis and Glutathione Synthesis

PubMed Central

Doherty, Joanne R.; Yang, Chunying; Scott, Kristen E. N.; Cameron, Michael D.; Fallahi, Mohammad; Li, Weimin; Hall, Mark A.; Amelio, Antonio L.; Mishra, Jitendra K.; Li, Fangzheng; Tortosa, Mariola; Genau, Heide Marika; Rounbehler, Robert J.; Lu, Yunqi; Dang, Chi. V.; Kumar, K. Ganesh; Butler, Andrew A.; Bannister, Thomas D.; Hooper, Andrea T.; Unsal-Kacmaz, Keziban; Roush, William R.; Cleveland, John L.

2014-01-01

Myc oncoproteins induce genes driving aerobic glycolysis, including lactate dehydrogenase-A that generates lactate. Here we report that Myc controls transcription of the lactate transporter SLC16A1/MCT1, and that elevated MCT1 levels are manifest in premalignant and neoplastic Eμ-Myc transgenic B cells and in human malignancies with MYC or MYCN involvement. Notably, disrupting MCT1 function leads to an accumulation of intracellular lactate that rapidly disables tumor cell growth and glycolysis, provoking marked alterations in glycolytic intermediates, and reductions in glucose transport, and in levels of ATP, NADPH and glutathione. Reductions in glutathione then lead to increases in hydrogen peroxide, mitochondrial damage and, ultimately, cell death. Finally, forcing glycolysis by metformin treatment augments this response and the efficacy of MCT1 inhibitors, suggesting an attractive combination therapy for MYC/MCT1-expressing malignancies. PMID:24285728

Blocking lactate export by inhibiting the Myc target MCT1 Disables glycolysis and glutathione synthesis.

PubMed

Doherty, Joanne R; Yang, Chunying; Scott, Kristen E N; Cameron, Michael D; Fallahi, Mohammad; Li, Weimin; Hall, Mark A; Amelio, Antonio L; Mishra, Jitendra K; Li, Fangzheng; Tortosa, Mariola; Genau, Heide Marika; Rounbehler, Robert J; Lu, Yunqi; Dang, Chi V; Kumar, K Ganesh; Butler, Andrew A; Bannister, Thomas D; Hooper, Andrea T; Unsal-Kacmaz, Keziban; Roush, William R; Cleveland, John L

2014-02-01

Myc oncoproteins induce genes driving aerobic glycolysis, including lactate dehydrogenase-A that generates lactate. Here, we report that Myc controls transcription of the lactate transporter SLC16A1/MCT1 and that elevated MCT1 levels are manifest in premalignant and neoplastic Eμ-Myc transgenic B cells and in human malignancies with MYC or MYCN involvement. Notably, disrupting MCT1 function leads to an accumulation of intracellular lactate that rapidly disables tumor cell growth and glycolysis, provoking marked alterations in glycolytic intermediates, reductions in glucose transport, and in levels of ATP, NADPH, and ultimately, glutathione (GSH). Reductions in GSH then lead to increases in hydrogen peroxide, mitochondrial damage, and ultimately, cell death. Finally, forcing glycolysis by metformin treatment augments this response and the efficacy of MCT1 inhibitors, suggesting an attractive combination therapy for MYC/MCT1-expressing malignancies.

Effectiveness of Metacognitive Therapy in Patients with Social Anxiety Disorder: A Pilot Investigation.

PubMed

Lakshmi, Jayasree; Sudhir, Paulomi Matam; Sharma, Mahendra Prakash; Math, Suresh Bada

2016-01-01

Metacognitive therapy (MCT) is a recent psychological intervention for emotional disorders. Its efficacy in social anxiety disorder (SAD) is yet to be established. We examined the effectiveness of an MCT in patients with SAD. A two group case-control design with baseline, post, and 3 months follow-up was adopted. The control group received training in applied relaxation (AR). Four patients with Diagnostic and Statistical Manual-IV diagnosis of social anxiety were sequentially allotted to receive either MCT or AR. Patients were assessed on postevent processing (PEP), social anxiety, depression, and fear on negative evaluation. Clinical significance was calculated. MCT was more effective than AR in reducing social avoidance, PEP, and self-consciousness. While overall both interventions were effective in reducing social anxiety, MCT was marginally more effective. MCT may be a promising therapeutic approach in the management of SAD.

Medium Chain Triglycerides enhances exercise endurance through the increased mitochondrial biogenesis and metabolism

PubMed Central

Han, Yi; Xu, Jiping; Li, Zhaoshen

2018-01-01

Medium Chain Triglycerides (MCT) is a dietary supplement and usually used along with medications for treating food absorption disorders including diarrhea, steatorrhea and liver disease. It has been shown that MCT plays a role in lowering weight, and decreasing metabolic syndrome, abdominal obesity and inflammation. However, it is still unknown whether MCT enhances exercise endurance. Here, we demonstrated that MCT containing diet improves high temperature induced exercise performance impairment. We found that MCT up-regulates the expression and protein levels of genes involved in mitochondrial biogenesis and metabolism. Further investigation demonstrated that the increased mitochondrial biogenesis and metabolism is mediated through the activation of Akt and AMPK signaling pathways and inhibition of TGF-β signaling pathway. Collectively, our findings indicate a beneficial effect of dietary MCT in exercise performance through the increase of mitochondrial biogenesis and metabolism. PMID:29420554

Kinematic Modeling of Central Nepal: Thermochronometer Cooling Ages as a Constraint for Balanced Cross Sections

NASA Astrophysics Data System (ADS)

Olree, E.; Robinson, D. M.; McQuarrie, N.; Ghoshal, S.; Olsen, J.

2016-12-01

Using balanced cross sections, one can visualize a valid and admissible interpretation of the surface and subsurface data. Khanal (2014) and Cross (2014) produced two valid and admissible cross sections along the Marsyandi River in central Nepal. However, thermochronologic data adds another dimension that must be adhered to when producing valid and admissible balanced cross sections. Since the previous cross sections were produced, additional zircon-helium (ZHe) cooling ages along the Marsyandi River show ages of 1 Ma near the Main Central thrust in the hinterland to 4 Ma near the Main Boundary thrust closer to the foreland. This distribution of cooling ages requires recent uplift in the hinterland, which is not present in the cross sections. Although a restored version of the Khanal (2014) cross section is sequentially deformed using 2D Move, the kinematic sequence implied in the cross section is inconsistent with the ZHe age distribution. The hinterland dipping duplex proposed by Khanal would require cooling ages that are oldest near the Main Central thrust and young southwards toward the active ramp located 80 km north of the Main Frontal thrust. Instead, the 4 Ma age near the Main Boundary thrust and the increasingly younger ages to the north could be produced by either a foreland-dipping Lesser Himalayan duplex, which would keep active uplift in the north, or by translation of the hinterland dipping duplex southward over the ramp, moving the active thrust ramp northward. To address this problem, a new balanced cross section was produced using both new mapping through the region and the ZHe age distribution as additional constraints. The section was then restored and sequentially deformed in 2D Move. This study illustrates that multiple cross sections can be viable and admissible; however, they can still be incorrect. Thermochronology places additional constraints on the permissible geometries, and thus increases our ability to predict subsurface geometries. The next step of this project is to link the uplift and erosion implied by the kinematic sequence of the new cross section to the measured cooling history by importing the cross section kinematics into advection diffusion modeling software that predicts cooling ages.

Cancer metabolism, stemness and tumor recurrence

PubMed Central

Curry, Joseph M.; Tuluc, Madalina; Whitaker-Menezes, Diana; Ames, Julie A.; Anantharaman, Archana; Butera, Aileen; Leiby, Benjamin; Cognetti, David M.; Sotgia, Federica; Lisanti, Michael P.; Martinez-Outschoorn, Ubaldo E.

2013-01-01

Here, we interrogated head and neck cancer (HNSCC) specimens (n = 12) to examine if different metabolic compartments (oxidative vs. glycolytic) co-exist in human tumors. A large panel of well-established biomarkers was employed to determine the metabolic state of proliferative cancer cells. Interestingly, cell proliferation in cancer cells, as marked by Ki-67 immunostaining, was strictly correlated with oxidative mitochondrial metabolism (OXPHOS) and the uptake of mitochondrial fuels, as detected via MCT1 expression (p < 0.001). More specifically, three metabolic tumor compartments were delineated: (1) proliferative and mitochondrial-rich cancer cells (Ki-67+/TOMM20+/COX+/MCT1+); (2) non-proliferative and mitochondrial-poor cancer cells (Ki-67−/TOMM20−/COX−/MCT1−); and (3) non-proliferative and mitochondrial-poor stromal cells (Ki-67−/TOMM20−/COX−/MCT1−). In addition, high oxidative stress (MCT4+) was very specific for cancer tissues. Thus, we next evaluated the prognostic value of MCT4 in a second independent patient cohort (n = 40). Most importantly, oxidative stress (MCT4+) in non-proliferating epithelial cancer cells predicted poor clinical outcome (tumor recurrence; p < 0.0001; log-rank test), and was functionally associated with FDG-PET avidity (p < 0.04). Similarly, oxidative stress (MCT4+) in tumor stromal cells was specifically associated with higher tumor stage (p < 0.03), and was a highly specific marker for cancer-associated fibroblasts (p < 0.001). We propose that oxidative stress is a key hallmark of tumor tissues that drives high-energy metabolism in adjacent proliferating mitochondrial-rich cancer cells, via the paracrine transfer of mitochondrial fuels (such as L-lactate and ketone bodies). New antioxidants and MCT4 inhibitors should be developed to metabolically target “three-compartment tumor metabolism” in head and neck cancers. It is remarkable that two “non-proliferating” populations of cells (Ki-67−/MCT4+) within the tumor can actually determine clinical outcome, likely by providing high-energy mitochondrial “fuels” for proliferative cancer cells to burn. Finally, we also show that in normal mucosal tissue, the basal epithelial “stem cell” layer is hyper-proliferative (Ki-67+), mitochondrial-rich (TOMM20+/COX+) and is metabolically programmed to use mitochondrial fuels (MCT1+), such as ketone bodies and L-lactate. Thus, oxidative mitochondrial metabolism (OXPHOS) is a common feature of both (1) normal stem cells and (2) proliferating cancer cells. As such, we should consider metabolically treating cancer patients with mitochondrial inhibitors (such as Metformin), and/or with a combination of MCT1 and MCT4 inhibitors, to target “metabolic symbiosis.” PMID:23574725

Low-thrust orbit transfer optimization with refined Q-law and multi-objective genetic algorithm

NASA Technical Reports Server (NTRS)

Lee, Seungwon; Petropoulos, Anastassios E.; von Allmen, Paul

2005-01-01

An optimization method for low-thrust orbit transfers around a central body is developed using the Q-law and a multi-objective genetic algorithm. in the hybrid method, the Q-law generates candidate orbit transfers, and the multi-objective genetic algorithm optimizes the Q-law control parameters in order to simultaneously minimize both the consumed propellant mass and flight time of the orbit tranfer. This paper addresses the problem of finding optimal orbit transfers for low-thrust spacecraft.

Timing of the end of motion along the South Tibet Detachment shear zone. An important constraint on collision models.

NASA Astrophysics Data System (ADS)

Hervé Leloup, Philippe; Mahéo, Gweltaz; Arnaud, Nicolas; Kali, Elise; Boutonnet, Emmanuelle; Liu, Dunyi; Xiaohan, Liu; Haibing, Li

2010-05-01

The South Tibet detachment system (STDS) is a major normal fault system that runs parallel to the Himalayan range for more than 1500km, and that is fundamental to the major models proposed the belt tectonic evolution. The STDS is a fossil structure, as it has no clear morphological expression, is crosscut by perpendicular (N-S) active normal faults (Gurla Mandata, Thakhola, Ama Drime, Yadong), and no crustal earthquake indicative of ~N-S extension has ever been documented in the South Tibetan crust. It has long been proposed that the STDS and the MCT slips where coeval during the Miocene, however the timing of the STDS all along its length has rarely been investigated. Near Dinggye (~ 28°10'N, 87°40'E), the South Tibet Detachment, main branch of the STDS, dips ~10±5° to the North and separates Paleozoic Tethyan series from Upper Himalayan Crystalline Series (UHCS). Immediately below the STD, the UHCS is highly deformed in the STD shear zone, stretching lineations trend NNE and the shear senses are top to the NE. In micaschist, P-T path constrained by pseudosection and garnet chemistry, shows successive metamorphic conditions of ~0.6 GPa and ~550°C and 0.5 GPa and 625°C. U/Pb dating of Monazite and zircons in deformed and undeformed leucogranites suggest that ductile deformation lasted until at least ~16 Ma but ended prior to ~15Ma in the STD shear zone ~100 meters below the detachment. Ar/Ar micas ages in the footwall span between ~14.6 and 13.6 Ma, indicating rapid cooling down to ~320°C, and suggesting persistence of normal faulting, at that time. The STDS is cut and offset by the N-S trending Dinggye active normal fault which initiated prior to 11Ma thus providing a minimum bound for the end of STDS motion. These data are interpreted as reflecting 0.3 GPa (11km) to 0.6 GPa (22km) of exhumation along the STDS starting prior to ~16 Ma and ending between 13.6 and 11 Ma. On both side of the Ama Drime, analysis of structural and geochronological constraints available from the literature allows us to propose a time interval for the end shearing on the STDS in 11 other sections along the Himalayan arc. It appears that the STDS stopped first in the west, at ~17 Ma in Zanskar but only after 13Ma east of the Gurla Mandata. This timing difference could be related to interactions with the Karakorum fault zone that shows a strong bent at the level of the Gurla Mandata. The 1000 km long stretch of the STDS east of the Gurla Mandata probably stopped almost synchronously between 13 and 11 Ma ago. This generalized stop appears coeval to a sudden switch from NNE-SSW to E-W extension at the top of the accretionary prism, with jump of the major thrust from the lower Main Central Thrust (MCTl) to the Main the Boundary Thrust (MBT), and with change in India and Asia convergence direction. This synchronism is probably better explain in the frame of a thrust wedge or thrust system model than a lower channel flow model.

Regulation of Monocarboxylic Acid Transporter 1 Trafficking by the Canonical Wnt/β-Catenin Pathway in Rat Brain Endothelial Cells Requires Cross-talk with Notch Signaling*

PubMed Central

Sneve, Mary; Haroldson, Thomas A.; Smith, Jeffrey P.

2016-01-01

The transport of monocarboxylate fuels such as lactate, pyruvate, and ketone bodies across brain endothelial cells is mediated by monocarboxylic acid transporter 1 (MCT1). Although the canonical Wnt/β-catenin pathway is required for rodent blood-brain barrier development and for the expression of associated nutrient transporters, the role of this pathway in the regulation of brain endothelial MCT1 is unknown. Here we report expression of nine members of the frizzled receptor family by the RBE4 rat brain endothelial cell line. Furthermore, activation of the canonical Wnt/β-catenin pathway in RBE4 cells via nuclear β-catenin signaling with LiCl does not alter brain endothelial Mct1 mRNA but increases the amount of MCT1 transporter protein. Plasma membrane biotinylation studies and confocal microscopic examination of mCherry-tagged MCT1 indicate that increased transporter results from reduced MCT1 trafficking from the plasma membrane via the endosomal/lysosomal pathway and is facilitated by decreased MCT1 ubiquitination following LiCl treatment. Inhibition of the Notch pathway by the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester negated the up-regulation of MCT1 by LiCl, demonstrating a cross-talk between the canonical Wnt/β-catenin and Notch pathways. Our results are important because they show, for the first time, the regulation of MCT1 in cerebrovascular endothelial cells by the multifunctional canonical Wnt/β-catenin and Notch signaling pathways. PMID:26872974

Structural geology of western part of Lemhi Range, east-central Idaho

USGS Publications Warehouse

Tysdal, Russell G.

2002-01-01

The Poison Creek Anticline is a major fold that occupies a large part of the western part of the Lemhi Range. The fold is now broken by normal faults, but removal of displacement on the normal faults permitted reconstruction of the anticline. The fold formed during late Mesozoic compressional deformation in the hinterland of the Cordilleran thrust belt. It is in the hanging wall of the Poison Creek thrust fault, a major fault in east-central Idaho, that displaced Proterozoic strata over lower Paleozoic rocks.

Effects of Medium-Chain Triglycerides, Long-Chain Triglycerides, or 2-Monododecanoin on Fatty Acid Composition in the Portal Vein, Intestinal Lymph, and Systemic Circulation in Rats

PubMed Central

Nancy You, Yi-Qian; Ling, Pei-Ra; Qu, Jason Zhensheng; Bistrian, Bruce R.

2011-01-01

Background Fatty acid absorption patterns can have a major impact on the fatty acid composition in the portal, intestinal lymph, and systemic circulation. This study sought to determine the effects of long-chain triglycerides (LCT), medium-chain triglycerides (MCT), and 2-monododecanoin (2mono) on intestinal fatty acid composition during continuous feeding over a brief period. Methods The lipid sources were 100% LCT, 100% MCT, a 50:50 mixture of LCT and MCT (LCT/MCT), and a 50:50 mixture of LCT and 2mono (LCT/2mono). A total of 27 rats were randomly given 1 of the 4 diets at 200 kcal/kg/d, with 30% of total calories from lipids over 3 hours. Results MCT significantly increased each of the medium-chain fatty acids (C6:0, C8:0, and C10:0) as free fatty acids in the portal vein and about 10%/mol of C10:0 as triglycerides in the lymph compared with the other groups. There was significantly less C10:0 in lymphatic triglycerides with LCT/MCT than with MCT, but more than in the LCT and LCT/2mono diets. MCT also significantly increased the contents of C16:0, C18:0, C18:1, and C20:4 in the lymphatic triglycerides compared with all other groups including LCT/MCT. The amount of linoleic acid (C18:2) in lymphatic triglycerides followed the relative amounts of this fatty acid in the diet, with the greatest in LCT followed by LCT/MCT and LCT/2mono and least in MCT. A so-called structured lipid composed of the medium-chain fatty acid dodecanoic acid on the 2 position and long-chain fatty acids on the 1 and 3 positions appeared to be endogenously synthesized in response to the LCT/2mono diet. Conclusions The original differences in MCT and LCT content in the diets were preserved in the fatty acid composition in the intestinal free fatty acids and triglycerides during feeding. In addition, the duration of lipid administration can play a role in altering fatty acid composition in the intestine. PMID:18407910

The metabolic consequences of infusing emulsions containing medium chain triglycerides for parenteral nutrition: a comparative study with conventional lipid.

PubMed Central

Dennison, A. R.; Ball, M.; Crowe, P. J.; White, K.; Hands, L.; Watkins, R. M.; Kettlewell, M.

1986-01-01

In order to test the hypothesis that medium chain triglycerides (MCT's) are a safe and potentially superior energy source during parenteral nutrition 13 patients were entered into a randomised cross over trial. They received either a long chain triglyceride emulsion (LCT) or a 50% medium chain (MCT)/50% LCT mixture as part of their energy supply. Nitrogen balance was significantly better when MCT/LCT was infused and the greater levels of plasma ketones and lower plasma triglyceride levels suggested that MCT was more readily metabolised in these patients. Routine haematology, biochemistry and liver function tests gave no indication of harmful side effects from MCT. PMID:3089123

Characterization and snubbing of a bidirectional MCT in a resonant ac link converter

NASA Technical Reports Server (NTRS)

Lee, Tony; Elbuluk, Malik E.; Zinger, Donald S.

1993-01-01

The MOS-Controlled Thyristor (MCT) is emerging as a powerful switch that combines the better characteristics of existing power devices. A study of switching stresses on an MCT switch under zero voltage resonant switching is presented. The MCT is used as a bidirectional switch in an ac/ac pulse density modulated inverter for induction motor drive. Current and voltage spikes are observed and analyzed with variations in the timing of the switching. Different snubber circuit configurations are under investigation to minimize the effect of these transients. The results will be extended to study and test the MCT switching in a medium power (5 hp) induction motor drive.

Medium-chain triglyceride feeding in premature infants: effects on calcium and magnesium absorption.

PubMed

Tantibhedhyangkul, P; Hashim, S A

1978-04-01

The effect of medium-chain triglycerides (MCT) on the absorption of calcium and magnesium in premature infants was studied in 34 infants with birth weights lower than 2,000 gm. The infants were divided into three groups and fed three formulas similar in nutrient content except for the type of fat, as follows: group 1 (control): corn oil, oleo, and coconut oil (39:41:20); group 2: MCT, corn oil, and coconut oil (40:40:20); group 3: MCT and corn oil (80:20). The infants fed MCT-containing formulas absorbed significantly more calcium than the control group. Magnesium absorption was significantly increased in the 80% MCT group.

Monocarboxylate transporter 1 deficiency and ketone utilization.

PubMed

van Hasselt, Peter M; Ferdinandusse, Sacha; Monroe, Glen R; Ruiter, Jos P N; Turkenburg, Marjolein; Geerlings, Maartje J; Duran, Karen; Harakalova, Magdalena; van der Zwaag, Bert; Monavari, Ardeshir A; Okur, Ilyas; Sharrard, Mark J; Cleary, Maureen; O'Connell, Nuala; Walker, Valerie; Rubio-Gozalbo, M Estela; de Vries, Maaike C; Visser, Gepke; Houwen, Roderick H J; van der Smagt, Jasper J; Verhoeven-Duif, Nanda M; Wanders, Ronald J A; van Haaften, Gijs

2014-11-13

Ketoacidosis is a potentially lethal condition caused by the imbalance between hepatic production and extrahepatic utilization of ketone bodies. We performed exome sequencing in a patient with recurrent, severe ketoacidosis and identified a homozygous frameshift mutation in the gene encoding monocarboxylate transporter 1 (SLC16A1, also called MCT1). Genetic analysis in 96 patients suspected of having ketolytic defects yielded seven additional inactivating mutations in MCT1, both homozygous and heterozygous. Mutational status was found to be correlated with ketoacidosis severity, MCT1 protein levels, and transport capacity. Thus, MCT1 deficiency is a novel cause of profound ketoacidosis; the present work suggests that MCT1-mediated ketone-body transport is needed to maintain acid-base balance.

A Moho ramp imaged beneath the High Himalaya in Garhwal, India

NASA Astrophysics Data System (ADS)

Caldwell, W. B.; Klemperer, S. L.; Lawrence, J.; Rai, S. S.; Ashish, A.

2011-12-01

In this study we image the Moho beneath the Himalaya of Garhwal, India (at approximately 79°E) using common conversion point (CCP) stacking of receiver functions (RFs). We calculate RFs using iterative time-domain deconvolution on a catalog of 450 events recorded on a linear array of 21 broadband seismometers operated for 21 months in 2005-2006 by India's National Geophysical Research Institute (NGRI). Our images show a horizontal Moho beneath the Lesser Himalaya and an abrupt increase of ≥ 5 km in Moho depth beneath the High Himalaya, implying a local dip of 20±5°. A steeply-dipping Moho beneath the High Himalaya has been proposed by some workers on the basis of gravity modeling, and is observed in some seismic images elsewhere in the range, but is not a widely-recognized feature of the Himalaya. Geophysical profiles across the Himalaya are not numerous enough to say whether the steep Moho is a local feature only, or is widespread but has not yet been consistently observed. A steeply-dipping Moho implies a flexure in the downgoing India plate, which we propose may play a role in the formation of the topographic front of the Himalaya. Recent studies have proposed that a ramp in the Main Himalayan Thrust-the basal décollement into which the Himalayan thrust faults root-may focus rock uplift, leading to an abrupt steepening of topography and the observed physiographic transition between the Lesser and Higher Himalaya. The mechanism of rock uplift may be out-of-sequence thrusting on the MCT-I, or stacking of imbricate thrust sheets which form as a result of underplating at the ramp. A flexure of the India plate, implied by the steep Moho dip that we observe, is a likely mechanism for controlling the formation and location of this décollement ramp, and thereby the initiation of high topography. Geophysical profiles across the Himalaya are not yet numerous enough to constrain along-strike variations in this steeply-dipping Moho, so its relationship to the formation of the topographic front of the Himalaya throughout the rest of the range remains a topic for further study.

Immune activation by medium-chain triglyceride-containing lipid emulsions is not modulated by n-3 lipids or toll-like receptor 4.

PubMed

Olthof, Evelyn D; Gülich, Alexandra F; Renne, Mike F; Landman, Sija; Joosten, Leo A B; Roelofs, Hennie M J; Wanten, Geert J A

2015-10-01

Saturated medium-chain triglycerides (MCT) as part of the parenteral lipid regimen (50% MCT and 50% long chain triglycerides (LCT)) activate the immune system in vitro. Fish oil (FO)-derived n-3 fatty acids (FA) inhibit saturated FA-induced immune activation via a toll-like receptor (TLR)-4 mediated mechanism. We hypothesized that effects of parenteral MCTs on immune cells involve TLR-4 signaling and that these effects are modulated by n-3 FA that are present in FO. To test this hypothesis we assessed effects of addition of various commercially available mixed parenteral lipid emulsions, n-3 FA and of TLR-4 inhibition on MCT-induced human immune cell activation by evaluation of the expression of leukocyte membrane activation markers and reactive oxygen species (ROS) production. All MCT-containing lipid emulsions activated leukocytes by inducing changes in expression of membrane markers and stimulus induced ROS production, whereas MCT-free lipid emulsions lacked this effect. Moreover, addition of n-3 FA to LCT/MCT did not prevent MCT-induced immune activation. TLR-4 inhibitors did not distinctly modulate MCT-induced changes in immune function. Taken together, these findings suggest that leukocyte activation by parenteral MCTs does not involve TLR-4 signaling and is not modulated by n-3 FA in FO-, but is exerted via different signaling pathways. Copyright © 2015 Elsevier Ltd. All rights reserved.

MACC1 mediates chemotherapy sensitivity of 5-FU and cisplatin via regulating MCT1 expression in gastric cancer.

PubMed

Wang, Chunlin; Wen, Zhaowei; Xie, Jianming; Zhao, Yang; Zhao, Liang; Zhang, Shuyi; Liu, Yajing; Xue, Yan; Shi, Min

2017-04-08

Chemotherapeutic insensitivity is a main obstacle for effective treatment of gastric cancer (GC), the underlying mechanism remains to be investigated. Metastasis-associated in colon cancer-1 (MACC1), a transcription factor highly expressed in GC, is found to be related to chemotherapy sensitivity. Monocarboxylate transporter 1 (MCT1), a plasma membrane protein co-transporting lactate and H + , mediates drug sensitivity by regulating lactate metabolism. Targeting MCT1 has recently been regarded as a promising way to treat cancers and MCT1 inhibitor has entered the clinical trial for GC treatment. However, the correlation of these two genes and their combined effects on chemotherapy sensitivity has not been clarified. In this study, we found that MACC1 and MCT1 were both highly expressed in GC and exhibited a positive correlation in clinical samples. Further, we demonstrated that MACC1 could mediate sensitivity of 5-FU and cisplatin in GC cells, and MACC1 mediated MCT1 regulation was closely related to this sensitivity. A MCT1 inhibitor AZD3965 recovered the sensitivity of 5-FU and cisplatin in GC cells which overexpressed MACC1. These results suggested that MACC1 could influence the chemotherapy sensitivity by regulating MCT1 expression, providing new ideas and strategy for GC treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

Pre-clinical pharmacology of AZD3965, a selective inhibitor of MCT1: DLBCL, NHL and Burkitt’s lymphoma anti-tumor activity

PubMed Central

Curtis, Nicola J.; Mooney, Lorraine; Hopcroft, Lorna; Michopoulos, Filippos; Whalley, Nichola; Zhong, Haihong; Murray, Clare; Logie, Armelle; Revill, Mitchell; Byth, Kate F.; Benjamin, Amanda D.; Firth, Mike A.; Green, Stephen; Smith, Paul D.; Critchlow, Susan E.

2017-01-01

Tumors frequently display a glycolytic phenotype with increased flux through glycolysis and concomitant synthesis of lactate. To maintain glycolytic flux and prevent intracellular acidification, tumors efflux lactate via lactate transporters (MCT1-4). Inhibitors of lactate transport have the potential to inhibit glycolysis and tumor growth. We developed a small molecule inhibitor of MCT1 (AZD3965) and assessed its activity across a panel of cell lines. We explored its antitumor activity as monotherapy and in combination with doxorubicin or rituximab. AZD3965 is a potent inhibitor of MCT1 with activity against MCT2 but selectivity over MCT3 and MCT4. In vitro, AZD3965 inhibited the growth of a range of cell lines especially haematological cells. Inhibition of MCT1 by AZD3965 inhibited lactate efflux and resulted in accumulation of glycolytic intermediates. In vivo, AZD3965 caused lactate accumulation in the Raji Burkitt’s lymphoma model and significant tumor growth inhibition. Moreover, AZD3965 can be combined with doxorubicin or rituximab, components of the R-CHOP standard-of-care in DLBCL and Burkitt’s lymphoma. Finally, combining lactate transport inhibition by AZD3965 with GLS1 inhibition in vitro, enhanced cell growth inhibition and cell death compared to monotherapy treatment. The ability to combine AZD3965 with novel, and standard-of-care inhibitors offers novel combination opportunities in haematological cancers. PMID:29050199

Pre-clinical pharmacology of AZD3965, a selective inhibitor of MCT1: DLBCL, NHL and Burkitt's lymphoma anti-tumor activity.

PubMed

Curtis, Nicola J; Mooney, Lorraine; Hopcroft, Lorna; Michopoulos, Filippos; Whalley, Nichola; Zhong, Haihong; Murray, Clare; Logie, Armelle; Revill, Mitchell; Byth, Kate F; Benjamin, Amanda D; Firth, Mike A; Green, Stephen; Smith, Paul D; Critchlow, Susan E

2017-09-19

Tumors frequently display a glycolytic phenotype with increased flux through glycolysis and concomitant synthesis of lactate. To maintain glycolytic flux and prevent intracellular acidification, tumors efflux lactate via lactate transporters (MCT1-4). Inhibitors of lactate transport have the potential to inhibit glycolysis and tumor growth. We developed a small molecule inhibitor of MCT1 (AZD3965) and assessed its activity across a panel of cell lines. We explored its antitumor activity as monotherapy and in combination with doxorubicin or rituximab. AZD3965 is a potent inhibitor of MCT1 with activity against MCT2 but selectivity over MCT3 and MCT4. In vitro , AZD3965 inhibited the growth of a range of cell lines especially haematological cells. Inhibition of MCT1 by AZD3965 inhibited lactate efflux and resulted in accumulation of glycolytic intermediates. In vivo , AZD3965 caused lactate accumulation in the Raji Burkitt's lymphoma model and significant tumor growth inhibition. Moreover, AZD3965 can be combined with doxorubicin or rituximab, components of the R-CHOP standard-of-care in DLBCL and Burkitt's lymphoma. Finally, combining lactate transport inhibition by AZD3965 with GLS1 inhibition in vitro , enhanced cell growth inhibition and cell death compared to monotherapy treatment. The ability to combine AZD3965 with novel, and standard-of-care inhibitors offers novel combination opportunities in haematological cancers.

Comparison of diet-induced thermogenesis of foods containing medium- versus long-chain triacylglycerols.

PubMed

Kasai, Michio; Nosaka, Naohisa; Maki, Hideaki; Suzuki, Yoshie; Takeuchi, Hiroyuki; Aoyama, Toshiaki; Ohra, Atsushi; Harada, Youji; Okazaki, Mitsuko; Kondo, Kazuo

2002-12-01

The purpose of this study was to investigate the effect of 5-10 g of medium-chain triacylglycerols (MCT) on diet-induced thermogenesis in healthy humans. The study compared diet-induced thermogenesis after ingestion of test foods containing MCT and long-chain triacylglycerols (LCT), using a double-blind, crossover design. Eight male and eight female subjects participated in study 1 and study 2, respectively. In both studies, the LCT was a blend of rapeseed oil and soybean oil. In study 1, the liquid meals contained 10 g MCT (10M), a mixture of 5 g MCT and 5 g LCT (5M5L), and 10 g LCT (10L). In study 2, the subjects were given a meal (sandwich and clear soup) with the mayonnaise or margarine containing 5 g of MCT or LCT. Postprandial energy expenditure was measured by indirect calorimetry before and during the 6 h after ingestion of the test meals. Diet-induced thermogenesis was significantly greater after 5M5L and 10M Ingestion as compared to 10L ingestion. Ingestion of the mayonnaise or margarine containing 5 g MCT caused significantly larger diet-induced thermogenesis as compared to that of LCT. These results suggest that, in healthy humans, the intake of 5-10 g of MCT causes larger diet-induced thermogenesis than that of LCT, irrespective of the form of meal containing the MCT.

Cellular and physiological effects of medium-chain triglycerides.

PubMed

Wanten, Geert J; Naber, Anton H

2004-10-01

From a nutritional standpoint, saturated triglycerides with a medium (6 to 12) carbon chain length (MCT) have traditionally been regarded as biologically inert substances, merely serving as a source of fuel calories that is relatively easily accessible for metabolic breakdown compared with long chain triglycerides (LCT). This quality of MCT has been shown to offer both benefits and risks depending on the clinical situation, with potential positive effects on protein metabolism in some studies on one side, and an increased risk for ketogenesis and metabolic acidosis on the other. At another level, studies regarding lipid effects of MCT on the immune system, as with LCT, so far have yielded equivocal results, although there is a recent experimental evidence to suggest that MCT possess immune modulating properties and should in fact be regarded as bioactive mediators. Most of this information comes from studies where effects of MCT have been compared with those of LCT in lipid emulsions, as part of parenteral (intravenous) nutrition formulations. Unfortunately, the relevance of these observations for clinical practice remains largely unclear because adequately powered trials that clearly point out the position of MCT in relation to structurally different lipids have not been performed. In the present paper we review the experimental and clinical evidence for cellular and physiological effects of nutritional MCT. In addition, studies describing possible mechanisms behind the observed effects of MCT will be discussed.

Nuclear factor E2-related factor-2 has a differential impact on MCT1 and MCT4 lactate carrier expression in colonic epithelial cells: a condition favoring metabolic symbiosis between colorectal cancer and stromal cells.

PubMed

Diehl, K; Dinges, L-A; Helm, O; Ammar, N; Plundrich, D; Arlt, A; Röcken, C; Sebens, S; Schäfer, H

2018-01-04

Malignant tumors, such as colorectal cancer (CRC), are heterogeneous diseases characterized by distinct metabolic phenotypes. These include Warburg- and reverse Warburg phenotypes depending on differential distribution of the lactate carrier proteins monocarboxylate transporter-4 and -1 (MCT4 and MCT1). Here, we elucidated the role of the antioxidant transcription factor nuclear factor E2-related factor-2 (Nrf2) as the key regulator of cellular adaptation to inflammatory/environmental stress in shaping the metabolism toward a reverse Warburg phenotype in malignant and premalignant colonic epithelial cells. Immunohistochemistry of human CRC tissues revealed reciprocal expression of MCT1 and MCT4 in carcinoma and stroma cells, respectively, accompanied by strong epithelial Nrf2 activation. In colorectal tissue from inflammatory bowel disease patients, MCT1 and Nrf2 were coexpressed as well, relating to CD68+inflammatory infiltrates. Indirect coculture of human NCM460 colonocytes with M1- but not M2 macrophages induces MCT1 as well as G6PD, LDHB and TALDO expression, whereas MCT4 expression was decreased. Nrf2 knockdown or reactive oxygen species (ROS) scavenging blocked these coculture effects in NCM460 cells. Likewise, Nrf2 knockdown inhibited similar effects of tBHQ-mediated Nrf2 activation on NCM460 and HCT15 CRC cells. M1 coculture or Nrf2 activation/overexpression greatly altered the lactate uptake but not glucose uptake and mitochondrial activities in these cells, reflecting the reverse Warburg phenotype. Depending on MCT1-mediated lactate uptake, Nrf2 conferred protection from TRAIL-induced apoptosis in NCM460 and HCT15 cells. Moreover, metabolism-dependent clonal growth of HCT15 cells was induced by Nrf2-dependent activation of MCT1-driven lactate exchange. These findings indicate that Nrf2 has an impact on the metabolism already in premalignant colonic epithelial cells exposed to inflammatory M1 macrophages, an effect accompanied by growth and survival alterations. Favoring the reverse Warburg effect, these Nrf2-dependent alterations add to malignant transformation of the colonic epithelium.

Altered Behavioral Performance and Live Imaging of Circuit-Specific Neural Deficiencies in a Zebrafish Model for Psychomotor Retardation

PubMed Central

Lerer-Goldshtein, Tali; Vatine, Gad David; Appelbaum, Lior

2014-01-01

The mechanisms and treatment of psychomotor retardation, which includes motor and cognitive impairment, are indefinite. The Allan-Herndon-Dudley syndrome (AHDS) is an X-linked psychomotor retardation characterized by delayed development, severe intellectual disability, muscle hypotonia, and spastic paraplegia, in combination with disturbed thyroid hormone (TH) parameters. AHDS has been associated with mutations in the monocarboxylate transporter 8 (mct8/slc16a2) gene, which is a TH transporter. In order to determine the pathophysiological mechanisms of AHDS, MCT8 knockout mice were intensively studied. Although these mice faithfully replicated the abnormal serum TH levels, they failed to exhibit the neurological and behavioral symptoms of AHDS patients. Here, we generated an mct8 mutant (mct8−/−) zebrafish using zinc-finger nuclease (ZFN)-mediated targeted gene editing system. The elimination of MCT8 decreased the expression levels of TH receptors; however, it did not affect the expression of other TH-related genes. Similar to human patients, mct8−/− larvae exhibited neurological and behavioral deficiencies. High-throughput behavioral assays demonstrated that mct8−/− larvae exhibited reduced locomotor activity, altered response to external light and dark transitions and an increase in sleep time. These deficiencies in behavioral performance were associated with altered expression of myelin-related genes and neuron-specific deficiencies in circuit formation. Time-lapse imaging of single-axon arbors and synapses in live mct8−/− larvae revealed a reduction in filopodia dynamics and axon branching in sensory neurons and decreased synaptic density in motor neurons. These phenotypes enable assessment of the therapeutic potential of three TH analogs that can enter the cells in the absence of MCT8. The TH analogs restored the myelin and axon outgrowth deficiencies in mct8−/− larvae. These findings suggest a mechanism by which MCT8 regulates neural circuit assembly, ultimately mediating sensory and motor control of behavioral performance. We also propose that the administration of TH analogs early during embryo development can specifically reduce neurological damage in AHDS patients. PMID:25255244

Effects of group metacognitive training (MCT) on mental capacity and functioning in patients with psychosis in a secure forensic psychiatric hospital: a prospective-cohort waiting list controlled study.

PubMed

Naughton, Marie; Nulty, Andrea; Abidin, Zareena; Davoren, Mary; O'Dwyer, Sarah; Kennedy, Harry G

2012-06-18

Metacognitive Training (MCT) is a manualised cognitive intervention for psychosis aimed at transferring knowledge of cognitive biases and providing corrective experiences. The aim of MCT is to facilitate symptom reduction and protect against relapse. In a naturalistic audit of clinical effectiveness we examined what effect group MCT has on mental capacity, symptoms of psychosis and global function in patients with a psychotic illness, when compared with a waiting list comparison group. Of 93 patients detained in a forensic mental health hospital under both forensic and civil mental health legislation, 19 were assessed as suitable for MCT and 11 commenced. These were compared with 8 waiting list patients also deemed suitable for group MCT who did not receive it in the study timeframe. The PANSS, GAF, MacArthur Competence Assessment Tool- Treatment (MacCAT-T) and MacArthur Competence Assessment Tool-Fitness to Plead (MacCAT-FP) were recorded at baseline and repeated after group MCT or following treatment as usual in the waiting list group. When baseline functioning was accounted for, patients that attended MCT improved in capacity to consent to treatment as assessed by the MacCAT-T (p = 0.019). The more sessions attended, the greater the improvements in capacity to consent to treatment, mainly due to improvement in MacCAT-T understanding (p = 0.014) and reasoning . The GAF score improved in patients who attended the MCT group when compared to the waiting list group (p = 0.038) but there were no changes in PANSS scores. Measures of functional mental capacity and global function can be used as outcome measures for MCT. MCT can be used successfully even in psychotic patients detained in a forensic setting. The restoration of elements of decision making capacity such as understanding and reasoning may be a hither-to unrecognised advantage of such treatment. Because pharmacotherapy can be optimised and there is likely to be enough time to complete the course, there are clear opportunities to benefit from such treatment programmes in forensic settings.

Effects of group metacognitive training (MCT) on mental capacity and functioning in patients with psychosis in a secure forensic psychiatric hospital: a prospective-cohort waiting list controlled study

PubMed Central

2012-01-01

Background Metacognitive Training (MCT) is a manualised cognitive intervention for psychosis aimed at transferring knowledge of cognitive biases and providing corrective experiences. The aim of MCT is to facilitate symptom reduction and protect against relapse. In a naturalistic audit of clinical effectiveness we examined what effect group MCT has on mental capacity, symptoms of psychosis and global function in patients with a psychotic illness, when compared with a waiting list comparison group. Methods Of 93 patients detained in a forensic mental health hospital under both forensic and civil mental health legislation, 19 were assessed as suitable for MCT and 11 commenced. These were compared with 8 waiting list patients also deemed suitable for group MCT who did not receive it in the study timeframe. The PANSS, GAF, MacArthur Competence Assessment Tool- Treatment (MacCAT-T) and MacArthur Competence Assessment Tool-Fitness to Plead (MacCAT-FP) were recorded at baseline and repeated after group MCT or following treatment as usual in the waiting list group. Results When baseline functioning was accounted for, patients that attended MCT improved in capacity to consent to treatment as assessed by the MacCAT-T (p = 0.019). The more sessions attended, the greater the improvements in capacity to consent to treatment, mainly due to improvement in MacCAT-T understanding (p = 0.014) and reasoning . The GAF score improved in patients who attended the MCT group when compared to the waiting list group (p = 0.038) but there were no changes in PANSS scores. Conclusion Measures of functional mental capacity and global function can be used as outcome measures for MCT. MCT can be used successfully even in psychotic patients detained in a forensic setting. The restoration of elements of decision making capacity such as understanding and reasoning may be a hither-to unrecognised advantage of such treatment. Because pharmacotherapy can be optimised and there is likely to be enough time to complete the course, there are clear opportunities to benefit from such treatment programmes in forensic settings. PMID:22709616

Increased densities of monocarboxylate transporter MCT1 after chronic hyperglycemia in rat brain.

PubMed

Canis, Martin; Maurer, Martin H; Kuschinsky, Wolfgang; Duembgen, Lutz; Duelli, Roman

2009-02-27

The brain is capable of taking up monocarboxylates as energy substrates. Under physiological conditions, plasma levels of monocarboxylates are very low and glucose is the primary energy substrate in brain metabolism. However, given conditions such as hyperglycemia and ketosis, levels of circulating monocarboxylates such as lactate and pyruvate are elevated. Previous studies reported an increased expression of monocarboxylate transporter MCT1 in brain following ketotic diet. The major aim of the present study was to answer the question whether chronic hyperglycemia is likewise sufficient to change local densities of MCT1 in the brain. Moreover, chronic hyperglycemia increases local cerebral glucose utilization (LCGU) in particular brain areas. Glucose hereby enters the brain parenchyma via glucose transporters and is partially metabolised by astrocytes, which then release lactate to meet the energetic demands of surrounding neurons. Streptozotocin was given intravenously to induce chronic hyperglycemia and local densities of MCT1 were measured by immunoautoradiographic methods in cryosections of rat brains. The density of monocarboxylate transporter MCT1 was significantly increased in 10 of 24 brain structures investigated (median increase 11.7+/-3.4 %). Immunocytochemical stainings of these substructures revealed an expression of MCT1 within endothelial cells and astrocytes. A comparison of MCT1 densities with LCGU measured in a previous study under normo- and hyperglycemic conditions revealed a partial correlation between both parameters and under both conditions. Four out of 10 brain areas, which showed a significant increase in MCT1 density due to hyperglycemia, also showed a significant increase in LCGU. In summary, our data show that chronic hyperglycemia induces a moderate increase of local and global density of MCT1 in several brain structures. However, in terms of brain topologies and substructures this phenomenon did only partially match with increased LCGU. It is concluded that MCT1 transporters were up-regulated during chronic hyperglycemia at the level of brain substructures and independently of LCGU.

Lactobacillus acidophilus counteracts enteropathogenic E. coli-induced inhibition of butyrate uptake in intestinal epithelial cells

PubMed Central

Kumar, Anoop; Alrefai, Waddah A.; Dudeja, Pradeep K.

2015-01-01

Butyrate, a key short-chain fatty acid metabolite of colonic luminal bacterial action on dietary fiber, serves as a primary fuel for the colonocytes, ameliorates mucosal inflammation, and stimulates NaCl absorption. Absorption of butyrate into the colonocytes is essential for these intracellular effects. Monocarboxylate transporter 1 (MCT1) plays a major role in colonic luminal butyrate absorption. Previous studies (Tan J, McKenzie C, Potamitis M, Thorburn AN, Mackay CR, Macia L. Adv Immunol 121: 91–119, 2014.) showed decreased MCT1 expression and function in intestinal inflammation. We have previously shown (Borthakur A, Gill RK, Hodges K, Ramaswamy K, Hecht G, Dudeja PK. Am J Physiol Gastrointest Liver Physiol 290: G30–G35, 2006.) impaired butyrate absorption in human intestinal epithelial Caco-2 cells due to decreased MCT1 level at the apical cell surface following enteropathogenic E. coli (EPEC) infection. Current studies, therefore, examined the potential role of probiotic Lactobacilli in stimulating MCT1-mediated butyrate uptake and counteracting EPEC inhibition of MCT1 function. Of the five species of Lactobacilli, short-term (3 h) treatment with L. acidophilus (LA) significantly increased MCT1-mediated butyrate uptake in Caco-2 cells. Heat-killed LA was ineffective, whereas the conditioned culture supernatant of LA (LA-CS) was equally effective in stimulating MCT1 function, indicating that the effects are mediated by LA-secreted soluble factor(s). Furthermore, LA-CS increased apical membrane levels of MCT1 protein via decreasing its basal endocytosis, suggesting that LA-CS stimulation of butyrate uptake could be secondary to increased levels of MCT1 on the apical cell surface. LA-CS also attenuated EPEC inhibition of butyrate uptake and EPEC-mediated endocytosis of MCT1. Our studies highlight distinct role of specific LA-secreted molecules in modulating colonic butyrate absorption. PMID:26272259

Microcystin-LR detection in water by the Fabry-Pérot interferometer using an optical fibre coated with a sol-gel imprinted sensing membrane.

PubMed

Queirós, Raquel B; Silva, S O; Noronha, J P; Frazão, O; Jorge, P; Aguilar, G; Marques, P V S; Sales, M G F

2011-05-15

Cyanobacteria deteriorate the water quality and are responsible for emerging outbreaks and epidemics causing harmful diseases in Humans and animals because of their toxins. Microcystin-LR (MCT) is one of the most relevant cyanotoxin, being the most widely studied hepatotoxin. For safety purposes, the World Health Organization recommends a maximum value of 1 μg L(-1) of MCT in drinking water. Therefore, there is a great demand for remote and real-time sensing techniques to detect and quantify MCT. In this work a Fabry-Pérot sensing probe based on an optical fibre tip coated with a MCT selective thin film is presented. The membranes were developed by imprinting MCT in a sol-gel matrix that was applied over the tip of the fibre by dip coating. The imprinting effect was obtained by curing the sol-gel membrane, prepared with (3-aminopropyl) trimethoxysilane (APTMS), diphenyl-dimethoxysilane (DPDMS), tetraethoxysilane (TEOS), in the presence of MCT. The imprinting effect was tested by preparing a similar membrane without template. In general, the fibre Fabry-Pérot with a Molecular Imprinted Polymer (MIP) sensor showed low thermal effect, thus avoiding the need of temperature control in field applications. It presented a linear response to MCT concentration within 0.3-1.4 μg L(-1) with a sensitivity of -12.4±0.7 nm L μg(-1). The corresponding Non-Imprinted Polymer (NIP) displayed linear behaviour for the same MCT concentration range, but with much less sensitivity, of -5.9±0.2 nm L μg(-1). The method shows excellent selectivity for MCT against other species co-existing with the analyte in environmental waters. It was successfully applied to the determination of MCT in contaminated samples. The main advantages of the proposed optical sensor include high sensitivity and specificity, low-cost, robustness, easy preparation and preservation. Copyright © 2011 Elsevier B.V. All rights reserved.

Rhinoscintigraphic analysis of nasal mucociliary function in patients with Bell's palsy.

PubMed

Boynuegri, S; Ozer, S; Peksoy, I; Acikalin, A; Tuna, E Ü; Dursun, E; Eryilmaz, A

2016-01-01

Mucociliary transport (MCT) is an important defense mechanism of the respiratory tract. One of the major factors determining MCT is the ciliary activity of the respiratory epithelium. Rhinoscintigraphy is the most commonly used method for the analysis of mucociliary activity. The aim of this study was to investigate the effect of facial paralysis on the nasal mucociliary clearance. This study included 38 Bell's palsy patients as the study group and 10 subjects without any history of paranasal sinus disease or facial paralysis as the control group. A drop of technetium 99m-labeled macroaggregated albumin (Tc-99m MAA) was placed posterior to the head of the inferior turbinate and followed with a gamma camera. MCT rate was measured as the velocity of Tc-99m MAA drop. The mean MCT rate was 4.27 ± 0.76 millimeters per minute (mm/min) on 20 sides of 10 healthy controls, 4.11 ± 2.91 mm/min on the affected sides of the patients with Bell's palsy, and 6.03 ± 3.13 mm/min on the nonparalyzed sides of the patients. MCT rate was statistically significantly faster in the nonparalyzed side when compared to the paralyzed side in Bell's palsy patients (P = 0.001). MCT rates were not significantly different in the control group and paralyzed sides of the Bell's palsy patients (P = 0.810). The MCT rate was statistically significantly faster in the nonparalyzed sides of Bell's palsy patients when compared to the controls (P = 0.017). This study showed a faster MCT rate on the nonparalyzed side in Bell's palsy patients when compared to the paralyzed side and the control subjects. A compensatory mechanism could be the underlying reason for faster MCT on the nonparalyzed side. Further studies on larger patient groups are needed to investigate the effect of facial paralysis on the MCT and changes of facial nerve function on the opposite, nonparalyzed side of the face.

MCT1 inhibitor AZD3965 increases mitochondrial metabolism, facilitating combination therapy and non-invasive magnetic resonance spectroscopy

PubMed Central

Beloueche-Babari, Mounia; Wantuch, Slawomir; Casals Galobart, Teresa; Koniordou, Markella; Parkes, Harold G; Arunan, Vaitha; Chung, Yuen-Li; Eykyn, Thomas R; Smith, Paul D; Leach, Martin O

2017-01-01

Monocarboxylate transporters (MCT) modulate tumor cell metabolism and offer promising therapeutic targets for cancer treatment. Understanding the impact of MCT blockade on tumor cell metabolism may help develop combination strategies or identify pharmacodynamic biomarkers to support the clinical development of MCT inhibitors now in clinical trials. In this study, we assessed the impact of the MCT1 inhibitor AZD3965 on cancer cell metabolism in vitro and in vivo. Exposing human lymphoma and colon carcinoma cells to AZD3965 increased MCT4-dependent accumulation of intracellular lactate, inhibiting monocarboxylate influx and efflux. AZD3965 also increased the levels of TCA cycle-related metabolites and 13C-glucose mitochondrial metabolism, enhancing oxidative pyruvate dehydrogenase and anaplerotic pyruvate carboxylase fluxes. Increased mitochondrial metabolism was necessary to maintain cell survival under drug stress. These effects were counteracted by co-administration of the mitochondrial complex I inhibitor metformin and the mitochondrial pyruvate carrier inhibitor UK5099. Improved bioenergetics were confirmed in vivo after dosing with AZD3965 in mouse xenograft models of human lymphoma. Our results reveal new metabolic consequences of MCT1 inhibition that might be exploited for therapeutic and pharmacodynamic purposes. PMID:28923861

Optimal Low-Thrust Limited-Power Transfers between Arbitrary Elliptic Coplanar Orbits

NASA Technical Reports Server (NTRS)

daSilvaFernandes, Sandro; dasChagasCarvalho, Francisco

2007-01-01

In this work, a complete first order analytical solution, which includes the short periodic terms, for the problem of optimal low-thrust limited-power transfers between arbitrary elliptic coplanar orbits in a Newtonian central gravity field is obtained through Hamilton-Jacobi theory and a perturbation method based on Lie series.

MCT Detectors and ROICS for Various Format MWIR and LWIR Arrays

DTIC Science & Technology

2009-10-01

ABSTRACT Silicon ROICs for MCT LWIR (4x288, 6x576) and MWIR (128x128) diode matrix arrays were designed, manufactured and tested. MCT layers...of polysilicon and two metallization levels. MCT Detectors and ROICs for Various Format MWIR and LWIR Arrays RTO-MP-SET-151 7 - 1...Format MWIR and LWIR Arrays 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e. TASK NUMBER 5f

Expression of the hypoxia-inducible monocarboxylate transporter MCT4 is increased in triple negative breast cancer and correlates independently with clinical outcome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Doyen, J.; Trastour, C.; Ettore, F.

2014-08-15

Highlights: • Glycolytic markers are highly expressed in triple negative breast cancers. • Lactate/H{sup +} symporter MCT4 demonstrated the strongest deleterious impact on survival. • MCT4 should serve as a new prognostic factor in node-negative breast cancers. - Abstract: Background: {sup 18}Fluor-deoxy-glucose PET-scanning of glycolytic metabolism is being used for staging in many tumors however its impact on prognosis has never been studied in breast cancer. Methods: Glycolytic and hypoxic markers: glucose transporter (GLUT1), carbonic anhydrase IX (CAIX), monocarboxylate transporter 1 and 4 (MCT1, 4), MCT accessory protein basigin and lactate-dehydrogenase A (LDH-A) were assessed by immunohistochemistry in two cohortsmore » of breast cancer comprising 643 node-negative and 127 triple negative breast cancers (TNBC) respectively. Results: In the 643 node-negative breast tumor cohort with a median follow-up of 124 months, TNBC were the most glycolytic (≈70%), followed by Her-2 (≈50%) and RH-positive cancers (≈30%). Tumoral MCT4 staining (without stromal staining) was a strong independent prognostic factor for metastasis-free survival (HR = 0.47, P = 0.02) and overall-survival (HR = 0.38, P = 0.002). These results were confirmed in the independent cohort of 127 cancer patients. Conclusion: Glycolytic markers are expressed in all breast tumors with highest expression occurring in TNBC. MCT4, the hypoxia-inducible lactate/H{sup +} symporter demonstrated the strongest deleterious impact on survival. We propose that MCT4 serves as a new prognostic factor in node-negative breast cancer and can perhaps act soon as a theranostic factor considering the current pharmacological development of MCT4 inhibitors.« less

Sexual dimorphism of lipid metabolism in very long-chain acyl-CoA dehydrogenase deficient (VLCAD-/-) mice in response to medium-chain triglycerides (MCT).

PubMed

Tucci, Sara; Flögel, Ulrich; Spiekerkoetter, Ute

2015-07-01

Medium-chain triglycerides (MCT) are widely applied in the treatment of long-chain fatty acid oxidation disorders. Previously it was shown that long-term MCT supplementation strongly affects lipid metabolism in mice. We here investigate sex-specific effects in mice with very-long-chain-acyl-CoA dehydrogenase (VLCAD) deficiency in response to a long-term MCT modified diet. We quantified blood lipids, acylcarnitines, glucose, insulin and free fatty acids, as well as tissue triglycerides in the liver and skeletal muscle under a control and an MCT diet over 1 year. In addition, visceral and hepatic fat content and muscular intramyocellular lipids (IMCL) were assessed by in vivo(1)H magnetic resonance spectroscopy (MRS) techniques. The long-term application of an MCT diet induced a marked alteration of glucose homeostasis. However, only VLCAD-/- female mice developed a severe metabolic syndrome characterized by marked insulin resistance, dyslipidemia, severe hepatic and visceral steatosis, whereas VLCAD-/- males seemed to be protected and only presented with milder insulin resistance. Moreover, the highly saturated MCT diet is associated with a decreased hepatic stearoyl-CoA desaturase 1 (SCD1) activity in females aggravating the harmful effects of a saturated MCT diet. Long-term MCT supplementation deeply affects lipid metabolism in a sexual dimorphic manner resulting in a severe metabolic syndrome only in female mice. These findings are striking since the first signs of insulin resistance already occur in female VLCAD-/- mice during their reproductive period. How these metabolic adaptations are finally regulated needs to be determined. More important, the relevance of these findings for humans under these dietary modifications needs to be investigated. Copyright © 2015 Elsevier B.V. All rights reserved.

Autophagy promotes metastasis and glycolysis by upregulating MCT1 expression and Wnt/β-catenin signaling pathway activation in hepatocellular carcinoma cells.

PubMed

Fan, Qing; Yang, Liang; Zhang, Xiaodong; Ma, Yingbo; Li, Yan; Dong, Lei; Zong, Zhihong; Hua, Xiangdong; Su, Dongming; Li, Hangyu; Liu, Jingang

2018-01-19

Autophagy is a dynamic physiological process that can generate energy and nutrients for cell survival during stress. Autophagy can regulate the migration and invasive ability in cancer cells. However, the connection between autophagy and metabolism is unclear. Monocarboxylate transporter 1 (MCT1) plays an important role in lactic acid transport and H + clearance in cancer cells, and Wnt/β-catenin signaling can increase cancer cell glycolysis. We investigated whether autophagy promotes glycolysis in hepatocellular carcinoma (HCC) cells by activating the Wnt/β-catenin signaling pathway, accompanied by MCT1 upregulation. Autophagic activity was evaluated using western blotting, immunoblotting, and transmission electron microscopy. The underlying mechanisms of autophagy activation on HCC cell glycolysis were studied via western blotting, and Transwell, lactate, and glucose assays. MCT1 expression was detected using quantitative reverse transcription-PCR (real-time PCR), western blotting, and immunostaining of HCC tissues and the paired adjacent tissues. Autophagy promoted HCC cell glycolysis accompanied by MCT1 upregulation. Wnt/β-catenin signaling pathway activation mediated the effect of autophagy on HCC cell glycolysis. β-Catenin downregulation inhibited the autophagy-induced glycolysis in HCC cells, and reduced MCT1 expression in the HCC cells. MCT1 was highly expressed in HCC tissues, and high MCT1 expression correlated positively with the expression of microtubule-associated protein light chain 3 (LC3). Activation of autophagy can promote metastasis and glycolysis in HCC cells, and autophagy induces MCT1 expression by activating Wnt/β-catenin signaling. Our study describes the connection between autophagy and glucose metabolism in HCC cells and may provide a potential therapeutic target for HCC treatment.

Post-natal changes in MCT1 expression in the forestomach of calves.

PubMed

Pfannkuche, H; Taifour, F; Steinhoff-Wagner, J; Hammon, H M; Gäbel, G

2014-02-01

The monocarboxylate transporter 1 (MCT1) has been demonstrated to be involved in the transfer of short-chain fatty acids (SCFA) and/or their intraepithelial metabolites from the rumen to the blood. As MCT1 plays a role in SCFA transfer, it is assumed that SCFA are the main substrates influencing its expression. However, there are hints that MCT1 may also be expressed during the early life of the animal when SCFA are not released in the forestomach. To figure out whether MCT1 expression in the forestomach is influenced independently of SCFA during that period, we studied post-natal MCT1 expression immunohistochemically in the epithelia of omasum, atrium ruminis, saccus dorsalis ruminis, saccus ventralis ruminis and reticulum of calves born preterm and at term. The calves were nourished by colostrum or by milk-based formula diet. MCT1 could be found in all the forestomach compartments tested, even in preterm calves. The protein was mainly oriented to the luminal side in the immature epithelium 24 h after birth. Orientation to the blood side of the cells developed during the first 4 days after birth. In the rumen epithelia (but not in the other forestomach compartments tested), orientation of MCT1 to the blood side of the cells was paralleled by an increase in the overall expression rate during the first 4 days after birth. As lactate levels were very high directly after birth, a lactate-dependent substrate induction may have been the underlying mechanism. However, non-specific changes due to general differential processes might also be the cause. Both early upregulation of MCT1 and high blood lactate levels may provide the epithelia with lactate as energy source. © 2013 Blackwell Verlag GmbH.

Exercise-induced expression of monocarboxylate transporter 2 in the cerebellum and its contribution to motor performance.

PubMed

Hoshino, Daisuke; Setogawa, Susumu; Kitaoka, Yu; Masuda, Hiroyuki; Tamura, Yuki; Hatta, Hideo; Yanagihara, Dai

2016-10-28

Monocarboxylate transporter 2 (MCT2) is an important component of the lactate transport system in neurons of the adult brain. Purkinje cells in the cerebellum have been shown to have high levels of MCT2, suggesting that this protein has a key function in energy metabolism and neuronal activities in these cells. However, it is not known whether inhibition of lactate transport via MCT2 in the cerebellum affects motor performance. To address this question, we examined motor performance in mice following the inhibition of lactate transport via MCT2 in the cerebellum using α-cyano-4-hydroxycinnamate (4-CIN). 4-CIN or saline was injected into the subarachnoidal space of the cerebellum of mice and motor performance was analyzed by a rotarod test both before and after injection. 4-CIN injection reduced retention time in the rotarod test by approximately 80% at 1h post-injection compared with pre-injection. No effect was observed at 2h post-injection or in mice treated with the vehicle control. Because we observed that MCT2 plays an important role in motor performance, we next investigated the effects of acute exercise on MCT2 transcription and protein levels in mice sampled pre-exercise and at 0 and 5h after 2h of treadmill running. We found a significant increase in MCT2 mRNA levels, but not of protein levels, in the cerebellum at 5h after exercise. Our results indicate that lactate transport via MCT2 in the cerebellum may play an important role in motor performance and that exercise can increase MCT2 expression at the transcriptional level. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

State-of-the-art MCT photodiodes for cutting-edge sensor applications by AIM

NASA Astrophysics Data System (ADS)

Figgemeier, H.; Hanna, S.; Eich, D.; Fries, P.; Mahlein, K.-M.; Wenisch, J.; Schirmacher, W.; Beetz, J.; Breiter, R.

2017-02-01

For about 30 years, AIM has been ranking among the leading global suppliers for high-performance MCT infrared detectors, with its portfolio spanning the photosensitivity cut-off range from the SWIR to the VLWIR and from 1st generation to 3rd generation FPA devices. To meet the market demands for SWaP-C- and IR-detectors with additional functionalities such as multicolor detection, AIM employs both LPE and MBE technology. From AIḾs line of highest-performance single color detectors fabricated by LPE, we will present our latest excellent results of 5.3 μm cut-off MWIR MCT detectors with 1024x768 pixels and a 10 μm pixel pitch. AIM's powerful low dark current LWIR and VLWIR p-on-n device technology on LPE-grown MCT has now been extended to the MWIR spectral range. A comparison of results from n-on-p and p-on-n MWIR MCT planar photodiode arrays is presented. Operating temperatures of 160 K and higher, in conjunction with low defect density and excellent thermal sensitivity (NETD) are attained. The results achieved for LPE MWIR are compared to MBE MWIR data. For both the cost-efficient production of MWIR single color MCT detectors, as well as 3rd generation multicolor MCT detectors, AIM makes use of MBE growth of MCT on large-area GaAs substrates. The now-available AIM MWIR single color MBE MCT detectors grown on GaAs are qualified, delivered, and have reached a maturity fully meeting customers' requirements. Representing AIM's multicolor detector development, latest test results on a 640x512 pixels with a 20 μm pitch design will be presented. The MWIR/MWIR diodes demonstrate high QE, very low color cross talk, and excellent NETD in conjunction with low defect densities.

Humid Heat Autoclaving of Hybrid Nanoparticles Achieved by Decreased Nanoparticle Concentration and Improved Nanoparticle Stability Using Medium Chain Triglycerides as a Modifier.

PubMed

Gou, Jingxin; Chao, Yanhui; Liang, Yuheng; Zhang, Ning; He, Haibing; Yin, Tian; Zhang, Yu; Xu, Hui; Tang, Xing

2016-09-01

Humid heat autoclaving is a facile technique widely used in the sterilization of injections, but the high temperature employed would destroy nanoparticles composed of biodegradable polymers. The aim of this study was to investigate whether incorporation of medium chain triglycerides (MCT) could stabilize nanoparticles composed of poly (ethylene glycol)-b-polycaprolactone (PEG-b-PCL) during autoclaving (121°C, 10 min). Polymeric nanoparticles with different MCT contents were prepared by dialysis. Block copolymer degradation was studied by GPC. The critical aggregation concentrations of nanoparticles at different temperatures were determined using pyrene fluorescence. The size, morphology and weight averaged molecular weight of pristine/autoclaved nanoparticles were studied using DLS, TEM and SLS, respectively. Drug loading content and release profile were determined using RP-HPLC. The protecting effect of MCT on nanoparticles was dependent on the amount of MCT incorporated. Nanoparticles with high MCT contents, which assumed an emulsion-like morphology, showed reduced block copolymer degradation and particle disassociation after incubation at 100°C for 24 h. Nanoparticles with high MCT content showed the lowest critical aggregation concentration (CAC) under either room temperature or 60°C and the lowest particle concentration among all samples. And the particle size, drug loading content, physical stability and release profile of nanoparticles with high MCT contents remained nearly unchanged after autoclaving. Incorporation of high amount of MCT changed the morphology of PEG-b-PCL based nanoparticles to an emulsion-like structure and the nanoparticles prepared could withstand autoclaving due to improved particle stability and decreased particle concentration caused by MCT incorporation.

Influence of medium-chain triglycerides on lipid metabolism in the chick.

PubMed

Leveille, G A; Pardini, R S; Tillotson, J A

1967-11-01

The effect of corn oil, coconut oil, and medium-chain triglyceride (MCT, a glyceride mixture consisting almost exclusively of fatty acids of 8 and 10 carbons in length) ingestion on lipid metabolism was studied in chicks. In chicks fed cholesterol-free diets, MCT ingestion elevated plasma total lipids and cholesterol and depressed liver total lipids and cholesterol when compared to chicks receiving the corn oil diet. As a consequence of the opposite effects of MCT ingestion on plasma and liver cholesterol and total lipids, the plasma-liver cholesterol pool was not altered. When cholesterol was included in the diets, dietary MCT depressed liver and plasma total lipids and cholesterol as compared with corn oil, consequently also lowered the plasmaliver cholesterol pool.The in vitro cholesterol and fatty acid synthesis from acetate-1-(14)C was higher in liver slices from chicks fed MCT than in those from chicks fed corn oil. The percentage of radioactivity from acetate-1-(14)C incorporated into the carboxyl carbon of fatty acids by liver slices was not altered by MCT feeding, indicating that the increased acetate incorporation represented de novo fatty acid synthesis. The conversion of palmitate-1-(14)C to C(18) acids was increased in liver of chicks fed MCT, implying that fatty acid chain elongating activity was also increased. Studies on the conversion of stearate-2-(14)C to mono- and di-unsaturated C(18) acids showed that hepatic fatty acid desaturation activity was enhanced by MCT feeding. Data are presented on the plasma and liver fatty acid composition of chicks fed MCT-, corn oil-, or coconut oil-supplemented diets.

Differential regulation of monocarboxylate transporter 8 expression in thyroid cancer and hyperthyroidism.

PubMed

Badziong, Julia; Ting, Saskia; Synoracki, Sarah; Tiedje, Vera; Brix, Klaudia; Brabant, Georg; Moeller, Lars Christian; Schmid, Kurt Werner; Fuhrer, Dagmar; Zwanziger, Denise

2017-09-01

Thyroid hormone (TH) transporters are expressed in thyrocytes and most play a role in TH release. We asked whether expression of the monocarboxylate transporter 8 (MCT8) and the L-type amino acid transporters LAT2 and LAT4 is changed with thyrocyte dedifferentiation and in hyperfunctioning thyroid tissues. Protein expression and localization of transporters was determined by immunohistochemistry in human thyroid specimen including normal thyroid tissue (NT, n  = 19), follicular adenoma (FA, n  = 44), follicular thyroid carcinoma (FTC, n  = 45), papillary thyroid carcinoma (PTC, n  = 40), anaplastic thyroid carcinoma (ATC, n  = 40) and Graves' disease (GD, n  = 50) by calculating the 'hybrid' (H) score. Regulation of transporter expression was investigated in the rat follicular thyroid cell line PCCL3 under basal and thyroid stimulating hormone (TSH) conditions. MCT8 and LAT4 were localized at the plasma membrane, while LAT2 transporter showed cytoplasmic localization. MCT8 expression was downregulated in benign and malignant thyroid tumours as compared to NT. In contrast, significant upregulation of MCT8, LAT2 and LAT4 was found in GD. Furthermore, a stronger expression of MCT8 was demonstrated in PCCL3 cells after TSH stimulation. Downregulation of MCT8 in thyroid cancers qualifies MCT8 as a marker of thyroid differentiation. The more variable expression of LATs in distinct thyroid malignancies may be linked with other transporter properties relevant to altered metabolism in cancer cells, i.e. amino acid transport. Consistent upregulation of MCT8 in GD is in line with increased TH release in hyperthyroidism, an assumption supported by our in vitro results showing TSH-dependent upregulation of MCT8. © 2017 European Society of Endocrinology.

Rapid cellular enrichment of eicosapentaenoate after a single intravenous injection of a novel medium-chain triacylglycerol:fish-oil emulsion in humans123

PubMed Central

Carpentier, Yvon A; Hacquebard, Mirjam; Portois, Laurence; Dupont, Isabelle E; Deckelbaum, Richard J

2010-01-01

Background: Dietary deficiency in n−3 (omega-3) polyunsaturated fatty acids (PUFAs) prevails in Western populations and potentially results in adverse health outcomes. To circumvent the slow n−3 PUFA incorporation in phospholipids of key cells after oral supplementation, a new preparation for intravenous bolus injection was developed with 20 g triacylglycerols/100 mL of a mixture of 80% medium-chain triacylglycerols (MCTs) and 20% fish oil (FO) (wt:wt), and 0.4 g α-tocopherol/100 mL of the same mixture. Objective: Our objective was to document the enrichment of n−3 PUFAs in leukocyte and platelet phospholipids after a bolus intravenous injection of MCT:FO in men. Design: Twelve healthy male subjects received injections over a 5-min period of 50 mL of either MCT:FO or a control MCT:long-chain triacylglycerol (MCT:LCT) emulsion containing 20 g triacylglycerols/100 mL with equal amounts (wt:wt) of MCT and soybean triacylglycerols (LCT) and containing 0.02 g α-tocopherol/100 mL; after an 8-wk interval, the subjects received injections of the other preparation. Results: Clinical and biological variables that assessed tolerance and safety remained unchanged. Plasma elimination was faster for MCT:FO than for MCT:LCT (half-life: 24.5 ± 3.5 min compared with 32.9 ± 3.0 min; P < 0.025). This was associated with a greater increase in the plasma nonesterified fatty acid concentration. The content of n−3 PUFAs, specifically eicosapentaenoic acid (20:5n−3), increased in leukocyte and platelet phospholipids within 60 min and ≥24 h after MCT:FO injection. Conclusion: Bolus intravenous injection of a novel MCT:FO emulsion allows rapid enrichment of cells with n−3 PUFAs. PMID:20147473

Thrust Belt Architecture of the Central and Southern Western Foothills of Taiwan

NASA Astrophysics Data System (ADS)

Rodriguez, F.; Wiltschko, D.

2006-12-01

A structural model of the central and southern Western Foothills Fold and Thrust Belt (WFFTB) was constructed from serial balanced cross sections using available surface, drill, seismic and thermochronologic data. The WFFTB is composed of four main thrust sheets with minor splays. On the east, the Tulungwan fault, which separates the sedimentary rocks of the WFFTB from the low grade meta-sediments of the Slate Belt, evolves from a basement cored fold in the north (around 24°10' N) where the conformable contact between foothills sediments and meta-sediments from the Slate Belt on its western flank is present. At this point the tip of the fault is below the unconformity and the displacement amount is small. To the south this fault breaks the back limb of the fold and gains displacement, and continues gaining displacement to the south. The next thrust sheet to the west includes the Schuantung, Fenghuangchan, Luku, Tatou, Hopiya, and Pingchi faults. This fault system is interpreted as characterized by a long flat with small ramps along a Miocene detachment, not a series of imbricates, as it has been interpreted before. The next thrust sheet to the west is the Chulungupu-Chukou-Lunhou, this system appears to gain displacement to the south as the Schuantung fault system decreases in amount of displacement. The Chulungpu-Chukou-Lunhou fault system contains a wide monocline in the central foothills related with the Chulungpu fault and two wide synclines in the southern part, the Yuching and Tinpligling synclines. Modeling of these two last structures shows that both are uplifted with respect to the regional level above a wide and flat feature; the footwall of the Lunhou fault is a monocline. A geometric solution to lift the Lunhou system involves a major fault-bend-fold anticline with a long ramp and a detachment at ~13 km of depth. It explains, 1) the frontal monocline, which is the from limb of this fault-bend- fold, 2) the minor structures associated with minor back-thrusts and wedging, and 3) the uplift of the structures above the regional level over a wide anticlinal crest. The last thrust system toward the west shows a series of structures which closely associated with the Peikang high implying that the structures are either inversion structures or new thrust faults whose ramps are located in pre-existing normal faults.

A comparison of medium-chain and long-chain triglycerides in surgical patients.

PubMed Central

Jiang, Z M; Zhang, S Y; Wang, X R; Yang, N F; Zhu, Y; Wilmore, D

1993-01-01

Available lipid emulsions made from soybean or safflower oil are classified as long-chain triglycerides (LCT). In contrast, medium-chain triglyceride (MCT) emulsions have different physical properties and are metabolized by other biochemical pathways. To compare the differences between these two fat emulsions, the authors studied 12 surgical patients and 6 volunteers. These subjects were randomly assigned to receive parenteral nutrition with MCT or LCT emulsion. Measurement of arterial and venous concentration differences across the forearm demonstrated that muscle utilization was significantly improved with MCT administration. There was also a trend toward improved nitrogen balance in the MCT group, and less weight loss in the postoperative period also was observed in this group. During the fat clearance test, the serum ketone concentrations were significantly higher in the MCT than the LCT group. The improvement in nitrogen retention may be associated with increasing ketone and insulin levels. Fat emulsions containing 50% MCT are safe for use in parenteral nutrition and may provide an alternate fuel that improves protein metabolism. PMID:8439215

Intratumoural interleukin-2 therapy can induce regression of non-resectable mastocytoma in dogs.

PubMed

Ziekman, Paul G P M; Otter, Willem D E N; Tan, Jurgen F V; Teske, Erik; Kirpensteijn, Jolle; Koten, Jan-Willem; Jacobs, John J L

2013-01-01

Mast cell tumours (MCT) are common skin tumours in dogs. If complete surgical removal of the tumours is not possible, then another therapy is needed. In the current study we tested the therapeutic effect of intratumoural injection of interleukin-2 (IL-2). Seven dogs had non-resectable cutaneous MCT. The tumours were injected with 4.5×10(6) IU IL-2. The early clinical effects in the seven dogs with cutaneous MCT were: complete regression (CR) in two dogs; partial regression (PR) in four, and stable disease (SD) in one dog. The final clinical effects were CR in three dogs, PR in two dogs, and PD in two dogs. This pilot study shows that intratumoural IL-2 application can exert an anti-MCT effect. A larger study would be required to precisely establish the magnitude of the therapeutic effect against MCT. A single application of IL-2 in cases of non-resectable MCT has no observable side-effects.

GLUT1 and CAIX expression profiles in breast cancer correlate with adverse prognostic factors and MCT1 overexpression.

PubMed

Pinheiro, C; Sousa, B; Albergaria, A; Paredes, J; Dufloth, R; Vieira, D; Schmitt, F; Baltazar, F

2011-10-01

The goal of the present work was to evaluate the correlation of glucose transporter 1 (GLUT1) and carbonic anhydrase IX (CAIX) with the monocarboxylate transporters 1 (MCT1) and 4 (MCT4) and their chaperone, CD147, in breast cancer. The clinico-pathological value of GLUT1 and CAIX was also evaluated. For that, we analysed the immunohistochemical expression of GLUT1 and CAIX, in a large series of invasive breast carcinoma samples (n=124), previously characterized for MCT1, MCT4 and CD147 expression. GLUT1 expression was found in 46% of the cases (57/124), while CAIX was found in 18% of the cases (22/122). Importantly, both MCT1 and CD147, but not MCT4, were associated with GLUT1 and CAIX expression. Also, GLUT1 and CAIX correlated with each other. Concerning the clinico-pathological values, GLUT1 was associated with high grade tumours, basal-like subtype, absence of progesterone receptor, presence of vimentin and high proliferative index as measured by Ki-67. Additionally, CAIX was associated with large tumour size, high histological grade, basal-like subtype, absence of estrogen and progesterone receptors and presence of basal cytokeratins and vimentin expression. Finally, patients with CAIX positive tumours had a significantly shorter disease-free survival. The association between MCT1 and both GLUT1 and CAIX may result from hypoxia-mediated metabolic adaptations, which confer a glycolytic, acid-resistant and more aggressive phenotype to cancer cells.

Transport mechanism for lovastatin acid in bovine kidney NBL-1 cells: kinetic evidences imply involvement of monocarboxylate transporter 4.

PubMed

Nagasawa, Kazuki; Nagai, Katsuhito; Ishimoto, Atsushi; Fujimoto, Sadaki

2003-08-27

We previously indicated that lovastatin acid, a 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, was transported by a monocarboxylate transporter (MCT) in cultured rat mesangial cells. In this study, to identify the MCT isoform(s) responsible for the lovastatin acid uptake, the transport mechanism was investigated using bovine kidney NBL-1 cells, which have been reported to express only MCT4 at the protein level. On RT-PCR analysis, the message of mRNAs for MCT1 and MCT4 was detected in the NBL-1 cells used in this study, which was confirmed by kinetic analysis of [14C]L-lactic acid uptake, consisting of high- and low-affinity components corresponding to MCT1 and MCT4, respectively. The lovastatin acid uptake depended on an inwardly directed H+-gradient, and was inhibited by representative monocarboxylates, but not by inhibitors/substrates for organic anion transporting polypeptides and organic anion transporters. In addition, L-lactic acid competitively inhibited the uptake of lovastatin acid and lovastatin acid inhibited the low affinity component of [14C]L-lactic acid uptake dose dependently. The inhibition constant of L-lactic acid for lovastatin acid uptake was almost the same as the Michaelis constant for [14C]L-lactic acid uptake by the low-affinity component. These kinetic evidences imply that lovastatin acid was taken up into NBL-1 cells via MCT4.

Medium-chain, triglyceride-containing lipid emulsions increase human neutrophil beta2 integrin expression, adhesion, and degranulation.

PubMed

Wanten, G J; Geijtenbeek, T B; Raymakers, R A; van Kooyk, Y; Roos, D; Jansen, J B; Naber, A H

2000-01-01

To test the hypothesis that lipid emulsions with different triglyceride structures have distinct immunomodulatory properties, we analyzed human neutrophil adhesion and degranulation after lipid incubation. Neutrophils, isolated from the blood of 10 healthy volunteers, were incubated in medium or physiologic (2.5 mmol/L) emulsions containing long-chain (LCT), medium-chain (MCT), mixed LCT/MCT, or structured (SL) triglycerides. Expression of adhesion molecules and degranulation markers was evaluated by flow cytometry. Also, functional adhesion was investigated by means of a flow cytometric assay using fluorescent beads coated with the integrin ligand intercellular adhesion molecule (ICAM)-1. Although LCT and SL had no effect, LCT/MCT significantly increased expression of the beta2 integrins lymphocyte-function-associated antigen 1 (+18%), macrophage antigen 1 (+387%), p150,95 (+82%), and (alphaDbeta2 (+230%). Degranulation marker expression for azurophilic (CD63, +210%) and specific granules (CD66b, +370%) also significantly increased, whereas L-selectin (CD62L, -70%) decreased. The effects of LCT/MCT were mimicked by the MCT emulsion. ICAM-1 adhesion (% beads bound) was increased by LCT/MCT (34% +/- 4%), whereas LCT (19% +/-3%) and SL (20% +/- 2%) had no effect compared with medium (17% +/- 3%). LCT/MCT and MCT, contrary to LCT and SL emulsions, increased neutrophil beta2 integrin expression, adhesion, and degranulation. Apart from other emulsion constituents, triglyceride chain length might therefore be a key feature in the interaction of lipid emulsions and the phagocyte immune system.

Hodgkin lymphoma: A complex metabolic ecosystem with glycolytic reprogramming of the tumor microenvironment.

PubMed

Mikkilineni, Lekha; Whitaker-Menezes, Diana; Domingo-Vidal, Marina; Sprandio, John; Avena, Paola; Cotzia, Paolo; Dulau-Florea, Alina; Gong, Jerald; Uppal, Guldeep; Zhan, Tingting; Leiby, Benjamin; Lin, Zhao; Pro, Barbara; Sotgia, Federica; Lisanti, Michael P; Martinez-Outschoorn, Ubaldo

2017-06-01

Twenty percent of patients with classical Hodgkin Lymphoma (cHL) have aggressive disease defined as relapsed or refractory disease to initial therapy. At present we cannot identify these patients pre-treatment. The microenvironment is very important in cHL because non-cancer cells constitute the majority of the cells in these tumors. Non-cancer intra-tumoral cells, such as tumor-associated macrophages (TAMs) have been shown to promote tumor growth in cHL via crosstalk with the cancer cells. Metabolic heterogeneity is defined as high mitochondrial metabolism in some tumor cells and glycolysis in others. We hypothesized that there are metabolic differences between cancer cells and non-cancer tumor cells, such as TAMs and tumor-infiltrating lymphocytes in cHL and that greater metabolic differences between cancer cells and TAMs are associated with poor outcomes. A case-control study was conducted with 22 tissue samples of cHL at diagnosis from a single institution. The case samples were from 11 patients with aggressive cHL who had relapsed after standard treatment with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) or were refractory to this treatment. The control samples were from 11 patients with cHL who achieved a remission and never relapsed after ABVD. Reactive non-cancerous lymph nodes from four subjects served as additional controls. Samples were stained by immunohistochemistry for three metabolic markers: translocase of the outer mitochondrial membrane 20 (TOMM20), monocarboxylate transporter 1 (MCT1), and monocarboxylate transporter 4 (MCT4). TOMM20 is a marker of mitochondrial oxidative phosphorylation (OXPHOS) metabolism. Monocarboxylate transporter 1 (MCT1) is the main importer of lactate into cells and is a marker of OXPHOS. Monocarboxylate transporter 4 (MCT4) is the main lactate exporter out of cells and is a marker of glycolysis. The immunoreactivity for TOMM20, MCT1, and MCT4 was scored based on staining intensity and percentage of positive cells, as follows: 0 for no detectable staining in > 50% of cells; 1+ for faint to moderate staining in > 50% of cells, and 2+ for high or strong staining in > 50% of cells. TOMM20, MCT1, and MCT4 expression was significantly different in Hodgkin and Reed Sternberg (HRS) cells, which are the cancerous cells in cHL compared with TAMs and tumor-associated lymphocytes. HRS have high expression of TOMM20 and MCT1, while TAMs have absent expression of TOMM20 and MCT1 in all but two cases. Tumor-infiltrating lymphocytes have low TOMM20 expression and absent MCT1 expression. Conversely, high MCT4 expression was found in TAMs, but absent in HRS cells in all but one case. Tumor-infiltrating lymphocytes had absent MCT4 expression. Reactive lymph nodes in contrast to cHL tumors had low TOMM20, MCT1, and MCT4 expression in lymphocytes and macrophages. High TOMM20 and MCT1 expression in cancer cells with high MCT4 expression in TAMs is a signature of high metabolic heterogeneity between cancer cells and the tumor microenvironment. A high metabolic heterogeneity signature was associated with relapsed or refractory cHL with a hazard ratio of 5.87 (1.16-29.71; two-sided P < .05) compared with the low metabolic heterogeneity signature. Aggressive cHL exhibits features of metabolic heterogeneity with high mitochondrial metabolism in cancer cells and high glycolysis in TAMs, which is not seen in reactive lymph nodes. Future studies will need to confirm the value of these markers as prognostic and predictive biomarkers in clinical practice. Treatment intensity may be tailored in the future to the metabolic profile of the tumor microenvironment and drugs that target metabolic heterogeneity may be valuable in this disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Minimum Competency Testing (MCT). Some Remarks.

ERIC Educational Resources Information Center

Howell, John F.

The effort to institute minimum competency testing (MCT) is nearly universal despite the need to debate its basic definitions, implications, and consequences beforehand. There are seven distinct reasons for the MCT movement: (1) legislative zeal; (2) unfavorable allegations by local and national press; (3) economic accountability; (4) the…

Monocarboxylate transporters in the brain and in cancer.

PubMed

Pérez-Escuredo, Jhudit; Van Hée, Vincent F; Sboarina, Martina; Falces, Jorge; Payen, Valéry L; Pellerin, Luc; Sonveaux, Pierre

2016-10-01

Monocarboxylate transporters (MCTs) constitute a family of 14 members among which MCT1-4 facilitate the passive transport of monocarboxylates such as lactate, pyruvate and ketone bodies together with protons across cell membranes. Their anchorage and activity at the plasma membrane requires interaction with chaperon protein such as basigin/CD147 and embigin/gp70. MCT1-4 are expressed in different tissues where they play important roles in physiological and pathological processes. This review focuses on the brain and on cancer. In the brain, MCTs control the delivery of lactate, produced by astrocytes, to neurons, where it is used as an oxidative fuel. Consequently, MCT dysfunctions are associated with pathologies of the central nervous system encompassing neurodegeneration and cognitive defects, epilepsy and metabolic disorders. In tumors, MCTs control the exchange of lactate and other monocarboxylates between glycolytic and oxidative cancer cells, between stromal and cancer cells and between glycolytic cells and endothelial cells. Lactate is not only a metabolic waste for glycolytic cells and a metabolic fuel for oxidative cells, but it also behaves as a signaling agent that promotes angiogenesis and as an immunosuppressive metabolite. Because MCTs gate the activities of lactate, drugs targeting these transporters have been developed that could constitute new anticancer treatments. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Exploiting the co-reliance of tumours upon transport of amino acids and lactate: Gln and Tyr conjugates of MCT1 inhibitors.

PubMed

Nair, Reji N; Mishra, Jitendra K; Li, Fangzheng; Tortosa, Mariola; Yang, Chunying; Doherty, Joanne R; Cameron, Michael; Cleveland, John L; Roush, William R; Bannister, Thomas D

2016-05-01

Glutamine and tyrosine-based amino acid conjugates of monocarboxylate transporter types 1 and 2 inhibitors (MCT1/2) were designed, synthesized and evaluated for their potency in blocking the proliferation of a human B lymphoma cell line that expresses the transporters Asct2, LAT1 and MCT1. Appropriate placement of an amino acid transporter recognition element was shown to augment anti-tumour efficacy vs. Raji cells. Amino acid conjugation also improves the pharmacodynamic properties of experimental MCT1/2 inhibitors.

Effect of two medium chain triglycerides-supplemented diets on synaptic morphology in the cerebellar cortex of late-adult rats.

PubMed

Balietti, Marta; Fattoretti, Patrizia; Giorgetti, Belinda; Casoli, Tiziana; Di Stefano, Giuseppina; Platano, Daniela; Aicardi, Giorgio; Lattanzio, Fabrizia; Bertoni-Freddari, Carlo

2009-12-01

Ketogenic diets (KDs) have shown beneficial effects in experimental models of neurodegeneration, designating aged individuals as possible recipients. However, few studies have investigated their consequences on aging brain. Here, late-adult rats (19 months of age) were fed for 8 weeks with two medium chain triglycerides-supplemented diets (MCT-SDs) and the average area (S), numeric density (Nv(s)), and surface density (S(v)) of synapses, as well as the average volume (V), numeric density (Nv(m)), and volume density (V(v)) of synaptic mitochondria were evaluated in granule cell layer of the cerebellar cortex (GCL-CCx) by computer-assisted morphometric methods. MCT content was 10 or 20%. About 10%MCT-SD induced the early appearance of senescent patterns (decreased Nv(s) and Nv(m); increased V), whereas 20%MCT-SD caused no changes. Recently, we have shown that both MCT-SDs accelerate aging in the stratum moleculare of CA1 (SM CA1), but are "antiaging" in the outer molecular layer of dentate gyrus (OML DG). Since GCL-CCx is more vulnerable to age than OML DG but less than SM CA1, present and previous results suggest that the effects of MCT-SDs in the aging brain critically depend on neuronal vulnerability to age, besides MCT percentage.

MCT1 Inhibitor AZD3965 Increases Mitochondrial Metabolism, Facilitating Combination Therapy and Noninvasive Magnetic Resonance Spectroscopy.

PubMed

Beloueche-Babari, Mounia; Wantuch, Slawomir; Casals Galobart, Teresa; Koniordou, Markella; Parkes, Harold G; Arunan, Vaitha; Chung, Yuen-Li; Eykyn, Thomas R; Smith, Paul D; Leach, Martin O

2017-11-01

Monocarboxylate transporters (MCT) modulate tumor cell metabolism and offer promising therapeutic targets for cancer treatment. Understanding the impact of MCT blockade on tumor cell metabolism may help develop combination strategies or identify pharmacodynamic biomarkers to support the clinical development of MCT inhibitors now in clinical trials. In this study, we assessed the impact of the MCT1 inhibitor AZD3965 on cancer cell metabolism in vitro and in vivo Exposing human lymphoma and colon carcinoma cells to AZD3965 increased MCT4-dependent accumulation of intracellular lactate, inhibiting monocarboxylate influx and efflux. AZD3965 also increased the levels of TCA cycle-related metabolites and 13 C-glucose mitochondrial metabolism, enhancing oxidative pyruvate dehydrogenase and anaplerotic pyruvate carboxylase fluxes. Increased mitochondrial metabolism was necessary to maintain cell survival under drug stress. These effects were counteracted by coadministration of the mitochondrial complex I inhibitor metformin and the mitochondrial pyruvate carrier inhibitor UK5099. Improved bioenergetics were confirmed in vivo after dosing with AZD3965 in mouse xenograft models of human lymphoma. Our results reveal new metabolic consequences of MCT1 inhibition that might be exploited for therapeutic and pharmacodynamic purposes. Cancer Res; 77(21); 5913-24. ©2017 AACR . ©2017 American Association for Cancer Research.

Oncolytic Reovirus in Canine Mast Cell Tumor

PubMed Central

Hwang, Chung Chew; Umeki, Saori; Kubo, Masahito; Hayashi, Toshiharu; Shimoda, Hiroshi; Mochizuki, Masami; Maeda, Ken; Baba, Kenji; Hiraoka, Hiroko; Coffey, Matt; Okuda, Masaru; Mizuno, Takuya

2013-01-01

The usage of reovirus has reached phase II and III clinical trials in human cancers. However, this is the first study to report the oncolytic effects of reovirus in veterinary oncology, focusing on canine mast cell tumor (MCT), the most common cutaneous tumor in dogs. As human and canine cancers share many similarities, we hypothesized that the oncolytic effects of reovirus can be exploited in canine cancers. The objective of this study was to determine the oncolytic effects of reovirus in canine MCT in vitro, in vivo and ex vivo. We demonstrated that MCT cell lines were highly susceptible to reovirus as indicated by marked cell death, high production of progeny virus and virus replication. Reovirus induced apoptosis in the canine MCT cell lines with no correlation to their Ras activation status. In vivo studies were conducted using unilateral and bilateral subcutaneous MCT xenograft models with a single intratumoral reovirus treatment and apparent reduction of tumor mass was exhibited. Furthermore, cell death was induced by reovirus in primary canine MCT samples in vitro. However, canine and murine bone marrow-derived mast cells (BMCMC) were also susceptible to reovirus. The combination of these results supports the potential value of reovirus as a therapy in canine MCT but warrants further investigation on the determinants of reovirus susceptibility. PMID:24073198

Combined neurocognitive and metacognitive rehabilitation in schizophrenia: Effects on bias against disconfirmatory evidence.

PubMed

Buonocore, M; Bosia, M; Riccaboni, R; Bechi, M; Spangaro, M; Piantanida, M; Cocchi, F; Guglielmino, C; Bianchi, L; Smeraldi, E; Cavallaro, R

2015-07-01

A Metacognitive Training for Schizophrenia patients (MCT) was developed to target the cognitive biases that characterize the illness. Results suggest positive MCT effects encompassing several aspects of psychopathology and subjective well-being. There are still open questions concerning the effect on different cognitive biases and the interplay between them and both psychopathology and neurocognition. Specifically, the bias against disconfirmatory evidence (BADE) has never been tested in previous trials on MCT. In this study we evaluated the feasibility of MCT combined with a cognitive remediation therapy (CACR) in schizophrenia and its effect on BADE. Moreover, we investigated the relationships between BADE and both neuropsychology and psychopathology, taking into account mutual influences on the degree of improvement. Fifty-seven schizophrenia outpatients were randomly assigned to CACR + control group or MCT+CACR and assessed at baseline and after treatment for psychopathology, neurocognition and BADE. After MCT+CACR patients showed significantly greater improvements on BADE. Although BADE baseline performances correlated with several cognitive domains, no association was found between BADE improvement and neurocognitive nor psychopathological measures. This study enlightened for the first time the efficacy of MCT+CACR on BADE in schizophrenia, suggesting the importance to develop a more specific intervention tailored on individual needs of patients. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Capsaicin pre- and post-treatment on rat monocrotaline pneumotoxicity.

PubMed

Katzman, N J; Lai, Y L

2000-12-31

Monocrotaline (MCT) produces respiratory dysfunction, pulmonary hypertension (PH), and right ventricular hypertrophy (RVH) in rats. Tachykinins, such as substance P (SP) and neurokinin A (NKA), may mediate these effects. The purpose of this study was to investigate the length of tachykinin depletion (via capsaicin treatment) is needed to prevent (or attenuate) PH and/or RVH. Six groups of rats were injected subcutaneously with saline (3 ml/kg); capsaicin followed by saline or MCT (60 mg/kg); or MCT followed 7, 11, or 14 days later by capsaicin. Capsaicin (cumulative dose, 500 mg/kg) was given over a period of 4-5 days. Respiratory function, pulmonary vascular parameters, lung tachykinin levels, and tracheal neutral endopeptidase (NEP) activity were measured 21 days after MCT or saline injection. Capsaicin significantly decreased lung levels of SP but not NKA. Both capsaicin pretreatment and posttreatment blocked the following MCT-induced alterations: increases in lung SP and airway constriction; decreases in tracheal NEP activity and dynamic respiratory compliance. Administration of capsaicin before or 7 days after MCT blocked MCT-induced PH and RVH. The above data suggest that the early tachykinin-mediated airway dysfunction requires only transient elevated tachykinins, while progression of late tachykinin-mediated effects (PH and RVH) requires elevated tachykinins for more than one week.

Out-of-Sequence Thrust in the Higher Himalaya- a Review & Possible Genesis

NASA Astrophysics Data System (ADS)

Mukherjee, S.; Koyi, H. A.; Talbot, C. J.

2009-04-01

An out-of-sequence thrust (OOST) has been established inside the Higher Himalaya by previous workers more frequently from Nepal- and Bhutan Himalaya. The OOST lies between the South Tibetan Detachment System-Upper (STDSU) and the South Tibetan Detachment System-Lower (STDSL). The thrust has been recognized as the Kakhtang Thrust in Bhutan (Grujic et al., 2002 and references therein); Khumbu Thrust (Searle, 1999), Modi Khola Shear Zone (Hodges et al., 1996), Kalopani Shear Zone (Vannay and Hodges, 1999), Toijem Shear Zone in Nepal (Carosi et al., 2007), Chaura Thrust (Jain et al., 2000)- also designated as the Sarahan Thrust (Chambers et al., 2008) in the western Indian Himalaya in Sutlej section, Zimithang Thrust in the eastern Indian Himalaya (Yin et al., 2006), as ‘physiographic transition' in Marsyandi valley, Nepal (Burbank et al., 2003). We note that considering the upper strand of the Main Central Thrust (the MCTU) as the lower boundary of the Higher Himalaya, the physiographic transition has also been referred to lie in the Lesser Himalaya.The period of activity of the OOST was 22.5-18.5 Ma (Hodges et al., 1996), 14-10 Ma (Grujic et al., 2002), 4.9-1.5 Ma (Jain et al., 2000), and from Late Pliocene to even Holocene Period (Burbank, 2005). The out-of-sequence thrusting was followed after the initiation of channel flow at ~ 15 Ma in the Higher Himalaya with a maximum delay of ~ 13 Ma. However, in the Bhutan Himalaya, the thrusting continued along with the extensional ductile shearing in the STDSU at 11-10 Ma (Hollister and Grujic, 2006). The OOST in the Higher Himalaya lies inside the zone of the top-to-SW sense of ductile shearing. The OOST, at Kakhtang, Toijem, and Chaura are ductile shear zones with a top-to-SW sense of shearing. The OOST merges with the MCT and the Main Himalayan Thrust (MHT) at a depth of 30 km or more and either runs 200-300 km beneath the Tibetan plateau (Grujic et al., 2002; Hollister and Grujic, 2006). The hanging wall side of the OOST is more dominant with migmatites and leucogranites (Searle, 1999; Yin et al., 2006; Carosi et al., 2007; Grujic et al., 2002; Hollister and Grujic, 2006), but the footwall side does contain these rocks (Hodges et al., 1996; Chambers et al., 2008). The thickness of the OOST are 50 m (Carosi et al., 2007), >150 m (Yin et al., 2006), 3-6 km (Searle, 1999) and ~ 1.5 km (Vannay and Hodges, 1996). A number of hypotheses have been put forward to explain the genesis of the OOST. These are (i) a disparity in erosion rates triggered mainly by a spatial variation in the intensity of rainfall (Wobus et al., 2005). (ii) The lower boundary of the channel flow extrusion defined the OOST (Hollister and Grujic, 2006). (iii) As a result of a heterogeneous velocity profile of channel flow extrusion across lithologic discontinuity (Carosi et al., 2007). The granitic melt at depth in some way led to this thrusting (Swapp and Hollister, 1991). Had channel flow been the extrusion mechanism of the Higher Himalaya, the genesis of the OOST might somehow be related to this extrusion. In this work, a channel flow box was prepared and polydimethylsiloxane was used as the model material. A channel flow was generated in the horizontal channel and was allowed to extrude through an inclined channel similar to the Higher Himalaya (Mukherjee, 2007). In different considerations, the walls of the Higher Himalaya are parallel and diverging-up. A late formed blind thrust plane forms at the corner joining the inclined and the horizontal wall and crops to the surface much later to the initiation of channel flow. On the basis of its late arrival to the surface than the channel flow and its relative position in the model Higher Himalaya, the thrust is comparable with the OOST. This means that (i) climatic factors nor lithologic discontinuity were a trigger to the OOST; and (ii) the OOST is a delayed product of channel flow that initiated at a sub-horizontal channel below the Tibetan plateau and extrude the Higher Himalaya. References. Burbank, D.W., 2005. Cracking the Himalaya. Nature 434, 963-964. Burbank, D.W., Blythe, A.E., Putkonen, J., Pratt-Sitaula, B., Gabet, E., Oskin, M., Barros, A., Ojha, T.P., 2003. Decoupling of erosion and precipitation in the Himalayas. Nature 426, 652-654. Carosi, R., Montomili, C., Visonà, D., 2007. A structural transect in the lower Dolpo: insights in the tectonic evolution of Western Nepal. Journal of Asian Earth Sciences 29, 407-423. Chambers J.A., Argles, T.W., Horstwood, M.S.A., Harris, N.B.W., Parrish, R.R., Ahmad, T., 2008. Tectonic implications of Palaeoproterozoic anatexis and Late Miocene metamorphism in the Lesser Himalayan Sequence, Sutlej valley, NW India. Journal of the Geological Society, London 165, 725-737. Godin, L., Grujic, D., Law, R.D. and Searle, M.P., 2006. Channel flow, extrusion and extrusion in continental collision zones: an introduction. In: R.D. Law and M.P. Searle (Editors) Channel Flow, Extrusion and Extrusion in Continental Collision Zones. Geological Society of London Special Publication 268, 1-23. Grujic, D., Casey, M., Davidson, C., 1996. Ductile extrusion of the Higher Himalayan Crystalline in Bhutan: evidence from quartz microfabrics. Tectonophysics 260, 21-43. Grujic, D., Hollister, L.S., Parrish, R.R., 2002. Himalayan metamorphic sequence as an orogenic channel: insight from Bhutan. Earth Planetary Science Letters 198, 177-191. Harris, N., 2007. Channel flow and the Himalayan-Tibetan orogen: a critical review. Journal of Geological Society, London 164, 511-523. Hollister, L.S. and Grujic, D., 2006. Himalaya Tiber Plateau. Pulsed channel flow in Bhutan. In: R.D. Law, M.P. Searle and L. Godin (Editors). Channel flow, Ductile Extrusion and Extrusion in Continental Collision Zones. Geological Society of London Special Publication 268, pp. 415-423. Jain, A.K., Kumar, D., Singh, S., Kumar, A., Lal, N., 2000. Timing, quantification and tectonic modelling of Pliocene-Quaternary movements in the NW Himalaya: evidences from fission track dating. Earth Planetary Science Letters 179, 437-451. Mukherjee, S. 2007. Geodynamics, deformation and mathematical analysis of metamorphic belts of the NW Himalaya. Unpublished Ph.D. thesis. Indian Institute of Technology Roorkee. pp. 1-267. Searle, M.P., 1999. Extensional and compressional faults in the Everest-Lhotse massif, Khumbu Himalaya, Nepal. Journal of Geological Society, London, 156, 227-240. Swapp, S.M., Hollister, L.S., 1991. Inverted metamorphism within the Tibetan slab of Bhutan: evidence for a tectonically transported heat source. Canadian Mineralogist 29, 1019-1041. Vannay, J-C., Hodges, K.V., 1996. Tectonomorphic evolution of the Himalayan metamorphic core between the Annapurna and Dhaulagiri, central Nepal. Journal of Metamorphic Geology 14, 635-656. Wobus, C., Heimsath, A., Whipple, K., Hodges, K., 2005. Active out-of-sequence thrust faulting in the central Nepalese Himalaya. Nature 434, 1008-1011. Yin, A., Dubey, C.S., Kelty, T.K., Gehrels, G.E., Chou, C.Y., Grove, M., Lovera, O., 2006. Structural evolution of the Arunachal Himalaya and implications for asymmetric development Himalayan orogen. Current Science 90, 195-206.

Changing seasonality patterns in Central Europe from Miocene Climate Optimum to Miocene Climate Transition deduced from the Crassostrea isotope archive

NASA Astrophysics Data System (ADS)

Harzhauser, Mathias; Piller, Werner E.; Müllegger, Stefan; Grunert, Patrick; Micheels, Arne

2011-03-01

The Western Tethyan estuarine oyster Crassostrea gryphoides is an excellent climate archive due to its large size and rapid growth. It is geologically long lived and allows a stable isotope-based insight into climatic trends during the Miocene. Herein we utilised the climate archive of 5 oyster shells from the Miocene Climate Optimum (MCO) and the subsequent Miocene Climate Transition (MCT) to evaluate changes of seasonality patterns. MCO shells exhibit highly regular seasonal rhythms of warm-wet and dry-cool seasons. Optimal conditions resulted in extraordinary growth rates of the oysters. δ 13C profiles are in phase with δ 18O although phytoplankton blooms may cause a slight offset. Estuarine waters during the MCO in Central Europe display a seasonal temperature range of c. 9-10 °C. Absolute water temperatures have ranged from 17 to 19 °C during cool seasons and up to 28 °C in warm seasons. Already during the early phase of the MCO, the growth rates are distinctly declining, although gigantic and extremely old shells have been formed at that time. Still, a very regular and well expressed seasonality is dominating the isotope profiles, but episodically occurring extreme climate events influence the environments. The seasonal temperature range is still c. 9 °C but the cool season temperature seems to be slightly lower (16 °C) and the warm season water temperature does not exceed c. 25 °C. In the later MCT at c. 12.5-12.0 Ma the seasonality pattern is breaking down and is replaced by successions of dry years with irregular precipitation events. No correlation between δ 18O and δ 13C is documented maybe due to a suboptimal nutrition level which would explain the low growth rates and small sizes. The amplitude of seasonal temperature range is decreasing to 5-8 °C. No clear cooling trend can be postulated for that time as the winter season water temperatures range from 15 to 20 °C. This may point to unstable precipitation rhythms on a multi-annual to decadal scale as main difference between MCO and MCT climates in Central Europe instead of a simple temperature decline scenario.

Geometry of a large-scale low-angle mid-crustal thrust (Woodroffe Thrust, Central Australia)

NASA Astrophysics Data System (ADS)

Wex, Sebastian; Mancktelow, Neil S.; Hawemann, Friedrich; Pennacchioni, Giorgio; Camacho, Alfredo

2015-04-01

Young orogens, such as the Alps, mainly expose the upper part of the continental crust and it is not possible to follow large-scale thrusts (e.g. the Glarus Thrust) to great depth in order to study their changing rheological behavior. This knowledge, however, is crucial for determining the overall kinematic and dynamic response during collision, as middle to lower crustal rocks represent the major part of the total crustal section. Information from deeper parts of the continental crust can only be obtained directly by investigating regions where these levels are now exhumed. The Musgrave Ranges in Central Australia is a very well exposed, semi-desert area, in which numerous large-scale shear zones developed during the Petermann Orogeny around 550 Ma. The most prominent structure is the ˜400 km long E-W trending Woodroffe Thrust, which placed ˜1.2 Ga granulites onto similarly-aged amphibolite and granulite facies gneisses along a generally south-dipping thrust plane with a top-to-north shear sense. Geothermobarometric calculations on the associated mylonites established that the structure developed under mid-crustal conditions (500-650°C, 0.8-1 GPa). Regional P/T variations in the direction of thrusting are small, but show trends consistent with the south-dipping orientation of the thrust plane, which predicts deeper levels and a higher metamorphic grade in the south than in the north. They imply a very low gradient of only around 3°C/km for a distance of some 30 km in the movement direction of the thrust. Combined with a geothermal gradient on the order of 20°C/km, calculated from four separate P/T estimates from the hanging wall and footwall, this regional gradient indicates that the Woodroffe Thrust was originally shallow-dipping at an average angle of only around 9°. This suggests that upper crustal brittle thrusts do not necessarily steepen into the middle to lower crust, but can define very shallow-dipping, large-scale planar features, with dimensions in the order of hundreds of kilometres. Such a geometry would require the rocks to be weak, but field observations (e.g. large volumes of syn-tectonic pseudotachylyte) argue for strong behaviour, involving alternating fast (seismic) fracturing and slow (aseismic) creep.

Medium-chain triglyceride ameliorates insulin resistance and inflammation in high fat diet-induced obese mice.

PubMed

Geng, Shanshan; Zhu, Weiwei; Xie, Chunfeng; Li, Xiaoting; Wu, Jieshu; Liang, Zhaofeng; Xie, Wei; Zhu, Jianyun; Huang, Cong; Zhu, Mingming; Wu, Rui; Zhong, Caiyun

2016-04-01

The aim of the present study was to investigate the in vivo effects of dietary medium-chain triglyceride (MCT) on inflammation and insulin resistance as well as the underlying potential molecular mechanisms in high fat diet-induced obese mice. Male C57BL/6J mice (n = 24) were fed one of the following three diets for a period of 12 weeks: (1) a modified AIN-76 diet with 5 % corn oil (normal diet); (2) a high-fat control diet (17 % w/w lard and 3 % w/w corn oil, HFC); (3) an isocaloric high-fat diet supplemented with MCT (17 % w/w MCT and 3 % w/w corn oil, HF-MCT). Glucose metabolism was evaluated by fasting blood glucose levels and intraperitoneal glucose tolerance test. Insulin sensitivity was evaluated by fasting serum insulin levels and the index of homeostasis model assessment-insulin resistance. The levels of serum interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-α were measured by ELISA, and hepatic activation of nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways was determined using western blot analysis. Compared to HFC diet, consumption of HF-MCT did not induce body weight gain and white adipose tissue accumulation in mice. HFC-induced increases in serum fasting glucose and insulin levels as well as glucose intolerance were prevented by HF-MCT diet. Meanwhile, HF-MCT resulted in significantly lower serum IL-6 level and higher IL-10 level, and lower expression levels of inducible nitric oxide synthase and cyclooxygenase-2 protein in liver tissues when compared to HFC. In addition, HF-MCT attenuated HFC-triggered hepatic activation of NF-κB and p38 MAPK. Our study demonstrated that MCT was efficacious in suppressing body fat accumulation, insulin resistance, inflammatory response, and NF-κB and p38 MAPK activation in high fat diet-fed mice. These data suggest that MCT may exert beneficial effects against high fat diet-induced insulin resistance and inflammation.

Seafloor expressions of tectonic structures in Isfjorden, Svalbard: implications for fluid migration

NASA Astrophysics Data System (ADS)

Roy, Srikumar; Noormets, Riko; Braathen, Alvar

2014-05-01

This study investigates the seafloor expressions of Isfjorden in western Svalbard, interlinked with sub-seafloor structures using a dense grid of 2D multichannel marine seismic and magnetic data integrated with high resolution multibeam bathymetric data. The underlying bedrock structures spans from Paleozoic carbonates and evaporates to Mesozoic and Paleogene sandstones and shales. This 4 to 6 km thick succession is truncated by structures linked to Eocene transpressional deformation that resulted in the formation of the West Spitsbergen Fold-and-Thrust Belt (WSFTB). The WSFTB divides into three major belts : (a) western zone characterized by a basement involved fold-thrust complex, (b) central zone consisting of three thin-skinned fold-thrust sheets with thrusts splaying from décollement layers and, east of a frontal duplex system, (c) eastern zone showing décollement in Mesozoic shales with some thrust splays, and with the décollement interacting with reactivated, steep and basement-rooted faults (Bergh et al., 1997). In the continuation, we discuss combined seafloor and bedrock observations, starting from the west. In the west, a 6.5 km long and 5 to 9 m high ridge demarcates the eastern boundary of the major basement involved fold complex, with thrusted and folded competent Cretaceous to Paleogene units reaching the seafloor. Three submarine slides originate from this ridge, possibly triggered by tectonic activities. In Central Isfjorden (central zone of the WSFTB), several NNW-SSE striking ridges with a relief of 5 to 25 m have been tied with shallow, steep faults and folds. In addition to the NNW-SSE striking ridges, a set of SW-NE striking ridges with relief of 2 to 5 m are observed in Nordfjorden. Based on the seismic data observations, these ridges can be linked to the surface expression of competent sandstones that are transported on splay-thrusts above a décollement in Triassic shales. Further, seafloor ridges with relief of 5 of 18 m, linked to high amplitude flat reflectors and high magnetic values have been interpreted as Cretaceous dolerite intrusions in Nordfjorden and central Isfjorden. In the eastern Isfjorden (eastern zone of WSFTB), a 10.5 km long N-S striking ridge in Billefjorden corresponds to the deep-seated Billefjorden Fault Zone, extending south across the mouth of Tempelfjorden where it is 8.5 km long. This composite ridge is bound by a steep east-dipping fault, placing competent Carboniferous and Permian carbonates at the seafloor. Overall, our study shows a distinct pattern of pockmarks concentrated along the identified ridges on the seafloor of Isfjorden. These ridges can be linked to fault-fold systems and dolerite intrusions in the bedrock, thereby suggesting various possible fluid migration pathways towards pockmarks: (i) along fracture networks associated with folds and intrusions, (ii) along décollement zones and faults acting as localized conduits, and (iii) directly from organic rich layers when exposed at the seafloor. Reference: Bergh, S. G., Braathen, A., and Andresen, A., 1997, Interaction of basement-involved and thin-skinned tectonism in the Tertiary fold-thrust belt of central Spitsbergen, Svalbard: AAPG Bulletin, v. 81, no. 4, p. 637-661.

Hydrodynamic aspects of thrust generation in gymnotiform swimming

NASA Astrophysics Data System (ADS)

Shirgaonkar, Anup A.; Curet, Oscar M.; Patankar, Neelesh A.; Maciver, Malcolm A.

2008-11-01

The primary propulsor in gymnotiform swimmers is a fin running along most of the ventral midline of the fish. The fish propagates traveling waves along this ribbon fin to generate thrust. This unique mode of thrust generation gives these weakly electric fish great maneuverability cluttered spaces. To understand the mechanical basis of gymnotiform propulsion, we investigated the hydrodynamics of a model ribbon-fin of an adult black ghost knifefish using high-resolution numerical experiments. We found that the principal mechanism of thrust generation is a central jet imparting momentum to the fluid with associated vortex rings near the free edge of the fin. The high-fidelity simulations also reveal secondary vortex rings potentially useful in rapid sideways maneuvers. We obtained the scaling of thrust with respect to the traveling wave kinematic parameters. Using a fin-plate model for a fish, we also discuss improvements to Lighthill's inviscid theory for gymnotiform and balistiform modes in terms of thrust magnitude, viscous drag on the body, and momentum enhancement.

Simple control laws for low-thrust orbit transfers

NASA Technical Reports Server (NTRS)

Petropoulos, Anastassios E.

2003-01-01

Two methods are presented by which to determine both a thrust direction and when to apply thrust to effect specified changes in any of the orbit elements except for true anomaly, which is assumed free. The central body is assumed to be a point mass, and the initial and final orbits are assumed closed. Thrust, when on, is of a constant value, and specific impulse is constant. The thrust profiles derived from the two methods are not propellant-optimal, but are based firstly on the optimal thrust directions and location on the osculating orbit for changing each of the orbit elements and secondly on the desired changes in the orbit elements. Two examples of transfers are presented, one in semimajor axis and inclination, and one in semimajor axis and eccentricity. The latter compares favourably with a propellant-optimized transfer between the same orbits. The control laws have few input parameters, but can still capture the complexity of a wide variety of orbit transfers.

Enteral diets enriched with medium-chain triglycerides and N-3 fatty acids prevent chemically induced experimental colitis in rats.

PubMed

Kono, Hiroshi; Fujii, Hideki; Ogiku, Masahito; Tsuchiya, Masato; Ishii, Kenichi; Hara, Michio

2010-11-01

The specific purpose of this study was to evaluate the significant effects of medium-chain triglycerides (MCTs) and N-3 fatty acids on chemically induced experimental colitis induced by 2,4,6-trinitrobenzene sulphonic acid (TNBS) in rats. Male Wistar rats were fed liquid diets enriched with N-6 fatty acid (control diets), N-3 fatty acid (MCT- diets), and N-3 fatty acid and MCT (MCT+ diets) for 2 weeks and then were given an intracolonic injection of TNBS. Serum and tissue samples were collected 5 days after ethanol or TNBS enema. The severity of colitis was evaluated pathologically, and tissue myeloperoxidase activity was measured in colonic tissues. Furthermore, protein levels for inflammatory cytokines and a chemokine were assessed by an enzyme-linked immunosorbent assay in colonic tissues. Induction of proinflammatory cytokines tumor necrosis factor-α and interleukin-1β in the colon by TNBS enema was markedly attenuated by the MCT+ diet among the 3 diets studied. Furthermore, the induction of chemokines macrophage inflammatory protein-2 and monocyte chemotactic protein-1 also was blunted significantly in animals fed the MCT+ diets. As a result, MPO activities in the colonic tissue also were blunted significantly in animals fed the MCT+ diets compared with those fed the control diets or the MCT- diets. Furthermore, the MCT+ diet improved chemically induced colitis significantly among the 3 diets studied. Diets enriched with both MCTs and N-3 fatty acids may be effective for the therapy of inflammatory bowel disease as antiinflammatory immunomodulating nutrients. Copyright © 2010 Mosby, Inc. All rights reserved.

Non-invasive airway health measurement using synchrotron x-ray microscopy of high refractive index glass microbeads

DOE Office of Scientific and Technical Information (OSTI.GOV)

Donnelley, Martin, E-mail: martin.donnelley@adelaide.edu.au; Farrow, Nigel; Parsons, David

Cystic fibrosis (CF) is caused by a gene defect that compromises the ability of the mucociliary transit (MCT) system to clear the airways of debris and pathogens. To directly characterise airway health and the effects of treatments we have developed a synchrotron X-ray microscopy method that non-invasively measures the local rate and patterns of MCT behaviour. Although the nasal airways of CF mice exhibit the CF pathophysiology, there is evidence that nasal MCT is not altered in CF mice1. The aim of this experiment was to determine if our non-invasive local airway health assessment method could identify differences in nasalmore » MCT rate between normal and CF mice, information that is potentially lost in bulk MCT measurements. Experiments were performed on the BL20XU beamline at the SPring-8 Synchrotron in Japan. Mice were anaesthetized, a small quantity of micron-sized marker particles were delivered to the nose, and images of the nasal airways were acquired for 15 minutes. The nasal airways were treated with hypertonic saline or mannitol to increase surface hydration and MCT. Custom software was used to locate and track particles and calculate individual and bulk MCT rates. No statistically significant differences in MCT rate were found between normal and CF mouse nasal airways or between treatments. However, we hope that the improved sensitivity provided by this technique will accelerate the ability to identify useful CF lung disease-modifying interventions in small animal models, and enhance the development and efficacy of proposed new therapies.« less

Decreased expression of monocarboxylate transporter 1 and 4 in the branching airway epithelium of nitrofen-induced congenital diaphragmatic hernia.

PubMed

Takahashi, Toshiaki; Friedmacher, Florian; Zimmer, Julia; Puri, Prem

2016-06-01

Monocarboxylate transporters (MCTs) are crucial for the maintenance of intracellular pH homeostasis in developing fetal lungs. MCT1/4 is strongly expressed by epithelial airway cells throughout lung branching morphogenesis. Functional inhibition of MCT1/4 in fetal rat lung explants has been shown to result in airway defects similar to pulmonary hypoplasia (PH) in congenital diaphragmatic hernia (CDH). We hypothesized that pulmonary expression of MCT1/4 is decreased during lung branching morphogenesis in the nitrofen model of CDH-associated PH. Timed-pregnant rats received nitrofen or vehicle on gestational day 9 (D9). Fetuses were harvested on D15, D18, and D21, and divided into control and nitrofen-exposed group. Pulmonary gene expression levels of MCT1/4 were analyzed by qRT-PCR. Immunofluorescence staining for MCT1/4 was combined with E-cadherin in order to evaluate protein expression in branching airway tissue. Relative mRNA levels of MCT1/4 were significantly reduced in lungs of nitrofen-exposed fetuses on D15, D18, and D21 compared to controls. Confocal laser scanning microscopy confirmed markedly decreased immunofluorescence of MCT1/4 in distal bronchial and primitive alveolar epithelium of nitrofen-exposed fetuses on D15, D18, and D21 compared to controls. Decreased expression of MCT1/4 in distal airway epithelium may disrupt lung branching morphogenesis and thus contribute to the development of PH in the nitrofen-induced CDH model. Copyright © 2016 Elsevier Inc. All rights reserved.

Parenteral medium-chain triglyceride-induced neutrophil activation is not mediated by a Pertussis Toxin sensitive receptor.

PubMed

Versleijen, Michelle W J; van Esterik, Joantine C J; Roelofs, Hennie M J; van Emst-de Vries, Sjenet E; Willems, Peter H G M; Wanten, Geert J A

2009-02-01

Lipid-induced immune modulation might contribute to the increased infection rate that is observed in patients using parenteral nutrition. We previously showed that emulsions containing medium-chain triglycerides (LCT/MCTs or pure MCTs), but not pure long-chain triglycerides (LCTs), impair neutrophil functions, modulate cell-signaling and induce neutrophil activation in vitro. It has recently been shown that medium-chain fatty acids are ligands for GPR84, a pertussis toxin (PT)-sensitive G-protein-coupled receptor (GPCR). This finding urged us to investigate whether MCT-induced neutrophil activation is mediated by PT-sensitive GPCRs. Neutrophils isolated from blood of healthy volunteers were pre-incubated with PT (0.5-1 microg/mL, 1.5 h) and analyzed for the effect of this pre-incubation on LCT/MCT (2.5 mmol/L)-dependent modulation of serum-treated zymosan (STZ)-induced intracellular Ca(2+) mobilization and on LCT/MCT (5 mmol/L)-induced expression of cell surface adhesion (CD11b) and degranulation (CD66b) markers and oxygen radical (ROS) production. PT did not inhibit the effects of LCT/MCT on the STZ-induced increase in cytosolic free Ca(2+) concentration. LCT/MCT increased ROS production to 146% of unstimulated cells. However, pre-incubation with PT did not inhibit the LCT/MCT-induced ROS production. Furthermore, the LCT/MCT-induced increase in CD11b and CD66b expression (196% and 235% of unstimulated cells, respectively) was not inhibited by pre-incubation with PT. LCT/MCT-induced neutrophil activation does not involve the action of a PT-sensitive G-protein-coupled receptor.

Influence of medium-chain triglycerides on lipid metabolism in the rat.

PubMed

Leveille, G A; Pardini, R S; Tillotson, J A

1967-07-01

Lipid metabolism was studied in rats fed diets containing corn oil, coconut oil, or medium-chain triglyceride (MCT), a glyceride mixture containing fatty acids of 8 and 10 carbons in length. The ingestion of MCT-supplemented, cholesterolfree diets depressed plasma and liver total lipids and cholesterol as compared with corn oil-supplemented diets. In rats fed cholesterol-containing diets, plasma cholesterol levels were not influenced by dietary MCT, but liver cholesterol levels were significantly lower than in animals fed corn oil. In vitro cholesterol synthesis from acetate-1-(14)C was lower in liver slices of rats that consumed MCT than in similar preparations from corn oil-fed rats. Studies of fatty acid carboxyl labeling from acetate-1-(14)C and the conversion of palmitate-1-(14)C to C(18) acids by liver slices showed that chain-lengthening activity is greater in the liver tissue of rats fed MCT than in the liver of animals fed corn oil. The hepatic fatty acid desaturation mechanisms, evaluated by measuring the conversion of stearate-2-(14)C to oleate, was also enhanced by feeding MCT.Adipose tissue of rats fed MCT converts acetate-1-(14)C to fatty acids at a much faster rate than does tissue from animals fed corn oil. Evidence is presented to show that the enhanced incorporation of acetate into fatty acids by the adipose tissue of rats fed MCT represents de novo synthesis of fatty acids and not chain-lengthening activity. Data are also presented on the fatty acid composition of plasma, liver, and adipose tissue lipids of rats fed the different fats under study.

CD147 and MCT1-potential partners in bladder cancer aggressiveness and cisplatin resistance.

PubMed

Afonso, Julieta; Santos, Lúcio L; Miranda-Gonçalves, Vera; Morais, António; Amaro, Teresina; Longatto-Filho, Adhemar; Baltazar, Fátima

2015-11-01

The relapsing and progressive nature of bladder tumors, and the heterogeneity in the response to cisplatin-containing regimens, are the major concerns in the care of urothelial bladder carcinoma (UBC) patients. The metabolic adaptations that alter the tumor microenvironment and thus contribute to chemoresistance have been poorly explored in UBC setting. We found significant associations between the immunoexpressions of the microenvironment-related molecules CD147, monocarboxylate transporters (MCTs) 1 and 4, CD44 and CAIX in tumor tissue sections from 114 UBC patients. The presence of MCT1 and/or MCT4 expressions was significantly associated with unfavorable clinicopathological parameters. The incidence of CD147 positive staining significantly increased with advancing stage, grade and type of lesion, and occurrence of lymphovascular invasion. Similar associations were observed when considering the concurrent expression of CD147 and MCT1. This expression profile lowered significantly the 5-year disease-free and overall survival rates. Moreover, when selecting patients who received platinum-based chemotherapy, the prognosis was significantly worse for those with MCT1 and CD147 positive tumors. CD147 specific silencing by small interfering RNAs (siRNAs) in UBC cells was accompanied by a decrease in MCT1 and MCT4 expressions and, importantly, an increase in chemosensitivity to cisplatin. Our results provide novel insights for the involvement of CD147 and MCTs in bladder cancer progression and resistance to cisplatin-based chemotherapy. We consider that the possible cooperative role of CD147 and MCT1 in determining cisplatin resistance should be further explored as a potential theranostics biomarker. © 2014 Wiley Periodicals, Inc.

Loss of caveolin-1 and gain of MCT4 expression in the tumor stroma

PubMed Central

Martins, Diana; Beça, Francisco F; Sousa, Bárbara; Baltazar, Fátima; Paredes, Joana; Schmitt, Fernando

2013-01-01

The progression from in situ to invasive breast carcinoma is still an event poorly understood. However, it has been suggested that interactions between the neoplastic cells and the tumor microenvironment may play an important role in this process. Thus, the determination of differential tumor-stromal metabolic interactions could be an important step in invasiveness. The expression of stromal Caveolin-1 (Cav-1) has already been implicated in the progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC). Additionally, stromal Cav-1 expression has been associated with the expression of stromal monocarboxylate transporter 4 (MCT4) in invasive breast cancer. However, the role of stromal MCT4 in invasiveness has never been explored, neither the association between Cav-1 and MCT4 in the transition from breast DCIS to IDC. Therefore, our aim was to investigate in a series of breast cancer samples including matched in situ and invasive components, if there was a relationship between stromal Cav-1 and MCT4 in the progression from in situ to invasive carcinoma. We found loss of stromal Cav-1 in the progression to IDC in 75% of the cases. In contrast, MCT4 stromal expression was acquired in 87% of the IDCs. Interestingly, a concomitant loss of Cav-1 and gain of MCT4 was observed in the stroma of 75% of the cases, when matched in situ and invasive carcinomas were compared. These results suggest that alterations in Cav-1 and MCT4 may thus mark a critical point in the progression from in situ to invasive breast cancer. PMID:23907124

Non-invasive airway health measurement using synchrotron x-ray microscopy of high refractive index glass microbeads

NASA Astrophysics Data System (ADS)

Donnelley, Martin; Morgan, Kaye; Farrow, Nigel; Siu, Karen; Parsons, David

2016-01-01

Cystic fibrosis (CF) is caused by a gene defect that compromises the ability of the mucociliary transit (MCT) system to clear the airways of debris and pathogens. To directly characterise airway health and the effects of treatments we have developed a synchrotron X-ray microscopy method that non-invasively measures the local rate and patterns of MCT behaviour. Although the nasal airways of CF mice exhibit the CF pathophysiology, there is evidence that nasal MCT is not altered in CF mice1. The aim of this experiment was to determine if our non-invasive local airway health assessment method could identify differences in nasal MCT rate between normal and CF mice, information that is potentially lost in bulk MCT measurements. Experiments were performed on the BL20XU beamline at the SPring-8 Synchrotron in Japan. Mice were anaesthetized, a small quantity of micron-sized marker particles were delivered to the nose, and images of the nasal airways were acquired for 15 minutes. The nasal airways were treated with hypertonic saline or mannitol to increase surface hydration and MCT. Custom software was used to locate and track particles and calculate individual and bulk MCT rates. No statistically significant differences in MCT rate were found between normal and CF mouse nasal airways or between treatments. However, we hope that the improved sensitivity provided by this technique will accelerate the ability to identify useful CF lung disease-modifying interventions in small animal models, and enhance the development and efficacy of proposed new therapies.

Minimum Competency Testing: Guidelines for Policymakers and Citizens.

ERIC Educational Resources Information Center

Gray, Dennis

Intended to help the laity find their way through the confusion and controversy surrounding minimum competency testing (MCT), this paper explains what MCT is, acknowledges its limitations, weighs the criticisms, and shows how MCT may be used constructively for the benefit of students and for the improvement of schools. Highlights from the paper…

Thyroid Hormone Transporters MCT8 and OATP1C1 Control Skeletal Muscle Regeneration.

PubMed

Mayerl, Steffen; Schmidt, Manuel; Doycheva, Denica; Darras, Veerle M; Hüttner, Sören S; Boelen, Anita; Visser, Theo J; Kaether, Christoph; Heuer, Heike; von Maltzahn, Julia

2018-06-05

Thyroid hormone (TH) transporters are required for the transmembrane passage of TH in target cells. In humans, inactivating mutations in the TH transporter MCT8 cause the Allan-Herndon-Dudley syndrome, characterized by severe neuromuscular symptoms and an abnormal TH serum profile, which is fully replicated in Mct8 knockout mice and Mct8/Oatp1c1 double-knockout (M/O DKO) mice. Analysis of tissue TH content and expression of TH-regulated genes indicate a thyrotoxic state in Mct8-deficient skeletal muscles. Both TH transporters are upregulated in activated satellite cells (SCs). In M/O DKO mice, we observed a strongly reduced number of differentiated SCs, suggesting an impaired stem cell function. Moreover, M/O DKO mice and mice lacking both transporters exclusively in SCs showed impaired skeletal muscle regeneration. Our data provide solid evidence for a unique gate-keeper function of MCT8 and OATP1C1 in SC activation, underscoring the importance of a finely tuned TH signaling during myogenesis. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Micro-seismicity and seismotectonic study in Western Himalaya-Ladakh-Karakoram using local broadband seismic data

NASA Astrophysics Data System (ADS)

Kanna, Nagaraju; Gupta, Sandeep; Prakasam, K. S.

2018-02-01

We document the seismic activity and fault plane solutions (FPSs) in the Western Himalaya, Ladakh and Karakoram using data from 16 broadband seismographs operated during June 2002 to December 2003. We locate 206 earthquakes with a local magnitude in the range of 1.5 to 4.9 and calculate FPSs of 19 selected earthquakes based on moment tensor solutions. The earthquakes are distributed throughout the study region and indicate active tectonics in this region. The observed seismicity pattern is quite different than a well-defined pattern of seismicity, along the Main Central Thrust zone, in the eastern side of the study region (i.e., Kumaon-Garhwal Himalaya). In the Himalaya region, the earthquakes are distributed in the crust and upper mantle, whereas in the Ladakh-Karakoram area the earthquakes are mostly confined up to crustal depths. The fault plane solutions show a mixture of thrust, normal and strike-slip type mechanisms, which are well corroborated with the known faults/tectonics of the region. The normal fault earthquakes are observed along the Southern Tibet Detachment, Zanskar Shear Zone, Tso-Morari dome, and Kaurik-Chango fault; and suggest E-W extension tectonics in the Higher and Tethys Himalaya. The earthquakes of thrust mechanism with the left-lateral strike-slip component are seen along the Kistwar fault. The right-lateral strike-slip faulting with thrust component along the bending of the Main Boundary Thrust and Main Central Thrust shows the transpressional tectonics in this part of the Himalaya. The observed earthquakes with right-lateral strike-slip faulting indicate seismically active nature of the Karakoram fault.

Structural framework of a major intracontinental orogenic termination zone: The easternmost Tien Shan, China

USGS Publications Warehouse

Cunningham, D.; Owen, L.A.; Snee, L.W.; Li, Ji

2003-01-01

The Barkol Tagh and Karlik Tagh ranges of the easternmost Tien Shan are a natural laboratory for studying the fault architecture of an active termination zone of a major intracontinental mountain range. Barkol and Karlik Tagh and lesser ranges to the north are bounded by active thrust faults that locally deform Quaternary sediments. Major thrusts in Karlik Tagh connect along strike to the east with the left-lateral Gobi-Tien Shan Fault System in SW Mongolia. From a Mongolian perspective. Karlik Tagh represents a large restraining bend for this regional strike-slip fault system, and the entire system of thrusts and strike-slip faults in the Karlik Tagh region defines a horsetail splay fault geometry. Regionally, there appears to be a kinematic transition from thrust-dominated deformation in the central Tien Shan to left-lateral transpressional deformation in the easternmost Tien Shan. This transition correlates with a general eastward decrease in mountain belt width and average elevation and a change in the angular relationship between the NNE-directed maximum horizontal stress in the region and the pre-existing basement structural grain, which is northwesterly in the central Tien Shan (orthogonal to SHmax) but more east-west in the eastern Tien Shan (acute angular relationship with SHmax . Ar-Ar ages indicate that major range-bounding thrusts in Barkol and Karlik Tagh are latest Permian-Triassic ductile thrust zones that underwent brittle reactivation in the Late Cenozoic. It is estimated that the modern mountain ranges of the extreme easternmost Tien Shan could have been constructed by only 10-15 km of Late Cenozoic horizontal shortening.

Importance of nutritional status in recovery from acute cholecystitis: benefit from enteral nutrition supplementation including medium chain triglycerides.

PubMed

Nomura, Yukinobu; Inui, Kazuo; Yoshino, Junji; Wakabayashi, Takao; Okushima, Kazumu; Kobayashi, Takashi; Miyoshi, Hironao; Nakamura, Yuta

2007-09-01

This study was undertaken to clarify the importance of nutritional status in patients with acute cholecystitis, and also evaluate whether they benefited from enteral nutrition supplementation, including medium-chain triglycerides (MCT), during the convalescent stage. Patients with acute cholecystitis admitted to our hospital between April 1994 and March 2002 were classified into a poor nutrition group (n=40; total serum protein<5.0 g/dl) or a fair nutrition group (n=71; >5.0 g/dl). Patients with poor nutrition were significantly more elderly than those with fair nutrition, and had significantly higher serum C-reactive protein (CRP) concentrations. The two groups did not differ significantly with respect to other laboratory data, gender distribution, or medical treatment. We supplemented ordinary meals with enteral nutrition including MCT in 16 patients during the convalescent stage (MCT group). We compared their length of hospital stay and days required to recovery to pre-admission functional status for activities of daily living (ADL) with the same intervals in 16 patients without supplementation (non-MCT group) selected to match for age, gender, and fair or poor nutritional status from among 111 patients. Hospitalizations were significantly longer in the poor nutrition group (43.0+/-2.2 days) than in the fair nutrition group (27.0+/-8.2 days). Significantly more days were required to recover ADL status in the poor nutrition group (12.0+/-7.2 days) than in the fair group (9.4+/-5.2 days). Hospitalizations were significantly shorter in the MCT group (20.1+/-15 days) than in the non-MCT group (35.4+/-12.8 days). Significantly fewer days were required to recover ADL status in the MCT group (10.9+/-7 days) than in the non-MCT group (13.1+/-6.8 days). Administration of enteral nutrition including MCT during convalescence from acute cholecystitis thus appears to promote functional recovery shorten hospital stay.

The two glycolytic markers GLUT1 and MCT1 correlate with tumor grade and survival in clear-cell renal cell carcinoma

PubMed Central

Dadone, Bérengère; Durand, Matthieu; Borchiellini, Delphine; Amiel, Jean; Pouyssegur, Jacques; Rioux-Leclercq, Nathalie; Pages, Gilles; Burel-Vandenbos, Fanny; Mazure, Nathalie M.

2018-01-01

Background Clear-cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. Although ccRCC is characterized by common recurrent genetic abnormalities, including inactivation of the von Hippel-Lindau (vhl) tumor suppressor gene resulting in stabilization of hypoxia-inducible factors (HIFs), the tumor aggressiveness and outcome of ccRCC is variable. New biomarkers are thus required to improve ccRCC diagnosis, prognosis and therapeutic options. This work aims to investigate the expression of HIF and proteins involved in metabolism and pH regulation. Their correlation to histoprognostic parameters and survival was analyzed. Methods ccRCC of 45 patients were analyzed. HIF-1α, HIF-2α, HAF, GLUT1, MCT1, MCT4, CAIX and CAXII expression was assessed by immunohistochemistry in a semi-quantitative and qualitative manner. The GLUT1, MCT1, MCT4, CAIX and CAXII mRNA levels were analyzed in an independent cohort of 43 patients. Results A significant correlation was observed between increased GLUT1, MCT1, CAXII protein expression and a high Fuhrman grade in ccRCC patients. Moreover, while HIF-1α, HIF-2α and HAF expression was heterogenous within tumors, we observed and confirmed that HIF-2α co-localized with HAF. We confirmed, in an independent cohort, that GLUT1, MCT1 and CAXII mRNA levels correlated with the Fuhrman grade. Moreover, we demonstrated that the high mRNA level of both MCT1 and GLUT1 correlated with poor prognosis. Conclusions This study demonstrates for the first time a link between the aggressiveness of high- Fuhrman grade ccRCC and metabolic reprogramming. It also confirms the role of HIF-2α and HAF in tumor invasiveness. Finally, these results demonstrate that MCT1 and GLUT1 are strong prognostic markers and promising therapeutic targets. PMID:29481555

Glucose-dependent growth arrest of leukemia cells by MCT1 inhibition: Feeding Warburg's sweet tooth and blocking acid export as an anticancer strategy.

PubMed

Pivovarova, Aleksandra I; MacGregor, Gordon G

2018-02-01

This study aims to investigate the utilization of The Warburg Effect, cancer's "sweet tooth" and natural greed for glucose to enhance the effect of monocarboxylate transporter inhibition on cellular acidification. By simulating hyperglycemia with high glucose we may increase the effectiveness of inhibition of lactate and proton export on the dysregulation of cell pH homeostasis causing cell death or disruption of growth in cancer cells. MCT1 and MCT4 expression was determined in MCF7 and K562 cell lines using RT-PCR. Cell viability, growth, intracellular pH and cell cycle analysis was measured in the cell lines grown in 5 mM and 25 mM glucose containing media in the presence and absence of the MCT1 inhibitor AR-C155858 (1 μM) and the NHE1 inhibitor cariporide (10 μM). The MCT1 inhibitor, AR-C155858 had minimal effect on the viability, growth and intracellular pH of MCT4 expressing MCF7 cells. AR-C155858 had no effect on the viability of the MCT1 expressing K562 cells, but decreased intracellular pH and cell proliferation, by a glucose-dependent mechanism. Inhibition of NHE1 on its own had a no effect on cell growth, but together with AR-C155858 showed an additive effect on inhibition of cell growth. In cancer cells that only express MCT1, increased glucose concentrations in the presence of an MCT1 inhibitor decreased intracellular pH and reduced cell growth by G1 phase cell-cycle arrest. Thus we propose a transient hyperglycemic-clamp in combination with proton export inhibitors be evaluated as an adjunct to cancer treatment in clinical studies. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Histopathological and genetic review of phosphaturic mesenchymal tumours, mixed connective tissue variant.

PubMed

Yamada, Yuichi; Kinoshita, Izumi; Kenichi, Kohashi; Yamamoto, Hidetaka; Iwasaki, Takeshi; Otsuka, Hiroshi; Yoshimoto, Masato; Ishihara, Shin; Toda, Yu; Kuma, Yuki; Setsu, Nokitaka; Koga, Yuki; Honda, Yumi; Inoue, Takeshi; Yanai, Hiroyuki; Yamashita, Kyoko; Ito, Ichiro; Takahashi, Mitsuru; Ohga, Shouichi; Furue, Masutaka; Nakashima, Yasuharu; Oda, Yoshinao

2018-02-01

Phosphaturic mesenchymal tumour, mixed connective tissue variant (PMT-MCT), is a tumour of uncertain differentiation, characterised by 'smudgy/grungy' calcification and vitamin D-resistant phosphaturic osteomalacia. Fibroblast growth factor (FGF)23 is recognised as a reliable marker of PMT-MCT, but quantitative evaluation has never been performed. We reviewed cases of tumour-associated osteomalacia or histologically definitive PMT-MCT without osteomalacia using histological, immunohistochemical and genetic methods and evaluated the diagnostic significance of these findings. A total of 19 tumours from 14 cases diagnosed previously as PMT-MCT were retrieved, on which immunohistochemical staining, reverse transcription-polymerase chain reaction (RT-PCR) and fluorescence in-situ hybridisation (FISH) analysis were performed. Histologically, fibrous capsule, calcification and giant cell reaction tended to be observed in soft-tissue PMT-MCT, while PMT-MCT of bone and multiple PMT-MCT showed an infiltrative growth pattern. The immunohistochemical results were as follows: the tumour cells were positive for FGF23 (nine of 12, 75%), FGFR1 (11 of 11, 100%), CD56 (12 of 14, 85.7%) and E26 oncogene homologue (ERG) (5 of 13, 38.4%). The sole malignant tumour was positive for p53. FGF23 mRNA was detected in seven of 14 formalin-fixed paraffin-embedded (FFPE) specimens and all five frozen specimens by RT-PCR. The level of FGF23 mRNA, which was determined by real-time PCR, varied among the phosphaturic cases. Two of 17 tumours were positive for FGFR1 gene rearrangement. It was considered that PMT-MCT is a histopathological entity with or without phosphaturia, with varying levels of FGF23 mRNA, and with or without fibronectin 1 (FN1)-FGFR1 fusion gene. The authors propose that the histology of PMT-MCT differs depending on its location, such as bone or soft tissue, which could complicate the differential diagnosis. © 2017 John Wiley & Sons Ltd.

The two glycolytic markers GLUT1 and MCT1 correlate with tumor grade and survival in clear-cell renal cell carcinoma.

PubMed

Ambrosetti, Damien; Dufies, Maeva; Dadone, Bérengère; Durand, Matthieu; Borchiellini, Delphine; Amiel, Jean; Pouyssegur, Jacques; Rioux-Leclercq, Nathalie; Pages, Gilles; Burel-Vandenbos, Fanny; Mazure, Nathalie M

2018-01-01

Clear-cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. Although ccRCC is characterized by common recurrent genetic abnormalities, including inactivation of the von Hippel-Lindau (vhl) tumor suppressor gene resulting in stabilization of hypoxia-inducible factors (HIFs), the tumor aggressiveness and outcome of ccRCC is variable. New biomarkers are thus required to improve ccRCC diagnosis, prognosis and therapeutic options. This work aims to investigate the expression of HIF and proteins involved in metabolism and pH regulation. Their correlation to histoprognostic parameters and survival was analyzed. ccRCC of 45 patients were analyzed. HIF-1α, HIF-2α, HAF, GLUT1, MCT1, MCT4, CAIX and CAXII expression was assessed by immunohistochemistry in a semi-quantitative and qualitative manner. The GLUT1, MCT1, MCT4, CAIX and CAXII mRNA levels were analyzed in an independent cohort of 43 patients. A significant correlation was observed between increased GLUT1, MCT1, CAXII protein expression and a high Fuhrman grade in ccRCC patients. Moreover, while HIF-1α, HIF-2α and HAF expression was heterogenous within tumors, we observed and confirmed that HIF-2α co-localized with HAF. We confirmed, in an independent cohort, that GLUT1, MCT1 and CAXII mRNA levels correlated with the Fuhrman grade. Moreover, we demonstrated that the high mRNA level of both MCT1 and GLUT1 correlated with poor prognosis. This study demonstrates for the first time a link between the aggressiveness of high- Fuhrman grade ccRCC and metabolic reprogramming. It also confirms the role of HIF-2α and HAF in tumor invasiveness. Finally, these results demonstrate that MCT1 and GLUT1 are strong prognostic markers and promising therapeutic targets.

Evidence for Crustal-Scale Imbrication and non-Equilibrium Topography in the Southern Central Range, Taiwan

NASA Astrophysics Data System (ADS)

Byrne, T. B.; Huang, C.; Ouimet, W. B.; Rau, R.; Hsieh, M.; Lee, Y.

2011-12-01

We integrate a suite of new and recently re-interpreted profiles of the 3-D crustal velocity structure from the southern Central Range of Taiwan with geomorphic data from the range and propose that the topography is supported by a crustal-scale, west-verging thrust. The extent and geometry of the thrust is indicated by contours of P-wave velocity that are progressively overturned from south to north, placing high Vp rocks above low Vp rocks. The interpreted thrust dips gently east (15-20 degrees) and carries pre-Tertiary metamorphic rocks and Eocene to Miocene rocks with a well-developed slaty cleavage in its hanging wall. The thrust is interpreted to cut up section to the west and link with the basal detachment of the fold-and-thrust belt. Leveling data1 along the South Cross-Island Highway also suggest that the thrust is active. Along-strike profiles suggest that the thrust is propagating southward, consistent with a progressive decrease in mean elevation and an increase in reset apatite fission track ages from north to south. The hanging wall of the propagating thrust also correlates with anomalous areas of low topographic relief that straddle the crest of the southern part of the range. The areas of low relief are fringed by stream channels with relatively high stream gradient indexes and do not appear related to weaker rock types, glacial erosion, or lower rock uplift rates along the range crest. We propose that the surfaces represent relict topography that formed prior to a recent acceleration in rock uplift rate, consistent with the presence of a propagating, crustal-scale thrust in the subsurface. Taken together, these results raise questions about the notion of steady state topography and critically tapered wedges in Taiwan. 1) Ching, Kuo-En, Hsieh, M.-L., Johnson, K. M., Chen, K-H., Rau, R.-J., Yang M., Modern vertical deformation rates and mountain building in Taiwan from precise leveling and continuous GPS observations, 2000-2008, in press, JGR.

Side wire feed for welding apparatus

NASA Technical Reports Server (NTRS)

Arnett, J. C.

1974-01-01

Coaxial electrode arrangement has solid central electrode, insulated outer electrode, and transverse channel for feeding wire through tip of electrode assembly. Polymeric insulation is thrust aside by pressure, which is provided by separately operated mechanism acting through central electrode.

Sobetirome and its Amide Prodrug Sob-AM2 Exert Thyromimetic Actions in Mct8-Deficient Brain.

PubMed

Bárez-López, Soledad; Hartley, Meredith D; Grijota-Martínez, Carmen; Scanlan, Thomas S; Guadaño-Ferraz, Ana

2018-06-29

Loss of function mutations in the thyroid hormone (TH)-specific cell membrane transporter, the monocarboxylate transporter 8 (MCT8), lead to profound psychomotor retardation and abnormal TH serum levels, with low thyroxine (T4) and high triiodothyronine (T3). Several studies point to impaired TH transport across brain barriers as a crucial pathophysiological mechanism resulting in cerebral hypothyroidism. Treatment options for MCT8-deficient patients are limited and are focused on overcoming the brain barriers. The aim of this study was to evaluate the ability of the TH analog sobetirome and its prodrug Sob-AM2 to access the brain and exert thyromimetic actions in the absence of Mct8. Juvenile wild-type (Wt) mice and mice lacking Mct8 and deiodinase type 2 (Mct8/Dio2KO) were treated systemically with daily injections of vehicle, 1 mg of sobetirome/kg body weight/day, or 0.3 mg of Sob-AM2/kg body weight/day for seven days. Sobetirome content was measured using liquid chromatography-tandem mass spectrometry, and T4 and T3 levels by specific radioimmunoassays. The effect of sobetirome treatment in the expression of T3-dependent genes was measured in the heart, liver, and cerebral cortex by real-time polymerase chain reaction. Sob-AM2 treatment in Mct8/Dio2KO animals led to 1.8-fold more sobetirome content in the brain and 2.5-fold less in plasma in comparison to the treatment with the parent drug sobetirome. Both sobetirome and Sob-AM2 treatments in Mct8/Dio2KO mice greatly decreased plasma T4 and T3 levels. Dio1 and Ucp2 gene expression was altered in the liver of Mct8/Dio2KO mice and was not affected by the treatments. In the heart, Hcn2 but not Atp2a2 expression was increased after treatment with the analogs. Interestingly, both sobetirome and Sob-AM2 treatments increased the expression of several T3-dependent genes in the brain such as Hr, Abcd2, Mme, and Flywch2 in Mct8/Dio2KO mice. Sobetirome and its amide prodrug Sob-AM2 can access the brain in the absence of Mct8 and exert thyromimetic actions modulating the expression of T3-dependent genes. At the peripheral level, the administration of these TH analogs results in the depletion of circulating T4 and T3. Therefore, sobetirome and Sob-AM2 have the potential to address the cerebral hypothyroidism and the peripheral hyperthyroidism characteristic of MCT8 deficiency.

Structure and Evolution of the Central Andes of Peru

NASA Astrophysics Data System (ADS)

Gonzalez, L.; Pfiffner, O. A.

2009-04-01

Three major units make up the Andes in Peru: (1) The Western Cordillera consists of the Cretaceous Coastal Batholith intruding Jurassic to Cretaceous volcaniclastics (Casma group) in the west, and a fold-and-thrust belt of Mesozoic sediments in the east. Eocene and Miocene volcanics (Calipuy group and equivalents) overly all of these rock types. (2) The Central Highland contains a folded Paleozoic-Mesozoic sedimentary sequence overlain by thick Quaternary deposits. A major fault puts Neoproterozoic basement rocks of the Eastern Cordillera next to these units. (3) In the Eastern Cordillera, Late Paleozoic clastic successions unconformably overly folded Early Paleozoic sediments and a Neoproterozoic basement in the east. Permian (locally Triassic) granitoids intruded these units and were affected by folding and thrusting. In the core of the Eastern Cordillera, Early Cretaceous overly Early or Late Paleozoic strata. To the west, a thrust belt of Paleozoic to Cenozoic strata forms the transition to the foreland of the Brasilian shield. The most external part of this thrust belt involves Pliocene sediments and is referred to as Subandine zone. The Coastal Batholith is internally undeformed. The adjacent fold-and-thrust belt to the east is characterized by tight, nearly isoclinal upright folds with amplitudes of up to 1000 m. At the surface only Cretaceous rocks are observed. Using balancing techniques, a detachment horizon at the base of the Lowermost Cretaceous (Goyallarisquizga group - Oyon Formation) can be proposed. Further east, folds are more open, asymmetric and east verging, Jurassic sediments appear in the cores of the anticlines. The abrupt change in style from upright tight folding in the west to more open folding in the east is explained by a primary difference in the depositional sequence, most probably associated with synsedimentary faulting. The overlying volcanics of the Calipuy group and equivalents are, in turn, only slightly folded. In the Northern part of the Western Cordillera, near Huaraz, a vertical fault puts a Late Miocene to Early Pliocene batholith (Cordillera Blanca) in direct contact to Miocene volcanics (Calipuy group, Cordillera Negra). The structure of the Central Highlands is characterized by relatively open folds in the Paleozoic to Mesozoic strata. Overlying Quaternary deposits are tilted and locally even folded. Eocene to Miocene undeformed granitoids intrude these structures. A swarm of NNW-SSE striking and steeply dipping faults separate the Eastern Cordillera from the Highlands. Some of these faults suggest block faulting. However, near Huancayo a clear indication of strike-slip motion could be found. The Neoproterozoic basement rocks and the Early Paleozoic sediments are unconformably overlain by Late Paleozoic sediments which in turn are folded. Within the Subandine zone, the structural style is characterized by east directed imbricate thrusting. The thrust faults cut down into the crystalline basement going west, suggesting a detachment within upper crustal crystalline basement rocks. In the Central Peruvian Andes, compressional deformation events progressed from west to east. Early Cretaceous plutons of the coast batholith intruded folded Jurassic to Early Cretaceous volcaniclastic rocks of the Casma group and suggest an Early Cretaceous phase of shortening in the Pacific coastal area of the Western Cordillera (referred to as Mochica phase in the literature). Within the Western Cordillera, a major phase of pre-Eocene erosion removed a substantial amount of the tight upright folds. The youngest strata folded are of Late Cretaceous to Early Paleocene age (Red Beds). The overlying volcanics are slightly younger (middle Eocene) and bracket the tight folding, referred to as Inca phase, to Late Paleocene to Early Eocene times. This is corroborated by Eocene to Miocene granitic intrusions in the adjacent fold-and-thrust belt. Still younger deformations, referred to as Quechua Phase, produced gentle folds within the Eocene volcanics. Vertical motions in the Cordillera Blanca juxtaposed a Late Miocene-Pliocene batholith to Late Miocene volcanics. These movements are post-Pleistonce in age and still active. In the Central High Zone, even Pleistocene deposits were tilted and locally folded. Timing of the steeply dipping faults bordering the Eastern Cordillera is more difficult to assess. Cretaceous strata in tectonic contact with Neoproterozoic basement indicate a Cenozoic age. But within the fold-and-thrust belt of the Subandine zone in the east, youngest strata affected by thrusting are progressively younger toward the east. They suggest thrust propagation ranging from Oligocene to Pliocene age. These young thrust faults were responsible for the uplift of the Central Highland to their present elevation.

Regulation of Monocarboxylic Acid Transporter-1 by cAMP Dependent Vesicular Trafficking in Brain Microvascular Endothelial Cells

PubMed Central

Uhernik, Amy L.; Li, Lun; LaVoy, Nathan; Velasquez, Micah J.; Smith, Jeffrey P.

2014-01-01

In this study, a detailed characterization of Monocarboxylic Acid Transporter-1 (Mct1) in cytoplasmic vesicles of cultured rat brain microvascular endothelial cells shows them to be a diverse population of endosomes intrinsic to the regulation of the transporter by a brief 25 to 30 minute exposure to the membrane permeant cAMP analog, 8Br-cAMP. The vesicles are heterogeneous in size, mobility, internal pH, and co-localize with discreet markers of particular types of endosomes including early endosomes, clathrin coated vesicles, caveolar vesicles, trans-golgi, and lysosomes. The vesicular localization of Mct1 was not dependent on its N or C termini, however, the size and pH of Mct1 vesicles was increased by deletion of either terminus demonstrating a role for the termini in vesicular trafficking of Mct1. Using a novel BCECF-AM based assay developed in this study, 8Br-cAMP was shown to decrease the pH of Mct1 vesicles after 25 minutes. This result and method were confirmed in experiments with a ratiometric pH-sensitive EGFP-mCherry dual tagged Mct1 construct. Overall, the results indicate that cAMP signaling reduces the functionality of Mct1 in cerebrovascular endothelial cells by facilitating its entry into a highly dynamic vesicular trafficking pathway that appears to lead to the transporter's trafficking to autophagosomes and lysosomes. PMID:24454947

A common polymorphism of the MCT1 gene and athletic performance.

PubMed

Fedotovskaya, Olga N; Mustafina, Leysan J; Popov, Daniil V; Vinogradova, Olga L; Ahmetov, Ildus I

2014-01-01

In red skeletal muscle, monocarboxylate transporter 1 (MCT1) is required for lactate to enter the myocytes for oxidation. The A1470T polymorphism (rs1049434) in the MCT1 gene was shown to be associated with lactate transport rates in human skeletal muscles. The aim of the study was to compare genotype and allele frequencies of the MCT1 gene polymorphism in 323 Russian athletes and 467 nonathletic controls and to investigate the association of the MCT1 gene A1470T polymorphism with maximal oxygen consumption and maximal lactate concentration in rowers (n = 79). Genotyping for the A1470T MCT1 polymorphism was performed by PCR-RFLP method. Physiological measurements of 79 Russian rowers of national competitive standard were determined during an incremental test to exhaustion on a rowing ergometer. Frequencies of the A allele (71.8% vs 62.5%, P < .0001) and AA genotype (59.8% vs 39.4%, P < .0001) were significantly higher in endurance-oriented athletes (n = 142) than in the control group. Mean blood lactate concentration was higher in male rowers with the T allele (AT+TT 10.26 ± 1.89 mmol/L, AA 8.75 ± 1.69 mmol/L, P = .005). MCT1 gene A1470T polymorphism is associated with endurance athlete status and blood lactate level after intensive exercise.

Medium-chain versus long-chain triacylglycerol emulsion hydrolysis by lipoprotein lipase and hepatic lipase: Implications for the mechanisms of lipase action

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deckelbaum, R.J.; Hamilton, J.A.; Butbul, E.

1990-02-06

To explore how enzyme affinities and enzyme activities regulate hydrolysis of water-insoluble substrates, the authors compared hydrolysis of phospholipid-stabilized emulsions of medium-chain (MCT) versus long-chain triacylglycerols (LCT). Because substrate solubility at the emulsion surface might modulate rates of hydrolysis, the ability of egg yolk phosphatidylcholine to solubilize MCT was examined by NMR spectroscopy. Chemical shift measurements showed that 11 mol % of ({sup 13}C)carbonyl enriched trioctanoin was incorporated into phospholipid vesicles as a surface component. Line widths of trioctanoin surface peaks were half that of LCT, and relaxation times, T{sub 1}, were also shorter for trioctanoin, showing greater mobility formore » MCT in phospholipid. In assessing the effects of these differences in solubility on lipolysis, they found that both purified bovine milk lipoprotein lipase and human hepatic lipase hydrolyzed MCT at rates at least 2-fold higher than for LCT. Differences in affinity were also demonstrated in mixed incubations where increasing amounts of LCT emulsion resulted in decreased hydrolysis of MCT emulsions. These results suggest that despite lower enzyme affinity for MCT emulsions, shorter chain triacylglycerols are more readily hydrolyzed by lipoprotein and hepatic lipases than long-chain triacylglycerols because of greater MCT solubility and mobility at the emulsion-water interface.« less

A novel approach of chemical mechanical polishing using environment-friendly slurry for mercury cadmium telluride semiconductors

PubMed Central

Zhang, Zhenyu; Wang, Bo; Zhou, Ping; Guo, Dongming; Kang, Renke; Zhang, Bi

2016-01-01

A novel approach of chemical mechanical polishing (CMP) is developed for mercury cadmium telluride (HgCdTe or MCT) semiconductors. Firstly, fixed-abrasive lapping is used to machine the MCT wafers, and the lapping solution is deionized water. Secondly, the MCT wafers are polished using the developed CMP slurry. The CMP slurry consists of mainly SiO2 nanospheres, H2O2, and malic and citric acids, which are different from previous CMP slurries, in which corrosive and toxic chemical reagents are usually employed. Finally, the polished MCT wafers are cleaned and dried by deionized water and compressed air, respectively. The novel approach of CMP is environment-friendly. Surface roughness Ra, and peak-to-valley (PV) values of 0.45, and 4.74 nm are achieved, respectively on MCT wafers after CMP. The first and second passivating processes are observed in electrochemical measurements on MCT wafers. The fundamental mechanisms of CMP are proposed according to the X-ray photoelectron spectroscopy (XPS) and electrochemical measurements. Malic and citric acids dominate the first passivating process, and the CMP slurry governs the second process. Te4+3d peaks are absent after CMP induced by the developed CMP slurry, indicating the removing of oxidized films on MCT wafers, which is difficult to achieve using single H2O2 and malic and citric acids solutions. PMID:26926622

New Thermal Infrared Hyperspectral Imagers

DTIC Science & Technology

2009-10-01

involve imaging systems based on both MCT and microbolometer detector . All the systems base on push-broom imaging spectrograph with transmission grating...application requirements. The studies involve imaging systems based on both MCT and microbolometer detector . All the systems base on push-broom...remote sensing imager utilizes MCT detector combined with BMC-technique (background monitoring on-chip), background suppression and temperature

Metabolic control during exercise with and without medium-chain triglycerides (MCT) in children with long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) or trifunctional protein (TFP) deficiency

PubMed Central

Gillingham, Melanie B.; Scott, Bradley; Elliott, Diane; Harding, Cary O.

2009-01-01

Exercise induced rhabdomyolysis is a complication of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (TFP) deficiency that frequently leads to exercise avoidance. Dietary therapy for most subjects includes medium-chain triglyceride (MCT) supplementation but analysis of diet records indicates that the majority of patients consume oral MCT only with breakfast and at bedtime. We hypothesized that MCT immediately prior to exercise would provide an alternative fuel source during that bout of exercise and improve exercise tolerance in children with LCHAD deficiency. Nine subjects completed two 45 min moderate intensity (60–70% predicted maximum heart rate (HR)) treadmill exercise tests. Subjects were given 4 oz of orange juice alone or orange juice and 0.5 g MCT per kg lean body mass, 20 min prior to exercise in a randomized cross-over design. ECG and respiratory gas exchange including respiratory quotient (RQ) were monitored. Blood levels of acylcarnitines, creatine kinase, lactate, and β-hydroxybutyrate were measured prior to and immediately after exercise, and again following 20min rest. Creatine kinase and lactate levels did not change with exercise. There was no significant difference in RQ between the two exercise tests but there was a decrease in steady-state HR following MCT supplementation. Cumulative long-chain 3-hydroxyacylcarnitines were 30% lower and β-hydroxybutyrate was three-fold higher after the MCT-pretreated exercise test compared to the test with orange juice alone. Coordinating MCT supplementation with periods of increased activity may improve the metabolic control of children with LCHAD and TFP deficiency following exercise. PMID:16876451

Down-regulation of monocarboxylate transporter 1 (MCT1) gene expression in the colon of piglets is linked to bacterial protein fermentation and pro-inflammatory cytokine-mediated signalling.

PubMed

Villodre Tudela, Carmen; Boudry, Christelle; Stumpff, Friederike; Aschenbach, Jörg R; Vahjen, Wilfried; Zentek, Jürgen; Pieper, Robert

2015-02-28

The present study investigated the influence of bacterial metabolites on monocarboxylate transporter 1 (MCT1) expression in pigs using in vivo, ex vivo and in vitro approaches. Piglets (n 24) were fed high-protein (26 %) or low-protein (18 %) diets with or without fermentable carbohydrates. Colonic digesta samples were analysed for a broad range of bacterial metabolites. The expression of MCT1, TNF-α, interferon γ (IFN-γ) and IL-8 was determined in colonic tissue. The expression of MCT1 was lower and of TNF-α and IL-8 was higher with high-protein diets (P< 0·05). MCT1 expression was positively correlated with l-lactate, whereas negatively correlated with NH₃ and putrescine (P< 0·05). The expression of IL-8 and TNF-α was negatively correlated with l-lactate and positively correlated with NH₃ and putrescine, whereas the expression of IFN-γ was positively correlated with histamine and 4-ethylphenol (P< 0·05). Subsequently, porcine colonic tissue and Caco-2 cells were incubated with Na-butyrate, NH₄Cl or TNF-α as selected bacterial metabolites or mediators of inflammation. Colonic MCT1 expression was higher after incubation with Na-butyrate (P< 0·05) and lower after incubation with NH₄Cl or TNF-α (P< 0·05). Incubation of Caco-2 cells with increasing concentrations of these metabolites confirmed the up-regulation of MCT1 expression by Na-butyrate (linear, P< 0·05) and down-regulation by TNF-α and NH₄Cl (linear, P< 0·05). The high-protein diet decreased the expression of MCT1 in the colon of pigs, which appears to be linked to NH₃- and TNF-α-mediated signalling.

Mitochondrial Metabolism as a Treatment Target in Anaplastic Thyroid Cancer

PubMed Central

Johnson, Jennifer M; Lai, Stephen Y.; Cotzia, Paolo; Cognetti, David; Luginbuhl, Adam; Pribitkin, Edmund A.; Zhan, Tingting; Mollaee, Mehri; Domingo-Vidal, Marina; Chen, Yunyun; Campling, Barbara; Bar-Ad, Voichita; Birbe, Ruth; Tuluc, Madalina; Outschoorn, Ubaldo Martinez; Curry, Joseph

2015-01-01

Aims Anaplastic thyroid cancer (ATC) is one of the most aggressive human cancers. Key signal transduction pathways that regulate mitochondrial metabolism are frequently altered in ATC. Our goal was to determine the mitochondrial metabolic phenotype of ATC by studying markers of mitochondrial metabolism, specifically Monocarboxylate Transporter 1 (MCT1) and Translocase of the Outer Mitochondrial Membrane Member 20 (TOMM20). Methods Staining patterns of MCT1 and TOMM20 in 35 human thyroid samples (15 ATC, 12 papillary thyroid cancer (PTC), and 8 non-cancerous thyroid) and 9 ATC mouse orthotopic xenografts were assessed by visual and Aperio digital scoring. Staining patterns of areas involved with cancer versus areas with no evidence of cancer were evaluated independently where available. Results MCT1 is highly expressed in human anaplastic thyroid cancer when compared to both non-cancerous thyroid tissues and papillary thyroid cancers (p<0.001 for both). TOMM20 is also highly expressed in both ATC and PTC compared to non-cancerous thyroid tissue (p<0.01 for both). High MCT1 and TOMM20 expression is also found in ATC mouse xenograft tumors compared to non-cancerous thyroid tissue (p<0.001). These xenograft tumors have high 13C- pyruvate uptake. Conclusions Anaplastic thyroid cancer has metabolic features that distinguish it from PTC and non-cancerous thyroid tissue, including high expression of MCT1 and TOMM20. PTC has low expression of MCT1 and non-cancerous thyroid tissue has low expression of both MCT1 and TOMM20. This work suggests that MCT1 blockade may specifically target ATC cells presenting an opportunity for a new drug target. PMID:26615136

Mitochondrial Metabolism as a Treatment Target in Anaplastic Thyroid Cancer.

PubMed

Johnson, Jennifer M; Lai, Stephen Y; Cotzia, Paolo; Cognetti, David; Luginbuhl, Adam; Pribitkin, Edmund A; Zhan, Tingting; Mollaee, Mehri; Domingo-Vidal, Marina; Chen, Yunyun; Campling, Barbara; Bar-Ad, Voichita; Birbe, Ruth; Tuluc, Madalina; Martinez Outschoorn, Ubaldo; Curry, Joseph

2015-12-01

Anaplastic thyroid cancer (ATC) is one of the most aggressive human cancers. Key signal transduction pathways that regulate mitochondrial metabolism are frequently altered in ATC. Our goal was to determine the mitochondrial metabolic phenotype of ATC by studying markers of mitochondrial metabolism, specifically monocarboxylate transporter 1 (MCT1) and translocase of the outer mitochondrial membrane member 20 (TOMM20). Staining patterns of MCT1 and TOMM20 in 35 human thyroid samples (15 ATC, 12 papillary thyroid cancer [PTC], and eight non-cancerous thyroid) and nine ATC mouse orthotopic xenografts were assessed by visual and Aperio digital scoring. Staining patterns of areas involved with cancer versus areas with no evidence of cancer were evaluated independently where available. MCT1 is highly expressed in human anaplastic thyroid cancer when compared to both non-cancerous thyroid tissues and papillary thyroid cancers (P<.001 for both). TOMM20 is also highly expressed in both ATC and PTC compared to non-cancerous thyroid tissue (P<.01 for both). High MCT1 and TOMM20 expression is also found in ATC mouse xenograft tumors compared to non-cancerous thyroid tissue (P<.001). These xenograft tumors have high (13)C- pyruvate uptake. ATC has metabolic features that distinguish it from PTC and non-cancerous thyroid tissue, including high expression of MCT1 and TOMM20. PTC has low expression of MCT1 and non-cancerous thyroid tissue has low expression of both MCT1 and TOMM20. This work suggests that MCT1 blockade may specifically target ATC cells presenting an opportunity for a new drug target. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Greater improvement in cardiorespiratory fitness using higher-intensity interval training in the standard cardiac rehabilitation setting.

PubMed

Keteyian, Steven J; Hibner, Brooks A; Bronsteen, Kyle; Kerrigan, Dennis; Aldred, Heather A; Reasons, Lisa M; Saval, Mathew A; Brawner, Clinton A; Schairer, John R; Thompson, Tracey M S; Hill, Jason; McCulloch, Derek; Ehrman, Jonathon K

2014-01-01

We tested the hypothesis that higher-intensity interval training (HIIT) could be deployed into a standard cardiac rehabilitation (CR) setting and would result in a greater increase in cardiorespiratory fitness (ie, peak oxygen uptake, (·)VO₂) versus moderate-intensity continuous training (MCT). Thirty-nine patients participating in a standard phase 2 CR program were randomized to HIIT or MCT; 15 patients and 13 patients in the HIIT and MCT groups, respectively, completed CR and baseline and followup cardiopulmonary exercise testing. No patients in either study group experienced an event that required hospitalization during or within 3 hours after exercise. The changes in resting heart rate and blood pressure at followup testing were similar for both HIIT and MCT. (·)VO₂ at ventilatory-derived anaerobic threshold increased more (P < .05) with HIIT (3.0 ± 2.8 mL·kg⁻¹·min⁻¹) versus MCT (0.7 ± 2.2 mL·kg⁻¹·min⁻¹). During followup testing, submaximal heart rate at the end of stage 2 of the exercise test was significantly lower within both the HIIT and MCT groups, with no difference noted between groups. Peak (·)VO₂ improved more after CR in patients in HIIT versus MCT (3.6 ± 3.1 mL·kg⁻¹·min⁻¹ vs 1.7 ± 1.7 mL·kg⁻¹·min⁻¹; P < .05). Among patients with stable coronary heart disease on evidence-based therapy, HIIT was successfully integrated into a standard CR setting and, when compared to MCT, resulted in greater improvement in peak exercise capacity and submaximal endurance.

Prognostic significance of monocarboxylate transporter expression in oral cavity tumors

PubMed Central

Simões-Sousa, Susana; Granja, Sara; Pinheiro, Céline; Fernandes, Daniela; Longatto-Filho, Adhemar; Laus, Ana Carolina; Alves, Cira Danielle Casado; Suárez-Peñaranda, J. M.; Pérez-Sayáns, Mario; Lopes Carvalho, Andre; Schmitt, Fernando C.; García-García, Abel; Baltazar, Fatima

2016-01-01

ABSTRACT Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common type of cancer. The majority of patients present advanced stage disease and has poor survival. Therefore, it is imperative to search for new biomarkers and new alternative and effective treatment options. Most cancer cells rely on aerobic glycolysis to generate energy and metabolic intermediates. This phenotype is a hallmark of cancer, characterized by an increase in glucose consumption and production of high amounts of lactate. Consequently, cancer cells need to up-regulate many proteins and enzymes related with the glycolytic metabolism. Thus, the aim of this study was to characterize metabolic phenotype of oral cavity cancers (OCC) by assessing the expression pattern of monocarboxylate transporters (MCTs) 1, 2 and 4 and other proteins related with the glycolytic phenotype. Material and Methods: We evaluated the immunohistochemical expression of MCT1, MCT4, CD147, GLUT1 and CAIX in 135 human samples of OCC and investigated the correlation with clinicopathological parameters and the possible association with prognosis. Results: We observed that all proteins analyzed presented significantly higher plasma membrane expression in neoplastic compared to non-neoplastic samples. MCT4 was significantly associated with T-stage and advanced tumoral stage, while CD147 was significantly correlated with histologic differentiation. Interestingly, tumors expressing both MCT1 and MCT4 but negative for MCT2 were associated with shorter overall survival. Conclusion: Overexpression of MCT1/4, CD147, GLUT1 and CAIX, supports previous findings of metabolic reprograming in OCC, warranting future studies to explore the hyper-glycolytic phenotype of these tumors. Importantly, MCT expression revealed to have a prognostic value in OCC survival. PMID:27232157

PyMCT: A Very High Level Language Coupling Tool For Climate System Models

NASA Astrophysics Data System (ADS)

Tobis, M.; Pierrehumbert, R. T.; Steder, M.; Jacob, R. L.

2006-12-01

At the Climate Systems Center of the University of Chicago, we have been examining strategies for applying agile programming techniques to complex high-performance modeling experiments. While the "agile" development methodology differs from a conventional requirements process and its associated milestones, the process remain a formal one. It is distinguished by continuous improvement in functionality, large numbers of small releases, extensive and ongoing testing strategies, and a strong reliance on very high level languages (VHLL). Here we report on PyMCT, which we intend as a core element in a model ensemble control superstructure. PyMCT is a set of Python bindings for MCT, the Fortran-90 based Model Coupling Toolkit, which forms the infrastructure for the inter-component communication in the Community Climate System Model (CCSM). MCT provides a scalable model communication infrastructure. In order to take maximum advantage of agile software development methodologies, we exposed MCT functionality to Python, a prominent VHLL. We describe how the scalable architecture of MCT allows us to overcome the relatively weak runtime performance of Python, so that the performance of the combined system is not severely impacted. To demonstrate these advantages, we reimplemented the CCSM coupler in Python. While this alone offers no new functionality, it does provide a rigorous test of PyMCT functionality and performance. We reimplemented the CPL6 library, presenting an interesting case study of the comparison between conventional Fortran-90 programming and the higher abstraction level provided by a VHLL. The powerful abstractions provided by Python will allow much more complex experimental paradigms. In particular, we hope to build on the scriptability of our coupling strategy to enable systematic sensitivity tests. Our most ambitious objective is to combine our efforts with Bayesian inverse modeling techniques toward objective tuning at the highest level, across model architectures.

The geology of a part of Acadia and the nature of the Acadian orogeny across Central and Eastern Maine

USGS Publications Warehouse

Tucker, R.D.; Osberg, P.H.; Berry, H.N.

2001-01-01

The zone of Acadian collision between the Medial New England and Composite Avalon terranes is well preserved in Maine. A transect from northwest (Rome) to southeast (Camden) crosses the eastern part of Medial New England comprising the Central Maine basin, Liberty-Orrington thrust sheet, and Fredericton trough, and the western part of Composite Avalon, including the Graham Lake, Clarry Hill, and Clam Cove thrust sheets. U-Pb geochronology of events before, during, and after the Acadian orogeny helps elucidate the nature and distribution of tectonostrati& graphic belts in this zone and the timing of some Acadian events in the Northern Appalachians. The Central Maine basin consists of sedimentary and volcanic rocks of Middle Ordovician (???470 to ???460 Ma) age overlain with probable conformity by latest Ordovician(?) through earliest Devonian marine rift and flysch sedimentary rocks; these are intruded by weakly to undeformed plutonic rocks of Early and Middle Devonian age (???399??378 Ma). The Fredericton trough consists of Early Silurian gray pelite and sandstone to earliest Late Silurian calcareous turbidite, deformed and variably metamorphosed prior to the emplacement of Late Silurian (???422 Ma) and Early to Late Devonian (???418 to ???368 Ma) plutons. The Liberty-Orrington thrust sheet consists of Cambrian(?)-Ordovician (>???474 to ???469 Ma and younger) clastic sedimentary and volcanic rocks intruded by highly deformed Late Silurian (???424 to ???422 Ma) and Devonian (???418 to ???389 Ma) plutons, possibly metamorphosed in Late Silurian time (prior to ???417 Ma), and metamorphosed to amphibolite facies in Early to Middle Devonian time (???400 to ???381 Ma). The Graham Lake thrust sheet contains possible Precambrian rocks, Cambrian sedimentary rocks with a volcanic unit dated at ???503 Ma, and Ordovician rocks with possible Caradocian Old World fossils, metamor& phosed and deformed in Silurian time and intruded by mildly to undeformed Late Silurian (???421 Ma) and Late Devonian (???371 to ???368 Ma) plutons. The Clarry Hill thrust sheet consists of poorly studied, highly metamorphosed Cambrian(?) rocks. The Clam Cove thrust sheet contains highly deformed Precambrian limestone, shale, sandstone, and conglomerate, metamorphosed to epidote amphibolite facies and intruded by a mildly deformed pluton dated at ???421 Ma. Metamorphism, deformation, and voluminous intrusive igneous activity of Silu& rian age are common to both the most southeastern parts of Medial New England and the thrust sheets of Composite Avalon. In contrast to Medial New England, the thrust sheets of Composite Avalon show only modest effects of Devonian deformation and metamorphism. Regional stratigraphic relations, paleontologic findings, and U-Pb geochronology suggest that the Graham Lake, Clarry Hill, and Clam Cove thrust sheets are far-traveled allochthons that were widely separated from Medial New England in the Silurian.

Interfibrillar stiffening of echinoderm mutable collagenous tissue demonstrated at the nanoscale

PubMed Central

Mo, Jingyi; Blowes, Liisa M.; Egertová, Michaela; Terrill, Nicholas J.; Wang, Wen; Elphick, Maurice R.; Gupta, Himadri S.

2016-01-01

The mutable collagenous tissue (MCT) of echinoderms (e.g., sea cucumbers and starfish) is a remarkable example of a biological material that has the unique attribute, among collagenous tissues, of being able to rapidly change its stiffness and extensibility under neural control. However, the mechanisms of MCT have not been characterized at the nanoscale. Using synchrotron small-angle X-ray diffraction to probe time-dependent changes in fibrillar structure during in situ tensile testing of sea cucumber dermis, we investigate the ultrastructural mechanics of MCT by measuring fibril strain at different chemically induced mechanical states. By measuring a variable interfibrillar stiffness (EIF), the mechanism of mutability at the nanoscale can be demonstrated directly. A model of stiffness modulation via enhanced fibrillar recruitment is developed to explain the biophysical mechanisms of MCT. Understanding the mechanisms of MCT quantitatively may have applications in development of new types of mechanically tunable biomaterials. PMID:27708167

Interfibrillar stiffening of echinoderm mutable collagenous tissue demonstrated at the nanoscale.

PubMed

Mo, Jingyi; Prévost, Sylvain F; Blowes, Liisa M; Egertová, Michaela; Terrill, Nicholas J; Wang, Wen; Elphick, Maurice R; Gupta, Himadri S

2016-10-18

The mutable collagenous tissue (MCT) of echinoderms (e.g., sea cucumbers and starfish) is a remarkable example of a biological material that has the unique attribute, among collagenous tissues, of being able to rapidly change its stiffness and extensibility under neural control. However, the mechanisms of MCT have not been characterized at the nanoscale. Using synchrotron small-angle X-ray diffraction to probe time-dependent changes in fibrillar structure during in situ tensile testing of sea cucumber dermis, we investigate the ultrastructural mechanics of MCT by measuring fibril strain at different chemically induced mechanical states. By measuring a variable interfibrillar stiffness (E IF ), the mechanism of mutability at the nanoscale can be demonstrated directly. A model of stiffness modulation via enhanced fibrillar recruitment is developed to explain the biophysical mechanisms of MCT. Understanding the mechanisms of MCT quantitatively may have applications in development of new types of mechanically tunable biomaterials.

Active out-of-sequence thrust faulting in the central Nepalese Himalaya.

PubMed

Wobus, Cameron; Heimsath, Arjun; Whipple, Kelin; Hodges, Kip

2005-04-21

Recent convergence between India and Eurasia is commonly assumed to be accommodated mainly along a single fault--the Main Himalayan Thrust (MHT)--which reaches the surface in the Siwalik Hills of southern Nepal. Although this model is consistent with geodetic, geomorphic and microseismic data, an alternative model incorporating slip on more northerly surface faults has been proposed to be consistent with these data as well. Here we present in situ cosmogenic 10Be data indicating a fourfold increase in millennial timescale erosion rates occurring over a distance of less than 2 km in central Nepal, delineating for the first time an active thrust fault nearly 100 km north of the surface expression of the MHT. These data challenge the view that rock uplift gradients in central Nepal reflect only passive transport over a ramp in the MHT. Instead, when combined with previously reported 40Ar-39Ar data, our results indicate persistent exhumation above deep-seated, surface-breaking structures at the foot of the high Himalaya. These results suggest that strong dynamic interactions between climate, erosion and tectonics have maintained a locus of active deformation well to the north of the Himalayan deformation front.

Crustal thickness variations in the Zagros continental collision zone (Iran) from joint inversion of receiver functions and surface wave dispersion

NASA Astrophysics Data System (ADS)

Tatar, M.; Nasrabadi, A.

2013-10-01

Variations in crustal thickness in the Zagros determined by joint inversion of P wave receiver functions (RFs) and Rayleigh wave group and phase velocity dispersion. The time domain iterative deconvolution procedure was employed to compute RFs from teleseismic recordings at seven broadband stations of INSN network. Rayleigh wave phase velocity dispersion curves were estimated employing two-station method. Fundamental mode Rayleigh wave group velocities for each station is taken from a regional scale surface wave tomographic imaging. The main variations in crustal thickness that we observe are between stations located in the Zagros fold and thrust belt with those located in the Sanandaj-Sirjan zone (SSZ) and Urumieh-Dokhtar magmatic assemblage (UDMA). Our results indicate that the average crustal thickness beneath the Zagros Mountain Range varies from ˜46 km in Western and Central Zagros beneath SHGR and GHIR up to ˜50 km beneath BNDS located in easternmost of the Zagros. Toward NE, we observe an increase in Moho depth where it reaches ˜58 km beneath SNGE located in the SSZ. Average crustal thickness also varies beneath the UDMA from ˜50 km in western parts below ASAO to ˜58 in central parts below NASN. The observed variation along the SSZ and UDMA may be associated to ongoing slab steepening or break off in the NW Zagros, comparing under thrusting of the Arabian plate beneath Central Zagros. The results show that in Central Iran, the crustal thickness decrease again to ˜47 km below KRBR. There is not a significant crustal thickness difference along the Zagros fold and thrust belt. We found the same crystalline crust of ˜34 km thick beneath the different parts of the Zagros fold and thrust belt. The similarity of crustal structure suggests that the crust of the Zagros fold and thrust belt was uniform before subsidence and deposition of the sediments. Our results confirm that the shortening of the western and eastern parts of the Zagros basement is small and has only started recently.

Late Alpine to recent thick-skinned tectonics of the central Swiss Molasse Basin, Canton of Bern, Switzerland

NASA Astrophysics Data System (ADS)

Mock, Samuel; Allenbach, Robin; Wehrens, Philip; Reynolds, Lance; Kurmann-Matzenauer, Eva; Michael, Salomè; Herwegh, Marco

2017-04-01

The Swiss Molasse Basin (SMB) forms part of the North Alpine Foreland Basin. It is a typical peripheral foreland basin, which developed in Paleogene and Neogene times in response to flexural bending of the European lithosphere induced by the orogenic loading of the advancing Alpine thrust wedge. The tectonics of the SMB and the role of Paleozoic and Mesozoic structures are still poorly understood. It is widely accepted that during the main deformation phase of the Jura fold-and-thrust belt, the SMB was riding piggy-back above a major detachment horizon situated within Triassic evaporites. In recent years it has been observed that the Jura fold-and-thrust belt is today deforming in a thick-skinned tectonic style. As for the western and central SMB, most authors still argue in favor of a classical foreland type, thin-skinned style of deformation. Based on the geological 3D modeling of seismic interpretations, we present new insights into the structural configuration of the central SMB. Revised and new interpretations of 2D reflection seismic data from the 1960s to the 1980s reveal a major strike-slip fault zone affecting not only the Mesozoic and Cenozoic cover, but also the crystalline basement beneath. The fault zone reactivated late Paleozoic synsedimentary normal faults bounding a Permo-Carboniferous trough. Basement-involved thrusting observed in the southern part of the SMB seems to be controlled by the presence of slightly inverted Permo-Carboniferous troughs as well. These observations, combined with a compiled structural map and the distribution of recent earthquake hypocenters suggest a late stage, NNW-SSE directed, compressional thick-skinned and strike-slip dominated tectonic activity of the central SMB, post-dating the main deformation phase of the Jura fold-and-thrust belt. This still ongoing deformation might be related to the slab rollback of the European plate and the associated lower crustal delamination as recently suggested by Singer et al. (2014). References: Singer, J., Diehl, T., Husen, S., Kissling, E., Duretz, T., 2014. Alpine lithosphere slab rollback causing lower crustal seismicity in northern foreland. Earth Planet. Sci. Lett. 397, 42-56. doi:10.1016/j.epsl.2014.04.002

A Study of Middle School Athletes and Their Performance on the MCT2

ERIC Educational Resources Information Center

McEwen, Terrance Jacob

2017-01-01

The goal of this study was to determine whether there was a significant relationship between participation in athletic activities and academic achievement. Academic achievement was to be measured by the Mississippi Curriculum Test, Second Edition (MCT2). This study focused on MCT2 scores in mathematics and language arts for 8th grade male and…

Regulation of Mct1 by cAMP-dependent internalization in rat brain endothelial cells.

PubMed

Smith, Jeffrey P; Uhernik, Amy L; Li, Lun; Liu, Zejian; Drewes, Lester R

2012-10-22

In the cerebrovascular endothelium, monocarboxylic acid transporter 1 (Mct1) controls blood-brain transport of short chain monocarboxylic and keto acids, including pyruvate and lactate, to support brain energy metabolism. Mct1 function is acutely decreased in rat brain cerebrovascular endothelial cells by β-adrenergic signaling through cyclic adenosine monophosphate (cAMP); however, the mechanism for this acute reduction in transport capacity is unknown. In this report, we demonstrate that cAMP induces the dephosphorylation and internalization of Mct1 from the plasma membrane into caveolae and early endosomes in the RBE4 rat brain cerebrovascular endothelial cell line. Additionally, we provide evidence that Mct1 constitutively cycles through clathrin vesicles and recycling endosomes in a pathway that is not dependent upon cAMP signaling in these cells. Our results are important because they show for the first time the regulated and unregulated vesicular trafficking of Mct1 in cerebrovascular endothelial cells; processes which have significance for better understanding normal brain energy metabolism, and the etiology and potential therapeutic approaches to treating brain diseases, such as stroke, in which lactic acidosis is a key component. Copyright © 2012 Elsevier B.V. All rights reserved.

Regulation of Mct1 by cAMP-dependent internalization in rat brain endothelial cells

PubMed Central

Smith, Jeffrey P.; Uhernik, Amy L.; Li, Lun; Liu, Zejian; Drewes, Lester R.

2012-01-01

In the cerebrovascular endothelium, monocarboxylic acid transporter 1 (Mct1) controls blood-brain transport of short chain monocarboxylic and keto acids, including pyruvate and lactate, to support brain energy metabolism. Mct1 function is acutely decreased in rat brain cerebrovascular endothelial cells by β-adrenergic signaling through cyclic adenosine monophosphate (cAMP); however, the mechanism for this acute reduction in transport capacity is unknown. In this report, we demonstrate that cAMP induces the dephosphorylation and internalization of Mct1 from the plasma membrane into caveolae and early endosomes in the RBE4 rat brain cerebrovascular endothelial cell line. Additionally, we provide evidence that Mct1 constitutively cycles through clathrin vesicles and recycling endosomes in a pathway that is not dependent upon cAMP signaling in these cells. Our results are important because they show for the first time the regulated and unregulated vesicular trafficking of Mct1 in cerebrovascular endothelial cells; processes which have significance for better understanding normal brain energy metabolism, and the etiology and potential therapeutic approaches to treating brain diseases, such as stroke, in which lactic acidosis is a key component PMID:22925948

High T3, Low T4 Serum Levels in Mct8 Deficiency Are Not Caused by Increased Hepatic Conversion through Type I Deiodinase

PubMed Central

Wirth, Eva K.; Rijntjes, Eddy; Meyer, Franziska; Köhrle, Josef; Schweizer, Ulrich

2015-01-01

Background The Allan-Herndon-Dudley syndrome is a severe psychomotor retardation accompanied by specific changes in circulating thyroid hormone levels (high T3, low T4). These are caused by mutations in the thyroid hormone transmembrane transport protein monocarboxylate transporter 8 (MCT8). Objective: To test the hypothesis that circulating low T4 and high T3 levels are caused by enhanced conversion of T4 via increased activity of hepatic type I deiodinase (Dio1). Methods We crossed mice deficient in Mct8 with mice lacking Dio1 activity in hepatocytes. Translation of the selenoenzyme Dio1 was abrogated by hepatocyte-specific inactivation of selenoprotein biosynthesis. Results Inactivation of Dio1 activity in the livers of global Mct8-deficient mice does not restore normal circulating thyroid hormone levels. Conclusions Our data suggest that although hepatic Dio1 activity is increased in Mct8-deficient mice, it does not cause the observed abnormal circulating thyroid hormone levels. Since global inactivation of Dio1 in Mct8-deficient mice does normalize circulating thyroid hormone levels, the underlying mechanism and relevant tissues involved remain to be elucidated. PMID:26601078

High T3, Low T4 Serum Levels in Mct8 Deficiency Are Not Caused by Increased Hepatic Conversion through Type I Deiodinase.

PubMed

Wirth, Eva K; Rijntjes, Eddy; Meyer, Franziska; Köhrle, Josef; Schweizer, Ulrich

2015-09-01

The Allan-Herndon-Dudley syndrome is a severe psychomotor retardation accompanied by specific changes in circulating thyroid hormone levels (high T3, low T4). These are caused by mutations in the thyroid hormone transmembrane transport protein monocarboxylate transporter 8 (MCT8). To test the hypothesis that circulating low T4 and high T3 levels are caused by enhanced conversion of T4 via increased activity of hepatic type I deiodinase (Dio1). We crossed mice deficient in Mct8 with mice lacking Dio1 activity in hepatocytes. Translation of the selenoenzyme Dio1 was abrogated by hepatocyte-specific inactivation of selenoprotein biosynthesis. Inactivation of Dio1 activity in the livers of global Mct8-deficient mice does not restore normal circulating thyroid hormone levels. Our data suggest that although hepatic Dio1 activity is increased in Mct8-deficient mice, it does not cause the observed abnormal circulating thyroid hormone levels. Since global inactivation of Dio1 in Mct8-deficient mice does normalize circulating thyroid hormone levels, the underlying mechanism and relevant tissues involved remain to be elucidated.

Alleviating Emotional Distress in Adolescent and Young Adult Cancer Survivors: An Open Trial of Metacognitive Therapy.

PubMed

Fisher, Peter L; McNicol, Kirsten; Young, Bridget; Smith, Ed; Salmon, Peter

2015-06-01

Metacognitive therapy (MCT) is an effective psychological treatment for a range of emotional disorders. However, the applicability of MCT to treating emotional distress in physical health populations has yet to be tested. The present study examined the potential of MCT for alleviating emotional distress in adolescent and young adult cancer (AYAC) survivors. Twelve AYAC survivors, aged 18-23, who had completed acute medical treatment participated in this pilot open trial with 6 months follow-up. Each participant completed a baseline period followed by 8-14 sessions of MCT that targeted perseverative thinking (worry and rumination), attentional control, and metacognitive beliefs. The primary outcome variable was severity of depression and anxiety symptoms as measured by the Hospital Anxiety and Depression Scale (HADS). MCT was associated with large and statistically significant reductions in anxiety, depression, trauma symptoms, and metacognitive beliefs and processes. In the intention-to-treat sample, 50% of participants met standardized criteria for recovery on the HADS at posttreatment and these gains were maintained through to 6-month follow-up. MCT is a promising transdiagnostic approach to treating different forms of emotional distress in AYAC survivors. Further investigation in controlled trials is now warranted.

Medium chain triglycerides (MCT) formulas in paediatric and allergological practice.

PubMed

Łoś-Rycharska, Ewa; Kieraszewicz, Zuzanna; Czerwionka-Szaflarska, Mieczysława

2016-01-01

Fats constitute the most significant nutritional source of energy. Their proper use by the body conditions a number of complex mechanisms of digestion, absorption, distribution, and metabolism. These mechanisms are facilitated by fats made of medium chain fatty acids; therefore, they are an easy and quick source of energy. Thus, an increased supply of medium chain triglycerides (MCT) is particularly important in patients with disturbances of digestion and absorption such as disturbed bile secretion, classic coeliac disease, short bowel syndrome, inflammatory diseases of the intestines, disturbed outflow of lymph, some metabolic disease, and severe food allergies, as well as in prematurely born neonates. Use of preparations containing an additive of MCT is limited, especially if they are to be used for a longer period of time. With a large quantity of MCT in a diet, there is a risk of deficiency of necessary unsaturated fatty acids and some fat-soluble vitamins. The caloricity of MTC compared to long-chain triglycerides is lower, and formulas with MCT are characterised by higher osmolality. Medium chain triglycerides is not recommended as an additive to standard formulas for healthy children. The use of MCT should be limited to strictly specified medical indications.

Medium chain triglycerides (MCT) formulas in paediatric and allergological practice

PubMed Central

Łoś-Rycharska, Ewa; Kieraszewicz, Zuzanna

2016-01-01

Fats constitute the most significant nutritional source of energy. Their proper use by the body conditions a number of complex mechanisms of digestion, absorption, distribution, and metabolism. These mechanisms are facilitated by fats made of medium chain fatty acids; therefore, they are an easy and quick source of energy. Thus, an increased supply of medium chain triglycerides (MCT) is particularly important in patients with disturbances of digestion and absorption such as disturbed bile secretion, classic coeliac disease, short bowel syndrome, inflammatory diseases of the intestines, disturbed outflow of lymph, some metabolic disease, and severe food allergies, as well as in prematurely born neonates. Use of preparations containing an additive of MCT is limited, especially if they are to be used for a longer period of time. With a large quantity of MCT in a diet, there is a risk of deficiency of necessary unsaturated fatty acids and some fat-soluble vitamins. The caloricity of MTC compared to long-chain triglycerides is lower, and formulas with MCT are characterised by higher osmolality. Medium chain triglycerides is not recommended as an additive to standard formulas for healthy children. The use of MCT should be limited to strictly specified medical indications. PMID:28053676

Aversion of the cat to dietary medium-chain triglycerides and caprylic acid.

PubMed

MacDonald, M L; Rogers, Q R; Morris, J G

1985-09-01

Young, specific-pathogen-free cats were fed purified diets containing different sources of fat. Food intake was depressed and cats lost weight when the diet contained either hydrogenated coconut oil (HCO) or medium-chain triglycerides (MCT). With an MCT preparation enriched in 8:0 (MCT8), cats would not eat after first tasting the diet. When cats were offered a choice of two high-fat diets, they chose the basal diet over a diet containing 30% HCO, by a ratio of 4.5:1. Low levels of MCT8 (5% or 10% by weight) were also rejected, whereas cats did not reject 5% or 15% MCT12. Caprylic acid, at 0.1-1.0% of the diet, was rejected. In other studies, food intake and body weight decreased when HCO was added to a fat-free diet. Cats fed 25% or 35% HCO lost weight. When 5% safflower seed oil was added to the HCO diets, body weights and food intake improved, but were still less than optimal. These studies indicate that the food intake depression in cats fed dietary HCO and MCT is primarily a result of impalatability, and that the fatty acid moiety may be responsible for the aversion.

Medium Chain Triglycerides in Paediatric Practice

PubMed Central

Gracey, Michael; Burke, Valerie; Anderson, Charlotte M.

1970-01-01

Medium chain triglycerides (MCT) bypass the steps necessary for the absorption of long chain fats (LCT), and so have theoretical grounds for their use in various disease states, particularly malabsorptive disorders. In childhood, MCT have particular advantages since they allow restriction of dietary long chain fats without limiting the intake of protein necessary for growth while providing adequate calories. In malabsorptive states, MCT have been used mostly in cystic fibrosis, where they may reduce steatorrhoea. However, the long-term growth patterns of these children are dependent on the extent and severity of their chest disease. MCT may be a useful source of calories for those with anorexia due to infection or liver disease and in babies recovering from meconium ileus. The decrease in offensive stools, flatus, and abdominal discomfort improves well-being and social acceptability which is important for many schoolchildren and adolescents. Rectal prolapse may be helped. Where there is loss of the small intestinal absorptive surface, particularly after massive small bowel resection, MCT can help to maintain weight and nutrition. They may also be a useful supplementary nutritional measure in patients severely affected with coeliac disease while awaiting response to a gluten-free diet, and in patients with regional enteritis. In children with liver disease, MCT provide a ready source of calories while avoiding the loss of fat in their stools. Infants with neonatal hepatitis or biliary atresia remain well nourished, and some older children with liver disease grow more rapidly and have fewer and less offensive stools and less abdominal discomfort. Where an abnormal number of faecal organisms colonize the small intestine (`contaminated small bowel syndrome' or `blind loop syndrome') intraluminal bile salts become deconjugated and cause steatorrhoea. A combination of antibiotic and surgical treatment is usually indicated, but MCT can be used to improve nutrition before operation and may be indicated for associated conditions, such as massive intestinal resection. MCT have also been helpful in patients with defective chylomicron formation due to a-β-lipoproteinaemia. In the congenital and less commonly encountered acquired lymphatic disorders in childhood, MCT have given encouraging results. This group includes patients with gross protein and fat loss due to intestinal lymphangiectasia and others with lymphatic anomalies at other sites. Hyperchylomicronaemia (familial fat-induced hypertriglyceridaemia) responds well to dietary treatment with MCT. PMID:4918706

The effects of different lipid emulsions on the lipid profile, fatty acid composition, and antioxidant capacity of preterm infants: A double-blind, randomized clinical trial.

PubMed

Wang, Ying; Feng, Yi; Lu, Li-Na; Wang, Wei-Ping; He, Zhen-Juan; Xie, Li-Juan; Hong, Li; Tang, Qing-Ya; Cai, Wei

2016-10-01

Olive oil (OO), medium-chain triglycerides (MCT)/long-chain triglycerides (LCT) mixture and soybean oil (SO) lipid emulsions are currently used for preterm infants in China. The aim of our study was to compare the lipid profile, fatty acid composition, and antioxidant capacity of preterm infants administered OO, MCT/LCT, or SO lipid emulsions. In this study, 156 preterm infants (birth weight < 2000 g and gestational age < 37 weeks) received parenteral nutrition (PN) containing OO, MCT/LCT, or SO lipid emulsions for a minimum of 14 d. On days 0, 7, and 14, the lipid profile, fatty acid composition and antioxidant capacity were analyzed. On day 7, HDL levels in the MCT/LCT group were significantly lower than in the OO (1.06 ± 0.40 mmol/L) or SO groups. LDL levels were higher in the OO group than in the MCT/LCT or SO groups on day 7. A-I/B was higher in MCT/LCT than in OO or SO groups. Myristic acid (C14:0) levels on days 7 and 14 increased in MCT/LCT compared to the OO and SO groups. The OO group had higher oleic acid (C18:1n9) levels than the two other groups. Linoleic acid (C18:2n6), linolenic acid (C18:3n3), and eicosapentaenoic acid (20:5n3) were significantly lower in the OO group than in MCT/LCT or SO groups. Monounsaturated fatty acid levels decreased, and ω-6 polyunsaturated fatty acid and essential fatty acids levels increased in MCT/LCT and SO groups. No significant differences were obtained in SOD, MDA, GSH-Px, and T-AOC among the groups. The three lipid emulsions were safe and well tolerated in preterm infants. Oleic acid (C18:1n9) levels increased and LA (C18:2n6), ALA (C18:3n3), and EPA (C20:5n23) levels decreased in OO compared to MCT/LCT or SO. NCT01683162, https://register.clinicaltrials.gov/. Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Geologic Map of the Sulphur Mountain Quadrangle, Park County, Colorado

USGS Publications Warehouse

Bohannon, Robert G.; Ruleman, Chester A.

2009-01-01

The main structural element in the Sulphur Mountain quadrangle is the Elkhorn thrust. This northwest-trending fault is the southernmost structure that bounds the west side of the Late Cretaceous and early Tertiary Front Range basement-rock uplift. The Elkhorn thrust and the Williams Range thrust that occurs in the Dillon area north of the quadrangle bound the west flank of the Williams Range and the Front Range uplift in the South Park area. Kellogg (2004) described widespread, intense fracturing, landsliding, and deep-rooted scarps in the crystalline rocks that comprise the upper plate of the Williams Range thrust. The latter thrust is also demonstrably a low-angle structure upon which the fractured bedrock of the upper plate was translated west above Cretaceous shales. Westward thrusting along the border of the Front Range uplift is probably best developed in that area. By contrast, the Elkhorn in the Sulphur Mountain quadrangle is poorly exposed and occurs in an area of relatively low relief. The thrust also apparently ends in the central part of the quadrangle, dying out into a broad area of open, upright folds with northwest axes in the Sulphur Mountain area.

Progressive deformation and superposed fabrics related to Cretaceous crustal underthrusting in western Arizona, U.S.A.

USGS Publications Warehouse

Laubach, S.E.; Reynolds, S.J.; Spencer, J.E.; Marshak, S.

1989-01-01

In the Maria fold and thrust belt, a newly recognized E-trending Cretaceous orogenic belt in the southwestern United States, ductile thrusts, large folds and superposed cleavages record discordant emplacement of crystalline thrust sheets across previously tilted sections of crust. Style of deformation and direction of thrusting are in sharp contrast to those of the foreland fold-thrust belt in adjacent segments of the Cordillera. The net effect of polyphase deformation in the Maria belt was underthrusting of Paleozoic and Mesozoic metasedimentary rocks under the Proterozoic crystalline basement of North America. The structure of the Maria belt is illustrated by the Granite Wash Mountains in west-central Arizona, where at least four non-coaxial deformation events (D1-D4) occurred during the Cretaceous. SSE-facing D1 folds are associated with S-directed thrusts and a low-grade slaty cleavage. D1 structures are truncated by the gently-dipping Hercules thrust zone (D2), a regional SW-vergent shear zone that placed Proterozoic and Jurassic crystalline rocks over upturned Paleozoic and Mesozoic supracrustal rocks. Exposures across the footwall margin of the Hercules thrust zone show the progressive development of folds, cleavage and metamorphism related to thrusting. D3 and D4 structures include open folds and spaced cleavages that refold or transect D1 and D2 folds. The D2 Hercules thrust zone and a D3 shear zone are discordantly crosscut by late Cretaceous plutons. ?? 1989.

miR-29a and miR-29b contribute to pancreatic beta-cell-specific silencing of monocarboxylate transporter 1 (Mct1).

PubMed

Pullen, Timothy J; da Silva Xavier, Gabriela; Kelsey, Gavin; Rutter, Guy A

2011-08-01

In pancreatic β cells, elevated glucose concentrations stimulate mitochondrial oxidative metabolism to raise intracellular ATP/ADP levels, prompting insulin secretion. Unusually low levels of expression of genes encoding the plasma membrane monocarboxylate transporter, MCT1 (SLC16A1), as well as lactate dehydrogenase A (LDHA) ensure that glucose-derived pyruvate is efficiently metabolized by mitochondria, while exogenous lactate or pyruvate is unable to stimulate metabolism and hence insulin secretion inappropriately. We show here that whereas DNA methylation at the Mct1 promoter is unlikely to be involved in cell-type-specific transcriptional repression, three microRNAs (miRNAs), miR-29a, miR-29b, and miR-124, selectively target both human and mouse MCT1 3' untranslated regions. Mutation of the cognate miR-29 or miR-124 binding sites abolishes the effects of the corresponding miRNAs, demonstrating a direct action of these miRNAs on the MCT1 message. However, despite reports of its expression in the mouse β-cell line MIN6, miR-124 was not detectably expressed in mature mouse islets. In contrast, the three isoforms of miR-29 are highly expressed and enriched in mouse islets. We show that inhibition of miR-29a in primary mouse islets increases Mct1 mRNA levels, demonstrating that miR-29 isoforms contribute to the β-cell-specific silencing of the MCT1 transporter and may thus affect insulin release.

The Dauki Thrust Fault and the Shillong Anticline: An incipient plate boundary in NE India?

NASA Astrophysics Data System (ADS)

Ferguson, E. K.; Seeber, L.; Steckler, M. S.; Akhter, S. H.; Mondal, D.; Lenhart, A.

2012-12-01

The Shillong Massif is a regional contractional structure developing across the Assam sliver of the Indian plate near the Eastern Syntaxis between the Himalaya and Burma arcs. Faulting associated with the Shillong Massif is a major source of earthquake hazard. The massif is a composite basement-cored asymmetric anticline and is 100km wide, >350km long and 1.8km high. The high relief southern limb preserves a Cretaceous-Paleocene passive margin sequence despite extreme rainfall while the gentler northern limb is devoid of sedimentary cover. This asymmetry suggests southward growth of the structure. The Dauki fault along the south limb builds this relief. From the south-verging structure, we infer a regional deeply-rooted north-dipping blind thrust fault. It strikes E-W and obliquely intersects the NE-SW margin of India, thus displaying three segments: Western, within continental India; Central, along the former passive margin; and Eastern, overridden by the west-verging Burma accretion system. We present findings from recent geologic fieldwork on the western and central segments. The broadly warped erosional surface of the massif defines a single anticline in the central segment, east of the intersection with the hinge zone of the continental margin buried by the Ganges-Brahmaputra Delta. The south limb of the anticline forms a steep topographic front, but is even steeper structurally as defined by the Cretaceous-Eocene cover. Below it, Sylhet Trap Basalts intrude and cover Precambrian basement. Dikes, presumably parallel to the rifted margin, are also parallel to the front, suggesting thrust reactivation of rift-related faults. Less competent Neogene clastics are preserved only near the base of the mountain front. Drag folds in these rocks suggest north-vergence and a roof thrust above a blind thrust wedge floored by the Dauki thrust fault. West of the hinge zone, the contractional structure penetrates the Indian continent and bifurcates. After branching into the Dapsi Fault, the Dauki Fault continues westward as the erosion-deposition boundary combined with a belt of N-S shortening. The Dapsi thrust fault strikes WNW across the Shillong massif and dips NNE. It is mostly blind below a topographically expressed fold involving basement and passive-margin cover. Recent fieldwork has shown that the fault is better exposed in the west, where eventually Archean basement juxtaposes folded and steeply dipping fluvial sediment. Both Dauki and Dapsi faults probably continue beyond the Brahmaputra River, where extreme fluvial processes mask them. The area between the two faults is a gentle southward monocline with little or no shortening. Thus uplift of this area stems from slip on the Dauki thrust fault, not from pervasive shortening. The Burma foldbelt overrides the Shillong Plateau and is warped but continuous across the eastern segment of the Dauki fault. The Haflong-Naga thrust front north of the Dauki merges with the fold-thrust belt in the Sylhet basin to the south, despite >150km of differential advance due to much greater advance of the accretionary prism in the basin. Where the Dauki and Haflong-Naga thrusts cross, the thrust fronts are nearly parallel and opposite vergence. We trace a Dauki-related topographic front eastward across the Burma Range. This and other evidence suggest that the Dauki Fault continues below the foldbelt.

Multistory duplexes with forward dipping roofs, north central Brooks Range, Alaska

USGS Publications Warehouse

Wallace, W.K.; Moore, Thomas E.; Plafker, G.

1997-01-01

The Endicott Mountains allochthon has been thrust far northward over the North Slope parautochthon in the northern Brooks Range. Progressively younger units are exposed northward within the allochthon. To the south, the incompetent Hunt Fork Shale has thickened internally by asymmetric folds and thrust faults. Northward, the competent Kanayut Conglomerate forms a duplex between a floor thrust in Hunt Fork and a roof thrust in the Kayak Shale. To the north, the competent Lisburne Group forms a duplex between a floor thrust in Kayak and a roof thrust in the Siksikpuk Formation. Both duplexes formed from north vergent detachment folds whose steep limbs were later truncated by south dipping thrust faults that only locally breach immediately overlying roof thrusts. Within the parautochthon, the Kayak, Lisburne, and Siksikpuk-equivalent Echooka Formation form a duplex identical to that in the allochthon. This duplex is succeeded abruptly northward by detachment folds in Lisburne. These folds are parasitic to an anticlinorium interpreted to reflect a fault-bend folded horse in North Slope "basement," with a roof thrust in Kayak and a floor thrust at depth. These structures constitute two northward tapered, internally deformed wedges that are juxtaposed at the base of the allochthon. Within each wedge, competent units have been shortened independently between detachments, located mainly in incompetent units. The basal detachment of each wedge cuts upsection forward (northward) to define a wedge geometry within which units dip regionally forward. These dips reflect forward decrease in internal structural thickening by forward vergent folds and hindward dipping thrust faults. Copyright 1997 by the American Geophysical Union.

Constraints on the tectonics of the Mule Mountains Thrust System, southeast California and southwest Arizona

NASA Astrophysics Data System (ADS)

Tosdal, Richard M.

1990-11-01

The Mule Mountains thrust system crops out discontinuously over a 100-km-strike length in the Blythe-Quartzsite region of southeast California and southwest Arizona. Along the thrust system, middle and upper crustal metamorphic and plutonic rocks of Proterozoic and Mesozoic age are thrust north-northeastward (015° to 035°) over a lower plate metamorphic terrane that formed part of the Proterozoic North American craton, its Paleozoic sedimentary rock cover, overlying Mesozoic volcanic and sedimentary rocks, and the intruding Jurassic and Cretaceous granitic rocks. Stratigraphic, petrologic, and Pb isotopic ties for Jurassic granitoids and for Jurassic(?) and Cretaceous sedimentary rocks across the various parts of the thrust system indicate that related crustal blocks are superposed and preclude it from having large displacements. The thick-skinned thrust system is structurally symmetrical along its length with a central domain of synmetamorphic thrust faults that are flanked by western and eastern domains where lower plate synclines underlie the thrusts. Deformation occurred under low greenschist facies metamorphic conditions in the upper crust. Movement along the thrust system was probably limited to no more than a few tens of kilometers and occurred between 79±2 Ma and 70±4 Ma. The superposition of related rocks and the geometry of the thrust system preclude it from being a major tectonic boundary of post-Middle Jurassic age, as has been previously proposed. Rather, the thrust system forms the southern boundary of the narrow zone of Cretaceous intracratonic deformation, and it is one of the last tectonic events in the zone prior to regional cooling.

How the structural architecture of the Eurasian continental margin affects the structure, seismicity, and topography of the south central Taiwan fold-and-thrust belt

NASA Astrophysics Data System (ADS)

Brown, Dennis; Alvarez-Marron, Joaquina; Biete, Cristina; Kuo-Chen, Hao; Camanni, Giovanni; Ho, Chun-Wei

2017-07-01

Studies of mountain belts worldwide show that along-strike changes are common in their foreland fold-and-thrust belts. These are typically caused by processes related to fault reactivation and/or fault focusing along changes in sedimentary sequences. The study of active orogens, like Taiwan, can also provide insights into how these processes influence transient features such as seismicity and topography. In this paper, we trace regional-scale features from the Eurasian continental margin in the Taiwan Strait into the south central Taiwan fold-and-thrust belt. We then present newly mapped surface geology, P wave velocity maps and sections, seismicity, and topography data to test the hypothesis of whether or not these regional-scale features of the margin are contributing to along-strike changes in structural style, and the distribution of seismicity and topography in this part of the Taiwan fold-and-thrust belt. These data show that the most important along-strike change takes place at the eastward prolongation of the upper part of the margin necking zone, where there is a causal link between fault reactivation, involvement of basement in the thrusting, concentration of seismicity, and the formation of high topography. On the area correlated with the necking zone, the strike-slip reactivation of east northeast striking extensional faults is causing sigmoidal offset of structures and topography along two main zones. Here basement is not involved in the thrusting; there is weak focusing of seismicity and localized development of topography. We also show that there are important differences in structure, seismicity, and topography between the margin shelf and its necking zone.

A geologic history of the north-central Appalachians, part 3. The Alleghany orogeny

USGS Publications Warehouse

Faill, R.T.

1998-01-01

The north-central Appalachians occupy a critical position within the 3000+ km-long Appalachian orogen, lying southwest of the boundary between the central and northern Appalachians (CNAB). The one-billion-year-long history of tectonic activity in eastern Laurentia includes the creation and evolution of the Appalachian orogen during the Paleozoic and the Mesozoic transformation of the orogen into a passive margin during Pangea's disassembly. A most important ingredient in the evolution of the orogen was the Alleghany orogeny, which was driven by the convergence and collision between Laurentia (Laurussia) and West Gondwana (Africa). The Alleghany orogeny in the central and southern Appalachians was a de??collement tectonism that involved a larger part of eastern Laurentia than had the previous three orogenies. The fundamental element was a very low-angle thrust (de??collement) that originated in mid-crustal levels east of the presently-exposed Appalachians and rose westwardly to progressively higher levels in the upper crust and the supra-crustal Paleozoic section. Alleghany deformation was widely developed in the hanging-wall block (allochthon), primarily in the form of thrust faults and fold-and-thrust structures, both of which splayed upward from the basal de??collement. The youngest manifestations of the Alleghany orogeny were northeast-trending strike-slip faults and dextral shear zones in the Piedmont. In the north-central Appalachians, the exposed allochthon consists of two parts: the sedimentary externides (Appalachian Plateau and Valley and Ridge provinces) and the crystalline externides (Reading Prong, Blue Ridge belt, and Piedmont province). Long, thrust-cored anticlines predominate in the sedimentary externides. A widespread layer-parallel shortening preceded the folding; it is largely coaxial with the folding but extends considerably farther to the northwest toward the craton. It is hypothesized that the folding developed in reverse order, sequentially from the northwest to the southeast The crystalline externides are dominated by low-angle thrust faults and upright folds trending east-northeast The first-order Valley and Ridge folds on the northwest side acted as a buttress and diverted the crystalline externides rocks north-northwestwardly, onto the topographic low area over the Anthracite region. This thrusting of the crystalline externides caused anthracitization of the coals within the Pennsylvanian rocks there. Metamorphism and magmatism were significant events during the earlier phase of the Alleghany orogeny in the southern Appalachians. Whatever magmatism and medium-to high-grade metamorphism developed in the north-central Appalachians are in the covered internides to the southeast. The Alleghany orogeny of the north-central Appalachians occurred during the Early Permian. Erosion of anticlinal crests probably began as the folds grew, with accumulation of this locally-derived sediment in the intervening synclines. A regional alluvial plain coalesced above the partially-eroded externides structures as erosion of the pre-Alleghany highland and the Alleghany hinterland mountains continued to the southeast, spreading sediment to the northwest. This erosion and northwest transport probably persisted, with diminishing intensity, throughout the remainder of the Permian and into the Mesozoic, and changed only with the beginning of crustal extension during the Late Triassic.

Hermatically sealed motor blower unit with stator inside hollow armature

DOEpatents

Donelian, Khatchik O.

1976-01-20

13. A hermetically sealed motor blower unit comprising, in combination, a sealed housing having a thrust plate mounted therein and having a re-entrant wall forming a central cavity in said housing, a rotor within said housing, said rotor comprising an impeller, a hollow shaft embracing said cavity and a thrust collar adapted to cooperate with said thrust plate to support the axial thrust of said shaft, one or more journal bearings within said housing for supporting the radial load of said shaft and electric motor means for rotating said rotor, said motor means comprising a motor-stator located within said cavity and adapted to cooperate through a portion of said re-entrant wall with a motor-rotor mounted within said hollow shaft, the portion of said re-entrant wall located between said motor-stator and said motor-rotor being made relatively thin to reduce electrical losses, the bearing surfaces of said thrust plate, thrust collar and journal bearings being in communication with the discharge of said impeller, whereby fluid pumped by said impeller can flow directly to said bearing surfaces to lubricate them.

Joint Terminal Attack Controllers Sensors and Lasers Modernization

DTIC Science & Technology

2012-09-01

and Evaluation Activity MCSC Marine Corps Systems Command MCT Marine Corps Task MCTL Marine Corps Task List MEMS MicroElectroMechanical Systems...functional relationship of the key performance requirements was associated to Marine Corps Tasks ( MCT ), Critical Operational Issues (COIs...to an accomplishment of mission objectives and achievement of desired results [5]. All COIs are linked to a MCT , which are provided within the

Development of occlusive neointimal lesions in distal pulmonary arteries of endothelin B receptor-deficient rats: a new model of severe pulmonary arterial hypertension.

PubMed

Ivy, D Dunbar; McMurtry, Ivan F; Colvin, Kelley; Imamura, Masatoshi; Oka, Masahiko; Lee, Dong-Seok; Gebb, Sarah; Jones, Peter Lloyd

2005-06-07

Human pulmonary arterial hypertension (PAH) is characterized by proliferation of vascular smooth muscle and, in its more severe form, by the development of occlusive neointimal lesions. However, few animal models of pulmonary neointimal proliferation exist, thereby limiting a complete understanding of the pathobiology of PAH. Recent studies of the endothelin (ET) system demonstrate that deficiency of the ET(B) receptor predisposes adult rats to acute and chronic hypoxic PAH, yet these animals fail to develop neointimal lesions. Herein, we determined and thereafter showed that exposure of ET(B) receptor-deficient rats to the endothelial toxin monocrotaline (MCT) leads to the development of neointimal lesions that share hallmarks of human PAH. The pulmonary hemodynamic and morphometric effects of 60 mg/kg MCT in control (MCT(+/+)) and ET(B) receptor-deficient (MCT(sl/sl)) rats at 6 weeks of age were assessed. MCT(sl/sl) rats developed more severe PAH, characterized by elevated pulmonary artery pressure, diminished cardiac output, and right ventricular hypertrophy. In MCT(sl/sl) rats, morphometric evaluation revealed the presence of neointimal lesions within small distal pulmonary arteries, increased medial wall thickness, and decreased arterial-to-alveolar ratio. In keeping with this, barium angiography revealed diminished distal pulmonary vasculature of MCT(sl/sl) rat lungs. Cells within neointimal lesions expressed smooth muscle and endothelial cell markers. Moreover, cells within neointimal lesions exhibited increased levels of proliferation and were located in a tissue microenvironment enriched with vascular endothelial growth factor, tenascin-C, and activated matrix metalloproteinase-9, factors already implicated in human PAH. Finally, assessment of steady state mRNA showed that whereas expression of ET(B) receptors was decreased in MCT(sl/sl) rat lungs, ET(A) receptor expression increased. Deficiency of the ET(B) receptor markedly accelerates the progression of PAH in rats treated with MCT and enhances the appearance of cellular and molecular markers associated with the pathobiology of PAH. Collectively, these results suggest an overall antiproliferative effect of the ET(B) receptor in pulmonary vascular homeostasis.

Further Insights into the Allan-Herndon-Dudley Syndrome: Clinical and Functional Characterization of a Novel MCT8 Mutation.

PubMed

Armour, Christine M; Kersseboom, Simone; Yoon, Grace; Visser, Theo J

2015-01-01

Mutations in the thyroid hormone (TH) transporter MCT8 have been identified as the cause for Allan-Herndon-Dudley Syndrome (AHDS), characterized by severe psychomotor retardation and altered TH serum levels. Here we report a novel MCT8 mutation identified in 4 generations of one family, and its functional characterization. Proband and family members were screened for 60 genes involved in X-linked cognitive impairment and the MCT8 mutation was confirmed. Functional consequences of MCT8 mutations were studied by analysis of [125I]TH transport in fibroblasts and transiently transfected JEG3 and COS1 cells, and by subcellular localization of the transporter. The proband and a male cousin demonstrated clinical findings characteristic of AHDS. Serum analysis showed high T3, low rT3, and normal T4 and TSH levels in the proband. A MCT8 mutation (c.869C>T; p.S290F) was identified in the proband, his cousin, and several female carriers. Functional analysis of the S290F mutant showed decreased TH transport, metabolism and protein expression in the three cell types, whereas the S290A mutation had no effect. Interestingly, both uptake and efflux of T3 and T4 was impaired in fibroblasts of the proband, compared to his healthy brother. However, no effect of the S290F mutation was observed on TH efflux from COS1 and JEG3 cells. Immunocytochemistry showed plasma membrane localization of wild-type MCT8 and the S290A and S290F mutants in JEG3 cells. We describe a novel MCT8 mutation (S290F) in 4 generations of a family with Allan-Herndon-Dudley Syndrome. Functional analysis demonstrates loss-of-function of the MCT8 transporter. Furthermore, our results indicate that the function of the S290F mutant is dependent on cell context. Comparison of the S290F and S290A mutants indicates that it is not the loss of Ser but its substitution with Phe, which leads to S290F dysfunction.

High-Intensity Interval Training in Patients With Heart Failure With Reduced Ejection Fraction

PubMed Central

Halle, Martin; Conraads, Viviane; Støylen, Asbjørn; Dalen, Håvard; Delagardelle, Charles; Larsen, Alf-Inge; Hole, Torstein; Mezzani, Alessandro; Van Craenenbroeck, Emeline M.; Videm, Vibeke; Beckers, Paul; Christle, Jeffrey W.; Winzer, Ephraim; Mangner, Norman; Woitek, Felix; Höllriegel, Robert; Pressler, Axel; Monk-Hansen, Tea; Snoer, Martin; Feiereisen, Patrick; Valborgland, Torstein; Kjekshus, John; Hambrecht, Rainer; Gielen, Stephan; Karlsen, Trine; Prescott, Eva; Linke, Axel

2017-01-01

Background: Small studies have suggested that high-intensity interval training (HIIT) is superior to moderate continuous training (MCT) in reversing cardiac remodeling and increasing aerobic capacity in patients with heart failure with reduced ejection fraction. The present multicenter trial compared 12 weeks of supervised interventions of HIIT, MCT, or a recommendation of regular exercise (RRE). Methods: Two hundred sixty-one patients with left ventricular ejection fraction ≤35% and New York Heart Association class II to III were randomly assigned to HIIT at 90% to 95% of maximal heart rate, MCT at 60% to 70% of maximal heart rate, or RRE. Thereafter, patients were encouraged to continue exercising on their own. Clinical assessments were performed at baseline, after the intervention, and at follow-up after 52 weeks. Primary end point was a between-group comparison of change in left ventricular end-diastolic diameter from baseline to 12 weeks. Results: Groups did not differ in age (median, 60 years), sex (19% women), ischemic pathogenesis (59%), or medication. Change in left ventricular end-diastolic diameter from baseline to 12 weeks was not different between HIIT and MCT (P=0.45); left ventricular end-diastolic diameter changes compared with RRE were −2.8 mm (−5.2 to −0.4 mm; P=0.02) in HIIT and −1.2 mm (−3.6 to 1.2 mm; P=0.34) in MCT. There was also no difference between HIIT and MCT in peak oxygen uptake (P=0.70), but both were superior to RRE. However, none of these changes was maintained at follow-up after 52 weeks. Serious adverse events were not statistically different during supervised intervention or at follow-up at 52 weeks (HIIT, 39%; MCT, 25%; RRE, 34%; P=0.16). Training records showed that 51% of patients exercised below prescribed target during supervised HIIT and 80% above target in MCT. Conclusions: HIIT was not superior to MCT in changing left ventricular remodeling or aerobic capacity, and its feasibility remains unresolved in patients with heart failure. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00917046. PMID:28082387

High-Intensity Interval Training in Patients With Heart Failure With Reduced Ejection Fraction.

PubMed

Ellingsen, Øyvind; Halle, Martin; Conraads, Viviane; Støylen, Asbjørn; Dalen, Håvard; Delagardelle, Charles; Larsen, Alf-Inge; Hole, Torstein; Mezzani, Alessandro; Van Craenenbroeck, Emeline M; Videm, Vibeke; Beckers, Paul; Christle, Jeffrey W; Winzer, Ephraim; Mangner, Norman; Woitek, Felix; Höllriegel, Robert; Pressler, Axel; Monk-Hansen, Tea; Snoer, Martin; Feiereisen, Patrick; Valborgland, Torstein; Kjekshus, John; Hambrecht, Rainer; Gielen, Stephan; Karlsen, Trine; Prescott, Eva; Linke, Axel

2017-02-28

Small studies have suggested that high-intensity interval training (HIIT) is superior to moderate continuous training (MCT) in reversing cardiac remodeling and increasing aerobic capacity in patients with heart failure with reduced ejection fraction. The present multicenter trial compared 12 weeks of supervised interventions of HIIT, MCT, or a recommendation of regular exercise (RRE). Two hundred sixty-one patients with left ventricular ejection fraction ≤35% and New York Heart Association class II to III were randomly assigned to HIIT at 90% to 95% of maximal heart rate, MCT at 60% to 70% of maximal heart rate, or RRE. Thereafter, patients were encouraged to continue exercising on their own. Clinical assessments were performed at baseline, after the intervention, and at follow-up after 52 weeks. Primary end point was a between-group comparison of change in left ventricular end-diastolic diameter from baseline to 12 weeks. Groups did not differ in age (median, 60 years), sex (19% women), ischemic pathogenesis (59%), or medication. Change in left ventricular end-diastolic diameter from baseline to 12 weeks was not different between HIIT and MCT ( P =0.45); left ventricular end-diastolic diameter changes compared with RRE were -2.8 mm (-5.2 to -0.4 mm; P =0.02) in HIIT and -1.2 mm (-3.6 to 1.2 mm; P =0.34) in MCT. There was also no difference between HIIT and MCT in peak oxygen uptake ( P =0.70), but both were superior to RRE. However, none of these changes was maintained at follow-up after 52 weeks. Serious adverse events were not statistically different during supervised intervention or at follow-up at 52 weeks (HIIT, 39%; MCT, 25%; RRE, 34%; P =0.16). Training records showed that 51% of patients exercised below prescribed target during supervised HIIT and 80% above target in MCT. HIIT was not superior to MCT in changing left ventricular remodeling or aerobic capacity, and its feasibility remains unresolved in patients with heart failure. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00917046. © 2017 The Authors.

MCT4 surpasses the prognostic relevance of the ancillary protein CD147 in clear cell renal cell carcinoma.

PubMed

Fisel, Pascale; Stühler, Viktoria; Bedke, Jens; Winter, Stefan; Rausch, Steffen; Hennenlotter, Jörg; Nies, Anne T; Stenzl, Arnulf; Scharpf, Marcus; Fend, Falko; Kruck, Stephan; Schwab, Matthias; Schaeffeler, Elke

2015-10-13

Cluster of differentiation 147 (CD147/BSG) is a transmembrane glycoprotein mediating oncogenic processes partly through its role as binding partner for monocarboxylate transporter MCT4/SLC16A3. As demonstrated for MCT4, CD147 is proposed to be associated with progression in clear cell renal cell carcinoma (ccRCC). In this study, we evaluated the prognostic relevance of CD147 in comparison to MCT4/SLC16A3 expression and DNA methylation. CD147 protein expression was assessed in two independent ccRCC-cohorts (n = 186, n = 59) by immunohistochemical staining of tissue microarrays and subsequent manual as well as automated software-supported scoring (Tissue Studio, Definien sAG). Epigenetic regulation of CD147 was investigated using RNAseq and DNA methylation data of The Cancer Genome Atlas. These results were validated in our cohort. Relevance of prognostic models for cancer-specific survival, comprising CD147 and MCT4 expression or SLC16A3 DNA methylation, was compared using chi-square statistics. CD147 protein expression generated with Tissue Studio correlated significantly with those from manual scoring (P < 0.0001, rS = 0.85), indicating feasibility of software-based evaluation exemplarily for the membrane protein CD147 in ccRCC. Association of CD147 expression with patient outcome differed between cohorts. DNA methylation in the CD147/BSG promoter was not associated with expression. Comparison of prognostic relevance of CD147/BSG and MCT4/SLC16A3, showed higher significance for MCT4 expression and superior prognostic power for DNA methylation at specific CpG-sites in the SLC16A3 promoter (e.g. CD147 protein: P = 0.7780,Harrell's c-index = 53.7% vs. DNA methylation: P = 0.0076, Harrell's c-index = 80.0%). Prognostic significance of CD147 protein expression could not surpass that of MCT4, especially of SLC16A3 DNA methylation, corroborating the role of MCT4 as prognostic biomarker for ccRCC.

MCT4 surpasses the prognostic relevance of the ancillary protein CD147 in clear cell renal cell carcinoma

PubMed Central

Winter, Stefan; Rausch, Steffen; Hennenlotter, Jörg; Nies, Anne T.; Stenzl, Arnulf; Scharpf, Marcus; Fend, Falko; Kruck, Stephan; Schwab, Matthias; Schaeffeler, Elke

2015-01-01

Cluster of differentiation 147 (CD147/BSG) is a transmembrane glycoprotein mediating oncogenic processes partly through its role as binding partner for monocarboxylate transporter MCT4/SLC16A3. As demonstrated for MCT4, CD147 is proposed to be associated with progression in clear cell renal cell carcinoma (ccRCC). In this study, we evaluated the prognostic relevance of CD147 in comparison to MCT4/SLC16A3 expression and DNA methylation. Methods CD147 protein expression was assessed in two independent ccRCC-cohorts (n = 186, n = 59) by immunohistochemical staining of tissue microarrays and subsequent manual as well as automated software-supported scoring (Tissue Studio, Definien sAG). Epigenetic regulation of CD147 was investigated using RNAseq and DNA methylation data of The Cancer Genome Atlas. These results were validated in our cohort. Relevance of prognostic models for cancer-specific survival, comprising CD147 and MCT4 expression or SLC16A3 DNA methylation, was compared using chi-square statistics. Results CD147 protein expression generated with Tissue Studio correlated significantly with those from manual scoring (P < 0.0001, rS = 0.85), indicating feasibility of software-based evaluation exemplarily for the membrane protein CD147 in ccRCC. Association of CD147 expression with patient outcome differed between cohorts. DNA methylation in the CD147/BSG promoter was not associated with expression. Comparison of prognostic relevance of CD147/BSG and MCT4/SLC16A3, showed higher significance for MCT4 expression and superior prognostic power for DNA methylation at specific CpG-sites in the SLC16A3 promoter (e.g. CD147 protein: P = 0.7780, Harrell's c-index = 53.7% vs. DNA methylation: P = 0.0076, Harrell's c-index = 80.0%). Conclusions Prognostic significance of CD147 protein expression could not surpass that of MCT4, especially of SLC16A3 DNA methylation, corroborating the role of MCT4 as prognostic biomarker for ccRCC. PMID:26384346

Further Insights into the Allan-Herndon-Dudley Syndrome: Clinical and Functional Characterization of a Novel MCT8 Mutation

PubMed Central

Yoon, Grace; Visser, Theo J.

2015-01-01

Background Mutations in the thyroid hormone (TH) transporter MCT8 have been identified as the cause for Allan-Herndon-Dudley Syndrome (AHDS), characterized by severe psychomotor retardation and altered TH serum levels. Here we report a novel MCT8 mutation identified in 4 generations of one family, and its functional characterization. Methods Proband and family members were screened for 60 genes involved in X-linked cognitive impairment and the MCT8 mutation was confirmed. Functional consequences of MCT8 mutations were studied by analysis of [125I]TH transport in fibroblasts and transiently transfected JEG3 and COS1 cells, and by subcellular localization of the transporter. Results The proband and a male cousin demonstrated clinical findings characteristic of AHDS. Serum analysis showed high T3, low rT3, and normal T4 and TSH levels in the proband. A MCT8 mutation (c.869C>T; p.S290F) was identified in the proband, his cousin, and several female carriers. Functional analysis of the S290F mutant showed decreased TH transport, metabolism and protein expression in the three cell types, whereas the S290A mutation had no effect. Interestingly, both uptake and efflux of T3 and T4 was impaired in fibroblasts of the proband, compared to his healthy brother. However, no effect of the S290F mutation was observed on TH efflux from COS1 and JEG3 cells. Immunocytochemistry showed plasma membrane localization of wild-type MCT8 and the S290A and S290F mutants in JEG3 cells. Conclusions We describe a novel MCT8 mutation (S290F) in 4 generations of a family with Allan-Herndon-Dudley Syndrome. Functional analysis demonstrates loss-of-function of the MCT8 transporter. Furthermore, our results indicate that the function of the S290F mutant is dependent on cell context. Comparison of the S290F and S290A mutants indicates that it is not the loss of Ser but its substitution with Phe, which leads to S290F dysfunction. PMID:26426690

Exercise-induced changes in tumour LDH-B and MCT1 expression are modulated by oestrogen-related receptor alpha in breast cancer-bearing BALB/c mice.

PubMed

Aveseh, Malihe; Nikooie, Rohollah; Aminaie, Mohsen

2015-06-15

Monocarboxylate transporters (MCTs) and lactate dehydrogenase A (LDH-A) play important roles in sustaining the glycolytic phenotype seen in cancer. Endurance training improves aerobic capacity; however, whether endurance training alters the metabolic phenotype of a solid tumour, from the perspective of lactate metabolism, is yet to be proven. This study showed that endurance training decreases expression of the MCT1 basigin (CD147) and LDH-A , and also increases LDH-B expression in solid tumours and attenuates tumour lactate metabolism. Similar results for MCT1 and LDH-B were found with inhibition of the oestrogen-related receptor alpha (ERRα). The training effects were not additive to the ERRα effects on MCT1 and LDH-B expression in the tumour, which indicated that exercise-induced alterations in MCT1 and LDH-B expression were modulated by ERRα. These results suggest that endurance training could be a useful tool in cancer therapy, especially in basal-like and luminal-like breast carcinomas. Several factors, including overexpression of lactate dehydrogenase (LDH) and monocarboxylate transporters (MCTs), promote an aerobic lactate production that allows some cancer cells to sustain higher proliferation rates in hostile environments outside the cell. To elucidate the effect of endurance training on the metabolic phenotype of solid tumours, we focused on the tumour expression of LDH-A, LDH-B, MCT1, MCT4, oestrogen-related receptor alpha (ERRα) and LDH isozymes in control (C), trained (T), control+XCT790 (CX) and trained+XCT790 (TX) mice. First, we found that the metabolically altered tumours from the trained animals exhibited lower values for lactate concentration than the control group. The decreased lactate concentration was associated with a shift in the tumour LDH isozyme profile towards LDH-1. These exercise-induced changes were also associated with decreases in the expression of the tumour MCT1, ERRα and CD147 in the trained animals. Secondly, the inhibition of ERRα by treatment of MC4-L2 human breast cancer cells with XCT790 (inverse agonist ligand of ERRα) before injection into the animals not only increased LDH-B expression in the tumour, but also decreased MCT1 expression in the CX group in comparison to the C group. The effects of ERRα inhibition were not additive to the training effects on the expressions of MCT1 and LDH-B in the solid tumours. In conclusion, our results suggest that exercise-induced suppression of ERRα expression modulates alterations in solid tumour expression of LDH-B and MCT1 and contributes towards the prevention of tumour development. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

Morphotectonics of the central Muertos thrust belt and Muertos Trough (northeastern Caribbean)

USGS Publications Warehouse

Granja, Bruna J.L.; ten Brink, Uri S.; Carbó-Gorosabel, Andrés; Muñoz-Martín, A.; Gomez, Ballesteros M.

2009-01-01

Multibeam bathymetry data acquired during the 2005 Spanish R/V Hesp??rides cruise and reprocessed multichannel seismic profiles provide the basis for the analysis of the morphology and deformation in the central Muertos Trough and Muertos thrust belt. The Muertos Trough is an elongated basin developed where the Venezuelan Basin crust is thrusted under the Muertos fold-and-thrust belt. Structural variations along the Muertos Trough are suggested to be a consequence of the overburden of the asymmetrical thrust belt and by the variable nature of the Venezuelan Basin crust along the margin. The insular slope can be divided into three east-west trending slope provinces with high lateral variability which correspond to different accretion stages: 1) The lower slope is composed of an active sequence of imbricate thrust slices and closed fold axes, which form short and narrow accretionary ridges and elongated slope basins; 2) The middle slope shows a less active imbricate structure resulting in lower superficial deformation and bigger slope basins; 3) The upper slope comprises the talus region and extended terraces burying an island arc basement and an inactive imbricate structure. The talus region is characterized by a dense drainage network that transports turbidite flows from the islands and their surrounding carbonate platform areas to the slope basins and sometimes to the trough. In the survey area the accommodation of the ongoing east-west differential motion between the Hispaniola and the Puerto Rico-Virgin Islands blocks takes place by means of diffuse deformation. The asymmetrical development of the thrust belt is not related to the geological conditions in the foreland, but rather may be caused by variations in the geometry and movement of the backstop. The map-view curves of the thrust belt and the symmetry of the recesses suggest a main north-south convergence along the Muertos margin. The western end of the Investigator Fault Zone comprises a broad band of active normal faults which result in high instability of the upper insular slope. ?? 2009 Elsevier B.V.

A comparison of long-chain triglycerides and medium-chain triglycerides on weight loss and tumour size in a cachexia model.

PubMed Central

Tisdale, M. J.; Brennan, R. A.

1988-01-01

A comparison has been made between the ability of long-chain triglycerides (LCT) and medium-chain triglycerides (MCT) to prevent weight loss induced by the cachexia-inducing colon adenocarcinoma (MAC16) and to reduce tumour size. There was no difference in calorie consumption or nitrogen intake between the various groups. When compared with a normal control high carbohydrate, low fat diet, animals fed MCT showed a reduced weight loss and a marked reduction in tumour size. In contrast neither weight loss nor tumour size differed significantly from the controls in animals fed the LCT diet. An elevated plasma level of 3-hydroxybuturate was found only in the animals fed the MCT diets. Administration of LCT caused an increase in the plasma level of FFA, which was not observed in the MCT group. These results suggest that diets containing MCT would provide the best ketogenic regime to reverse the weight loss in cancer cachexia with a concomitant reduction in tumour size. PMID:3219268

Prospective and current secondary mathematics teachers' criteria for evaluating mathematical cognitive technologies

NASA Astrophysics Data System (ADS)

Smith, Ryan C.; Shin, Dongjo; Kim, Somin

2017-07-01

As technology becomes more ubiquitous in the mathematics classroom, teachers are being asked to incorporate it into their lessons more than ever before. The amount of resources available online is staggering and teachers need to be able to analyse and identify resources that would be most appropriate and effective with their students. This study examines the criteria prospective and current secondary mathematics teachers use and value most when evaluating mathematical cognitive technologies (MCTs). Results indicate all groups of participants developed criteria focused on how well an MCT represents the mathematics, student interaction and engagement with the MCT, and whether the MCT was user-friendly. However, none of their criteria focused on how well an MCT would reflect students' solution strategies or illuminate their thinking. In addition, there were some differences between the criteria created by participants with and without teaching experience, specifically the types of supports available in an MCT. Implications for mathematics teacher educators are discussed.

Growth characteristics of (100)HgCdTe layers in low-temperature MOVPE with ditertiarybutyltelluride

NASA Astrophysics Data System (ADS)

Yasuda, K.; Hatano, H.; Ferid, T.; Minamide, M.; Maejima, T.; Kawamoto, K.

1996-09-01

Low-temperature growth of (100)HgCdTe (MCT) layers in MOVPE has been studied using ditertiarybutyltelluride (DtBTe), dimethylcadmium (DMCd), and elementary mercury as precursors. MCT layers were grown at 275°C on (100)GaAs substrates. Growths were carried out in a vertical growth cell which has a narrow spacing between the substrate and cell ceiling. Using the growth cell, the Cd-composition ( x) of MCT layers was controlled over a wide range from 0 to 0.98 by the DMCd flow. The growth rate of the MCT layers was constant at 5 μm h -1 for the increased DMCd flow. Preferential Cd-incorporation into MCT layers and an increase of the growth rate were observed in the presence of mercury vapor. The growth characteristics were considered to be due to the alkyl-exchange reaction between DMCd and mercury. The electrical properties and crystallinity of grown layers were also evaluated, which showed that layers with high quality can be grown at 275°C.

Optimal orbit transfer suitable for large flexible structures

NASA Technical Reports Server (NTRS)

Chatterjee, Alok K.

1989-01-01

The problem of continuous low-thrust planar orbit transfer of large flexible structures is formulated as an optimal control problem with terminal state constraints. The dynamics of the spacecraft motion are treated as a point-mass central force field problem; the thrust-acceleration magnitude is treated as an additional state variable; and the rate of change of thrust-acceleration is treated as a control variable. To ensure smooth transfer, essential for flexible structures, an additional quadratic term is appended to the time cost functional. This term penalizes any abrupt change in acceleration. Numerical results are presented for the special case of a planar transfer.

Inhibition of hypothalamic MCT1 expression increases food intake and alters orexigenic and anorexigenic neuropeptide expression

PubMed Central

Elizondo-Vega, Roberto; Cortés-Campos, Christian; Barahona, María José; Carril, Claudio; Ordenes, Patricio; Salgado, Magdiel; Oyarce, Karina; García-Robles, María de los Angeles

2016-01-01

Hypothalamic glucosensing, which involves the detection of glucose concentration changes by brain cells and subsequent release of orexigenic or anorexigenic neuropeptides, is a crucial process that regulates feeding behavior. Arcuate nucleus (AN) neurons are classically thought to be responsible for hypothalamic glucosensing through a direct sensing mechanism; however, recent data has shown a metabolic interaction between tanycytes and AN neurons through lactate that may also be contributing to this process. Monocarboxylate transporter 1 (MCT1) is the main isoform expressed by tanycytes, which could facilitate lactate release to hypothalamic AN neurons. We hypothesize that MCT1 inhibition could alter the metabolic coupling between tanycytes and AN neurons, altering feeding behavior. To test this, we inhibited MCT1 expression using adenovirus-mediated transfection of a shRNA into the third ventricle, transducing ependymal wall cells and tanycytes. Neuropeptide expression and feeding behavior were measured in MCT1-inhibited animals after intracerebroventricular glucose administration following a fasting period. Results showed a loss in glucose regulation of orexigenic neuropeptides and an abnormal expression of anorexigenic neuropeptides in response to fasting. This was accompanied by an increase in food intake and in body weight gain. Taken together, these results indicate that MCT1 expression in tanycytes plays a role in feeding behavior regulation. PMID:27677351

Inhibition of hypothalamic MCT1 expression increases food intake and alters orexigenic and anorexigenic neuropeptide expression.

PubMed

Elizondo-Vega, Roberto; Cortés-Campos, Christian; Barahona, María José; Carril, Claudio; Ordenes, Patricio; Salgado, Magdiel; Oyarce, Karina; García-Robles, María de Los Angeles

2016-09-28

Hypothalamic glucosensing, which involves the detection of glucose concentration changes by brain cells and subsequent release of orexigenic or anorexigenic neuropeptides, is a crucial process that regulates feeding behavior. Arcuate nucleus (AN) neurons are classically thought to be responsible for hypothalamic glucosensing through a direct sensing mechanism; however, recent data has shown a metabolic interaction between tanycytes and AN neurons through lactate that may also be contributing to this process. Monocarboxylate transporter 1 (MCT1) is the main isoform expressed by tanycytes, which could facilitate lactate release to hypothalamic AN neurons. We hypothesize that MCT1 inhibition could alter the metabolic coupling between tanycytes and AN neurons, altering feeding behavior. To test this, we inhibited MCT1 expression using adenovirus-mediated transfection of a shRNA into the third ventricle, transducing ependymal wall cells and tanycytes. Neuropeptide expression and feeding behavior were measured in MCT1-inhibited animals after intracerebroventricular glucose administration following a fasting period. Results showed a loss in glucose regulation of orexigenic neuropeptides and an abnormal expression of anorexigenic neuropeptides in response to fasting. This was accompanied by an increase in food intake and in body weight gain. Taken together, these results indicate that MCT1 expression in tanycytes plays a role in feeding behavior regulation.

Medium chain triglycerides (MCT) in aging and arteriosclerosis.

PubMed

Kaunitz, H

1986-01-01

Some of the nutritional work with triglycerides consisting mainly of C8 and C10 fatty acids (MCT) lends itself to speculations about their influence on arteriosclerosis. Arteriosclerosis is thought to be part of the normal aging process which is due to age associated molecular biological changes. The lipid theory of arteriosclerosis is rejected. Pertinent studies with MCT include these observations. Feeding of MCT to rats resulted in animals of low body weight, small fat deposits and excellent survival rate. This deserves emphasis because of the beneficial influence of low body weight on aging and arteriosclerosis. MCT feeding was associated with low linoleate and low tocopherol requirements in rats. This may lead to reduced formation of those linoleate derived prostaglandins which favor thrombosis formation. Lower linoleate requirements may also lead to the presence of fewer uncontrolled free radicals in the cells. MCT feeding is associated with low levels of serum and liver cholesterol involving speculations that tissue conditions are such that an adaptive increase of cholesterol is unnecessary. The Demographic Yearbook of the United Nations (1978) reported that Sri Lanka has the lowest death rate from ischemic heart disease. Sri Lanka is the only of the countries giving reliable data where coconut oil (containing over 50% medium chain fatty acids) is the main dietary fat.

Hyaluronan, CD44, and Emmprin Regulate Lactate Efflux and Membrane Localization of Monocarboxylate Transporters in Human Breast Carcinoma Cells

PubMed Central

Slomiany, Mark G.; Grass, G. Daniel; Robertson, Angela D.; Yang, Xiao Y.; Maria, Bernard L.; Beeson, Craig; Toole, Bryan P.

2013-01-01

Interactions of hyaluronan with CD44 in tumor cells play important cooperative roles in various aspects of malignancy and drug resistance. Emmprin (CD147; basigin)is a cell surface glycoprotein of the immunoglobulin superfamily that is highly up-regulated in malignant cancer cells and stimulates hyaluronan production, as well as several downstream signaling pathways. Emmprin also interacts with various monocarboxylate transporters (MCT). Malignant cancer cells use the glycolytic pathway and require MCTs to efflux lactate that results from glycolysis. Glycolysis and lactate secretion contribute to malignant cell behaviors and drug resistance in tumor cells. In the present study, we find that perturbation of endogenous hyaluronan, using small hyaluronan oligosaccharides, rapidly inhibits lactate efflux from breast carcinoma cells; down-regulation of emmprin, using emmprin small interfering RNA, also results in decreased efflux. In addition, we find that CD44 coimmunoprecipitates with MCT1, MCT4, and emmprin and colocalizes with these proteins at the plasma membrane. Moreover, after treatment of the cells with hyaluronan oligosaccharides, CD44, MCT1, and MCT4 become localized intracellularly whereas emmprin remains at the cell membrane. Together, these data indicate that constitutive interactions among hyaluronan, CD44, and emmprin contribute to regulation of MCT localization and function in the plasma membrane of breast carcinoma cells. PMID:19176383

Upregulation of GLUT-4 in right ventricle of rats with monocrotaline-induced pulmonary hypertension.

PubMed

Broderick, Tom L; King, Tiffany M

2008-12-01

Pulmonary hypertension is characterized by abnormal vascular remodeling leading to occlusion of pulmonary arteries and increased stress placed on the right ventricle (RV). This causes the RV to hypertrophy and eventually to failure. This study was designed to examine the effects of pulmonary hypertension in rats on right ventricular remodeling and glucose transporter protein (GLUT4) content in right (RV) and left ventricle (LV). Pulmonary hypertension was induced in male Sprague-Dawley rat by a single subcutaneous injection of monocrotaline (MCT) at the concentration of 60 mg/kg. Forty-six days following the injection of MCT, animals were sacrificed. MCT-treated rats displayed significant increases in lung weight and RV weight. Marked RV hypertrophy was evident as the ratio of the RV to LV plus septum weight was nearly 40% higher in MCT-treated rats compared to control rats. Total GLUT4 content from whole homogenates from the RV was increased by approximately 28% in MCT-treated hearts compared to control hearts. No differences, however, in the LV content between groups were observed. Our findings indicate that the structural remodeling of the RV in MCT-induced pulmonary hypertension results in the upregulation of glucose transporters. This increase in RV GLUT4 levels may potentially result in alterations in substrate energy metabolism.

Imaging Water in Deformed Quartzites: Examples from Caledonian and Himalayan Shear Zones

NASA Astrophysics Data System (ADS)

Kronenberg, Andreas; Ashley, Kyle; Hasnan, Hasnor; Holyoke, Caleb; Jezek, Lynna; Law, Richard; Thomas, Jay

2016-04-01

Infrared IR measurements of OH absorption bands due to water in deformed quartz grains have been collected from major shear zones of the Caledonian and Himalayan orogens. Mean intragranular water contents were determined from the magnitude of the broad OH absorption at 3400 cm-1 as a function of structural position, averaging over multiple grains, using an IR microscope coupled to a conventional FTIR spectrometer with apertures of 50-100 μm. Images of water content were generated by scanning areas of up to 4 mm2 of individual specimens with a 10 μm synchrotron-generated IR beam and contouring OH absorptions. Water contents vary with structural level relative to the central cores of shear zones and they vary at the grain scale corresponding to deformation and recrystallization microstructures. Gradients in quartz water content expressed over structural distances of 10 to 400 m from the centers of the Moine Thrust (Stack of Glencoul, NW Scotland), the Main Central Thrust (Sutlej valley of NW India), and the South Tibetan Detachment System (Rongbuk valley north of Mount Everest) indicate that these shear zones functioned as fluid conduits. However, the gradients differ substantially: in some cases, enhanced fluid fluxes appear to have increased quartz water contents, while in others, they served to decrease water contents. Water contents of Moine thrust quartzites appear to have been reduced during shear at greenschist facies by processes of regime II BLG/SGR dislocation creep. Intragranular water contents of the protolith 70 m below the central fault core are large (4078 ± 247 ppm, H/106 Si) while mylonites within 5 mm of the Moine hanging wall rocks have water contents of only 1570 (± 229) ppm. Water contents between these extremes vary systematically with structural level and correlate inversely with the extent of dynamic recrystallization (20 to 100%). Quartz intragranular water contents of Himalayan thrust and low-angle detachment zones sheared at upper amphibolite conditions by regime III GBM creep show varying trends with structural level. Water contents increase toward the Lhotse detachment of the Rongbuk valley, reaching 11,350 (± 1095) ppm, whereas they decrease toward the Main Central Thrust exposed in the western part of the Sutlej valley to values as low as 170 (± 25) ppm. Maps of intragranular water content correspond to populations of fluid inclusions, which depend on the history of deformation and dynamic recrystallization. Increases in water content require the introduction of secondary fluid inclusions, generally by brittle microcracking followed by crack healing and processes of inclusion redistribution documented in milky quartz experiments. Decreases in water content result from dynamic recrystallization, as mobile grain boundaries sweep through wet porphyroclasts, leaving behind dry recrystallized grains. Intragranular water contents throughout greenschist mylonites of the Moine thrust are comparable to those of quartz weakened by water in laboratory experiments. However, water contents of upper amphibolite mylonites of the Main Central Thrust are far below those required for water weakening at experimental strain rates and offer challenges to our understanding of quartz rheology.

Mapping from multiple-control Toffoli circuits to linear nearest neighbor quantum circuits

NASA Astrophysics Data System (ADS)

Cheng, Xueyun; Guan, Zhijin; Ding, Weiping

2018-07-01

In recent years, quantum computing research has been attracting more and more attention, but few studies on the limited interaction distance between quantum bits (qubit) are deeply carried out. This paper presents a mapping method for transforming multiple-control Toffoli (MCT) circuits into linear nearest neighbor (LNN) quantum circuits instead of traditional decomposition-based methods. In order to reduce the number of inserted SWAP gates, a novel type of gate with the optimal LNN quantum realization was constructed, namely NNTS gate. The MCT gate with multiple control bits could be better cascaded by the NNTS gates, in which the arrangement of the input lines was LNN arrangement of the MCT gate. Then, the communication overhead measurement model on inserted SWAP gate count from the original arrangement to the new arrangement was put forward, and we selected one of the LNN arrangements with the minimum SWAP gate count. Moreover, the LNN arrangement-based mapping algorithm was given, and it dealt with the MCT gates in turn and mapped each MCT gate into its LNN form by inserting the minimum number of SWAP gates. Finally, some simplification rules were used, which can further reduce the final quantum cost of the LNN quantum circuit. Experiments on some benchmark MCT circuits indicate that the direct mapping algorithm results in fewer additional SWAP gates in about 50%, while the average improvement rate in quantum cost is 16.95% compared to the decomposition-based method. In addition, it has been verified that the proposed method has greater superiority for reversible circuits cascaded by MCT gates with more control bits.

Effect of small hairpin RNA targeting endothelin-converting enzyme-1 in monocrotaline-induced pulmonary hypertensive rats.

PubMed

Son, Jae Sung; Kim, Kwan Chang; Kim, Bo Kyung; Cho, Min-Sun; Hong, Young Mi

2012-12-01

The purpose of this study was to investigate the therapeutic effects of small hairpin RNA (shRNA) targeting endothelin-converting enzyme (ECE)-1 in monocrotaline (MCT)-induced pulmonary hypertensive rats. Ninty-four Sprague-Dawley rats were divided into three groups: control (n = 24), MCT (n = 35) and shRNA (n = 35). Four-week survival rate in the shRNA group was significantly increased compared to that in the MCT group. The shRNA group showed a significant improvement of right ventricular (RV) pressure compared with the MCT group. The MCT and shRNA groups also showed an increase in RV/(left ventricle + septum) ratio and lung/body weight. Plasma endothelin (ET)-1 concentrations in the shRNA group were lower than those in the MCT group. Medial wall thickness of pulmonary arterioles were increased after MCT injection and was significantly decreased in the shRNA group. The number of intra-acinar muscular pulmonary arteries was decreased in the shRNA group. The mRNA expressions of ET-1 and ET receptor A (ET(A)) were significantly decreased in the shRNA group in week 4. The protein levels of ET(A) were decreased in the shRNA group in week 2. The protein levels of tumor necrosis factor-α and vascular endothelial growth factor were decreased in the shRNA group in week 4. In conclusion, the gene silencing with lentiviral vector targeting ECE-1 could be effective against hemodynamic, histopathological and gene expression changes in pulmonary hypertension.

Preliminary study of the safety and efficacy of medium-chain triglycerides for use as an intraocular tamponading agent in minipigs.

PubMed

Soler, Vincent J; Laurent, Camille; Sakr, Frédéric; Regnier, Alain; Tricoire, Cyrielle; Cases, Olivier; Kozyraki, Renata; Douet, Jean-Yves; Pagot-Mathis, Véronique

2017-08-01

To date, only silicone oils and gases have the appropriate characteristics for use in vitreo-retinal surgery as vitreous substitutes with intraocular tamponading properties. This preliminary study evaluated the safety and efficacy of medium-chain triglycerides (MCTs) for use as a tamponading agent in minipigs. In 15 minipigs, 15 right eyes underwent vitrectomies followed by injection of MCT tamponade (day 1). Two groups were defined. In Group A (ten eyes), the surgical procedure before MCT injection included induced rhegmatogenous retinal detachment (RRD), retina flattening, and retinopexy. In Group B (five eyes), MCT was injected without inducing RRD; in these eyes, MCT was removed on day 90. Pigs were sacrificed on day 45 (Group A) or 120 (Group B). Eyes were examined on days 1, 5, 15, and 45 in both groups and on days 90 and 120 in Group B. In Group B only, we performed bilateral electroretinography examinations on days 1 and 120, and histological examinations of MCTs and controlateral eyes were performed after sacrifice. In Group A eyes (n = 9; one eye was non-assessable), on day 45, the retina was flat in seven eyes and two RRD detachments were observed in insufficiently MCT-filled eyes. In Group B, electroretinography showed no significant differences between MCT eyes and controls on days 1 or 120. Histological analyses revealed no signs of retinal toxicity. This study showed that MCT tamponade seems to be effective and safe; however, additional studies are needed before it becomes commonly used as a tamponading agent in humans.

Differential expression of endothelial nutrient transporters (MCT1 and GLUT1) in the developing eyes of mice.

PubMed

Kishimoto, Ayuko; Takahashi-Iwanaga, Hiromi; Watanabe M, Masahiko; Iwanaga, Toshihiko

2016-12-01

The blood-brain barrier in the neonatal brain expresses the monocarboxylate transporter (MCT)-1 rather than the glucose transporter (GLUT)-1, due to the special energy supply during the suckling period. The hyaloid vascular system, consisting of the vasa hyaloidea propria and tunica vasculosa lentis, is a temporary vasculature present only during the early development of mammalian eyes and later regresses. Although the ocular vasculature manifests such a unique developmental process, no information is available concerning the expression of endothelial nutrient transporters in the developing eye. The present immunohistochemical study using whole mount preparations of murine eyes found that the hyaloid vascular system predominantly expressed GLUT1 in the endothelium, in contrast to the brain endothelium. Characteristically, the endothelium in peripheral regions of the neonatal hyaloid vessels displayed a mosaic pattern of MCT1-immunoreactive cells scattered within the GLUT1-expressing endothelium. The proper retinal vessels first developed by sprouting angiogenesis endowed with filopodia, which were absolutely free from the immunoreactivities of GLUT1 and MCT1. The remodeling retinal capillary networks and veins in the surface layer of the retina mainly expressed MCT1 until the weaning period. Immunostaining of MCT1 in the retina revealed fine radicular processes projecting from the endothelium, differing from the MCT1-immunonegative filopodia. These findings suggest that the expression of nutrient transporters in the ocular blood vessels is differentially regulated at a cellular level and that the neonatal eyes provide an interesting model for research on nutrient transporters in the endothelium. Copyright © 2016 Elsevier Ltd. All rights reserved.

miR-29a and miR-29b Contribute to Pancreatic β-Cell-Specific Silencing of Monocarboxylate Transporter 1 (Mct1) ▿ †

PubMed Central

Pullen, Timothy J.; da Silva Xavier, Gabriela; Kelsey, Gavin; Rutter, Guy A.

2011-01-01

In pancreatic β cells, elevated glucose concentrations stimulate mitochondrial oxidative metabolism to raise intracellular ATP/ADP levels, prompting insulin secretion. Unusually low levels of expression of genes encoding the plasma membrane monocarboxylate transporter, MCT1 (SLC16A1), as well as lactate dehydrogenase A (LDHA) ensure that glucose-derived pyruvate is efficiently metabolized by mitochondria, while exogenous lactate or pyruvate is unable to stimulate metabolism and hence insulin secretion inappropriately. We show here that whereas DNA methylation at the Mct1 promoter is unlikely to be involved in cell-type-specific transcriptional repression, three microRNAs (miRNAs), miR-29a, miR-29b, and miR-124, selectively target both human and mouse MCT1 3′ untranslated regions. Mutation of the cognate miR-29 or miR-124 binding sites abolishes the effects of the corresponding miRNAs, demonstrating a direct action of these miRNAs on the MCT1 message. However, despite reports of its expression in the mouse β-cell line MIN6, miR-124 was not detectably expressed in mature mouse islets. In contrast, the three isoforms of miR-29 are highly expressed and enriched in mouse islets. We show that inhibition of miR-29a in primary mouse islets increases Mct1 mRNA levels, demonstrating that miR-29 isoforms contribute to the β-cell-specific silencing of the MCT1 transporter and may thus affect insulin release. PMID:21646425

Evidence for medium chain triglycerides in the treatment of primary intestinal lymphangiectasia.

PubMed

Desai, A P; Guvenc, B H; Carachi, R

2009-08-01

Primary intestinal lymphangiectasia is an uncommon congenital anomaly. It is an intrinsic abnormality of the intestinal lymphatics system. Over the years, various treatment options such as diuretics, albumin transfusions and a medium chain triglycerides (MCT) diet as well as surgical options such as resection of isolated segments and peritoneal-venous shunts have been used. An MCT diet, which is a low fat, high protein diet, is increasingly used in the management of this anomaly. The aim was to review the evidence for medium chain triglycerides as a therapeutic option in patients with primary intestinal lymphangiectasia. A literature search was performed and individual case details were extracted. We found 55 cases, of which 3 were from our own institute. The cases were divided in 2 groups: Group A (n=27) consisted of patients treated with MCT, and Group B (n=28) consisted patients not treated with MCT. Cases were analysed for symptomatic response to MCT as well as mortality. 17 of 27 cases (63%) treated with MCT had complete resolution of symptoms while only 10 of 28 (35.7%) patients in group B showed complete resolution. Mortality for Group A was 1 out of 27 (3.7%), while mortality in group B was 5 of 28 (17.85%) patients. We conclude that, although an MCT diet is not completely curative in all cases, it does improve the symptoms of primary intestinal lymphangiectasia and reduces mortality. Hence it is a valid option in the paediatric age group. Copyright Georg Thieme Verlag KG Stuttgart . New York.

Increased Oxidative Metabolism and Neurotransmitter Cycling in the Brain of Mice Lacking the Thyroid Hormone Transporter Slc16a2 (Mct8)

PubMed Central

Rodrigues, Tiago B.; Ceballos, Ainhoa; Grijota-Martínez, Carmen; Nuñez, Barbara; Refetoff, Samuel; Cerdán, Sebastian; Morte, Beatriz; Bernal, Juan

2013-01-01

Mutations of the monocarboxylate transporter 8 (MCT8) cause a severe X-linked intellectual deficit and neurological impairment. MCT8 is a specific thyroid hormone (T4 and T3) transporter and the patients also present unusual abnormalities in the serum profile of thyroid hormone concentrations due to altered secretion and metabolism of T4 and T3. Given the role of thyroid hormones in brain development, it is thought that the neurological impairment is due to restricted transport of thyroid hormones to the target neurons. In this work we have investigated cerebral metabolism in mice with Mct8 deficiency. Adult male mice were infused for 30 minutes with (1-13C) glucose and brain extracts prepared and analyzed by 13C nuclear magnetic resonance spectroscopy. Genetic inactivation of Mct8 resulted in increased oxidative metabolism as reflected by increased glutamate C4 enrichment, and of glutamatergic and GABAergic neurotransmissions as observed by the increases in glutamine C4 and GABA C2 enrichments, respectively. These changes were distinct to those produced by hypothyroidism or hyperthyroidism. Similar increments in glutamate C4 enrichment and GABAergic neurotransmission were observed in the combined inactivation of Mct8 and D2, indicating that the increased neurotransmission and metabolic activity were not due to increased production of cerebral T3 by the D2-encoded type 2 deiodinase. In conclusion, Mct8 deficiency has important metabolic consequences in the brain that could not be correlated with deficiency or excess of thyroid hormone supply to the brain during adulthood. PMID:24098341

Increased oxidative metabolism and neurotransmitter cycling in the brain of mice lacking the thyroid hormone transporter SLC16A2 (MCT8).

PubMed

Rodrigues, Tiago B; Ceballos, Ainhoa; Grijota-Martínez, Carmen; Nuñez, Barbara; Refetoff, Samuel; Cerdán, Sebastian; Morte, Beatriz; Bernal, Juan

2013-01-01

Mutations of the monocarboxylate transporter 8 (MCT8) cause a severe X-linked intellectual deficit and neurological impairment. MCT8 is a specific thyroid hormone (T4 and T3) transporter and the patients also present unusual abnormalities in the serum profile of thyroid hormone concentrations due to altered secretion and metabolism of T4 and T3. Given the role of thyroid hormones in brain development, it is thought that the neurological impairment is due to restricted transport of thyroid hormones to the target neurons. In this work we have investigated cerebral metabolism in mice with Mct8 deficiency. Adult male mice were infused for 30 minutes with (1-(13)C) glucose and brain extracts prepared and analyzed by (13)C nuclear magnetic resonance spectroscopy. Genetic inactivation of Mct8 resulted in increased oxidative metabolism as reflected by increased glutamate C4 enrichment, and of glutamatergic and GABAergic neurotransmissions as observed by the increases in glutamine C4 and GABA C2 enrichments, respectively. These changes were distinct to those produced by hypothyroidism or hyperthyroidism. Similar increments in glutamate C4 enrichment and GABAergic neurotransmission were observed in the combined inactivation of Mct8 and D2, indicating that the increased neurotransmission and metabolic activity were not due to increased production of cerebral T3 by the D2-encoded type 2 deiodinase. In conclusion, Mct8 deficiency has important metabolic consequences in the brain that could not be correlated with deficiency or excess of thyroid hormone supply to the brain during adulthood.

Pathophysiology of infantile pulmonary arterial hypertension induced by monocrotaline.

PubMed

Dias-Neto, Marina; Luísa-Neves, Ana; Pinho, Sónia; Gonçalves, Nádia; Mendes, Maria; Eloy, Catarina; Lopes, José M; Gonçalves, Daniel; Ferreira-Pinto, Manuel; Leite-Moreira, Adelino F; Henriques-Coelho, Tiago

2015-06-01

Pediatric pulmonary arterial hypertension (PAH) presents certain specific features. In this specific age group, experimental models to study the pathophysiology of PAH are lacking. To characterize hemodynamic, morphometric, and histological progression as well as the expression of neurohumoral factors and regulators of cardiac transcription in an infantile model of PAH induced by monocrotaline (MCT), eight-day-old Wistar rats were randomly injected with MCT (30 mg/kg, sc, n = 95) or equal volume of saline solution (n = 92). Animals were instrumented for biventricular hemodynamic recording 7, 14, and 21 days after MCT, whereas samples were collected at 1, 3, 7, 14, and 21 days after MCT. Different time point postinjections were defined for further analysis. Hearts and lungs were collected for morphometric characterization, assessment of right- and left-ventricle (RV and LV) cardiomyocyte diameter and collagen type-I and type-III ratio, RV collagen volume fraction, and pulmonary vessels wall thickness. mRNA quantification was undertaken for brain natriuretic peptide (BNP), endothelin-1 (ET-1), and for cardiac transcription regulators (HOP and Islet1). Animals treated with MCT at the 8th day of life presented RV hypertrophy since day 14 after MCT injection. There were no differences on the RV collagen volume fraction or collagen type-I and type-III ratio. Pulmonary vascular remodelling and PAH were present on day 21, which were accompanied by an increased expression of BNP, ET-1, HOP, and Islet1. The infantile model of MCT-induced PAH can be useful for the study of its pathophysiology and to test new therapeutic targets in pediatric age group.

Treatment with medium chain fatty acids milk of CD36-deficient preschool children.

PubMed

Nagasaka, Hironori; Hirano, Ken-Ichi; Yorifuji, Tohru; Komatsu, Haruki; Takatani, Tomonozumi; Morioka, Ichiro; Hirayama, Satoshi; Miida, Takashi

2018-06-01

CD36 deficiency is characterized by limited cellular long chain fatty acid uptake in the skeletal and cardiac muscles and often causes energy crisis in these muscles. However, suitable treatment for CD36 deficiency remains to be established. The aim of this study was to evaluate the clinical and metabolic effects of medium chain triacylglycerols (MCTs) in two CD36-deficient preschool children who often developed fasting hypoglycemia and exercise-induced myalgia. Fasting blood glucose, total ketone bodies, and free fatty acids were examined and compared for usual supper diets and for diets with replacement of one component with 2 g/kg of 9% MCT-containing milk (MCT milk). Changes in serum creatine kinase and alanine aminotransferase levels, resulting from replacement of glucose water intake with 1 g/kg of MCT milk and determined by using bicycle pedaling tasks, were examined and compared. Hypoglycemic and/or myalgia episodes in daily life were also investigated. Biochemically, participants' blood glucose and total ketone bodies levels after overnight fasting substantially increased after dietary suppers containing MCT milk. Increases in serum creatine kinase and alanine aminotransferase levels resulting from the bicycle pedaling task were suppressed by MCT milk. Hypoglycemia leading to unconsciousness and tachycardia before breakfast decreased after introduction of dietary suppers containing MCT milk. Occurrence of myalgia in the lower limbs also decreased after intakes of MCT milk before long and/or strenuous exercising. Our results suggest that MCTs can prevent fasting hypoglycemia and exercise-induced myalgia in CD36-deficient young children. Copyright © 2017 Elsevier Inc. All rights reserved.

Mercury-Cadmium-Telluride Focal Plane Array Performance Under Non-Standard Operating Conditions

NASA Technical Reports Server (NTRS)

Richardson, Brandon S.; Eastwood, Michael L.; Bruce, Carl F.; Green, Robert O.; Coles, J. B.

2011-01-01

This paper highlights a new technique that allows the Teledyne Scientific & Imaging LLC TCM6604A Mercury-Cadmium-Telluride (MCT) Focal Plane Array (FPA) to operate at room temperature. The Teledyne MCT FPA has been a standard in Imaging Spectroscopy since its creation in the 1980's. This FPA has been used in applications ranging from space instruments such as CRISM, M3 and ARTEMIS to airborne instruments such as MaRS and the Next Generation AVIRIS Instruments1. Precise focal plane alignment is always a challenge for such instruments. The current FPA alignment process results in multiple cold cycles requiring week-long durations, thereby increasing the risk and cost of a project. These alignment cycles are necessary because optimal alignment is approached incrementally and can only be measured with the FPA and Optics at standard operating conditions, requiring a cold instrument. Instruments using this FPA are normally cooled to temperatures below 150K for the MCT FPA to properly function. When the FPA is run at higher temperatures the dark current increases saturating the output. This paper covers the prospect of warm MCT FPA operation from a theoretical and experimental perspective. We discuss the empirical models and physical laws that govern MCT material properties and predict the optimal settings that will result in the best MCT PA performance at 300K. Theoretical results are then calculated for the proposed settings. We finally present the images and data obtained using the actual system with the warm MCT FPA settings. The paper concludes by emphasizing the strong positive correlation between the measured values and the theoretical results.

Pharmacoeconomics of parenteral nutrition in surgical and critically ill patients receiving structured triglycerides in China.

PubMed

Wu, Guo Hao; Ehm, Alexandra; Bellone, Marco; Pradelli, Lorenzo

2017-01-01

A prior meta-analysis showed favorable metabolic effects of structured triglyceride (STG) lipid emulsions in surgical and critically ill patients compared with mixed medium-chain/long-chain triglycerides (MCT/LCT) emulsions. Limited data on clinical outcomes precluded pharmacoeconomic analysis. We performed an updated meta-analysis and developed a cost model to compare overall costs for STGs vs MCT/LCTs in Chinese hospitals. We searched Medline, Embase, Wanfang Data, the China Hospital Knowledge Database, and Google Scholar for clinical trials comparing STGs to mixed MCT/LCTs in surgical or critically ill adults published between October 10, 2013 and September 19, 2015. Newly identified studies were pooled with the prior studies and an updated meta-analysis was performed. A deterministic simulation model was used to compare the effects of STGs and mixed MCT/LCT's on Chinese hospital costs. The literature search identified six new trials, resulting in a total of 27 studies in the updated meta-analysis. Statistically significant differences favoring STGs were observed for cumulative nitrogen balance, pre- albumin and albumin concentrations, plasma triglycerides, and liver enzymes. STGs were also associated with a significant reduction in the length of hospital stay (mean difference, -1.45 days; 95% confidence interval, -2.48 to -0.43; p=0.005) versus mixed MCT/LCTs. Cost analysis demonstrated a net cost benefit of ¥675 compared with mixed MCT/LCTs. STGs are associated with improvements in metabolic function and reduced length of hospitalization in surgical and critically ill patients compared with mixed MCT/LCT emulsions. Cost analysis using data from Chinese hospitals showed a corresponding cost benefit.

Lack of toxicity by medium chain triglycerides (MCT) in canines during a 90-day feeding study.

PubMed

Matulka, Ray A; Thompson, D V M Larry; Burdock, George A

2009-01-01

Dietary fats in food are natural energy sources to animals and are included in the American Association of Feed Control Officials (AAFCO) manual as a requirement for dog food. Medium chain triglycerides are comprised of a glycerol backbone esterified to medium chain length (8-12 carbon) fatty acids (FA) and, in the context of this report, are all saturated FA. Unlike esterified long chain (>12 carbons) FA (long chain triglycerides or LCT), MCT are lower in caloric value, and are eliminated from the body more quickly than LCT. The objective of this study was to determine the safety of MCT when fed to beagles for 90 days at levels of 0%, 5%, 10%, and 15% MCT added to conventional feed. The beagles were monitored for signs of toxicity by clinical observations, body weight measurements, food consumption level, physical examinations, hematology and serum chemistry, ophthalmic examinations, and urinalysis. There were no signs of toxic effects observed in any of the animals that were related to feed, and the animal viability was 100% at the end of the study. Some animals exhibited significant increased blood urea nitrogen, potassium and cholesterol levels in the 10% and 15% MCT-fed groups. Also, in the same groups with elevated nitrogen, there were concomitant reductions in total blood protein and urine volumes. These changes in serum chemistry may be the result of protein sparing effects due to the high levels of MCT intake, and are not deemed to be pathological in nature. Animals receiving 15% MCT in feed had lower levels of food intake due to palatability issues. From the other examination parameters, there were no significant changes noted between groups receiving MCT and vehicle feed. No safety concerns were noted at any dose level, although an issue with palatability precluded identifying 15% as the highest dose level tested.

Mechanisms underlying modulation of monocarboxylate transporter 1 (MCT1) by somatostatin in human intestinal epithelial cells.

PubMed

Saksena, Seema; Theegala, Saritha; Bansal, Nikhil; Gill, Ravinder K; Tyagi, Sangeeta; Alrefai, Waddah A; Ramaswamy, Krishnamurthy; Dudeja, Pradeep K

2009-11-01

Somatostatin (SST), an important neuropeptide of the gastrointestinal tract has been shown to stimulate sodium chloride absorption and inhibit chloride secretion in the intestine. However, the effects of SST on luminal butyrate absorption in the human intestine have not been investigated. Earlier studies from our group and others have shown that monocarboxylate transporter (MCT1) plays an important role in the transport of butyrate in the human intestine. The present studies were undertaken to examine the effects of SST on butyrate uptake utilizing postconfluent human intestinal epithelial Caco2 cells. Apical SST treatment of Caco-2 cells for 30-60 min significantly increased butyrate uptake in a dose-dependent manner with maximal increase at 50 nM ( approximately 60%, P < 0.05). SST receptor 2 agonist, seglitide, mimicked the effects of SST on butyrate uptake. SST-mediated stimulation of butyrate uptake involved the p38 MAP kinase-dependent pathway. Kinetic studies demonstrated that SST increased the maximal velocity (V(max)) of the transporter by approximately twofold without any change in apparent Michaelis-Menten constant (K(m)). The higher butyrate uptake in response to SST was associated with an increase in the apical membrane levels of MCT1 protein parallel to a decrease in the intracellular MCT1 pool. MCT1 has been shown to interact specifically with CD147 glycoprotein/chaperone to facilitate proper expression and function of MCT1 at the cell surface. SST significantly enhanced the membrane levels of CD147 as well as its association with MCT1. This association was completely abolished by the specific p38 MAP kinase inhibitor, SB203580. Our findings demonstrate that increased MCT1 association with CD147 at the apical membrane in response to SST is p38 MAP kinase dependent and underlies the stimulatory effects of SST on butyrate uptake.

The adsorption of allergoids and 3-O-desacyl-4'-monophosphoryl lipid A (MPL®) to microcrystalline tyrosine (MCT) in formulations for use in allergy immunotherapy.

PubMed

Bell, A J; Heath, M D; Hewings, S J; Skinner, M A

2015-11-01

Infectious disease vaccine potency is affected by antigen adjuvant adsorption. WHO and EMA guidelines recommend limits and experimental monitoring of adsorption in vaccines and allergy immunotherapies. Adsorbed allergoids and MPL® in MATA-MPL allergy immunotherapy formulations effectively treat IgE mitigated allergy. Understanding vaccine antigen adjuvant adsorption allows optimisation of potency and should be seen as good practice; however current understanding is seldom applied to allergy immunotherapies. The allergoid and MPL® adsorption to MCT in MATA-MPL allergy immunotherapy formulations was experimental determination using specific allergen IgE allerginicity and MPL® content methods. Binding forces between MPL® and MCT were investigated by competition binding experiments. MATA-MPL samples with different allergoids gave results within 100-104% of the theoretical 50μg/mL MPL® content. Unmodified drug substance samples showed significant desirable IgE antigenicity, 1040-170 QAU/mL. MATA-MPL supernatant samples with different allergoids gave results of ≤2 μg/mL MPL® and ≤0.1-1.4 QAU/mL IgE antigenicity, demonstrating approximately ≥96 & 99% adsorption respectively. Allergoid and MPL® adsorption in different MATA-MPL allergy immunotherapy formulations is consistent and meets guideline recommendations. MCT formulations treated to disrupt electrostatic, hydrophobic and ligand exchange interactions, gave an MPL® content of ≤2 μg/mL in supernatant samples. MCT formulations treated to disrupt aromatic interactions, gave an MPL® content of 73-92 μg/mL in supernatant samples. MPL® adsorption to l-tyrosine in MCT formulations is based on interactions between the 2-deoxy-2-aminoglucose backbone on MPL® and aromatic ring of l-tyrosine in MCT, such as C-H⋯π interaction. MCT could be an alternative adjuvant depot for some infectious disease antigens. Copyright © 2015. Published by Elsevier Inc.

Lactate-H+ Transport Is a Significant Component of the In Vivo Corneal Endothelial Pump

PubMed Central

Nguyen, Tracy T.; Bonanno, Joseph A.

2012-01-01

Purpose. To confirm the expression of monocarboxylate transporters (MCT) 1, 2, and 4 in rabbit CE and to test the hypothesis that cellular buffering contributed by HCO3−, NBCe1, and carbonic anhydrase (CA) activity facilitates lactate-H+ efflux thereby controlling corneal hydration in vivo. Methods. MCT1–4 expression of rabbit endothelium was examined by Western blotting and immunofluorescence staining. Lactate-induced acidification (LIA) was measured in perfused CE in the presence and absence of HCO3− and acetazolamide (ACTZ) using tissue treated with siRNA specific to MCT1, 2, and 4. Corneal thickness and lactate concentration were measured in New Zealand White rabbits treated with the topical CA inhibitor Azopt, and from eyes that were injected intracamerally with ouabain, disodium 4,4′-diisothiocyanatostilbene-2,2′-disulfonate (DIDS), and shRNA specific to the 1Na+:2HCO3− cotransporter NBCe1. Results. MCT1 and MCT4 are localized to the lateral membrane, while MCT2 is apical. Cell pH measurements showed LIA in response to 40 mM lactate in bicarbonate free (BF) Ringer's that was inhibited by niflumic acid and by MCT siRNA knockdown, and significantly reduced in the presence of HCO3−. Lactate-dependent proton flux in vitro was not significantly greater in the presence of HCO3− or reduced by ACTZ. However, when active transport, NBCe1, or CA activity was disrupted in vivo, corneal edema ensued and was associated with significant corneal lactate accumulation. Conclusions. MCT1, 2, and 4 are expressed in rabbit CE on both the apical and basolateral surfaces and function to transport lactate-H+. Lactate-H+ flux is facilitated by active transport, HCO3− transport and CA activity, disruption of which causes corneal edema in vivo and indicates that facilitation of lactate efflux is a component of the endothelial pump. PMID:22410572

The Addition of Medium-Chain Triglycerides to a Purified Fish Oil Based Diet Alters Inflammatory Profiles in Mice

PubMed Central

Carlson, SJ; Nandivada, P; Chang, MI; Mitchell, PD; O’Loughlin, A; Cowan, E; Gura, KM; Nose, V; Bistrian, B; Puder, M

2014-01-01

Objective Parenteral nutrition associated liver disease (PNALD) is a deadly complication of long term parenteral nutrition (PN) use in infants. Fish oil-based lipid emulsion has been shown in recent years to effectively treat PNALD. Alternative fat sources free of essential fatty acids have recently been investigated for health benefits related to decreased inflammatory response. We hypothesized that the addition of medium-chain triglycerides (MCT) to a purified fish oil-based diet would decrease the response to inflammatory challenge in mice, while allowing for sufficient growth and development. Materials/Methods Six groups of ten adult male C57/Bl6 mice were pair-fed different dietary treatments for a period of twelve weeks, varying only in fat source (percent calories by weight): 10.84% soybean oil (SOY), 10% coconut oil (HCO), 10% medium-chain triglycerides (MCT), 3% purified fish oil (PFO), 3% purified fish oil with 3% medium-chain triglycerides (50:50 MCT:PFO) and 3% purified fish oil with 7.59% medium-chain triglycerides (70:30 MCT:PFO). An endotoxin challenge was administered to half of the animals in each group at the completion of dietary treatment. Results All groups demonstrated normal growth throughout the study period. Groups fed MCT and HCO diets demonstrated biochemical essential fatty acid deficiency and decreased IL-6 and TNF-α response to endotoxin challenge. Groups containing PFO had increased inflammatory response to endotoxin challenge, and the addition of MCT to PFO mitigated this inflammatory response. Conclusion These results suggest that the addition of MCT to PFO formulations may decrease the host response to inflammatory challenge, which may pose potential for optimized PN formulations. Inclusion of MCT in lipid emulsions given with PN formulations may be of use in therapeutic interventions for disease states resulting from chronic inflammation. PMID:25458829

The addition of medium-chain triglycerides to a purified fish oil-based diet alters inflammatory profiles in mice.

PubMed

Carlson, Sarah J; Nandivada, Prathima; Chang, Melissa I; Mitchell, Paul D; O'Loughlin, Alison; Cowan, Eileen; Gura, Kathleen M; Nose, Vania; Bistrian, Bruce R; Puder, Mark

2015-02-01

Parenteral nutrition associated liver disease (PNALD) is a deadly complication of long term parenteral nutrition (PN) use in infants. Fish oil-based lipid emulsion has been shown in recent years to effectively treat PNALD. Alternative fat sources free of essential fatty acids have recently been investigated for health benefits related to decreased inflammatory response. We hypothesized that the addition of medium-chain triglycerides (MCT) to a purified fish oil-based diet would decrease the response to inflammatory challenge in mice, while allowing for sufficient growth and development. Six groups of ten adult male C57/Bl6 mice were pair-fed different dietary treatments for a period of twelve weeks, varying only in fat source (percent calories by weight): 10.84% soybean oil (SOY), 10% coconut oil (HCO), 10% medium-chain triglycerides (MCT), 3% purified fish oil (PFO), 3% purified fish oil with 3% medium-chain triglycerides (50:50 MCT:PFO) and 3% purified fish oil with 7.59% medium-chain triglycerides (70:30 MCT:PFO). An endotoxin challenge was administered to half of the animals in each group at the completion of dietary treatment. All groups demonstrated normal growth throughout the study period. Groups fed MCT and HCO diets demonstrated biochemical essential fatty acid deficiency and decreased IL-6 and TNF-α response to endotoxin challenge. Groups containing PFO had increased inflammatory response to endotoxin challenge, and the addition of MCT to PFO mitigated this inflammatory response. These results suggest that the addition of MCT to PFO formulations may decrease the host response to inflammatory challenge, which may pose potential for optimized PN formulations. Inclusion of MCT in lipid emulsions given with PN formulations may be of use in therapeutic interventions for disease states resulting from chronic inflammation. Copyright © 2015 Elsevier Inc. All rights reserved.

Duplex thrusting in the South Dabashan arcuate belt, central China

NASA Astrophysics Data System (ADS)

Li, Wangpeng; Liu, Shaofeng; Wang, Yi; Qian, Tao; Gao, Tangjun

2017-10-01

Due to later tectonic superpositioning and reworking, the South Dabashan arcuate belt extending NW to SE has experienced several episodes of deformation. The earlier deformational style and formation mechanism of this belt remain controversial. Seismic interpretations and fieldwork show that the curved orogen can be divided into three sub-belts perpendicular to the strike of the orogen, the imbricate thrust fault belt, the detachment fold belt and the frontal belt from NE to SW. The imbricate thrust fault belt is characterized by a series of SW-directed thrust faults and nappes. Two regional detachment layers at different depths have been recognized in the detachment fold and frontal belts, and these detachment layers divide the sub-belts into three structural layers: the lower, middle, and upper structural layers. The middle structural layer is characterized by a passive roof duplex structure, which is composed of a roof thrust at the top of the Sinian units, a floor thrust in the upper Lower Triassic units, and horses in between. Apatite fission track dating results and regional structural analyses indicate that the imbricate thrust fault belt may have formed during the latest Early Cretaceous to earliest Paleogene and that the detachment fold belt may have formed during the latest Late Cretaceous to earliest Neogene. Our findings provide important reference values for researching intra-continental orogenic and deformation mechanisms in foreland fold-thrust belts.

Late thrusting extensional collapse at the mountain front of the northern Apennines (Italy)

NASA Astrophysics Data System (ADS)

Tavani, Stefano; Storti, Fabrizio; Bausã, Jordi; MuñOz, Josep A.

2012-08-01

Thrust-related anticlines exposed at the mountain front of the Cenozoic Appenninic thrust-and-fold belt share the presence of hinterlandward dipping extensional fault zones running parallel to the hosting anticlines. These fault zones downthrow the crests and the backlimbs with displacements lower than, but comparable to, the uplift of the hosting anticline. Contrasting information feeds a debate about the relative timing between thrust-related folding and beginning of extensional faulting, since several extensional episodes, spanning from early Jurassic to Quaternary, are documented in the central and northern Apennines. Mesostructural data were collected in the frontal anticline of the Sibillini thrust sheet, the mountain front in the Umbria-Marche sector of the northern Apennines, with the aim of fully constraining the stress history recorded in the deformed multilayer. Compressional structures developed during thrust propagation and fold growth, mostly locating in the fold limbs. Extensional elements striking about perpendicular to the shortening direction developed during two distinct episodes: before fold growth, when the area deformed by outer-arc extension in the peripheral bulge, and during a late to post thrusting stage. Most of the the extensional deformation occurred during the second stage, when the syn-thrusting erosional exhumation of the structures caused the development of pervasive longitudinal extensional fracturing in the crestal sector of the growing anticline, which anticipated the subsequent widespread Quaternary extensional tectonics.

Constraints on the tectonics of the Mule Mountains thrust system, southeast California and southwest Arizona

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tosdal, R.M.

1990-11-10

The Mule Mountains thrust system crops out discontinuously over a 100-km-strike length in the Blythe-Quartzsite region of southeast California and southwest Arizona. Along the thrust system, middle and upper crustal metamorphic and plutonic rocks of Proterozoic and Mesozoic age are thrust north-northeastward (015{degree} to 035{degree}) over a lower plate metamorphic terrane that formed part of the Proterozoic North American craton, its Paleozoic sedimentary rock cover, overlying Mesozoic volcanic and sedimentary rocks, and the intruding Jurassic and Cretaceous granitic rocks. Stratigraphic, petrologic, and Pb isotopic ties for Jurassic granitoids and for Jurassic( ) and Cretaceous sedimentary rocks across the various partsmore » of the thrust system indicate that related crustal blocks are superposed and preclude it from having large displacements. The thick-skinned thrust system is structurally symmetrical along its length with a central domain of synmetamorphic thrust faults that are flanked by western and eastern domains where lower plate domains where lower plate synclines underlie the thrusts. Deformation occurred under low greenschist facies metamorphic conditions in the upper crust. Movement along the thrust system was probably limited to no more than a few tens of kilometers and occurred between 79{plus minus}2 Ma and 70{plus minus}4 Ma. The superposition of related rocks and the geometry of the thrust system preclude it from being a major tectonic boundary of post-Middle Jurassic age, as has been previously proposed. Rather, the thrust system forms the southern boundary of the narrow zone of Cretaceous intracratonic deformation, and it is one of the last tectonic events in the zone prior to regional cooling.« less

Active tectonics and strain partitioning along dextral fault system in Central Iran: Analysis of geomorphological observations and geophysical data in the Kashan region

NASA Astrophysics Data System (ADS)

Jamali, Farshad; Hessami, Khaled; Ghorashi, Manoochehr

2011-03-01

This paper uses high-resolution images and field investigations, in conjunction with seismic reflection data, to constrain active structural deformation in the Kashan region of Central Iran. Offset stream beds and Qanats indicate right-lateral strike slip motion at a rate of about 2 mm/yr along the NW-SE trending Qom-Zefreh fault zone which has long been recognized as one of the major faults in Central Iran. However, the pattern of drainage systems across the active growing folds including deep incision of stream beds and deflected streams indicate uplift at depth on thrust faults dipping SW beneath the anticlines. Therefore, our studies in the Kashan region indicate that deformation occurs within Central Iran which is often considered to behave as a non-deforming block within the Arabia-Eurasia collision zone. The fact that the active Qom-Zefreh strike-slip fault runs parallel to the active folds, which overlie blind thrust faults, suggests that oblique motion of Arabia with respect to Eurasia is partitioned in this part of Central Iran.

Changes in the electro-physical properties of MCT epitaxial films affected by a plasma volume discharge induced by an avalanche beam in atmospheric-pressure air

NASA Astrophysics Data System (ADS)

Grigoryev, D. V.; Voitsekhovskii, A. V.; Lozovoy, K. A.; Tarasenko, V. F.; Shulepov, M. A.

2015-11-01

In this paper the influence of the plasma volume discharge of nanosecond duration formed in a non-uniform electric field at atmospheric pressure on samples of epitaxial films HgCdTe (MCT) films are discussed. The experimental data show that the action of pulses of nanosecond volume discharge in air at atmospheric pressure leads to changes in the electrophysical properties of MCT epitaxial films due to formation of a near-surface high- conductivity layer of the n-type conduction. The preliminary results show that it is possible to use such actions in the development of technologies for the controlled change of the properties of MCT.

Shear zones bounding the central zone of the Limpopo Mobile Belt, southern Africa

NASA Astrophysics Data System (ADS)

McCouri, Stephen; Vearncombe, Julian R.

Contrary to previously suggested north-directed thrust emplacement of the central zone of the Limpopo mobile belt, we present evidence indicating west-directed emplacement. The central zone differs from the marginal zones in rock types, structural style and isotopic signature and is an allochthonous thrust sheet. It is bounded in the north by the dextral Tuli-Sabi shear zone and in the south by the sinistral Palala shear zone which are crustal-scale lateral ramps. Published gravity data suggest that the lateral ramps are linked at depth and they probably link at the surface, in a convex westward frontal ramp, in the vicinity of longitude 26°30'E in eastern Botswana. Two phases of movement, the first between 2.7 and 2.6 Ga and the second between 2.0 and 1.8 Ga. occurred on both the Tuli-Sabi and the Palala shear zones.

Saturn Apollo Program

NASA Image and Video Library

1969-01-01

In the clustering procedure, an initial assembly step for the Saturn IB launch vehicle's S-IB (first) stage, workers at the Michoud Assembly Facility (MAF) near New Orleans, Louisiana, position the central liquid-oxygen tank. Developed by the Marshall Space Flight Center and built by the Chrysler Corporation at Michoud Assembly Facility (MAF), the S-IB utilized eight H-1 engines and each produced 200,000 pounds of thrust, a combined thrust of 1,600,000 pounds.

Characterising the metamorphic discontinuity across the Main Central Thrust Zone of eastern-central Nepal

NASA Astrophysics Data System (ADS)

Wang, Jiamin; Zhang, Jinjiang; Wei, Chunjing; Rai, SantaMan; Wang, Meng; Qian, Jiahui

2015-04-01

The Main Central Thrust Zone (MCTZ) is a top-to-south shear zone that has exhumed the high-grade Himalayan metamorphic core during the orogeny. Identifying the location of the MCTZ is a major challenge and the characteristics of the metamorphic discontinuity remain under debate. To clarify this issue, petrologic and thermobarometric studies were carried out on metapelites and metapsammites that were collected from the basal Nyalam transect in eastern-central Nepal. Results reveal that the metamorphic discontinuity across the MCTZ is characterised by a continuous increase in peak P-T conditions toward higher structural levels, a relatively high field temperature gradient (25-50 °C km-1) and different types of P-T paths. Specifically, representative rocks in the MCTZ record sub-solidus peak conditions (637 ± 16 °C and 9.2 ± 1.0 kbar) and a hairpin-type P-T path. The lower GHC rocks record supra-solidus peak conditions (690 ± 32 °C and 10.3 + 1.1/-1.4 kbar) and a prograde loading path with a small segment of decompression. The presence of a high field pressure gradient across the MCTZ is debatable in the Nyalam transect due to the large uncertainties in pressure estimates. Comparison between obtained P-T results and model predictions indicates that a multiple thrusting process dominated exhumation of the MCTZ and lower GHC rocks, while crustal flow contributed partly to exhumation of the lower GHC rocks.

Get Out of the Rut and into a Circle--Cycle of Inquiry Professional Development for Central Office Leaders

ERIC Educational Resources Information Center

Nelson, Eric A.

2010-01-01

Under the federal policy No Child Left Behind, school district central office administrators have been thrust into the role of orchestrating substantial increases in student learning. However, there is mounting research recognizing that most central office administrators are ill-prepared for the work of instructional improvement at a systems level…

Oncogenes and inflammation rewire host energy metabolism in the tumor microenvironment: RAS and NFκB target stromal MCT4.

PubMed

Martinez-Outschoorn, Ubaldo E; Curry, Joseph M; Ko, Ying-Hui; Lin, Zhao; Tuluc, Madalina; Cognetti, David; Birbe, Ruth C; Pribitkin, Edmund; Bombonati, Alessandro; Pestell, Richard G; Howell, Anthony; Sotgia, Federica; Lisanti, Michael P

2013-08-15

Here, we developed a model system to evaluate the metabolic effects of oncogene(s) on the host microenvironment. A matched set of "normal" and oncogenically transformed epithelial cell lines were co-cultured with human fibroblasts, to determine the "bystander" effects of oncogenes on stromal cells. ROS production and glucose uptake were measured by FACS analysis. In addition, expression of a panel of metabolic protein biomarkers (Caveolin-1, MCT1, and MCT4) was analyzed in parallel. Interestingly, oncogene activation in cancer cells was sufficient to induce the metabolic reprogramming of cancer-associated fibroblasts toward glycolysis, via oxidative stress. Evidence for "metabolic symbiosis" between oxidative cancer cells and glycolytic fibroblasts was provided by MCT1/4 immunostaining. As such, oncogenes drive the establishment of a stromal-epithelial "lactate-shuttle", to fuel the anabolic growth of cancer cells. Similar results were obtained with two divergent oncogenes (RAS and NFκB), indicating that ROS production and inflammation metabolically converge on the tumor stroma, driving glycolysis and upregulation of MCT4. These findings make stromal MCT4 an attractive target for new drug discovery, as MCT4 is a shared endpoint for the metabolic effects of many oncogenic stimuli. Thus, diverse oncogenes stimulate a common metabolic response in the tumor stroma. Conversely, we also show that fibroblasts protect cancer cells against oncogenic stress and senescence by reducing ROS production in tumor cells. Ras-transformed cells were also able to metabolically reprogram normal adjacent epithelia, indicating that cancer cells can use either fibroblasts or epithelial cells as "partners" for metabolic symbiosis. The antioxidant N-acetyl-cysteine (NAC) selectively halted mitochondrial biogenesis in Ras-transformed cells, but not in normal epithelia. NAC also blocked stromal induction of MCT4, indicating that NAC effectively functions as an "MCT4 inhibitor". Taken together, our data provide new strategies for achieving more effective anticancer therapy. We conclude that oncogenes enable cancer cells to behave as selfish "metabolic parasites", like foreign organisms (bacteria, fungi, viruses). Thus, we should consider treating cancer like an infectious disease, with new classes of metabolically targeted "antibiotics" to selectively starve cancer cells. Our results provide new support for the "seed and soil" hypothesis, which was first proposed in 1889 by the English surgeon, Stephen Paget.

Ease of oral administration and owner-perceived acceptability of triglyceride oil, dissolving thin film strip, and gelatin capsule formulations to healthy cats.

PubMed

Traas, Anne M; Fleck, Timothy; Ellings, Andrea; Mahabir, Sean; Stuebner, Kathy; Brown, Dorothy C; Durso, Dana; DiGregorio, Michael; Bode, Lora; Kievit, Kelly I; McCall, Robert

2010-06-01

To compare owner-assessed ease of administration and overall acceptability of 3 chemically inactive formulations administered PO to cats. 90 healthy client-owned cats. Cats were randomly assigned to receive 1 of 3 formulations PO once daily for 14 days: medium chain triglyceride (MCT) oil, dissolving thin film strips (proprietary ingredients), or gelatin capsules filled with microcrystalline cellulose. Owners administered the formulations and rated ease of administration daily on a 10-cm visual analogue scale (VAS). At the end of the study, owners rated overall acceptability of formulations from their own perspective and their overall perception of acceptability to their cat. Mean VAS scores for daily ease of administration of MCT oil and film strips were significantly higher than scores for gelatin capsules at all time points, except on days 2, 4, and 7. There was no difference between MCT oil and film strip formulation scores. Mean VAS scores were 8.8 (MCT oil), 8.9 (film strips), and 7.4 (gelatin capsules) for overall acceptability to owners and 8.0 (MCT oil), 8.3 (film strips), and 6.7 (gelatin capsules) for overall owner-perceived acceptability to cats. Daily ease of administration on 11 of 14 days and overall owner-perceived acceptability to cats were scored significantly higher for film strips and MCT oil, compared with scores for gelatin capsules. Overall acceptability to owners followed a similar pattern; however, the differences were not significant. Dissolving thin film strip or MCT oil vehicles may allow for easier PO administration of medication to cats than does administration of gelatin capsules.

Production of microparticles of molinate degrading biocatalysts using the spray drying technique.

PubMed

Lopes, Ana R; Sousa, Vera M; Estevinho, Berta N; Leite, José P; Moreira, Nuno F F; Gales, Luís; Rocha, Fernando; Nunes, Olga C

2016-10-01

Previous studies demonstrated the capability of mixed culture DC1 to mineralize the thiocarbamate herbicide molinate through the activity of molinate hydrolase (MolA). Because liquid suspensions are not compatible with long-term storage and are not easy to handle when bioremediation strategies are envisaged, in this study spray drying was evaluated as a cost-effective method to store and transport these molinate biocatalysts. Microparticles of mixed culture DC1 (DC1) and of cell free crude extracts containing MolA (MA) were obtained without any carrier polymer, and with calcium alginate (CA) or modified chitosan (MCt) as immobilizing agents. All the DC1 microparticles showed high molinate degrading activity upon storage for 6 months, or after 9 additions of ∼0.4 mM molinate over 1 month. The DC1-MCt microparticles were those with the highest survival rate and lowest heterogeneity. For MA microparticles, only MA-MCt degraded molinate. However, its Vmax was only 1.4% of that of the fresh cell free extract (non spray dried). The feasibility of using the DC1-MCt and MA-MCt microparticles in bioaugmentation processes was assessed in river water microcosms, using mass (g):volume (L) ratios of 1:13 and 1:0.25, respectively. Both type of microparticles removed ∼65-75% of the initial 1.5 mg L(-1) molinate, after 7 days of incubation. However, only DC1-MCt microparticles were able to degrade this environmental concentration of molinate without disturbing the native bacterial community. These results suggest that spray drying can be successfully used to produce DC1-MCt microparticles to remediate molinate polluted sites through a bioaugmentation strategy. Copyright © 2016 Elsevier Ltd. All rights reserved.

Medium-chain TAG improve energy metabolism and mitochondrial biogenesis in the liver of intra-uterine growth-retarded and normal-birth-weight weanling piglets.

PubMed

Zhang, Hao; Li, Yue; Hou, Xiang; Zhang, Lili; Wang, Tian

2016-05-01

We previously reported that medium-chain TAG (MCT) could alleviate hepatic oxidative damage in weanling piglets with intra-uterine growth retardation (IUGR). There is a relationship between oxidative status and energy metabolism, a process involved in substrate availability and glucose flux. Therefore, the aim of this study was to investigate the effects of IUGR and MCT on hepatic energy metabolism and mitochondrial function in weanling piglets. Twenty-four IUGR piglets and twenty-four normal-birth-weight (NBW) piglets were fed a diet of either soyabean oil (SO) or MCT from 21 d of postnatal age to 49 d of postnatal age. Then, the piglets' biochemical parameters and gene expressions related to energy metabolism and mitochondrial function were determined (n 4). Compared with NBW, IUGR decreased the ATP contents and succinate oxidation rates in the liver of piglets, and reduced hepatic mitochondrial citrate synthase (CS) activity (P<0·05). IUGR piglets exhibited reductions in hepatic mitochondrial DNA (mtDNA) contents and gene expressions related to mitochondrial biogenesis compared with NBW piglets (P<0·05). The MCT diet increased plasma ghrelin concentration and hepatic CS and succinate dehydrogenase activities, but decreased hepatic pyruvate kinase activity compared with the SO diet (P<0·05). The MCT-fed piglets showed improved mtDNA contents and PPARγ coactivator-1α expression in the liver (P<0·05). The MCT diet alleviated decreased mRNA abundance of the hepatic PPARα induced by IUGR (P<0·05). It can therefore be postulated that MCT may have beneficial effects in improving energy metabolism and mitochondrial function in weanling piglets.

Dietary medium-chain triglycerides promote oral allergic sensitization and orally induced anaphylaxis to peanut protein in mice.

PubMed

Li, Jianing; Wang, Yu; Tang, Lihua; de Villiers, Willem J S; Cohen, Donald; Woodward, Jerold; Finkelman, Fred D; Eckhardt, Erik R M

2013-02-01

The prevalence of peanut allergies is increasing. Peanuts and many other allergen sources contain significant amounts of triglycerides, which affect absorption of antigens but have unknown effects on sensitization and anaphylaxis. We recently reported that dietary medium-chain triglycerides (MCTs), which bypass mesenteric lymph and directly enter portal blood, reduce intestinal antigen absorption into blood compared with long-chain triglycerides (LCTs), which stimulate mesenteric lymph flow and are absorbed in chylomicrons through mesenteric lymph. We sought to test how dietary MCTs affect food allergy. C3H/HeJ mice were fed peanut butter protein in MCT, LCT (peanut oil), or LCT plus an inhibitor of chylomicron formation (Pluronic L81). Peanut-specific antibodies in plasma, responses of the mice to antigen challenges, and intestinal epithelial cytokine expression were subsequently measured. MCT suppressed antigen absorption into blood but stimulated absorption into Peyer patches. A single gavage of peanut protein with MCT, as well as prolonged feeding in MCT-based diets, caused spontaneous allergic sensitization. MCT-sensitized mice experienced IgG-dependent anaphylaxis on systemic challenge and IgE-dependent anaphylaxis on oral challenge. MCT feeding stimulated jejunal-epithelial thymic stromal lymphopoietin, Il25, and Il33 expression compared with that seen after LCT feeding and promoted T(H)2 cytokine responses in splenocytes. Moreover, oral challenges of sensitized mice with antigen in MCT significantly aggravated anaphylaxis compared with challenges with the LCT. Importantly, the effects of MCTs could be mimicked by adding Pluronic L81 to LCTs, and in vitro assays indicated that chylomicrons prevent basophil activation. Dietary MCTs promote allergic sensitization and anaphylaxis by affecting antigen absorption and availability and by stimulating T(H)2 responses. Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Impact of medium and long chain triglycerides consumption on appetite and food intake in overweight men.

PubMed

St-Onge, M-P; Mayrsohn, B; O'Keeffe, M; Kissileff, H R; Choudhury, A R; Laferrère, B

2014-10-01

Medium chain triglycerides (MCT) enhance thermogenesis and may reduce food intake relative to long chain triglycerides (LCT). The goal of this study was to establish the effects of MCT on appetite and food intake and determine whether differences were due to differences in hormone concentrations. Two randomized, crossover studies were conducted in which overweight men consumed 20 g of MCT or corn oil (LCT) at breakfast. Blood samples were obtained over 3 h. In Study 1 (n=10), an ad lib lunch was served after 3 h. In Study 2 (n=7), a preload containing 10 g of test oil was given at 3 h and lunch was served 1 h later. Linear mixed model analyses were performed to determine the effects of MCT and LCT oil on change in hormones and metabolites from fasting, adjusting for body weight. Correlations were computed between differences in hormones just before the test meals and differences in intakes after the two oils for Study 1 only. Food intake at the lunch test meal after the MCT preload (Study 2) was (mean±s.e.m.) 532±389 kcal vs 804±486 kcal after LCT (P<0.05). MCT consumption resulted in a lower rise in triglycerides (P=0.014) and glucose (P=0.066) and a higher rise in peptide YY (PYY, P=0.017) and leptin (P=0.036) compared with LCT (combined data). Correlations between differences in hormone levels (glucagon-like peptide (GLP-1), PYY) and differences in food intake were in the opposite direction to expectations. MCT consumption reduced food intake acutely but this does not seem to be mediated by changes in GLP-1, PYY and insulin.

Exercise-induced changes in tumour LDH-B and MCT1 expression are modulated by oestrogen-related receptor alpha in breast cancer-bearing BALB/c mice

PubMed Central

Aveseh, Malihe; Nikooie, Rohollah; Aminaie, Mohsen

2015-01-01

Several factors, including overexpression of lactate dehydrogenase (LDH) and monocarboxylate transporters (MCTs), promote an aerobic lactate production that allows some cancer cells to sustain higher proliferation rates in hostile environments outside the cell. To elucidate the effect of endurance training on the metabolic phenotype of solid tumours, we focused on the tumour expression of LDH-A, LDH-B, MCT1, MCT4, oestrogen-related receptor alpha (ERRα) and LDH isozymes in control (C), trained (T), control+XCT790 (CX) and trained+XCT790 (TX) mice. First, we found that the metabolically altered tumours from the trained animals exhibited lower values for lactate concentration than the control group. The decreased lactate concentration was associated with a shift in the tumour LDH isozyme profile towards LDH-1. These exercise-induced changes were also associated with decreases in the expression of the tumour MCT1, ERRα and CD147 in the trained animals. Secondly, the inhibition of ERRα by treatment of MC4-L2 human breast cancer cells with XCT790 (inverse agonist ligand of ERRα) before injection into the animals not only increased LDH-B expression in the tumour, but also decreased MCT1 expression in the CX group in comparison to the C group. The effects of ERRα inhibition were not additive to the training effects on the expressions of MCT1 and LDH-B in the solid tumours. In conclusion, our results suggest that exercise-induced suppression of ERRα expression modulates alterations in solid tumour expression of LDH-B and MCT1 and contributes towards the prevention of tumour development. PMID:25907793

Alterations of nasal mucociliary clearance in association with HIV infection and the effect of guaifenesin therapy.

PubMed

Rosen, Elizabeth J; Calhoun, Karen H

2005-01-01

To determine if human immunodeficiency virus (HIV) infection is associated with a prolonged mucociliary clearance time (MCT) and to evaluate the effect of guaifenesin on MCT in HIV+ patients. A cross-sectional study comparing HIV+ and HIV- volunteers followed by a prospective, randomized, double-blind, placebo-controlled study of HIV+ patients before and after guaifenesin treatment. Twenty-five HIV+ patients and 29 HIV- controls were enrolled and MCT was measured using the saccharin method. A separate group of 20 HIV+ patients participated in the second arm of the study and underwent saccharin testing before and after a 3-week course of guaifenesin or placebo. All study participants completed a medical history questionnaire, a sinonasal symptom (SNOT-16) survey, and were examined with both anterior rhinoscopy and rigid nasal endoscopy. There was a significant difference (P < .002) in the MCT between the HIV+ group (13.3 +/- SD 7.5 minutes) and the HIV- controls (9.2 +/- SD 3.9 minutes). The difference in MCT between the guaifenesin and placebo groups did not reach statistical significance (P >.05). The HIV+ group had a higher SNOT-16 score compared to HIV- controls (21.1 vs. 7.4, P < .001). Guaifenesin therapy in HIV+ patients led to a significant improvement in the SNOT-16 score (P < .05). Compared to HIV- controls, HIV+ patients have a prolonged MCT and more sinonasal symptoms as indicated by a higher SNOT-16 score. Guaifenesin therapy was associated with improved SNOT-16 scores, although there was not a detectable improvement in MCT. Use of guaifenesin in HIV+ patients with sinonasal disease may lead to improved patient perception of quality of life.

Influence of Polysorbate 60 on Formulation Properties and Bioavailability of Morin-Loaded Nanoemulsions with and without Low-Saponification-Degree Polyvinyl Alcohol.

PubMed

Ikeuchi-Takahashi, Yuri; Kobayashi, Ayaka; Ishihara, Chizuko; Matsubara, Takumi; Matsubara, Hiroaki; Onishi, Hiraku

2018-01-01

The aim of the present study was to investigate the influence of polysorbate 60 (Tween 60) on the development of morin-loaded nanoemulsions to improve the oral bioavailability of morin. Nanoemulsions were prepared using Tween 60 and polyvinyl alcohol (PVA) as emulsifiers, and medium chain triglycerides (MCT) as the lipid base. Low-saponification-degree PVA (LL-810) was also added to stabilize dispersed droplets. MCT-LL810 nanoemulsion containing LL-810 was prepared with a reduced amount of Tween 60. However, the area under the blood concentration-time curve (AUC) of MCT-LL810 (0.18) nanoemulsion containing a small amount of Tween 60 did not increase because the absorption of morin was limited by P-glycoprotein (P-gp)-mediated efflux. MCT-LL810 (0.24) nanoemulsion containing a large amount of Tween 60 showed the highest AUC, dispersed droplets containing Tween 60 may have been transported into epithelial cells in the small intestine, and P-gp transport activity appeared to be suppressed by permeated Tween 60. Based on the plasma concentration profile, dispersed droplets in MCT-LL810 (0.24) nanoemulsion permeated more rapidly through the mucus layer and the intestinal membrane than MCT (0.24) nanoemulsion without LL-810. In conclusion, a novel feature of Tween 60 incorporated into the dispersed droplets of a nanoemulsion interacting with P-gp was demonstrated herein. Dispersed droplets in MCT-LL810 (0.24) nanoemulsion containing LL-810 permeated rapidly through the mucus layer and intestinal membrane, and Tween 60 incorporated in dispersed droplets interacted with P-gp-mediated efflux, increasing the bioavailability of morin.

Effect of High-Intensity Interval Versus Continuous Exercise Training on Functional Capacity and Quality of Life in Patients With Coronary Artery Disease: A RANDOMIZED CLINICAL TRIAL.

PubMed

Jaureguizar, Koldobika Villelabeitia; Vicente-Campos, Davinia; Bautista, Lorena Ruiz; de la Peña, Cesar Hernández; Gómez, María José Arriaza; Rueda, María José Calero; Fernández Mahillo, Ignacio

2016-01-01

There is strong evidence that exercise training has beneficial health effects in patients with cardiovascular disease. Most studies have focused on moderate continuous training (MCT); however, a body of evidence has begun to emerge demonstrating that high-intensity interval training (HIIT) has significantly better results in terms of morbidity and mortality. The aim of this study was to compare the effects of MCT versus HIIT on functional capacity and quality of life and to assess safety. Seventy-two patients with ischemic heart disease were assigned to either HIIT or MCT for 8 weeks. We analyzed cardiopulmonary exercise test data, quality of life, and adverse events. High-intensity interval training resulted in a significantly greater increase in (Equation is included in full-text article.)O2peak (4.5 ± 4.7 mL·kg·min) compared with MCT (2.5 ± 3.6 mL·kg·min) (P < .05). The aerobic threshold (VT1) increased by 21% in HIIT and 14% in MCT. Furthermore, there was a significant (P < .05) increase in the distance covered in the 6-minute walk distance test in the HIIT group (49.6 ± 6.3 m) when compared with the MCT group (29.6 ± 12.0 m). Both training protocols improved quality of life. No adverse events were reported in either of the groups. On the basis of the results of this study, HIIT should be considered for use in cardiac rehabilitation as it resulted in a greater increase in functional capacity compared with MCT. We also observed greater improvement in quality of life without any increase in cardiovascular risk.

The anti-tumour agent lonidamine is a potent inhibitor of the mitochondrial pyruvate carrier and plasma membrane monocarboxylate transporters

PubMed Central

Nancolas, Bethany; Guo, Lili; Zhou, Rong; Nath, Kavindra; Nelson, David S.; Leeper, Dennis B.; Blair, Ian A.; Glickson, Jerry D.; Halestrap, Andrew P.

2016-01-01

Lonidamine (LND) is an anti-tumour drug particularly effective at selectively sensitising tumours to chemotherapy, hyperthermia and radiotherapy, although its precise mode of action remains unclear. It has been reported to perturb the bioenergetics of cells by inhibiting glycolysis and mitochondrial respiration, while indirect evidence suggests it may also inhibit L-lactic acid efflux from cells mediated by members of the proton-linked monocarboxylate transporter (MCT) family and also pyruvate uptake into the mitochondria by the mitochondrial pyruvate carrier (MPC). Here we test these possibilities directly. We demonstrate that LND potently inhibits MPC activity in isolated rat liver mitochondria (Ki 2.5 μM) and cooperatively inhibits L-lactate transport by MCT1, MCT2 and MCT4 expressed in Xenopus laevis oocytes with K0.5 and Hill Coefficient values of 36–40 μM and 1.65–1.85. In rat heart mitochondria LND inhibited the MPC with similar potency and uncoupled oxidation of pyruvate was inhibited more effectively (IC50 ~7 μM) than other substrates including glutamate (IC50 ~20 μM). In isolated DB-1 melanoma cells 1–10 μM LND increased L-lactate output, consistent with MPC inhibition, but higher concentrations (150 μM) decreased L-lactate output while increasing intracellular [L-lactate] > five-fold, consistent with MCT inhibition. We conclude that MPC inhibition is the most sensitive anti-tumour target for LND, with additional inhibitory effects on MCT-mediated L-lactic acid efflux and glutamine/glutamate oxidation. Together these actions can account for published data on the selective tumour effects of LND on L-lactate, intracellular pH (pHi) and ATP levels that can be partially mimicked by the established MPC and MCT inhibitor α-cyano-4-hydroxycinnamate. PMID:26831515

Impact of medium and long chain triglycerides consumption on appetite and food intake in overweight men

PubMed Central

St-Onge, Marie-Pierre; Mayrsohn, Brian; O’Keeffe, Majella; Kissileff, Harry R.; Choudhury, Arindam Roy; Laferrère, Blandine

2014-01-01

Background Medium chain triglycerides (MCT) enhance thermogenesis and may reduce food intake relative to long chain triglycerides (LCT). The goal of this study was to establish the effects of MCT on appetite and food intake and determine whether differences were due to differences in hormone concentrations. Methods Two randomized, crossover studies were conducted in which overweight men consumed 20 g of MCT or corn oil (LCT) at breakfast. Blood samples were obtained over 3 h. In Study 1 (n=10), an ad lib lunch was served after 3 h. In Study 2 (n=7), a pre-load containing 10 g of test oil was given at 3 h and lunch was served 1 h later. Linear mixed model analyses were performed to determine the effects of MCT and LCT oil on change in hormones and metabolites from fasting, adjusting for body weight. Correlations were computed between differences in hormones just before the test meals and differences in intakes after the two oils for Study 1 only. Results Food intake at the lunch test meal after the MCT pre-load (Study 2) was (mean ± SEM) 532 ± 389 kcal vs. 804 ± 486 kcal after LCT (P < 0.05). MCT consumption resulted in a lower rise in triglycerides (P = 0.014) and glucose (P = 0.066) and a higher rise in peptide YY (P = 0.017) and leptin (P = 0.036) compared to LCT (combined data). Correlations between differences in hormone levels (GLP-1, PYY) and differences in food intake were in the opposite direction to expectations. Conclusions MCT consumption reduced food intake acutely but this does not seem to be mediated by changes in GLP-1, PYY, and insulin. PMID:25074387

Silychristin, a Flavonolignan Derived From the Milk Thistle, Is a Potent Inhibitor of the Thyroid Hormone Transporter MCT8.

PubMed

Johannes, Jörg; Jayarama-Naidu, Roopa; Meyer, Franziska; Wirth, Eva Katrin; Schweizer, Ulrich; Schomburg, Lutz; Köhrle, Josef; Renko, Kostja

2016-04-01

Thyroid hormones (THs) are charged and iodinated amino acid derivatives that need to pass the cell membrane facilitated by thyroid hormone transmembrane transporters (THTT) to exert their biological function. The importance of functional THTT is affirmed by the devastating effects of mutations in the human monocarboxylate transporter (MCT) 8, leading to a severe form of psychomotor retardation. Modulation of THTT function by pharmacological or environmental compounds might disturb TH action on a tissue-specific level. Therefore, it is important to identify compounds with relevant environmental exposure and THTT-modulating activity. Based on a nonradioactive TH uptake assay, we performed a screening of 13 chemicals, suspicious for TH receptor interaction, to test their potential effects on THTT in MCT8-overexpressing MDCK1-cells. We identified silymarin, an extract of the milk thistle, to be a potent inhibitor of T3 uptake by MCT8. Because silymarin is a complex mixture of flavonolignan substances, we further tested its individual components and identified silychristin as the most effective one with an IC50 of approximately 100 nM. The measured IC50 value is at least 1 order of magnitude below those of other known THTT inhibitors. This finding was confirmed by T3 uptake in primary murine astrocytes expressing endogenous Mct8 but not in MCT10-overexpressing MDCK1-cells, indicating a remarkable specificity of the inhibitor toward MCT8. Because silymarin is a frequently used adjuvant therapeutic for hepatitis C infection and chronic liver disease, our observations raise questions regarding its safety with respect to unwanted effects on the TH axis.

Acute effects of interval versus continuous endurance training on pulse wave reflection in healthy young men.

PubMed

Hanssen, Henner; Nussbaumer, Monique; Moor, Christoph; Cordes, Mareike; Schindler, Christian; Schmidt-Trucksäss, Arno

2015-02-01

Our aim was to investigate the acute and 24-hour (h) effects of high-intensity interval training (HIIT) and moderate continuous training (MCT) on arterial pulse wave reflection, an established marker of arterial stiffness and cardiovascular risk. In a randomized cross-over design, 21 young healthy male participants performed a HIIT or a MCT on separate visits. Before and 5 (t5), 20 (t20), 35 (t35), and 50 (t50) minutes after the acute exercise bouts, the crude augmentation index (AIx) and the AIx at a set heart rate (AIx@75) were analysed by applanation tonometry. Starting 1 h post-exercise, both indices were captured over 24-h with an oscillometric monitoring device. AIx did not change significantly after MCT but declined progressively after HIIT, reaching significantly lower values compared to MCT at t35 (P = 0.045) and t50 (P = 0.008). AIx@75 increased after both acute exercise types but was higher after HIIT at t5 (P < 0.001), t20 (P < 0.001) and t35 (P = 0.009) compared to MCT. The 24-h follow-up revealed a significant decline in AIx@75 after HIIT (P = 0.007) but not after MCT (P = 0.813). Exercise intensity affects pulse wave reflection, with different time courses for AIx and AIx@75 post-exercise. Although initially higher after HIIT, AIx@75 declines in the 24-h recovery period indicating more favourable effects on pulse wave reflection compared to MCT. This may result in substantial positive chronic training effects on arterial stiffness in health and cardiovascular disease. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Administration of structured lipid composed of MCT and fish oil reduces net protein catabolism in enterally fed burned rats.

PubMed Central

Teo, T C; DeMichele, S J; Selleck, K M; Babayan, V K; Blackburn, G L; Bistrian, B R

1989-01-01

The effects of enteral feeding with safflower oil or a structured lipid (SL) derived from 60% medium-chain triglyceride (MCT) and 40% fish oil (MCT/fish oil) on protein and energy metabolism were compared in gastrostomy-fed burned rats (30% body surface area) by measuring oxygen consumption, carbon dioxide production, nitrogen balance, total liver protein, whole-body leucine kinetics, and rectus muscle and liver protein fractional synthetic rates (FSR, %/day). Male Sprague-Dawley rats (195 +/- 5g) received 50 ml/day of an enteral regimen containing 50 kcal, 2 g amino acids, and 40% nonprotein calories as lipid for three days. Protein kinetics were estimated by using a continuous L-[1-14C] leucine infusion technique on day 2. Thermally injured rats enterally fed MCT/fish oil yielded significantly higher daily and cumulative nitrogen balances (p less than or equal to 0.025) and rectus muscle (39%) FSR (p less than or equal to 0.05) when compared with safflower oil. MCT/fish oil showed a 22% decrease (p less than or equal to 0.005) in per cent flux oxidized and a 7% (p less than or equal to 0.05) decrease in total energy expenditure (TEE) versus safflower oil. A 15% increase in liver FSR was accompanied by a significant elevation (p less than or equal to 0.025) in total liver protein with MCT/fish oil. This novel SL shares the properties of other structured lipids in that it reduces the net protein catabolic effects of burn injury, in part, by influencing tissue protein synthetic rates. The reduction in TEE is unique to MCT/fish oil and may relate to the ability of fish oil to diminish the injury response. PMID:2500898

Biophysical elucidation of the mechanism of enhanced drug release and topical delivery from polymeric film-forming systems.

PubMed

Garvie-Cook, Hazel; Frederiksen, Kit; Petersson, Karsten; Guy, Richard H; Gordeev, Sergey N

2015-08-28

The effect of incorporating the lipidic medium-chain triglyceride (MCT) into polymeric film-forming systems (FFS) for topical drug delivery has been evaluated. First, the in vitro release of betamethasone-17-valerate (BMV), a representative dermatological drug, was determined from FFS comprising either hydrophobic polyacrylate co-polymers, or hydrophilic hydroxypropyl cellulose, with and without MCT. Release was enhanced from both polymers in the presence of MCT. Atomic force microscopy imaging and nanoindentation of FFS with MCT revealed two-phase structured films with softer inclusions (0.5 to 4μm in diameter) surrounded by a more rigid structure. Chemical mapping with Raman micro-spectroscopy showed that MCT was primarily confined to the inclusions within the polymer, which predominated in the surrounding film. BMV was distributed throughout the film but was more concentrated outside the inclusions. Furthermore, while BMV dissolved better into the hydrophobic films, it was more soluble in the MCT inclusions in hydrophilic films, suggesting its increased availability for diffusion from these softer regions of the polymer and explaining the release enhancement observed. Second, ex vivo skin penetration studies clearly revealed that uptake of BMV was higher from hydrophobic FFS than that from the more hydrophilic polymer due, at least in part, to the superior anti-nucleation efficiency of the former. Drug was quickly taken up into the SC from which it then diffused continuously over a sustained period into the lower, viable skin layers. In the presence of MCT, the overall uptake of BMV was increased and provides the basis for further optimisation of FFS as simple, convenient and sustained formulations for topical therapy. Copyright © 2015 Elsevier B.V. All rights reserved.

Impurity-induced photoconductivity of narrow-gap Cadmium–Mercury–Telluride structures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kozlov, D. V., E-mail: dvkoz@impras.ru; Rumyantsev, V. V.; Morozov, S. V.

2015-12-15

The photoconductivity (PC) spectra of CdHgTe (MCT) solid solutions with a Cd fraction of 17 and 19% are measured. A simple model for calculating the states of doubly charged acceptors in MCT solid solutions, which makes it possible to describe satisfactorily the observed photoconductivity spectra, is proposed. The found lines in the photoconductivity spectra of narrow-gap MCT structures are associated with transitions between the states of both charged and neutral acceptor centers.

Evaluation of MCT1, MCT4 and CD147 Genes in Peripheral Blood Cells of Breast Cancer Patients and Their Potential Use as Diagnostic and Prognostic Markers.

PubMed

Luz, Maria Cláudia de B; Perez, Matheus M; Azzalis, Ligia A; Sousa, Luiz Vinícius de A; Adami, Fernando; Fonseca, Fernando L A; Alves, Beatriz da C A

2017-03-23

Patients with breast cancer-the deadliest cancer among women-are at constant risk of developing metastasis. Oxidative stress and hypoxia are common feature of tumor cells that can proliferate even in a resultant metabolic acidosis. Despite the low extracellular pH, intracellular pH of tumor cells remains relatively normal, or even more alkaline due to the action of a membrane protein family known as monocarboxylate transporters (MCTs). The objective of this study was to verify the diagnostic and prognostic value of MCT1 , MCT4 and CD147 in tumor and peripheral blood samples of patients with breast cancer undergoing chemotherapic treatment. Differential expression of MCT1 , MCT4 and CD147 obtained by qPCR was determined by 2 -ΔΔ C q method between biological samples (tumor and serial samples of peripheral) of patients ( n = 125) and healthy women ( n = 25). tumor samples with higher histological grades have shown higher expression of these markers; this higher expression was also observed in blood samples obtained at diagnosis of patients when compared to healthy women and in patients with positive progression of the disease (metastasis development). markers studied here could be a promising strategy in routine laboratory evaluations as breast cancer diagnosis and prognosis.

Effect of Acylglycerol Composition and Fatty Acyl Chain Length on Lipid Digestion in pH-Stat Digestion Model and Simulated In Vitro Digestion Model.

PubMed

Qi, Jin F; Jia, Cai H; Shin, Jung A; Woo, Jeong M; Wang, Xiang Y; Park, Jong T; Hong, Soon T; Lee, K-T

2016-02-01

In this study, a pH-stat digestion model and a simulated in vitro digestion model were employed to evaluate the digestion degree of lipids depending on different acylglycerols and acyl chain length (that is, diacylglycerol [DAG] compared with soybean oil representing long-chain triacylglycerol compared with medium-chain triacylglycerol [MCT]). In the pH-stat digestion model, differences were observed among the digestion degrees of 3 oils using digestion rate (k), digestion half-time (t1/2 ), and digestion extent (Φmax). The results showed the digestion rate order was MCT > soybean oil > DAG. Accordingly, the order of digestion half-times was MCT < soybean oil < DAG. In simulated in vitro digestion model, digestion rates (k') and digestion half-times (t'1/2 ) were also obtained and the results showed a digestion rate order of MCT (k' = 0.068 min(-1) ) > soybean oil (k' = 0.037 min(-1) ) > DAG (k' = 0.024 min(-1) ). Consequently, the order of digestion half-times was MCT (t'1/2 = 10.20 min) < soybean oil (t'1/2 = 18.74 min) < DAG (t'1/2 = 29.08 min). The parameters obtained using the 2 models showed MCT was digested faster than soybean oil, and that soybean oil was digested faster than DAG. © 2015 Institute of Food Technologists®

Docosahexaenoic acid inhibits monocrotaline-induced pulmonary hypertension via attenuating endoplasmic reticulum stress and inflammation.

PubMed

Chen, Rui; Zhong, Wei; Shao, Chen; Liu, Peijing; Wang, Cuiping; Wang, Zhongqun; Jiang, Meiping; Lu, Yi; Yan, Jinchuan

2018-02-01

Endoplasmic reticulum (ER) stress and inflammation contribute to pulmonary hypertension (PH) pathogenesis. Previously, we confirmed that docosahexaenoic acid (DHA) could improve hypoxia-induced PH. However, little is known about the link between DHA and monocrotaline (MCT)-induced PH. Our aims were, therefore, to evaluate the effects and molecular mechanisms of DHA on MCT-induced PH in rats. Rat PH was induced by MCT. Rats were treated with DHA daily in the prevention group (following MCT injection) and the reversal group (after MCT injection for 2 wk) by gavage. After 4 wk, mean pulmonary arterial pressure (mPAP), right ventricular (RV) hypertrophy index, and morphological and immunohistochemical analyses were evaluated. Rat pulmonary artery smooth muscle cells (PASMCs) were used to investigate the effects of DHA on cell proliferation stimulated by platelet-derived growth factor (PDGF)-BB. DHA decreased mPAP and attenuated pulmonary vascular remodeling and RV hypertrophy, which were associated with suppressed ER stress. DHA blocked the mitogenic effect of PDGF-BB on PASMCs and arrested the cell cycle via inhibiting nuclear factor of activated T cells-1 (NFATc1) expression and activation and regulating cell cycle-related proteins. Moreover, DHA ameliorated inflammation in lung and suppressed macrophage and T lymphocyte accumulation in lung and adventitia of resistance pulmonary arteries. These findings suggest that DHA could protect against MCT-induced PH by reducing ER stress, suppressing cell proliferation and inflammation.

Recovery time for inflamed middle ear mucosa in chronic otitis media.

PubMed

Pakır, Onur; Dinç, Aykut Erdem; Damar, Murat; Akyıldız, İlker; Eliçora, Sultan Şevik; Erdem, Duygu

2016-01-01

The present study shows that 2-3 weeks after medical treatment the status of middle ear mucosa in draining ears is similar to that of dry ears for at least 3 months. To measure the time required for an inflamed middle ear mucosa to return into optimal state after appropriate medical treatment in chronic suppurative otitis media (CSOM). To assess optimal timing for elective surgical treatment of draining ears in uncomplicated CSOM. In this prospective study, the Eustachian tube (ET) mucociliary clearance time (MCT) was used as the method to demonstrate the status of middle ear mucosa. In group 1 (28 patients) ET-MCT was measured in ears that were free of drainage for at least 3 months. In Group 2 (21 patients), ET-MCT was measured in draining ears, who responded to 10-14 days medical treatment, at presentation, after 10 days and 1 month. The ET-MCT was 8.63 ± 1.32 min in group 1 and 28.96 ± 8.19 min in group 2 at presentation; and the difference was statistically significant (p < 0.001). The ET-MCT was 14.76 ± 5.11 min after 10 days and 9.31 ± 2.33 min after 1 month in group 2. The ET-MCT was indifferent between groups 1 and 2 after 1 month (p = 0.235).

Metacognitive therapy versus disorder-specific CBT for comorbid anxiety disorders: A randomized controlled trial.

PubMed

Johnson, Sverre Urnes; Hoffart, Asle; Nordahl, Hans M; Wampold, Bruce E

2017-08-01

Few studies have compared the effects of Metacognitive therapy (MCT) and Cognitive behavioral therapy (CBT) for comorbid anxiety disorders. In the current study we compared CBT and MCT for heterogeneous anxiety disorders in a residential setting. Ninety patients with a primary diagnosis of Post Traumatic Stress Disorder, Social Phobia or Panic disorder, with and without Agoraphobia, were randomized to either CBT or MCT. Patients were assessed at pre-treatment, post-treatment and one-year follow-up. Primary outcome measures were Beck Anxiety Inventory and ADIS IV and secondary outcome measures were SCID II, Beck Depression Inventory, Penn State Worry Questionnaire, The Symptom Checklist-90 and the Inventory of Interpersonal Problems-64. Treatment fidelity was satisfactory and therapist credibility was equal in both treatments. There was a significant difference in the level of anxiety favouring MCT at post-treatment (d=0.7), but there were no differences at one-year follow-up, mainly due to a further improvement in the CBT group during the follow-up period. Both treatments were efficacious. No differences in effect on comorbid diagnoses and symptoms were found, but MCT produced larger change in personality problems. MCT seems to have a more rapid effect on anxiety symptoms, but there were no significant differences in the long term for patients with comorbid anxiety disorders. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Immunomodulatory drugs disrupt the cereblon-CD147-MCT1 axis to exert antitumor activity and teratogenicity.

PubMed

Eichner, Ruth; Heider, Michael; Fernández-Sáiz, Vanesa; van Bebber, Frauke; Garz, Anne-Kathrin; Lemeer, Simone; Rudelius, Martina; Targosz, Bianca-Sabrina; Jacobs, Laura; Knorn, Anna-Maria; Slawska, Jolanta; Platzbecker, Uwe; Germing, Ulrich; Langer, Christian; Knop, Stefan; Einsele, Herrmann; Peschel, Christian; Haass, Christian; Keller, Ulrich; Schmid, Bettina; Götze, Katharina S; Kuster, Bernhard; Bassermann, Florian

2016-07-01

Immunomodulatory drugs (IMiDs), such as thalidomide and its derivatives lenalidomide and pomalidomide, are key treatment modalities for hematologic malignancies, particularly multiple myeloma (MM) and del(5q) myelodysplastic syndrome (MDS). Cereblon (CRBN), a substrate receptor of the CRL4 ubiquitin ligase complex, is the primary target by which IMiDs mediate anticancer and teratogenic effects. Here we identify a ubiquitin-independent physiological chaperone-like function of CRBN that promotes maturation of the basigin (BSG; also known as CD147) and solute carrier family 16 member 1 (SLC16A1; also known as MCT1) proteins. This process allows for the formation and activation of the CD147-MCT1 transmembrane complex, which promotes various biological functions, including angiogenesis, proliferation, invasion and lactate export. We found that IMiDs outcompete CRBN for binding to CD147 and MCT1, leading to destabilization of the CD147-MCT1 complex. Accordingly, IMiD-sensitive MM cells lose CD147 and MCT1 expression after being exposed to IMiDs, whereas IMiD-resistant cells retain their expression. Furthermore, del(5q) MDS cells have elevated CD147 expression, which is attenuated after IMiD treatment. Finally, we show that BSG (CD147) knockdown phenocopies the teratogenic effects of thalidomide exposure in zebrafish. These findings provide a common mechanistic framework to explain both the teratogenic and pleiotropic antitumor effects of IMiDs.

Effects of Shiitake Intake on Serum Lipids in Rats Fed Different High-Oil or High-Fat Diets.

PubMed

Asada, Norihiko; Kairiku, Rumi; Tobo, Mika; Ono, Akifumi

2018-04-27

Shiitake (Lentinula edodes) extract, eritadenine, has been shown to reduce cholesterol levels, and its hypocholesterolemic actions are involved in the metabolism of methionine. However, the mechanisms by which eritadenine affects cholesterol metabolism in animals fed a high-fat diet containing different sources of lipids have not yet been elucidated in detail. This study was conducted to investigate the effects of shiitake supplementation on serum lipid concentrations in rats fed a diet including a high amount of a plant oil (HO [high oil] and HOS [high oil with shiitake] groups), animal fat (HF [high fat] and HFS [high fat with shiitake] groups), or MCT- (medium-chain triglyceride-) rich plant oil (HM [high MCT] and HMS [high MCT with shiitake] groups). Rats in the HOS, HFS, and HMS groups were fed shiitake. When rats were fed a diet containing shiitake, serum triglyceride, cholesterol levels, and LCAT (lecithin-cholesterol acyltransferase) activities were lower in rats given MCT-rich plant oil than in those that consumed lard. The lipid type in the diet with shiitake also affected serum cholesterol levels and LCAT activities. The diet containing MCT-rich plant oil showed the greatest rates of decrease in all serum lipid profiles and LCAT activities. These results suggest that shiitake and MCT-rich plant oil work together to reduce lipid profiles and LCAT activity in serum.

Morphing continuum theory for turbulence: Theory, computation, and visualization.

PubMed

Chen, James

2017-10-01

A high order morphing continuum theory (MCT) is introduced to model highly compressible turbulence. The theory is formulated under the rigorous framework of rational continuum mechanics. A set of linear constitutive equations and balance laws are deduced and presented from the Coleman-Noll procedure and Onsager's reciprocal relations. The governing equations are then arranged in conservation form and solved through the finite volume method with a second-order Lax-Friedrichs scheme for shock preservation. A numerical example of transonic flow over a three-dimensional bump is presented using MCT and the finite volume method. The comparison shows that MCT-based direct numerical simulation (DNS) provides a better prediction than Navier-Stokes (NS)-based DNS with less than 10% of the mesh number when compared with experiments. A MCT-based and frame-indifferent Q criterion is also derived to show the coherent eddy structure of the downstream turbulence in the numerical example. It should be emphasized that unlike the NS-based Q criterion, the MCT-based Q criterion is objective without the limitation of Galilean invariance.

A curly-tail modifier locus, mct1, on mouse chromosome 17

DOE Office of Scientific and Technical Information (OSTI.GOV)

Letts, V.A.; Schork, N.J.; Frankel, W.N.

1995-10-10

The major gene for neural tube defects, ct, in the curly-tail (CT) mouse strain was mapped previously to mouse chromosome 4 by combining linkage data from several backcrosses. The penetrance of the neural tube trait, already incomplete in the CT strain, was further reduced in several of these backcrosses, suggesting the existence of recessive modifiers or strain-specific susceptibility alleles. Here we describe the mapping of a curly-tail modifier locus, mct1, to chromosome 17 in moderate and low penetrance crosses of CT with BALB/cByJ and Mus spretus. No effect of mct1 was seen in a higher penetrance cross with the BXD-8/Tymore » strain, confirming that ct is the major gene in the model. Homozygosity at both ct and mct1 loci was sufficient to account for all of the affected individuals in the BALB/cByJ cross and most of the affected individuals in the M. spretus cross and was the preferred model overall. No evidence was found for epistatic interaction between ct and mct1. 30 refs., 2 figs., 3 tabs.« less

MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors

PubMed Central

Birsoy, Kivanc; Wang, Tim; Possemato, Richard; Yilmaz, Omer H.; Koch, Catherine E.; Chen, Walter W.; Hutchins, Amanda W.; Gultekin, Yetis; Peterson, Tim R.; Carette, Jan E.; Brummelkamp, Thijn R.; Clish, Clary B.; Sabatini, David M.

2012-01-01

SUMMARY There is increasing evidence that oncogenic transformation modifies the metabolic program of cells. A common alteration is the upregulation of glycolysis, and efforts to target glycolytic enzymes for anti-cancer therapy are underway. Here, we performed a genome-wide haploid genetic screen to identify resistance mechanisms to 3-bromopyruvate (3-BrPA), a drug candidate that inhibits glycolysis in a poorly understood fashion. We identified the SLC16A1 gene product, MCT1, as the main determinant of 3-BrPA sensitivity. MCT1 is necessary and sufficient for 3-BrPA uptake by cancer cells. Additionally, MCT1 mRNA levels are the best predictor of 3-BrPA sensitivity and are most elevated in glycolytic cancer cells. Lastly, forced MCT1 expression in 3-BrPA resistant cancer cells sensitizes tumor xenografts to 3-BrPA treatment in vivo. Our results identify a potential biomarker for 3-BrPA sensitivity and provide proof of concept that the selectivity of cancer-expressed transporters can be exploited for delivering toxic molecules to tumors. PMID:23202129

Recurrence rates and clinical outcome for dogs with grade II mast cell tumours with a low AgNOR count and Ki67 index treated with surgery alone.

PubMed

Smith, J; Kiupel, M; Farrelly, J; Cohen, R; Olmsted, G; Kirpensteijn, J; Brocks, B; Post, G

2017-03-01

Grade II mast cell tumours (MCT) are tumours with variable biologic behaviour. Multiple factors have been associated with outcome, including proliferation markers. The purpose of this study was to determine if extent of surgical excision affects recurrence rate in dogs with grade II MCT with low proliferation activity, determined by Ki67 and argyrophilic nucleolar organising regions (AgNOR). Eighty-six dogs with cutaneous MCT were evaluated. All dogs had surgical excision of their MCT with a low Ki67 index and combined AgNORxKi67 (Ag67) values. Twenty-three (27%) dogs developed local or distant recurrence during the median follow-up time. Of these dogs, six (7%) had local recurrence, one had complete and five had incomplete histologic margins. This difference in recurrence rates between dogs with complete and incomplete histologic margins was not significant. On the basis of this study, ancillary therapy may not be necessary for patients with incompletely excised grade II MCT with low proliferation activity. © 2015 John Wiley & Sons Ltd.

Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier.

PubMed

Vatine, Gad D; Al-Ahmad, Abraham; Barriga, Bianca K; Svendsen, Soshana; Salim, Ariel; Garcia, Leslie; Garcia, Veronica J; Ho, Ritchie; Yucer, Nur; Qian, Tongcheng; Lim, Ryan G; Wu, Jie; Thompson, Leslie M; Spivia, Weston R; Chen, Zhaohui; Van Eyk, Jennifer; Palecek, Sean P; Refetoff, Samuel; Shusta, Eric V; Svendsen, Clive N

2017-06-01

Inactivating mutations in the thyroid hormone (TH) transporter Monocarboxylate transporter 8 (MCT8) cause severe psychomotor retardation in children. Animal models do not reflect the biology of the human disease. Using patient-specific induced pluripotent stem cells (iPSCs), we generated MCT8-deficient neural cells that showed normal TH-dependent neuronal properties and maturation. However, the blood-brain barrier (BBB) controls TH entry into the brain, and reduced TH availability to neural cells could instead underlie the diseased phenotype. To test potential BBB involvement, we generated an iPSC-based BBB model of MCT8 deficiency, and we found that MCT8 was necessary for polarized influx of the active form of TH across the BBB. We also found that a candidate drug did not appreciably cross the mutant BBB. Our results therefore clarify the underlying physiological basis of this disorder, and they suggest that circumventing the diseased BBB to deliver active TH to the brain could be a viable therapeutic strategy. Copyright © 2017 Elsevier Inc. All rights reserved.

Development and performance of a new version of the OASIS coupler, OASIS3-MCT_3.0

NASA Astrophysics Data System (ADS)

Craig, Anthony; Valcke, Sophie; Coquart, Laure

2017-09-01

OASIS is coupling software developed primarily for use in the climate community. It provides the ability to couple different models with low implementation and performance overhead. OASIS3-MCT is the latest version of OASIS. It includes several improvements compared to OASIS3, including elimination of a separate hub coupler process, parallelization of the coupling communication and run-time grid interpolation, and the ability to easily reuse mapping weight files. OASIS3-MCT_3.0 is the latest release and includes the ability to couple between components running sequentially on the same set of tasks as well as to couple within a single component between different grids or decompositions such as physics, dynamics, and I/O. OASIS3-MCT has been tested with different configurations on up to 32 000 processes, with components running on high-resolution grids with up to 1.5 million grid cells, and with over 10 000 2-D coupling fields. Several new features will be available in OASIS3-MCT_4.0, and some of those are also described.

Association Between MCT1 A1470T Polymorphism and Fat-Free Mass in Well-Trained Young Soccer Players.

PubMed

Massidda, Myosotis; Eynon, Nir; Bachis, Valeria; Corrias, Laura; Culigioni, Claudia; Cugia, Paolo; Scorcu, Marco; Calò, Carla M

2016-04-01

The aim of this study was to investigate the association between the MCT1 A1470T polymorphism and fat-free mass in young Italian elite soccer players. Participants were 128 Italian male soccer players. Fat-free mass was estimated for each of the soccer player using age- and gender-specific formulas with plicometry. Genotyping for the MCT1 A1470T polymorphism was performed using polymerase chain reaction. The MCT1 A1470T genotypes were in agreement with the Hardy-Weinberg equilibrium distribution. The percentage of fat-free mass was significantly higher in soccer players with the TT genotype and in the T-allele-dominant model group (TT + AT) compared with the soccer players with the AA genotype. The MCT1 T allele is associated with the percentage of fat-free mass in young elite male soccer players. Elucidating the genetic basis of body composition in athletes could potentially be used as an additional tool for strength and conditioning professionals in planning and adjusting training. However, these results are preliminary and need to be replicated in more cohorts.

Effects of different endurance exercise modalities on migraine days and cerebrovascular health in episodic migraineurs: A randomized controlled trial.

PubMed

Hanssen, H; Minghetti, A; Magon, S; Rossmeissl, A; Rasenack, M; Papadopoulou, A; Klenk, C; Faude, O; Zahner, L; Sprenger, T; Donath, L

2018-03-01

Aerobic exercise training is a promising complementary treatment option in migraine and can reduce migraine days and improve retinal microvascular function. Our aim was to elucidate whether different aerobic exercise programs at high vs moderate intensities distinctly affect migraine days as primary outcome and retinal vessel parameters as a secondary. In this randomized controlled trial, migraine days were recorded by a validated migraine diary in 45 migraineurs of which 36 (female: 28; age: 36 (SD:10)/BMI: 23.1 (5.3) completed the training period (dropout: 20%). Participants were assigned (Strata: age, gender, fitness and migraine symptomatology) to either high intensity interval training (HIT), moderate continuous training (MCT), or a control group (CON). Intervention groups trained twice a week over a 12-week intervention period. Static retinal vessel analysis, central retinal arteriolar (CRAE) and venular (CRVE) diameters, as well as the arteriolar-to-venular diameter ratio (AVR) were obtained for cerebrovascular health assessment. Incremental treadmill testing yielded maximal and submaximal fitness parameters. Overall, moderate migraine day reductions were observed (ηP2 = .12): HIT revealed 89% likely beneficial effects (SMD = 1.05) compared to MCT (SMD = 0.50) and CON (SMD = 0.59). Very large intervention effects on AVR improvement (ηP2 = 0.27), slightly favoring HIT (SMD=-0.43) over CON (SMD=0), were observed. HIT seems more effective for migraine day reduction and improvement of cerebrovascular health compared to MCT. Intermittent exercise programs of higher intensities may need to be considered as an additional treatment option in migraine patients. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Applying Low Temperature Thermochronology to Constrain Exhumation Patterns along the Eastern Denali Fault Corner, Alaska

NASA Astrophysics Data System (ADS)

Warfel, T. S.; Fitzgerald, P. G.; Benowitz, J.; Ridgway, K.; Allen, W. K.

2017-12-01

The Denali Fault (DF) constitutes a long ( 2000 km), arcuate, dextrally transpressive intracontinental fault system sketching across south-central Alaska. Strain-partitioning along the DF is accommodated as slip on the fault and fault-normal motion on a series of thrusts located north and south of the fault itself. High topography in the central and eastern Alaska Range, also locations of the greatest exhumation along the fault, are associated with restraining bends in those regions. East of the Richardson Highway, along the eastern Denali fault corner (or east-central segment of the DF), thrust faults south of the DF, including the McCallum thrust have accommodated the fault-normal component of motion along the DF. The aim of this project is to better understand what controls exhumation along large strike-slip faults, in particular the DF. Previous work along the DF in the central and eastern Alaska Range (to the west of this region) indicate the importance of fault geometry and rheological contrasts between terranes that have been juxtaposed against one another in controlling the location of exhumation. Our area of interest is a largely unstudied section along the Denali Fault (eastern DF corner) located between the DF/Hines Creek fault intersection and the Totschunda/DF intersection. We are applying a combination of apatite fission track thermochronology and apatite (U-Th)/He dating to samples collected north and south of the DF, and across thrust faults south of the DF. Thermochronology is being applied to bedrock samples, collected in vertical profiles and/or hanging wall - footwall pairs. Cobbles were also collected within a stratigraphic framework (constrained by tephras), from Miocene sediments in inverted basins south of the DF. Thermochronologic data from these cobbles; using lag-time analyses and inverse thermal models, will constrain the exhumation history of the hinterland. Assuming modern rates for slip along the DF will allow constraints to be placed on spatial and temporal patterns of exhumation and hence, help constrain the underlying control on exhumation patterns. Preliminary results indicate older AFT and AHe ages (up to 50 Ma) away from the DF but yield apatite (U-Th)/He ages as young as 2 Ma for a sample from the footwall of the closest thrust south of the DF.

Three-thrust fault system at the plate suture of arc-continent collision in the southernmost Longitudinal Valley, eastern Taiwan

NASA Astrophysics Data System (ADS)

Lee, J.; Chen, H.; Hsu, Y.; Yu, S.

2013-12-01

Active faults developed into a rather complex three-thrust fault system at the southern end of the narrow Longitudinal Valley in eastern Taiwan, a present-day on-land plate suture between the Philippine Sea plate and Eurasia. Based on more than ten years long geodetic data (including GPS and levelling), field geological investigation, seismological data, and regional tomography, this paper aims at elucidating the architecture of this three-thrust system and the associated surface deformation, as well as providing insights on fault kinematics, slip behaviors and implications of regional tectonics. Combining the results of interseismic (secular) horizontal and vertical velocities, we are able to map the surface traces of the three active faults in the Taitung area. The west-verging Longitudinal Valley Fault (LVF), along which the Coastal Range of the northern Luzon arc is thrusting over the Central Range of the Chinese continental margin, braches into two active strands bounding both sides of an uplifted, folded Quaternary fluvial deposits (Peinanshan massif) within the valley: the Lichi fault to the east and the Luyeh fault to the west. Both faults are creeping, to some extent, in the shallow surface level. However, while the Luyeh fault shows nearly pure thrust type, the Lichi fault reveals transpression regime in the north and transtension in the south end of the LVF in the Taitung plain. The results suggest that the deformation in the southern end of the Longitudinal Valley corresponds to a transition zone from present arc-collision to pre-collision zone in the offshore SE Taiwan. Concerning the Central Range, the third major fault in the area, the secular velocities indicate that the fault is mostly locked during the interseismic period and the accumulated strain would be able to produce a moderate earthquake, such as the example of the 2006 M6.1 Peinan earthquake, expressed by an oblique thrust (verging toward east) with significant left-lateral strike slip component. Taking into account of the recent study on the regional seismic Vp tomography, it shows a high velocity zone with steep east-dipping angle fills the gap under the Longitudinal Valley between the opposing verging LVF and the Central Range fault, implying a possible rolled-back forearc basement under the Coastal Range.

Rotational reflectance of dispersed vitrinite from the Arkoma basin

USGS Publications Warehouse

Houseknecht, D.W.; Weesner, C.M.B.

1997-01-01

Rotational reflectance of dispersed vitrinite provides superior documentation of thermal maturity and a capability for interpreting relative timing between thermal and kinematic events in Arkoma Basin strata characterized by vitrinite reflectances up to 5%. Rotational reflectance (R(rot)) is a more precise and less ambiguous index of thermal maturity than maximum (R'(max)), minimum (R(min)), and random (R(ran)) reflectance. Vitrinite reflectance anisotropy becomes sufficiently large to be measurable (using a microscope equipped with an automated rotating polarizer) at ???2% R(rot) and increases following a power function with increasing thermal maturity. Rotational reflectance data can be used to infer the shape of the vitrinite reflectance indicating surface (i.e. indicatrix) and, in turn, to enhance interpretations of the timing between thermal maxima and compressional tectonic events. Data from three wells in the Arkoma Basin Ouachita frontal thrust belt are used as examples. The absence of offsets in measured R(rot) across thrust faults combined with a predominance of uniaxial vitrinite in the thrust faulted part of the section suggest thermal maximum postdated thrust faulting in the western Ouachita frontal thrust belt of Oklahoma. In contrast, the general absence of offsets in measured R(rot) across thrust faults combined with a predominance of biaxial vitrinite in the thrust faulted part of the section suggest that the thermal maximum was coeval with thrust faulting in the eastern Ouachita frontal thrust belt of Arkansas. The presence of biaxial vitrinite in an allochthonous section and uniaxial vitrinite in an underlying, autochthonous section suggests that the thermal maximum was coeval with listric thrust faulting in the central Arkoma Basin of Oklahoma, and that rotational reflectance data can be used as a strain indicator to detect subtle decollement zones.

Paleozoic-involving thrust array in the central Sierras Interiores (South Pyrenean Zone, Central Pyrenees): regional implications

NASA Astrophysics Data System (ADS)

Rodriguez, L.; Cuevas, J.; Tubía, J. M.

2012-04-01

This work deals with the structural evolution of the Sierras Interiores between the Tena and Aragon valleys. The Sierras Interiores is a WNW-trending mountain range that bounds the South Pyrenean Zone to the north and that is characterized by a thrust-fold system with a strong lithological control that places preferably decollements in Triassic evaporites. In the studied area of the Sierras Interiores Cenomanian limestones cover discordantly the Paleozoic rocks of the Axial Zone because there is a stratigraphic lacuna developed from Triassic to Late Cretaceous times. A simple lithostratigraphy of the study area is made up of Late Cenomanian to Early Campanian limestones with grey colour and massive aspect in landscape (170 m, Lower calcareous section), Campanian to Maastrichtian brown coloured sandstones (400-600 m, Marboré sandstones) and, finally, Paleocene light-coloured massive limestones (130-230 m), that often generate the higher topographic levels of the Sierras Interiores due to their greater resistance to erosion. Above the sedimentary sequence of the Sierras Interiores, the Jaca Basin flysch succession crops out discordantly. Based on a detailed mapping of the studied area of the Sierras Interiores, together with well and structural data of the Jaca Basin (Lanaja, 1987; Rodríguez and Cuevas, 2008) we have constructed a 12 km long NS cross section, approximately parallel to the movement direction deduced for this region (Rodríguez et al., 2011). The main structure is a thrust array made up of at least four Paleozoic-involving thrusts (the deeper thrust system) of similar thickness in a probably piggyback sequence, some of which are blind thrusts that generate fold-propagation-folds in upper levels. The higher thrust of the thrust array crops out duplicating the lower calcareous section all over the Sierras Interiores. The emplacement of the deeper thrust system generated the tightness of previous structures: south directed piggyback duplexes (the upper thrust system) affecting the Marboré sandstones and the Paleocene limestones, deformed by angular south-vergent folds and their related axial plane foliation. The transect explained above clearly summarizes the alpine evolution of northern part of the Sierras Interiores. Moreover, well data available indicate the presence of two thrust soled in the lower calcareous section covering Triassic evaporites at 5 km depth and 8 km to the south of the Sierras Interiores. Because the Triassic evaporites constitute a main decollement level in the South Pyrenean Zone, the deeper thrust system is associated to the emplacement of the Gavarnie nappe. Lanaja, J.M., 1987, Contribución de la exploración petrolífera al conocimiento de la Geología de España, IGME, Madrid, 465 p. Rodríguez, L., Cuevas, J., 2008. Geogaceta 44, 51-54. Rodríguez, L., Cuevas, J., Tubia, J.M., 2011. Geophysical Research Abstracts 13, 2273.

Enhanced Vibrational Echo Correlation Spectrometer for the Study of Molecular Dynamics, Structures, and Analytical Applications

DTIC Science & Technology

2006-09-10

ultrafast IR 2D vibrational echo spectrometer. The major improvement involved a new dual MCT array detector composed of two 32 x 1 element MCT IR... detector arrays. The dual array makes it possible to improve signal- to- noise ratio in the heterodyne detection of the vibrational echo signal. To...are dispersed in a monochromator and then detected with the new 2x32-element MCT IR array detector . As discussed above, the function of the local

Noninvasive Spatially Offset and Transmission Raman Mapping of Breast Tissue: A Multimodal Approach Towards the In Vivo assessment of Tissue Pathology

DTIC Science & Technology

2013-04-01

liquid nitrogen cooled mercury cadmium telluride ( MCT ) detector and compare their performance to a commercial FT-IR imaging instrument. We examine the...telluride ( MCT ) detector (InfraRed Associates, Stuart, FL), and in a second widefield imaging configuration, we employed a cooled focal plane array (FPA...experiment, a cooled focal plane array (FPA) was substituted for the bolometer. (b) A cooled single-element MCT detector is utilized with an adjustable

Detection of Bioaerosols Using Single Particle Thermal Emission Spectroscopy (First-year Report)

DTIC Science & Technology

2012-02-01

cooled MCT detector with a noise equivalent power (NEP) of 7x10(–13) W/Hz, yields a detection S/N > 13 (assuming a sufficiently cooled background). We...dispersively resolved using 190-mm Horiba spectrometer that houses a time-gated 32-element mercury cadmium telluride ( MCT ) linear array. In this report...to 10.0 ms. Minimum integration (and readout) periods for the time-gated 32-element mercury cadmium telluride ( MCT ) linear array are 10 µs. Based

Effect of medium chain triglycerides (MCT) on jejunal mucosa mass and protein synthesis.

PubMed Central

Schwartz, S; Farriol, M; Garcia-Arumi, E; Andreu, A L; López Hellín, J; Arbós, M A

1994-01-01

The effects of medium chain triglycerides (MCT) on jejunal mucosa mass and protein synthesis were compared with results from previous experiments with rats fed by parenteral nutrition or enteral nutrition. Other published studies have also been analysed. Three experimental models were studied. In the traumatic model, production of a femoral fracture was followed by Kirschner pin insertion into the medullary canal of both fragments at reduction. (Forty ras were fed enteral nutrition and 93 were given parenteral nutrition.) A second model entailed resection under ether anaesthesia using the technique described by Higgins. (Fifty five rats were fed enteral nutrition and 28 with parenteral nutrition.) A third model entailed a terminolateral portocaval shunt under anaesthesia with pentobarbital. (Sixty nine rats were treated this way and then given enteral nutrition.) Proportions of medium chain/long chain triglycerides (LCT) were as follows: 0/100, 20/80, 40/60, 50/50, and 92/8 for enteral nutrition and 0/100, 30/70, 50/50, and 70/30 for parenteral nutrition. Faecal losses of alpha amino nitrogen, protein, total fats, and free fatty acids were analysed together with the quantitative intake, weight gain of the rats, jejunal mucosal mass, and protein synthesis in relation to the MCT proportion ingested or given by enteral nutrition or parenteral nutrition. From analysis of our results and those of others, several conclusions could be drawn. Firstly, the route of administration of MCT is extremely important and enterocytes might be considered one of the main target sites. Secondly, a high proportion of MCT (more than 80%) offers no advantage for jejunal mucosa and produces undesirable side effects. Thirdly, the effect of MCT on jejunal mucosal protein synthesis depends on the metabolic state. Finally, an increase in jejunal mucosal mass directly correlated with MCT concentrations, but no correlation was found between mass and protein synthesis. A positive correlation, however, between MCT proportion and enzyme activity (alkaline phosphatase and sucrase) in the brush border membrane was seen as well as a positive correlation with the concentration of phospholipids in the microvilli. PMID:8125388

Effects of medium-chain triglycerides on intestinal morphology and energy metabolism of intrauterine growth retarded weanling piglets.

PubMed

Zhang, Li-Li; Zhang, Hao; Li, Yue; Wang, Tian

2017-06-01

It has been shown that there is a relationship between intrauterine growth retardation (IUGR) and postnatal intestinal damage involved in energy deficits. Therefore, the present study was conducted to investigate the effect of medium-chain triglycerides (MCT) on the intestinal morphology, intestinal function and energy metabolism of piglets with IUGR. At weaning (21 ± 1.1 d of age), 24 IUGR piglets and 24 normal birth weight (NBW) piglets were selected according to their birth weights (BW) (IUGR: 0.95 ± 0.04 kg BW; NBW: 1.58 ± 0.04 kg BW) and their weights at the time of weaning (IUGR: 5.26 ± 0.15 kg BW; NBW: 6.98 ± 0.19 kg BW). The piglets were fed a diet of either long-chain triglycerides (LCT) (containing 5% LCT) or MCT (containing 1% LCT and 4% MCT) for 28 d. Then, the piglets' intestinal morphology, biochemical parameters and mRNA abundance related to intestinal damage and energy metabolism were determined. IUGR was found to impair intestinal morphology, with evidence of decreased villus height and increased crypt depth; however, these negative effects of IUGR were ameliorated by MCT treatment. IUGR piglets showed compromised intestinal digestion and absorption functions when compared with NBW piglets. However, feeding MCT increased the maltase activity in the jejunum and alleviated IUGR-induced reductions in plasma d-xylose concentrations and jejunal sucrase activity. IUGR decreased the efficiency of the piglets' intestinal energy metabolism; however, piglets fed an MCT diet exhibited increased adenosine triphosphate (ATP) concentrations and ATP synthase F1 complex beta polypeptide expression, as well as decreased adenosine monophosphate-activated kinase alpha 1 expression in the jejunum of piglets. In addition, up-regulation of the piglets' citrate synthase and succinate dehydrogenase levels was found to occur following MCT treatment at both the activity and the transcriptional levels of the jejunum. Therefore, it can be postulated that MCT treatment has beneficial effects in alleviating IUGR-induced intestinal morphologic damage, which is associated with improved intestinal energy metabolism.

Dry deposition of pollutant and marker particles onto live mouse airway surfaces enhances monitoring of individual particle mucociliary transit behaviour.

PubMed

Donnelley, Martin; Morgan, Kaye S; Siu, Karen K W; Parsons, David W

2012-07-01

Particles suspended in the air are inhaled during normal respiration and unless cleared by airway defences, such as the mucociliary transit (MCT) system, they can remain and affect lung and airway health. Synchrotron phase-contrast X-ray imaging (PCXI) methods have been developed to non-invasively monitor the behaviour of individual particles in live mouse airways and in previous studies the MCT behaviour of particles and fibres in the airways of live mice after deposition in a saline carrier fluid have been examined. In this study a range of common respirable pollutant particles (lead dust, quarry dust and fibreglass fibres) as well as marker particles (hollow glass micro-spheres) were delivered into the trachea of live mice using a dry powder insufflator to more accurately mimic normal environmental particulate exposure and deposition via inhalation. The behaviour of the particles once delivered onto the airway surface was tracked over a five minute period via PCXI. All particles were visible after deposition. Fibreglass fibres remained stationary throughout while all other particle types transited the tracheal surface throughout the imaging period. In all cases the majority of the particle deposition and any airway surface activity was located close to the dorsal tracheal wall. Both the individual and bulk motions of the glass bead marker particles were visible and their behaviour enabled otherwise hidden MCT patterns to be revealed. This study verified the value of PCXI for examining the post-deposition particulate MCT behaviour in the mouse trachea and highlighted that MCT is not a uniform process as suggested by radiolabel studies. It also directly revealed the advantages of dry particle delivery for establishing adequate particulate presence for visualizing MCT behaviour. The MCT behaviour and rate seen after dry particle delivery was different from that in previous carrier-fluid studies. It is proposed that dry particle delivery is essential for producing environmentally realistic particle deposition and studying how living airway surfaces handle different types of inhaled particles by MCT processes.

Geologic map of the Hogback Mountain quadrangle, Lewis and Clark and Meagher Counties, Montana

USGS Publications Warehouse

Reynolds, Mitchell W.

2003-01-01

The geologic map of the Hogback Mountain quadrangle, scale 1:24,000, was made as part of the Montana Investigations Project to provide new information on the stratigraphy, structure, and geologic history of an area in the geologically complex southern part of the Montana disturbed belt. In the Hogback Mountain area, rocks ranging in age from Middle Proterozoic through Cretaceous are strongly folded within and under thrust plates of equivalent rocks. Continental rocks of successive thrust plates have been telescoped eastward over a buttress of the stable continent. Erosional remnants of Oligocene andesitic basalt lie on highest surfaces eroded across the strongly deformed older rocks; younger erosion has dissected the terrain deeply, producing Late Tertiary and Quaternary deposits of alluvium, colluvium, and local landslide debris in the valleys and canyons. Different stratigraphic successions are exposed at different structural levels across the quadrangle. In the northeastern part of the quadrangle at the lowest structural level, rocks of the Upper Mississippian Big Snowy Group, including the Kibbey Formation and the undivided Otter and Heath Formations, the overlying Pennsylvanian Amsden and undivided Quadrant and Phosphoria Formations, the Ellis Group, and the Kootenai Formation, are folded and broken by thrust faults. The next higher structural level, the Avalanche Butte thrust plate, exposes strongly folded and, in places, attenuated strata of Cambrian (Flathead Sandstone, Wolsey Shale, Meagher Limestone, and undivided Pilgrim Formation and Park Shale), Devonian (Maywood Formation, Jefferson Formation, and most of the Three Forks Formation), and Mississippian (uppermost part of the Three Forks Formation and Lodgepole and Mission Canyon Limestones) ages. The overlying Hogback Mountain thrust plate contains strongly folded rocks ranging in age from the Middle Proterozoic Greyson Formation to the Upper and Lower Mississippian Mission Canyon Limestone and Cretaceous diorite sills. The highest structural level, the Moors Mountain thrust plate, contains the Middle Proterozoic Greyson and Newland Formations and discontinuous Upper Proterozoic diabase sills. Rocks are complexly folded and faulted across the quadrangle. At the lowest level in the northeastern part of the quadrangle, Upper Mississippian and younger strata are folded along northwest-trending axes and broken by thrust faults that at outcrop level displace the same rocks. The central core of the quadrangle is formed by the Avalanche Butte thrust plate, which contains recumbently folded and thrust faulted Paleozoic rocks. A succession of four tight recumbent folds within the plate have axial traces that trend northwest and north-northwest, and that are both arched and downfolded along east- and northeast-trending axes. Carbonate rocks of the Mission Canyon and Lodgepole Limestones in the upper part of the Avalanche Butte thrust plate exposed in the canyon of Trout Creek are folded and attenuated in stacked east-directed recumbent folds that developed as a succession of folded duplex thrust slices. The exposed remnant of the next higher structural level, the Hogback Mountain thrust plate, contains northeast- and east-trending folds that are inverted on the upper overturned limb of a younger northwest-trending recumbent fold. The Hogback Mountain thrust fault is itself folded and, in its northernmost exposures, is overturned to dip west beneath the overlying Moors Mountain thrust plate. During post-middle Tertiary deformation, the Hogback Mountain thrust fault moved as a normal fault, down on the east. The structurally highest Moors Mountain thrust plate rests on the Avalanche Butte thrust plate in the southwestern part of the quadrangle and across both the Avalanche Butte and Hogback Mountain thrust plates along the northwest edge of the quadrangle. In the central eastern part of the map area, the edge of a large klippen of the Moors Mounta

Reconnaissance geology of the Central Mastuj Valley, Chitral State, Pakistan

USGS Publications Warehouse

Stauffer, Karl W.

1975-01-01

The Mastuj Valley in Chitral State is a part of the Hindu Kush Range, and is one of the structurally most complicated areas in northern Pakistan. Sedimentary rocks ranging from at least Middle Devonian to Cretaceous, and perhaps Early Tertiary age lie between ridge-forming granodiorite intrusions and are cut by thrust faults. The thrust planes dip 10? to 40? to the north- west. Movement of the upper thrust plates has been toward the southeast relative to the lower blocks. If this area is structurally typical of the Hindu-Kush and Karakoram Ranges, then these mountains are much more tectonically disturbed than previously recorded, and suggest compression on a scale compatible with the hypothesis that the Himalayan, Karakoram, and Hindu Kush Ranges form part of a continental collision zone. The thrust faults outline two plates consisting of distinctive sedimentary rocks. The lower thrust plate is about 3,000 feet thick and consists of the isoclinally folded Upper Cretaceous to perhaps lower Tertiary Reshun Formation. It has overridden the Paleozoic metasedimentary rocks of the Chitral Slate unit. This thrust plate is, in turn, overridden by an 8,000-foot thick sequence consisting largely of Devonian to Carboniferous limestones and quartzites. A key factor in the tectonic processes has been the relatively soft and plastic lithology of the siltstone layers in the Reshun Formation which have acted as lubricants along the principal thrust faults, where they are commonly found today as fault slices and smears. The stratigraphic sequence, in the central Mastuj Valley was tentatively divided into 9 mapped units. The fossiliferous shales and carbonates of the recently defined Shogram Formation and the clastlcs of the Reshun Formation have been fitted into a sequence of sedimentary rocks that has a total thick- ness of at least 13,000 feet and ranges in age from Devonian to Neogene. Minerals of potential economic significance include antimony sulfides which have been mined elsewhere in Chitral, the tungstate, scheelite, which occurs in relatively high concentrations in heavy-mineral fractions of stream sands, and an iron-rich lateritic rock.

Coseismic fold scarp associated with historic earthquakes upon the Yoro active blind thrust, the Nobi-Ise fault zone, central Japan

NASA Astrophysics Data System (ADS)

Ishiyama, T.; Mueller, K.; Togo, M.

2004-12-01

We present structural models constrained by tectonic geomorphology, surface geologic mapping, shallow borehole transects and a high-resolution S-wave seismic reflection profile to define the kinematic evolution of a coseismic fold scarp along the Nobi-Ise fault zone (NIFZ). The NIFZ is an active intraplate fault system in central Japan, and consists of a 110-km-long array of active, east-verging reverse faults. Fold scarps along the Yoro fault are interpreted as produced during a large historic blind-thrust earthquake. The Yoro Mountains form the stripped core of the largest structure in the NIFZ and expose Triassic-Jurassic basement that are thrust eastward over a 2-km-thick sequence of Pliocene-Pleistocene strata deposited in the Nobi basin. This basement-cored fold is underlain by an active blind thrust that is expressed as late Holocene fold scarps along its eastern flank. Drilling investigations across the fold scarp at a site near Shizu identified at least three episodes of active folding associated with large earthquakes on the Yoro fault. Radiocarbon ages constrain the latest event as having occurred in a period that contains historical evidence for a large earthquake in A.D. 1586. A high resolution, S-wave seismic reflection profile at the same site shows that the topographic fold scarp coincides with the projected surface trace of the synclinal axis, across which the buried, early Holocene to historic sedimentary units are folded. This is interpreted to indicate that the structure accommodated coseismic fault-propagation folding during the A.D. 1586 blind thrust earthquake. Flexural-slip folding associated with secondary bedding-parallel thrusts may also deform late Holocene strata and act to consume slip on the primary blind thrust across the synclinal axial surfaces. The best-fitting trishear model for folded ca. 13 ka gravels deposited across the forelimb requires a 28\\deg east-dipping thrust fault. This solution suggests that a 4.2 mm/yr of slip rate has been accommodated on the Yoro fault during the late Holocene, with an average vertical rate of 1.9 mm/yr. This is consistent with longer-term slip rates calculated by a structural relief across a ca. 7.3 ka volcanic ash horizon (1.6 mm/yr), and ca. 110 ka innerbay clays (1.3 mm/yr) deposited across the forelimb. Our trishear model is thus able to account for the bulk of the folding history accommodated at shorter millennial timescales, suggesting that this technique may be used to adequately define slip rates on blind thrust faults.

The development of a multi-criteria decision analysis aid to help with contraceptive choices: My Contraception Tool.

PubMed

French, Rebecca S; Cowan, Frances M; Wellings, Kaye; Dowie, Jack

2014-04-01

My Contraception Tool (MCT) applies the principles of multi-criteria decision analysis to the choice of contraceptive method. Its purpose is to make the decision-making process transparent to the user and to suggest a method to them based on their own preferences. The contraceptive option that emerges as optimal from the analysis takes account of the probability of a range of outcomes and the relative weight ascribed to them by the user. The development of MCT was a collaborative project between London School of Hygiene & Tropical Medicine, Brook, FPA and Maldaba Ltd. MCT is available online via the Brook and FPA websites. In this article we describe MCT's development and how it works. Further work is needed to assess the impact it has on decision quality and contraceptive behaviour.

Wide-band (2.5 - 10.5 µm), high-frame rate IRFPAs based on high-operability MCT on silicon

NASA Astrophysics Data System (ADS)

Crosbie, Michael J.; Giess, Jean; Gordon, Neil T.; Hall, David J.; Hails, Janet E.; Lees, David J.; Little, Christopher J.; Phillips, Tim S.

2010-04-01

We have previously presented results from our mercury cadmium telluride (MCT, Hg1-xCdxTe) growth on silicon substrate technology for different applications, including negative luminescence, long waveband and mid/long dual waveband infrared imaging. In this paper, we review recent developments in QinetiQ's combined molecular beam epitaxy (MBE) and metal-organic vapor phase epitaxy (MOVPE) MCT growth on silicon; including MCT defect density, uniformity and reproducibility. We also present a new small-format (128 x 128) focal plane array (FPA) for high frame-rate applications. A custom high-speed readout integrated circuit (ROIC) was developed with a large pitch and large charge storage aimed at producing a very high performance FPA (NETD ~10mK) operating at frame rates up to 2kHz for the full array. The array design allows random addressing and this allows the maximum frame rate to be increased as the window size is reduced. A broadband (2.5-10.5 μm) MCT heterostructure was designed and grown by the MBE/MOVPE technique onto silicon substrates. FPAs were fabricated using our standard techniques; wet-etched mesa diodes passivated with epitaxial CdTe and flip-chip bonded to the ROIC. The resulting focal plane arrays were characterized at the maximum frame rate and shown to have the high operabilities and low NETD values characteristic of our LWIR MCT on silicon technology.

Merkel Cell Polyomavirus Small T Antigen Promotes Pro-Glycolytic Metabolic Perturbations Required for Transformation

PubMed Central

Keibler, Mark A.; Park, Donglim Esther; Molla, Vadim; Cheng, Jingwei; Stephanopoulos, Gregory

2016-01-01

Merkel cell polyomavirus (MCPyV) is an etiological agent of Merkel cell carcinoma (MCC), a highly aggressive skin cancer. The MCPyV small tumor antigen (ST) is required for maintenance of MCC and can transform normal cells. To gain insight into cellular perturbations induced by MCPyV ST, we performed transcriptome analysis of normal human fibroblasts with inducible expression of ST. MCPyV ST dynamically alters the cellular transcriptome with increased levels of glycolytic genes, including the monocarboxylate lactate transporter SLC16A1 (MCT1). Extracellular flux analysis revealed increased lactate export reflecting elevated aerobic glycolysis in ST expressing cells. Inhibition of MCT1 activity suppressed the growth of MCC cell lines and impaired MCPyV-dependent transformation of IMR90 cells. Both NF-κB and MYC have been shown to regulate MCT1 expression. While MYC was required for MCT1 induction, MCPyV-induced MCT1 levels decreased following knockdown of the NF-κB subunit RelA, supporting a synergistic activity between MCPyV and MYC in regulating MCT1 levels. Several MCC lines had high levels of MYCL and MYCN but not MYC. Increased levels of MYCL was more effective than MYC or MYCN in increasing extracellular acidification in MCC cells. Our results demonstrate the effects of MCPyV ST on the cellular transcriptome and reveal that transformation is dependent, at least in part, on elevated aerobic glycolysis. PMID:27880818

The critical micelle concentration of lecithin in bulk oils and medium chain triacylglycerol is influenced by moisture content and total polar materials.

PubMed

Kim, JiSu; Kim, Mi-Ja; Lee, JaeHwan

2018-09-30

Effects of different moisture contents and oxidised compounds on the critical micelle concentration (CMC) of lecithin were determined in bulk oils and in medium-chain triacylglycerols (MCT). CMC of lecithin in MCT was significantly higher than that in other vegetable oils including olive, soybean, corn, and rapeseed oils (p < 0.05). Presence of moisture significantly affected the CMC of lecithin in MCT (p < 0.05). CMC of lecithin was high when the moisture content was below 900 ppm, whereas at a moisture content of 1000 ppm, CMC of lecithin decreased significantly (p < 0.05), and then started to increase. Addition of total polar materials (TPM), which are oxidation products, at 3 and 5% concentrations, decreased CMC of lecithin significantly (p < 0.05) in MCT, compared to when 0, 1, and 1.5% of TPM was added to MCT. As the degree of oxidation increased in corn oil, CMC of lecithin gradually decreased. Additionally, under different moisture contents, corn oils showed a similar pattern of CMC of lecithin in MCT, whereas oxidised corn oil had a little lower CMC of lecithin than unoxidised corn oil. The results clearly showed that the concentration of lecithin for the formation of micelles is greatly influenced by the presence of oxidation products and the moisture content in bulk oils. Copyright © 2018 Elsevier Ltd. All rights reserved.

Liquiritigenin and liquiritin alleviated MCT-induced HSOS by activating Nrf2 antioxidative defense system.

PubMed

Huang, Zhenlin; Sheng, Yuchen; Chen, Minwei; Hao, Zhanxia; Hu, Feifei; Ji, Lili

2018-06-14

Hepatic sinusoidal obstruction syndrome (HSOS) is a serious and life-threatening liver disease. Liquiritigenin (LG) and liquiritin (LQ) are natural flavonoids distributed in Glycyrrhizae Radix et Rhizoma (Gan-cao). This study aims to investigate the protective effect and mechanism of LG and LQ against monocrotaline (MCT)-induced HSOS. Results of serum alanine/aspartate aminotransferases (ALT/AST) activities, liver histological evaluation and scanning electron microscope observation, and hepatic metalloproteinase-9 (MMP-9) expression demonstrated that LG and LQ both alleviated HSOS induced by MCT in rats. Results of hepatic reactive oxygen species (ROS), malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), oxidized glutathione (GSSG) and reduced glutathione (GSH) contents, glutathione reductase (GR) and superoxide dismutase (SOD) activities showed that LG and LQ attenuated MCT-induced liver oxidative stress injury. Furthermore, LG and LQ were found to promote Nrf2 nuclear translocation and lead to the increased expression of Nrf2 downstream antioxidative genes. Molecule docking analysis indicated the potential interaction of LG and LQ with Nrf2 binding site in the kelch-like ECH-associated protein-1 (Keap1) protein. Finally, Nrf2 knock-out mice were used. The results showed that LG and LQ both alleviated MCT-induced HSOS in wild-type mice, but such protection was totally diminished in Nrf2 knock-out mice. In conclusion, our study revealed that LG and LQ alleviated MCT-induced HSOS by inducing the activation of hepatic Nrf2 antioxidative defense system. Copyright © 2018. Published by Elsevier Inc.

A new mixed subgrid-scale model for large eddy simulation of turbulent drag-reducing flows of viscoelastic fluids

NASA Astrophysics Data System (ADS)

Li, Feng-Chen; Wang, Lu; Cai, Wei-Hua

2015-07-01

A mixed subgrid-scale (SGS) model based on coherent structures and temporal approximate deconvolution (MCT) is proposed for turbulent drag-reducing flows of viscoelastic fluids. The main idea of the MCT SGS model is to perform spatial filtering for the momentum equation and temporal filtering for the conformation tensor transport equation of turbulent flow of viscoelastic fluid, respectively. The MCT model is suitable for large eddy simulation (LES) of turbulent drag-reducing flows of viscoelastic fluids in engineering applications since the model parameters can be easily obtained. The LES of forced homogeneous isotropic turbulence (FHIT) with polymer additives and turbulent channel flow with surfactant additives based on MCT SGS model shows excellent agreements with direct numerical simulation (DNS) results. Compared with the LES results using the temporal approximate deconvolution model (TADM) for FHIT with polymer additives, this mixed SGS model MCT behaves better, regarding the enhancement of calculating parameters such as the Reynolds number. For scientific and engineering research, turbulent flows at high Reynolds numbers are expected, so the MCT model can be a more suitable model for the LES of turbulent drag-reducing flows of viscoelastic fluid with polymer or surfactant additives. Project supported by the China Postdoctoral Science Foundation (Grant No. 2011M500652), the National Natural Science Foundation of China (Grant Nos. 51276046 and 51206033), and the Specialized Research Fund for the Doctoral Program of Higher Education of China (Grant No. 20112302110020).

Energy metabolism of medium-chain triglycerides versus carbohydrates during exercise.

PubMed

Décombaz, J; Arnaud, M J; Milon, H; Moesch, H; Philippossian, G; Thélin, A L; Howald, H

1983-01-01

Medium-chain triglycerides (MCT) are known to be rapidly digested and oxidized. Their potential value as a source of dietary energy during exercise was compared with that of maltodextrins (MD). Twelve subjects exercised for 1 h on a bicycle ergometer (60% VO2 max), 1 h after the test meal (1MJ). The metabolism of MCT was followed using 1-13C-octanoate (Oc) as tracer and U-13C-glucose (G) was added to the 13C-naturally enriched MD. After MCT ingestion no insulin peak was observed with some accumulation of ketone bodies (KB), blood levels not exceeding 1 mM. Total losses of KB during exercise in urine, sweat and as breath acetone were small (less than 0.2 mmol X h-1). Hence, the influence of KB loss and storage on gas exchange data was negligible. The partition of fat and carbohydrate utilization during exercise as obtained by indirect calorimetry was practically the same after the MCT and the CHO meals. Oxidation over the 2-h period was 30% of dose for Oc and 45% for G. Glycogen decrements in the Vastus lateralis muscle were equal. It appears that with normal carbohydrate stores, a single meal of MCT or CHO did not alter the contribution of carbohydrates during 1 h of high submaximal exercise. The moderate ketonemia after MCT, despite substantial oxidation of this fat, led to no difference in muscle glycogen sparing between the diets.

Cellular Action of Vasopressin in Medullary Tubules of Mice with Hereditary Nephrogenic Diabetes Insipidus

PubMed Central

Jackson, Brian A.; Edwards, Richard M.; Valtin, Heinz; Dousa, Thomas P.

1980-01-01

Our previous studies (1974. J. Clin. Invest.54: 753-762.) suggested that impaired metabolism of cyclic AMP (cAMP) may be involved in the renal unresponsiveness to vasopressin (VP) in mice with hereditary nephrogenic diabetes insipidus (NDI). To localize such a defect to specific segments of the nephron, we studied the activities of VP-sensitive adenylate cyclase, cAMP phosphodiesterase (cAMP-PDIE), as well as accumulation of cAMP in medullary collecting tubules (MCT) and in medullary thick ascending limbs of Henle's loop (MAL) microdissected from control mice with normal concentrating ability and from mice with hereditary NDI. Adenylate cyclase activity stimulated by VP or by NaF was only slightly lower (−24%) in MCT from NDI mice, compared with controls. In MAL of NDI mice, basal, VP-sensitive, and NaF-sensitive adenylate cyclase was markedly (> −60%) lower compared with MAL of controls. The specific activity of cAMP-PDIE was markedly higher in MCT of NDI mice compared with controls, but was not different between MAL of control and NDI mice. Under present in vitro conditions, incubation of intact MCT from control mice with VP caused a striking increase in cAMP levels (>10), but VP failed to elicit a change in cAMP levels in MCT from NDI mice. When the cAMP-PDIE inhibitor 1-methyl-3-isobutyl xanthine (MIX) was added to the above incubation, VP caused a significant increase in cAMP levels in MCT from both NDI mice and control mice. Under all tested conditions, cAMP levels in MCT of NDI mice were lower than corresponding values in control MCT. Under the present experimental setting, VP and other stimulating factors (MIX, cholera toxin) did not change cAMP levels in MAL from either control mice or from NDI mice. The results of the present in vitro experiments suggest that the functional unresponsiveness of NDI mice to VP is perhaps mainly the result of the inability of collecting tubules to increase intracellular cAMP levels in response to VP. In turn, this inability to increase cAMP in response to VP is at least partly the result of abnormally high activity of cAMP-PDIE, a somewhat lower activity of VP-sensitive adenylate cyclase in MCT of NDI mice, and perhaps to a deficiency of some other as yet unidentified factors. The possible contribution of low VP-sensitive adenylate cyclase activity in MAL of NDI mice to the renal resistance to VP remains to be defined. PMID:6249843

Meteorite Impact Structures as Outcrop-Scale Analogues for Mountain Building Events: Weaubleau and Decaturville, MO

NASA Astrophysics Data System (ADS)

Wu, S.; McKay, M.; Evans, K. R.

2017-12-01

Understanding the architecture of mountain belts is limited because studies are typically confined to surficial exposures with lesser amounts of subsurface data and active margins are prone to successive tectonism that obscures the rock record. In west-central Missouri, two Paleozoic meteorite impacts are exposed that contain a range of outcrop-scale structures. While the strain rate in a meteorite impact is an order of magnitude greater than that in orogeny-scale structures, the morphology and spatial relationships in these impact structures may provide insight into larger tectonic features. The entire crater could not be compared to an orogenic event because the amount of strain diffuses as distance increases from the impactor during an impacting event. The center of an impact crater could not be compared to an orogenic event because it has become too deformed. However, the crater rim and the immediate surrounding area could be used as a comparison because it has undergone the right amount of deformation to have recognizable structures. High-detail mapping and structural analyses of road cut exposures near Decaturville, MO reveals thrust fault sequences contain 1-2 m thick mixed carbonate and clastic sheets that include rollover anticlines, structural orphans, and lateral ramp features. Thrust faults dip away from the impact structure and represent gravitational collapse of the central uplift seconds after collision. Thrust sheet thickness, thrust fault spacing, ramp/flat morphology, and shortening of within these structures will be presented and assessed as an analogue for map-scale features in the Southern Appalachian fold and thrust belt. Because temperature controls rock mechanic properties, a thermal model based on thermochronology and thermobarometry for the section will also be presented and discussed in the context of orogenic thermomechanics.

Structural analysis of the Gachsar sub-zone in central Alborz range; constrain for inversion tectonics followed by the range transverse faulting

NASA Astrophysics Data System (ADS)

Yassaghi, A.; Naeimi, A.

2011-08-01

Analysis of the Gachsar structural sub-zone has been carried out to constrain structural evolution of the central Alborz range situated in the central Alpine Himalayan orogenic system. The sub-zone bounded by the northward-dipping Kandovan Fault to the north and the southward-dipping Taleghan Fault to the south is transversely cut by several sinistral faults. The Kandovan Fault that controls development of the Eocene rocks in its footwall from the Paleozoic-Mesozoic units in the fault hanging wall is interpreted as an inverted basin-bounding fault. Structural evidences include the presence of a thin-skinned imbricate thrust system propagated from a detachment zone that acts as a footwall shortcut thrust, development of large synclines in the fault footwall as well as back thrusts and pop-up structures on the fault hanging wall. Kinematics of the inverted Kandovan Fault and its accompanying structures constrain the N-S shortening direction proposed for the Alborz range until Late Miocene. The transverse sinistral faults that are in acute angle of 15° to a major magnetic lineament, which represents a basement fault, are interpreted to develop as synthetic Riedel shears on the cover sequences during reactivation of the basement fault. This overprinting of the transverse faults on the earlier inverted extensional fault occurs since the Late Miocene when the south Caspian basin block attained a SSW movement relative to the central Iran. Therefore, recent deformation in the range is a result of the basement transverse-fault reactivation.

How to treat the untreated: effectiveness of a self-help metacognitive training program (myMCT) for obsessive-compulsive disorder

PubMed Central

Moritz, Steffen; Jelinek, Lena; Hauschildt, Marit; Naber, Dieter

2010-01-01

Despite advances in the understanding and treatment of obsessive-compulsive disorder (OCD), many patients undergoing interventions display incomplete symptom reduction. Our research group has developed a self-help manual entitled “My Metacognitive Training for OCD” (myMCT) aimed at raising patients' awareness about cognitive biases that seem to subserve OCD. The training is particularly intended for patients currently unable or unwilling to attend standard therapy, or in cases where such a treatment option is not available. For the present study, 86 individuals suffering from OCD were recruited over the Internet. Following the initial assessment participants were either immediately emailed the myMCT manual or allocated to a waitlist group. After 4 weeks, a second assessment was performed. The myMCT group showed significantly greater improvement for OCD symptoms according to the Y-BOCS total score compared with the waitlist group (d =.63), particularly for obsessions (d=.69). Medium to strong differences emerged for the OCI-R (d =.70) and the BDI-SF (d =.50). The investigation provides the first evidence for the effectiveness of the myMCT for OCD. PMID:20623925

Image reconstruction and scan configurations enabled by optimization-based algorithms in multispectral CT

NASA Astrophysics Data System (ADS)

Chen, Buxin; Zhang, Zheng; Sidky, Emil Y.; Xia, Dan; Pan, Xiaochuan

2017-11-01

Optimization-based algorithms for image reconstruction in multispectral (or photon-counting) computed tomography (MCT) remains a topic of active research. The challenge of optimization-based image reconstruction in MCT stems from the inherently non-linear data model that can lead to a non-convex optimization program for which no mathematically exact solver seems to exist for achieving globally optimal solutions. In this work, based upon a non-linear data model, we design a non-convex optimization program, derive its first-order-optimality conditions, and propose an algorithm to solve the program for image reconstruction in MCT. In addition to consideration of image reconstruction for the standard scan configuration, the emphasis is on investigating the algorithm’s potential for enabling non-standard scan configurations with no or minimum hardware modification to existing CT systems, which has potential practical implications for lowered hardware cost, enhanced scanning flexibility, and reduced imaging dose/time in MCT. Numerical studies are carried out for verification of the algorithm and its implementation, and for a preliminary demonstration and characterization of the algorithm in reconstructing images and in enabling non-standard configurations with varying scanning angular range and/or x-ray illumination coverage in MCT.

Tertiary structural evolution of the Gangdese thrust system southeastern Tibet

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yin, An; Harrison, M.; Ryerson, F.J.

1994-09-10

Structural and thermochronological investigations of southern Tibet (Xizang) suggest that intracontinental thrusting has been the dominant cause for formation of thickened crust in the southernmost Tibetan plateau since late Oligocene. Two thrust systems are documented in this study: the north dipping Gangdese system (GTS) and the younger south dipping Renbu-Zedong system (RZT). West of Lhasa, the Gangdese thrust juxtaposes the Late Cretaceous forearc basin deposits of the Lhasa Block (the Xigaze Group) over the Tethyan sedimentary rocks of the Indian plate, whereas east of Lhasa, the fault juxtaposes the Late Cretaceous-Eocene, Andean-type arc (the Gangdese batholith) over Tethyan sedimentary rocks.more » Near Zedong, 150 km southeast of Lhasa, the Gangdese thrust is marked by a >200-m-thick mylonitic shear zone that consists of deformed granite and metasedimentary rocks. A major south dipping backthrust in the hanging wall of the Gangdese thrust puts the Xigaze Group over Tertiary conglomerates and the Gangdese plutonics north of Xigaze and west of Lhasa. A lower age bound for the Gangdese thrust of 18.3{+-}0.5 Ma is given by crosscutting relationships. The timing of slip on the Gangdese thrust is estimate to be 27-23 Ma from {sup 40}Ar/{sup 39}Ar thermochronology, and a displacement of at least 46{+-}9 km is indicated near Zedong. The age of the Gangdese thrust (GT) is consistent with an upper age limit of {approximately}24 Ma for the initiation of movement on the Main Central thrust. In places, the younger Renbu-Zedong fault is thrust over the trace of the GT, obscuring its exposure. The RZT appears to have been active at circa 18 Ma but had ceased movement by 8{+-}1 Ma. The suture between India and Asia has been complexely modified by development of the GTS, RZT, and, locally, strike-slip and normal fault systems. 64 refs., 14 figs., 2 tabs.« less

Measured sections and correlations of mid-Cretaceous rocks near the Lombard thrust of the Helena Salient in southwestern Montana

USGS Publications Warehouse

Dyman, T.S.; Tysdal, R.G.; Porter, K.W.; Thompson, G.A.

1995-01-01

Two surface sections that generally characterize mid-Cretaceous strata in the central to southern part of the Helena salient of the Montana thrust belt (Figs. 1 and 2) are presented here. We have not published detailed descriptions of the lithic units of these sections, and the stratigraphic correlations are tentative. The sections are presented in this preliminary form because they may aid interpretations of seismic and borehole data of petroleum exploration companies active in the salient.

Saturn Apollo Program

NASA Image and Video Library

1969-01-01

In the clustering procedure, an initial assembly step for the Saturn IB launch vehicle's S-IB (first) stage, workers at the Michoud Assembly Facility (MAF) near New Orleans, Louisiana, place the first of eight outboard fuel tanks atop the central liquid-oxygen tank. Developed by the Marshall Space Flight Center and built by the Chrysler Corporation at Michoud Assembly Facility (MAF), the S-IB utilized eight H-1 engines and each produced 200,000 pounds of thrust, a combined thrust of 1,600,000 pounds.

Multiphysics Computational Analysis of a Solid-Core Nuclear Thermal Engine Thrust Chamber

NASA Technical Reports Server (NTRS)

Wang, Ten-See; Canabal, Francisco; Cheng, Gary; Chen, Yen-Sen

2007-01-01

The objective of this effort is to develop an efficient and accurate computational heat transfer methodology to predict thermal, fluid, and hydrogen environments for a hypothetical solid-core, nuclear thermal engine - the Small Engine. In addition, the effects of power profile and hydrogen conversion on heat transfer efficiency and thrust performance were also investigated. The computational methodology is based on an unstructured-grid, pressure-based, all speeds, chemically reacting, computational fluid dynamics platform, while formulations of conjugate heat transfer were implemented to describe the heat transfer from solid to hydrogen inside the solid-core reactor. The computational domain covers the entire thrust chamber so that the afore-mentioned heat transfer effects impact the thrust performance directly. The result shows that the computed core-exit gas temperature, specific impulse, and core pressure drop agree well with those of design data for the Small Engine. Finite-rate chemistry is very important in predicting the proper energy balance as naturally occurring hydrogen decomposition is endothermic. Locally strong hydrogen conversion associated with centralized power profile gives poor heat transfer efficiency and lower thrust performance. On the other hand, uniform hydrogen conversion associated with a more uniform radial power profile achieves higher heat transfer efficiency, and higher thrust performance.

Differential Regulation of Thyroid Hormone Metabolism Target Genes during Non-thyroidal Illness Syndrome Triggered by Fasting or Sepsis in Adult Mice

PubMed Central

Fontes, Klaus N.; Cabanelas, Adriana; Bloise, Flavia F.; de Andrade, Cherley Borba Vieira; Souza, Luana L.; Wilieman, Marianna; Trevenzoli, Isis H.; Agra, Lais C.; Silva, Johnatas D.; Bandeira-Melo, Christianne; Silva, Pedro L.; Rocco, Patricia R. M.; Ortiga-Carvalho, Tania M.

2017-01-01

Fasting and sepsis induce profound changes in thyroid hormone (TH) central and peripheral metabolism. These changes affect TH action and are called the non-thyroidal illness syndrome (NTIS). To date, it is still debated whether NTIS represents an adaptive response or a real hypothyroid state at the tissue level. Moreover, even though it has been considered the same syndrome, we hypothesized that fasting and sepsis induce a distinct set of changes in thyroid hormone metabolism. Herein, we aimed to evaluate the central and peripheral expression of genes involved in the transport (MCT8/Slc16a2 and MCT10/Slc16a10), metabolism (Dio1, Dio2, and Dio3) and action (Thra and Thrb) of TH during NTIS induced by fasting or sepsis. Male mice were subjected to a 48 h period of fasting or cecal ligation and puncture (CLP)-induced sepsis. At the peripheral level, fasting led to: (1) reduced serum thyroxine (T4) and triiodothyronine (T3), expression of Dio1, Thra, Slc16a2, and MCT8 protein in liver; (2) increased hepatic Slc16a10 and Dio3 expression; and (3) decreased Slc16a2 and Slc16a10 expressions in the thyroid gland. Fasting resulted in reduction of Tshb expression in the pituitary and increased expression of Dio2 in total hypothalamus, arcuate (ARC) and paraventricular (PVN) nucleus. CLP induced sepsis resulted in reduced: (1) T4 serum levels; (2) Dio1, Slc16a2, Slc16a10, Thra, and Thrb expression in liver as well as Slc16a2 expression in the thyroid gland (3) Thrb and Tshb mRNA expression in the pituitary; (4) total leukocyte counts in the bone marrow while increased its number in peritoneal and pleural fluids. In summary, fasting- or sepsis-driven NTIS promotes changes in the set point of hypothalamus-pituitary-thyroid axis through different mechanisms. Reduced hepatic THRs expression in conjunction with reduced TH transporters expression in the thyroid gland may indicate, respectively, reduction in the peripheral action and in the secretion of TH, which may contribute to the low TH serum levels observed in both models. PMID:29118715

Differential Regulation of Thyroid Hormone Metabolism Target Genes during Non-thyoidal Illness Syndrome Triggered by Fasting or Sepsis in Adult Mice.

PubMed

Fontes, Klaus N; Cabanelas, Adriana; Bloise, Flavia F; de Andrade, Cherley Borba Vieira; Souza, Luana L; Wilieman, Marianna; Trevenzoli, Isis H; Agra, Lais C; Silva, Johnatas D; Bandeira-Melo, Christianne; Silva, Pedro L; Rocco, Patricia R M; Ortiga-Carvalho, Tania M

2017-01-01

Fasting and sepsis induce profound changes in thyroid hormone (TH) central and peripheral metabolism. These changes affect TH action and are called the non-thyroidal illness syndrome (NTIS). To date, it is still debated whether NTIS represents an adaptive response or a real hypothyroid state at the tissue level. Moreover, even though it has been considered the same syndrome, we hypothesized that fasting and sepsis induce a distinct set of changes in thyroid hormone metabolism. Herein, we aimed to evaluate the central and peripheral expression of genes involved in the transport (MCT8/ Slc16a2 and MCT10/ Slc16a10 ), metabolism ( Dio1, Dio2 , and Dio3 ) and action ( Thra and Thrb ) of TH during NTIS induced by fasting or sepsis. Male mice were subjected to a 48 h period of fasting or cecal ligation and puncture (CLP)-induced sepsis. At the peripheral level, fasting led to: (1) reduced serum thyroxine (T 4 ) and triiodothyronine (T 3 ), expression of Dio1, Thra, Slc16a2 , and MCT8 protein in liver; (2) increased hepatic Slc16a10 and Dio3 expression; and (3) decreased Slc16a2 and Slc16a10 expressions in the thyroid gland. Fasting resulted in reduction of Tshb expression in the pituitary and increased expression of Dio2 in total hypothalamus, arcuate (ARC) and paraventricular (PVN) nucleus. CLP induced sepsis resulted in reduced: (1) T 4 serum levels; (2) Dio1, Slc16a2, Slc16a10, Thra , and Thrb expression in liver as well as Slc16a2 expression in the thyroid gland (3) Thrb and Tshb mRNA expression in the pituitary; (4) total leukocyte counts in the bone marrow while increased its number in peritoneal and pleural fluids. In summary, fasting- or sepsis-driven NTIS promotes changes in the set point of hypothalamus-pituitary-thyroid axis through different mechanisms. Reduced hepatic THRs expression in conjunction with reduced TH transporters expression in the thyroid gland may indicate, respectively, reduction in the peripheral action and in the secretion of TH, which may contribute to the low TH serum levels observed in both models.

Simulated glass-forming polymer melts: dynamic scattering functions, chain length effects, and mode-coupling theory analysis.

PubMed

Frey, S; Weysser, F; Meyer, H; Farago, J; Fuchs, M; Baschnagel, J

2015-02-01

We present molecular-dynamics simulations for a fully flexible model of polymer melts with different chain length N ranging from short oligomers (N = 4) to values near the entanglement length (N = 64). For these systems we explore the structural relaxation of the supercooled melt near the critical temperature T c of mode-coupling theory (MCT). Coherent and incoherent scattering functions are analyzed in terms of the idealized MCT. For temperatures T > T c we provide evidence for the space-time factorization property of the β relaxation and for the time-temperature superposition principle (TTSP) of the α relaxation, and we also discuss deviations from these predictions for T ≈ T c. For T larger than the smallest temperature where the TTSP holds we perform a quantitative analysis of the dynamics with the asymptotic MCT predictions for the late β regime. Within MCT a key quantity, in addition to T c, is the exponent parameter λ. For the fully flexible polymer models studied we find that λ is independent of N and has a value (λ = 0.735 ) typical of simple glass-forming liquids. On the other hand, the critical temperature increases with chain length toward an asymptotic value T c (∞) . This increase can be described by T c (∞) - T c(N) ∼ 1/N and may be interpreted in terms of the N dependence of the monomer density ρ, if we assume that the MCT glass transition is ruled by a soft-sphere-like constant coupling parameter Γ c = ρ c T c (-1/4), where ρ c is the monomer density at T c. In addition, we also estimate T c from a Hansen-Verlet-like criterion and MCT calculations based on structural input from the simulation. For our polymer model both the Hansen-Verlet criterion and the MCT calculations suggest T c to decrease with increasing chain length, in contrast to the direct analysis of the simulation data.

Fluticasone propionate in clinically suspected asthma patients with negative methacholine challenge test.

PubMed

Peiman, Soheil; Abtahi, Hamidreza; Akhondzadeh, Shahin; Safavi, Enayat; Moin, Mostafa; Rahimi Foroushani, Abbas

2017-07-01

Despite reports of response to steroid inhaler in some clinically suspected asthma patients with negative methacholine challenge test (CSA/MCT-), treatment in these patients has not been prospectively studied. We studied the role of a 12 week high dose inhaled fluticasone trial in CSA/MCT- patients. After a 2 week run-in period, CSA/MCT-patients were treated with 12 weeks of Fluticasone propionate 1000 µg/day. The Asthma Control Test (ACT), numeric cough score (NCS) and bronchodilator use were compared with their pretreatment values. Thirty-four of 42 CSA/MCT-patients completed the study. Mean pretreatment ACT score (pACT) was significantly increased after treatment (14.7 ± 3.37 to 20.9 ± 3.1, P < 0.001). Posttreatment values of daytime (1.0 ± 1.0) and night-time (0.6 ± 0.9) NCS decreased compared to their pretreatment values (2.8 ± 1.1 and 1.9 ± 1.3, respectively; P < 0.001). ACT score change (ΔACT) were significantly greater in those with pACT < 15 than in those ≥15 (P < 0.001) . Fifteen of 21 patients with ΔACT > 5 did not need to use bronchodilator for their symptom relief. Wheeze disappeared in all six patients with ΔACT > 5 after the trial. Six months after the study, steroid inhaler continued to be used by 72.2% of patients. A significant portion of CSA/MCT- (especially those with pretreatment ACT score <15) respond to high dose fluticasone inhaler in terms of symptoms relief, disappearance of wheeze and need to bronchodilator use. ΔACT could not be predicted with any individual symptoms or signs before MCT, % FEV1 decline or symptoms during MCT and exhaled nitric oxide. © 2015 John Wiley & Sons Ltd.

Effects of interval and continuous exercise training on CD4 lymphocyte apoptotic and autophagic responses to hypoxic stress in sedentary men.

PubMed

Weng, Tzu-Pin; Huang, Shu-Chun; Chuang, Yu-Fen; Wang, Jong-Shyan

2013-01-01

Exercise is linked with the type/intensity-dependent adaptive immune responses, whereas hypoxic stress facilitates the programmed death of CD4 lymphocytes. This study investigated how high intensity-interval (HIT) and moderate intensity-continuous (MCT) exercise training influence hypoxia-induced apoptosis and autophagy of CD4 lymphocytes in sedentary men. Thirty healthy sedentary males were randomized to engage either HIT (3-minute intervals at 40% and 80%VO2max, n=10) or MCT (sustained 60%VO2max, n=10) for 30 minutes/day, 5 days/week for 5 weeks, or to a control group that did not received exercise intervention (CTL, n=10). CD4 lymphocyte apoptotic and autophagic responses to hypoxic exercise (HE, 100 W under 12%O2 for 30 minutes) were determined before and after various regimens. The results demonstrated that HIT exhibited higher enhancements of pulmonary ventilation, cardiac output, and VO2 at ventilatory threshold and peak performance than MCT did. Before the intervention, HE significantly down-regulated autophagy by decreased beclin-1, Atg-1, LC3-II, Atg-12, and LAMP-2 expressions and acridine orange staining, and simultaneously enhanced apoptosis by increased phospho-Bcl-2 and active caspase-9/-3 levels and phosphotidylserine exposure in CD4 lymphocytes. However, five weeks of HIT and MCT, but not CTL, reduced the extents of declined autophagy and potentiated apoptosis in CD4 lymphocytes caused by HE. Furthermore, both HIT and MCT regimens manifestly lowered plasma myeloperoxidase and interleukin-4 levels and elevated the ratio of interleukin-4 to interferon-γ at rest and following HE. Therefore, we conclude that HIT is superior to MCT for enhancing aerobic fitness. Moreover, either HIT or MCT effectively depresses apoptosis and promotes autophagy in CD4 lymphocytes and is accompanied by increased interleukin-4/interferon-γ ratio and decreased peroxide production during HE.

The anti-tumour agent lonidamine is a potent inhibitor of the mitochondrial pyruvate carrier and plasma membrane monocarboxylate transporters.

PubMed

Nancolas, Bethany; Guo, Lili; Zhou, Rong; Nath, Kavindra; Nelson, David S; Leeper, Dennis B; Blair, Ian A; Glickson, Jerry D; Halestrap, Andrew P

2016-04-01

Lonidamine (LND) is an anti-tumour drug particularly effective at selectively sensitizing tumours to chemotherapy, hyperthermia and radiotherapy, although its precise mode of action remains unclear. It has been reported to perturb the bioenergetics of cells by inhibiting glycolysis and mitochondrial respiration, whereas indirect evidence suggests it may also inhibit L-lactic acid efflux from cells mediated by members of the proton-linked monocarboxylate transporter (MCT) family and also pyruvate uptake into the mitochondria by the mitochondrial pyruvate carrier (MPC). In the present study, we test these possibilities directly. We demonstrate that LND potently inhibits MPC activity in isolated rat liver mitochondria (Ki2.5 μM) and co-operatively inhibits L-lactate transport by MCT1, MCT2 and MCT4 expressed in Xenopus laevisoocytes with K0.5 and Hill coefficient values of 36-40 μM and 1.65-1.85 respectively. In rat heart mitochondria LND inhibited the MPC with similar potency and uncoupled oxidation of pyruvate was inhibited more effectively (IC50~ 7 μM) than other substrates including glutamate (IC50~ 20 μM). In isolated DB-1 melanoma cells 1-10 μM LND increased L-lactate output, consistent with MPC inhibition, but higher concentrations (150 μM) decreased L-lactate output whereas increasing intracellular [L-lactate] > 5-fold, consistent with MCT inhibition. We conclude that MPC inhibition is the most sensitive anti-tumour target for LND, with additional inhibitory effects on MCT-mediated L-lactic acid efflux and glutamine/glutamate oxidation. Together these actions can account for published data on the selective tumour effects of LND onL-lactate, intracellular pH (pHi) and ATP levels that can be partially mimicked by the established MPC and MCT inhibitor α-cyano-4-hydroxycinnamate (CHC). © 2016 Authors; published by Portland Press Limited.

Targeted Delivery of Pulmonary Arterial Endothelial Cells Overexpressing Interleukin-8 Receptors Attenuates Monocrotaline-Induced Pulmonary Vascular Remodeling

PubMed Central

Fu, Jinyan; Chen, Yiu-Fai; Zhao, Xiangmin; Creighton, Judy; Guo, Yuan-Yuan; Hage, Fadi G.; Oparil, Suzanne; Xing, Daisy D.

2014-01-01

Objective Interleukin-8 (IL8) receptors IL8RA and IL8RB (ILRA/B) on neutrophil membranes bind to IL8 with high affinity and play a critical role in neutrophil recruitment to sites of injury and/or inflammation. This study tested the hypothesis that administration of rat pulmonary arterial endothelial cells (ECs) overexpressing IL8RA/B can accelerate the adhesion of ECs to the injured lung and inhibit monocrotaline (MCT)-induced pulmonary inflammation, arterial thickening and hypertension, and right ventricular (RV) hypertrophy. Approach and Results The treatment groups included 10-wk-old ovariectomized Sprague-Dawley rats that received s.c. injection of phosphate-buffered-saline (Vehicle); a single injection of MCT (MCT alone, 60 mg/kg, s.c.); MCT followed by i.v. transfusion of ECs transduced with the empty adenoviral vector (Null-EC); and MCT followed by i.v. transfusion of ECs overexpressing IL8RA/B (IL8RA/B-EC, 1.5×106 cells/rat). Two days or 4 wks after MCT treatment, eNOS, iNOS, CINC-2β (IL8 equivalent in rat) and MCP-1 expression; neutrophil and macrophage infiltration into pulmonary arterioles, and arteriolar and alveolar morphology were measured by histological and immunohistochemical techniques. Pro-inflammatory cytokine/chemokine protein levels were measured by Multiplexed rat specific magnetic beads based sandwich immunoassay in total lung homogenates. Transfusion of IL8RA/B-ECs significantly reduced MCT-induced neutrophil infiltration and pro-inflammatory mediator (IL-8, MCP-1, iNOS, CINC and MIP-2) expression in lungs and pulmonary arterioles and alveoli, pulmonary artery pressure, and pulmonary arteriole and RV hypertrophy and remodeling. Conclusion These provocative findings suggest that targeted delivery of ECs overexpressing IL8RA/B is effective in repairing the injured pulmonary vasculature. PMID:24790141

Endogenous fat oxidation during medium chain versus long chain triglyceride feeding in healthy women.

PubMed

Papamandjaris, A A; White, M D; Raeini-Sarjaz, M; Jones, P J

2000-09-01

To compare the effect of medium chain triglycerides (MCT) vs long chain triglycerides (LCT) feeding on exogenous and endogenous oxidation of long chain saturated fatty acids (LCSFA) in women. Twelve healthy female subjects (age 19-26 y, body mass index (BMI) 17.5-28.6 kg/m2) In a randomized cross-over design, subjects were fed weight maintenance diets providing 15%, 45% and 40% of energy as protein, carbohydrate and fat, respectively, with 80% of this fat comprising either a combination of butter and coconut oil (MCT) or beef tallow (LCT). Following 6 days of feeding, subjects were given daily oral doses of 1-(13)C labelled-myristic, -palmitic and -stearic acids for 8 days. Expired 13CO2 was used as an index of LCSFA oxidation with CO2 production assessed by respiratory gas exchange. No difference in exogenous LCSFA oxidation was observed as a function of diet on day 7. On day 14, greater combined cumulative fractional LCSFA oxidation (16.9 +/- 2.5%/5.5 h vs 9.1 +/- 1.2%/5.5 h, P < 0.007), net LCSFA oxidation (2956 +/- 413 mg/5.5 h vs 1669 +/- 224 mg/5.5 h, P < 0.01), and percentage dietary LCSFA contribution to total fat oxidation (16.3 +/- 2.3%/5.5 h vs 9.5 +/- 1.5%/5.5 h; P < 0.01) were observed in women fed the MCT vs LCT diet. With the MCT diet, but not the LCT diet, combined cumulative fractional LCSFA oxidation (P < 0.03), net LCSFA oxidation (P < 0.03), and percentage dietary LCSFA contribution to total fat oxidation (P < 0.02) were increased at day 14 as compared to day 7. Day 14 results indicated increased endogenous LCSFA oxidation during MCT feeding. The capacity of MCT to increase endogenous oxidation of LCSFA suggests a role for MCT in body weight control over the long term.

Partial replacement of dietary (n-6) fatty acids with medium-chain triglycerides decreases the incidence of spontaneous colitis in interleukin-10-deficient mice.

PubMed

Mañé, Josep; Pedrosa, Elisabet; Lorén, Violeta; Ojanguren, Isabel; Fluvià, Lourdes; Cabré, Eduard; Rogler, Gerhard; Gassull, Miquel A

2009-03-01

Enteral nutrition has a primary therapeutic effect in active Crohn's disease. It is unknown which nutrient(s) account for this action, but a role for both the amount and type of dietary fat has been postulated. Some clinical and experimental data suggest that medium-chain triglycerides (MCT) may reduce intestinal inflammation. We aimed to assess the effect of replacing part of the dietary fat with MCT on the incidence and severity of colitis in interleukin (IL)-10(-/-) mice under specific pathogen-free conditions. Twenty-four IL-10(-/-) 4-wk-old mice were randomized to receive a control diet based on sunflower oil [(n-6) fatty acids (FA)] and an experimental isocaloric, isonitrogenous diet with 50% sunflower and 50% coconut oil (MCT diet). When the mice were 12 wk old, they were killed and the colon was examined for the presence of colitis, lymphocyte subpopulations and apoptosis, ex vivo cytokine production in supernatant of colon explants, toll-like receptor (TLR)-2 and TLR-9 mRNA, and FA profile in colonic tissue homogenates. Colitis incidence was lower in the IL-10(-/-) mice fed the MCT diet (1/12) than in the mice fed the control diet (8/12; P = 0.03). The histological damage score was also lower in the former (P < 0.0005). Feeding the MCT diet resulted in fewer total and apoptotic intraepithelial CD3+ and lamina propria CD3+CD4+ lymphocytes, as well as downregulated production of IL-6 and interferon-gamma, and reduced TLR-9 mRNA. We conclude that partial replacement of dietary (n-6) FA with MCT decreases the incidence of colitis in a model of spontaneous intestinal inflammation and provide experimental arguments for a possible primary therapeutic effect of MCT in human Crohn's disease.

N-acetylcysteine improves established monocrotaline-induced pulmonary hypertension in rats

PubMed Central

2014-01-01

Background The outcome of patients suffering from pulmonary arterial hypertension (PAH) are predominantly determined by the response of the right ventricle to the increase afterload secondary to high vascular pulmonary resistance. However, little is known about the effects of the current available or experimental PAH treatments on the heart. Recently, inflammation has been implicated in the pathophysiology of PAH. N-acetylcysteine (NAC), a well-known safe anti-oxidant drug, has immuno-modulatory and cardioprotective properties. We therefore hypothesized that NAC could reduce the severity of pulmonary hypertension (PH) in rats exposed to monocrotaline (MCT), lowering inflammation and preserving pulmonary vascular system and right heart function. Methods Saline-treated control, MCT-exposed, MCT-exposed and NAC treated rats (day 14–28) were evaluated at day 28 following MCT for hemodynamic parameters (right ventricular systolic pressure, mean pulmonary arterial pressure and cardiac output), right ventricular hypertrophy, pulmonary vascular morphometry, lung inflammatory cells immunohistochemistry (monocyte/macrophages and dendritic cells), IL-6 expression, cardiomyocyte hypertrophy and cardiac fibrosis. Results The treatment with NAC significantly decreased pulmonary vascular remodeling, lung inflammation, and improved total pulmonary resistance (from 0.71 ± 0.05 for MCT group to 0.50 ± 0.06 for MCT + NAC group, p < 0.05). Right ventricular function was also improved with NAC treatment associated with a significant decrease in cardiomyocyte hypertrophy (625 ± 69 vs. 439 ± 21 μm2 for MCT and MCT + NAC group respectively, p < 0.001) and heart fibrosis (14.1 ± 0.8 vs. 8.8 ± 0.1% for MCT and MCT + NAC group respectively, p < 0.001). Conclusions Through its immuno-modulatory and cardioprotective properties, NAC has beneficial effect on pulmonary vascular and right heart function in experimental PH. PMID:24929652

Co-seismic ruptures of the 12 May 2008, Ms 8.0 Wenchuan earthquake, Sichuan: East-west crustal shortening on oblique, parallel thrusts along the eastern edge of Tibet

USGS Publications Warehouse

Liu-Zeng, J.; Zhang, Z.; Wen, L.; Tapponnier, P.; Sun, Jielun; Xing, X.; Hu, G.; Xu, Q.; Zeng, L.; Ding, L.; Ji, C.; Hudnut, K.W.; van der Woerd, J.

2009-01-01

The Ms 8.0, Wenchuan earthquake, which devastated the mountainous western rim of the Sichuan basin in central China, produced a surface rupture over 200??km-long with oblique thrust/dextral slip and maximum scarp heights of ~ 10??m. It thus ranks as one of the world's largest continental mega-thrust events in the last 150??yrs. Field investigation shows clear surface breaks along two of the main branches of the NE-trending Longmen Shan thrust fault system. The principal rupture, on the NW-dipping Beichuan fault, displays nearly equal amounts of thrust and right-lateral slip. Basin-ward of this rupture, another continuous surface break is observed for over 70??km on the parallel, more shallowly NW-dipping Pengguan fault. Slip on this latter fault was pure thrusting, with a maximum scarp height of ~ 3.5??m. This is one of the very few reported instances of crustal-scale co-seismic slip partitioning on parallel thrusts. This out-of-sequence event, with distributed surface breaks on crustal mega-thrusts, highlights regional, ~ EW-directed, present day crustal shortening oblique to the Longmen Shan margin of Tibet. The long rupture and large offsets with strong horizontal shortening that characterize the Wenchuan earthquake herald a re-evaluation of tectonic models anticipating little or no active shortening of the upper crust along this edge of the plateau, and require a re-assessment of seismic hazard along potentially under-rated active faults across the densely populated western Sichuan basin and mountains. ?? 2009 Elsevier B.V.

Disrupted fat distribution and composition due to medium-chain triglycerides in mice with a β-oxidation defect.

PubMed

Tucci, Sara; Flögel, Ulrich; Sturm, Marga; Borsch, Elena; Spiekerkoetter, Ute

2011-08-01

Because of the enhanced recognition of inherited long-chain fatty acid oxidation disorders by worldwide newborn screening programs, an increasing number of asymptomatic patients receive medium-chain triglyceride (MCT) supplements to prevent the development of cardiomyopathy and myopathy. MCT supplementation has been recognized as a safe dietary intervention, but long-term observations into later adulthood are still not available. We investigated the consequences of a prolonged MCT diet on abdominal fat distribution and composition and on liver fat. Mice with very-long-chain acyl-coenzyme A dehydrogenase deficiency (VLCAD(-/-)) were supplemented for 1 y with a diet in which MCTs replaced long-chain triglycerides without increasing the total fat content. The dietary effects on abdominal fat accumulation and composition were analyzed by in vivo (1)H- and (13)C-magnetic resonance spectroscopy (9.4 Tesla). After 1 y of MCT supplementation, VLCAD(-/-) mice accumulated massive visceral fat and had a dramatic increase in the concentration of serum free fatty acids. Furthermore, we observed a profound shift in body triglyceride composition, ie, concentrations of physiologically important polyunsaturated fatty acids dramatically decreased. (1)H-Magnetic resonance spectroscopy analysis and histologic evaluation of the liver also showed pronounced fat accumulation and marked oxidative stress. Although the MCT-supplemented diet has been reported to prevent the development of cardiomyopathy and skeletal myopathy in fatty acid oxidation disorders, our data show that long-term MCT supplementation results in a severe clinical phenotype similar to that of nonalcoholic steatohepatitis and the metabolic syndrome.

Effects of a Series of Acidic Drugs on L-Lactic Acid Transport by the Monocarboxylate Transporters MCT1 and MCT4.

PubMed

Leung, Yat H; Belanger, Francois; Lu, Jennifer; Turgeon, Jacques; Michaud, Veronique

2017-01-01

Drug-induced myopathy is a serious side effect that often requires removal of a medication from a drug regimen. For most drugs, the underlying mechanism of drug-induced myopathy remains unclear. Monocarboxylate transporters (MCTs) mediate L-lactic acid transport, and inhibition of MCTs may potentially lead to perturbation of L-lactic acid accumulation and muscular disorders. Therefore, we hypothesized that L-lactic acid transport may be involved in the development of drug-induced myopathy. The aim of this study was to assess the inhibitory potential of 24 acidic drugs on L-lactic acid transport using breast cancer cell lines Hs578T and MDA-MB-231, which selectively express MCT1 and MCT4, respectively. The influx transport of L-lactic acid was minimally inhibited by all drugs tested. The efflux transport was next examined: loratadine (IC50: 10 and 61 µM) and atorvastatin (IC50: 78 and 41 µM) demonstrated the greatest potency for inhibition of L-lactic acid efflux by MCT1 and MCT4, respectively. Acidic drugs including fluvastatin, cerivastatin, simvastatin acid, lovastatin acid, irbesartan and losartan exhibited weak inhibitory potency on L-lactic acid efflux. Our results suggest that some acidic drugs, such as loratadine and atorvastatin, can inhibit the efflux transport of L-lactic acid. This inhibition may cause an accumulation of intracellular L-lactic acid leading to acidification and muscular disorders. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Comparison of mandibular first molar mesial root canal morphology using micro-computed tomography and clearing technique.

PubMed

Kim, Yeun; Perinpanayagam, Hiran; Lee, Jong-Ki; Yoo, Yeon-Jee; Oh, Soram; Gu, Yu; Lee, Seung-Pyo; Chang, Seok Woo; Lee, Woocheol; Baek, Seung-Ho; Zhu, Qiang; Kum, Kee-Yeon

2015-08-01

Micro-computed tomography (MCT) with alternative image reformatting techniques shows complex and detailed root canal anatomy. This study compared two-dimensional (2D) and 3D MCT image reformatting with standard tooth clearing for studying mandibular first molar mesial root canal morphology. Extracted human mandibular first molar mesial roots (n=31) were scanned by MCT (Skyscan 1172). 2D thin-slab minimum intensity projection (TS-MinIP) and 3D volume rendered images were constructed. The same teeth were then processed by clearing and staining. For each root, images obtained from clearing, 2D, 3D and combined 2D and 3D techniques were examined independently by four endodontists and categorized according to Vertucci's classification. Fine anatomical structures such as accessory canals, intercanal communications and loops were also identified. Agreement among the four techniques for Vertucci's classification was 45.2% (14/31). The most frequent were Vertucci's type IV and then type II, although many had complex configurations that were non-classifiable. Generally, complex canal systems were more clearly visible in MCT images than with standard clearing and staining. Fine anatomical structures such as intercanal communications, accessory canals and loops were mostly detected with a combination of 2D TS-MinIP and 3D volume-rendering MCT images. Canal configurations and fine anatomic structures were more clearly observed in the combined 2D and 3D MCT images than the clearing technique. The frequency of non-classifiable configurations demonstrated the complexity of mandibular first molar mesial root canal anatomy.

Fat-soluble vitamins and plasma and erythrocyte membrane fatty acids in chylothorax pediatric patients receiving a medium-chain triglyceride-rich diet.

PubMed

Densupsoontorn, Narumon; Jirapinyo, Pipop; Tirapongporn, Hathaichanok; Wongarn, Renu; Chotipanang, Kwanjai; Phuangphan, Phakkanan; Chongviriyaphan, Nalinee

2014-11-01

Post-operative chylothorax can be cured by a medium-chain triglyceride (MCT)-rich diet. However, there is concern that an MCT-rich diet results in clinical and biochemical deficiencies in fat-soluble vitamins and fatty acids. We compared fat-soluble vitamins status and fatty acids status before and after administration of an MCT-rich diet. Nine children with congenital heart disease developed chylothorax after cardiac surgery. Blood samples were drawn from each subject twice, first prior to administration of an MCT-rich diet and secondly when the chylothorax was clinically cured and the MCT diet discontinued. Both blood samples were analyzed for retinol and 25-hydroxy vitamin D concentrations, the ratio of α-tocopherol to total lipids (α-TE/TL), coagulogram, and the fatty acid composition in plasma and erythrocyte membrane phospholipids. In spite of a decrease in the α-TE/TL ratio (3.78 ± 0.89 vs 2.36 ± 0.44 mg/g, p<0.05), this decrease did not reach the deficiency cut-off level. Linoleic acid in both plasma and erythrocyte membrane lipids decreased significantly (25.25 ± 8.06 vs 14.25 ± 2.88%, and 11.19 ± 2.15 vs 6.89 ± 2.45%, respectively). Administration of an MCT-rich diet for treatment of postoperative chylothorax caused a reduction in vitamin E status and linoleic acid, but without any symptoms of deficiency.

Advances in SELEX ES infrared detectors for space and astronomy

NASA Astrophysics Data System (ADS)

Knowles, P.; Hipwood, L.; Baker, I.; Weller, H.

2017-11-01

Selex ES produces a wide range of infrared detectors from mercury cadmium telluride (MCT) and triglycine sulfate (TGS), and has supplied both materials into space programmes spanning a period of over 40 years. Current development activities that underpin potential future space missions include large format arrays for near- and short-wave infrared (NIR and SWIR) incorporating radiation-hard designs and suppression of glow. Improved heterostructures are aimed at the reduction of dark currents and avalanche photodiodes (APDs), and parallel studies have been undertaken for low-stress MCT array mounts. Much of this development work has been supported by ESA, UK Space, and ESO, and some has been performed in collaboration with the UK Astronomy Technology Centre and E2V. This paper focuses on MCT heterostructure developments and novel design elements in silicon read-out chips (ROICs). The 2048 x 2048 element, 17um pitch ROIC for ESA's SWIR array development forms the basis for the largest cooled infrared detector manufactured in Europe. Selex ES MCT is grown by metal organic vapour phase epitaxy (MOVPE), currently on 75mm diameter GaAs substrates. The MCT die size of the SWIR array is 35mm square and only a single array can be printed on the 75mm diameter wafer, utilising only 28% of the wafer area. The situation for 100mm substrates is little better, allowing only 2 arrays and 31% utilisation. However, low cost GaAs substrates are readily available in 150mm diameter and the MCT growth is scalable to this size, offering the real possibility of 6 arrays per wafer with 42% utilisation. A similar 2k x 2k ROIC is the goal of ESA's NIR programme, which is currently in phase 2 with a 1k x 1k demonstrator, and a smaller 320 x 256 ROIC (SAPHIRA) has been designed for ESO for the adaptive optics application in the VLT Gravity instrument. All 3 chips have low noise source-follower architecture and are enabled for MCT APD arrays, which have been demonstrated by ESO to be capable of single photon detection. The possibility therefore exists in the near future of demonstrating a photon counting, 2k x 2k SWIR MCT detector manufactured on an affordable wafer scale of 6 arrays per wafer.

Oncogenes and inflammation rewire host energy metabolism in the tumor microenvironment

PubMed Central

Martinez-Outschoorn, Ubaldo E; Curry, Joseph M; Ko, Ying-Hui; Lin, Zhao; Tuluc, Madalina; Cognetti, David; Birbe, Ruth C; Pribitkin, Edmund; Bombonati, Alessandro; Pestell, Richard G; Howell, Anthony; Sotgia, Federica; Lisanti, Michael P

2013-01-01

Here, we developed a model system to evaluate the metabolic effects of oncogene(s) on the host microenvironment. A matched set of “normal” and oncogenically transformed epithelial cell lines were co-cultured with human fibroblasts, to determine the “bystander” effects of oncogenes on stromal cells. ROS production and glucose uptake were measured by FACS analysis. In addition, expression of a panel of metabolic protein biomarkers (Caveolin-1, MCT1, and MCT4) was analyzed in parallel. Interestingly, oncogene activation in cancer cells was sufficient to induce the metabolic reprogramming of cancer-associated fibroblasts toward glycolysis, via oxidative stress. Evidence for “metabolic symbiosis” between oxidative cancer cells and glycolytic fibroblasts was provided by MCT1/4 immunostaining. As such, oncogenes drive the establishment of a stromal-epithelial “lactate-shuttle”, to fuel the anabolic growth of cancer cells. Similar results were obtained with two divergent oncogenes (RAS and NFκB), indicating that ROS production and inflammation metabolically converge on the tumor stroma, driving glycolysis and upregulation of MCT4. These findings make stromal MCT4 an attractive target for new drug discovery, as MCT4 is a shared endpoint for the metabolic effects of many oncogenic stimuli. Thus, diverse oncogenes stimulate a common metabolic response in the tumor stroma. Conversely, we also show that fibroblasts protect cancer cells against oncogenic stress and senescence by reducing ROS production in tumor cells. Ras-transformed cells were also able to metabolically reprogram normal adjacent epithelia, indicating that cancer cells can use either fibroblasts or epithelial cells as “partners” for metabolic symbiosis. The antioxidant N-acetyl-cysteine (NAC) selectively halted mitochondrial biogenesis in Ras-transformed cells, but not in normal epithelia. NAC also blocked stromal induction of MCT4, indicating that NAC effectively functions as an “MCT4 inhibitor”. Taken together, our data provide new strategies for achieving more effective anticancer therapy. We conclude that oncogenes enable cancer cells to behave as selfish “metabolic parasites”, like foreign organisms (bacteria, fungi, viruses). Thus, we should consider treating cancer like an infectious disease, with new classes of metabolically targeted “antibiotics” to selectively starve cancer cells. Our results provide new support for the “seed and soil” hypothesis, which was first proposed in 1889 by the English surgeon, Stephen Paget. PMID:23860378

Effects of parenteral infusion with medium-chain triglycerides and safflower oil emulsions on hepatic lipids, plasma amino acids and inflammatory mediators in septic rats.

PubMed

Yeh, S; Chao, C; Lin, M; Chen, W

2000-04-01

This study was designed to investigate the effects of preinfusion with total parenteral nutrition (TPN) using medium-chain triglycerides (MCT) versus safflower oil (SO) emulsion as fat sources on hepatic lipids, plasma amino acid profiles, and inflammatory-related mediators in septic rats. Normal rats, with internal jugular catheters, were divided into two groups and received TPN. TPN provided 300kcal/kg/day with 40% of the non-protein energy provided as fat. All TPN solutions were isonitrogenous and identical in nutrient composition except for the fat emulsion, which was made of SO or a mixture of MCT and soybean oil (9:1) (MO). After receiving TPN for 6 days, each group of rats was further divided into control and sepsis subgroups. Sepsis was induced by cecal ligation and puncture, whereas control rats received sham operation. All rats were classified into four groups as follows: MCT control group (MOC, n= 8), MCT sepsis group (MOS, n= 8), safflower oil control group (SOC, n= 8), and safflower oil sepsis group (SOS, n= 11). The results of the study demonstrated that the MOS group had lower hepatic lipids than did the SOS group. Plasma leucine and isoleucine levels were significantly lower in the SOS than in the SOC group, but no differences in these two amino acids were observed between the MOC and MOS groups. Plasma arginine levels were significantly lower in septic groups than in those without sepsis despite whether MCT or safflower oil was infused. Plasma glutamine and alanine levels, however, did not differ between septic and non-septic groups either in the SO or MO groups. No differences in interleukin-1b, interleukin-6, tumor necrosis factor-alpha, and leukotriene B(4)concentrations in peritoneal lavage fluid were observed between the two septic groups. These results suggest that catabolic reaction is septic rats preinfused MCT is not as obvious as those preinfused safflower oil. Compared with safflower oil, TPN with MCT administration has better effects on reducing sepsis-induced liver fat deposition. Preinfusion with MCT before sepsis, however, had no effect on inflammatory-related cytokines or leukotriene in peritoneal lavage fluid. In addition, plasma arginine appears to be a more sensitive indicator than glutamine for septic insult. Copyright 2000 Harcourt Publishers Ltd.

Late Cretaceous fluvial systems and inferred tectonic history, central Utah

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lawton, T.F.

1983-08-01

Upper Campanian nonmarine sedimentary rocks exposed between the Wasatch Plateau and the Green River in central Utah record a tectonic transition from thin-skinned deformation in the thrust belt to basement-cored uplift in the foreland region. Sandstones within the section consist of two distinct compositional suites, a lower quartzose petrofacies and an upper lithic petrofacies. The volcanic lithic grains of the Farrer and Tuscher Formations were derived from more distal arc sources to the southwest, and transported through the thrust belt somewhere west of the Kaiparowits region, where time-equivalent sedimentary rocks are also rich in volcanic lithic fragments. Disappearance of volcanicmore » lithics and appearance of pebbles at the top of the Tuscher Formation is interpreted to reflect a latest Campanian reorganization of drainage patterns that marked initial growth of the San Rafael swell and similar basement uplifts to the south of the swell. Contemporaneous fluvial systems that deposited the uppermost part of the Price River Formation in the Wasatch Plateau were apparently unaffected by the uplift and continued to flow northeast. Depositional patterns thus indicate that initial growth of the San Rafael swell was probably concurrent with late deformation in the thrust belt. Depositional onlap across the Mesaverde Group by a largely post-tectonic assemblage of fluvial and lacustrine strata (North Horn Formation) indicates a minimum late Paleocene age for growth of the San Rafael swell and deformation within the thrust belt.« less

Fluvial systems of Upper Cretaceous Mesaverde Group and Paleocene North Horn formation, central Utah: record of transition from thin-skinned deformation in foreland region

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lawton, T.F.

1985-05-01

Nonmarine strata of the upper part of the Mesaverde Group and North Horn Formation exposed between the Wasatch Plateau and the Green River in central Utah record a late Campanian tectonic transition from thrust-belt deformation to basement-cored uplift. Mesaverde Group sediments were deposited by synorogenic braided and meandering rivers. During most of Campanian time, sediment transport was east and northeast away from the thrust belt across a fluvial coastal plain. Subsequent development of the San Rafael swell, a basement uplift, between western and eastern localities caused erosional thinning of the section. Sandstones within the upper part of the Mesaverde Groupmore » form two distinct compositional suites, a lower quartzose petrofacies and an upper lithic petrofacies. Lithic grain populations of the upper petrofacies are dominated by sedimentary lithic grains were derived from the thrust belt, whereas volcanic lithic grains were derived from a volcanic terrane to the southwest. Tributary streams carrying quartzose detritus from the thrust belt entered a northeast-flowing trunk system and caused a basinward dilution of volcanic detritus. Disappearance of volcanic grains and local changes in paleocurrent directions in latest Campanian time reflect initial growth of the San Rafael swell and development of an intermontane trunk-tributary fluvial system. Depositional onlap across the Mesaverde Group by the post-tectonic North Horn Formation indicates a minimum late Paleocene age for uplift of the San Rafael swell.« less

Great paleoearthquakes of the central Himalaya and their implications for seismotectonic models and seismic hazard assessment

NASA Astrophysics Data System (ADS)

Yule, D.; Lave, J.; Kumar, S.; Wesnousky, S.

2007-12-01

A growing body of paleoseismic data collected from more than ten sites in Nepal and India has documented large coseismic displacements at the thrust front (Main Frontal thrust (MFT)). Three great earthquakes have been identified: in ~A.D. 1410 centered north of Delhi, in A.D. 1505 centered in far-western Nepal, and in ~A.D. 1100 centered in eastern Nepal. It is noteworthy that wherever exposures of the MFT have been studied estimates of surface slip are consistently large; with a range of 9-26 m. Historic accounts of the 1505 earthquake describe strong shaking across a 600-km-long stretch of the central Himalaya. A magnitude for this event is estimated to be >Mw 8.5 based on the maximum extent of felt strong shaking, the 100 km width of the locked portion of the basal detachment, and an average slip of 10-15 m. Though no historic accounts exist for the ~1410 and ~1100 earthquakes, the similarity between their surface expression and the 1505 rupture suggests that these events may have been equally large. These surface-rupturing earthquakes are distinctly different from a host of blind thrust events (Mw 7.5-8.4) that dominate the historic record since A.D. 1505. Both blind and emergent earthquakes are presumed to rupture the basal detachment and release interseismic strain that accumulates near the base of the High Himalaya and carry it to the thrust front where Holocene shortening occurs at rates of 15-22 mm/yr. Whereas the surface-rupturing earthquakes clearly deform the thrust front, survey data from the region affected by the 1906 Dehra Dun earthquake suggest that blind events contribute negligible, if any, deformation to the frontal structures. The factors controlling whether or not surface rupture occurs on the MFT remain unconstrained, but the current data seem to suggest that >Mw 8.5 surface-rutpuring earthquakes are the primary contributors to the shortening observed at the thrust front. It is sobering to consider that the 'Big One' has not struck the Himalaya in over 500 years and that Mw 7.5-8.4 earthquakes are the 'moderate' earthquakes'. Further study to constrain the lateral extent and recurrence of the great paleoearthquakes of the central Himalaya is critical to answer important questions about the Himalaya earthquake cycle and the seismic hazard facing the rapidly urbanizing population of the region.

Scattering, Adsorption, and Langmuir-Hinshelwood Desorption Models for Physisorptive and Chemisorptive Gas-Surface Systems

DTIC Science & Technology

2013-09-01

respectively, and ΦQw is the reflected flux of Q at complete accommodation. Typical properties of Q are tangential momentum mct , normal mo- mentum mcn, and...that σt ≡ mct −mc′t mct −mcw = ct − c′t ct , (9) 23 where c′t is the post-collisional tangential speed, and cw is the speed of the wall, which in this...was measured within an experimental error of ±0.02, and the coverage θ noise level was about 0.01 ML. 35 MKS simulations are compared with data in

Shock Wave Dynamics of Novel Aluminized Detonations and Empirical Model for Temperature Evolution from Post-Detonation Combustion Fireballs

DTIC Science & Technology

2011-03-01

Aerospace Corporation and had both an imager and a spectrometer [34, p. 4] that employed a 60-element mercury-cadmium-telluride ( MCT ) detector array...resolution (∆λ/λ) of 0.01. Using the CVIF and the MCT detector array, they concluded the following: Table 1. Summary of previous research on...304LN FTS using HgCdTe ( MCT ) (667–2500cm−1) and InSb (1,800–10,000 cm−1) detectors , with the InSb channel fitted with an optical density (OD) filter

Comparison of effects of ingested medium- and long-chain triglyceride on gallbladder volume and release of cholecystokinin and other gut peptides.

PubMed

Isaacs, P E; Ladas, S; Forgacs, I C; Dowling, R H; Ellam, S V; Adrian, T E; Bloom, S R

1987-05-01

In a double-blind, crossover study of the effect of ingested medium-chain triglyceride (MCT) and long-chain triglyceride (LCT) in six normal subjects, the gallbladder did not contract after ingestion of MCT but instead had significantly increased in volume at 2 hr after the meal. Plasma cholecystokinin (CCK) increased after the MCT meal, but gastrin, motilin, pancreatic polypeptide (PP), and GIP were unaffected. The long-chain triglyceride meal evoked a brisk and sustained gallbladder contraction, higher levels of CCK, and a significant increase in plasma PP and GIP levels.

Late Neogene and Active Tectonics along the Northern Margin of the Central Anatolian Plateau,TURKEY

NASA Astrophysics Data System (ADS)

Yildirim, C.; Schildgen, T. F.; Melnick, D.; Echtler, H. P.; Strecker, M. R.

2009-12-01

Margins of orogenic plateaus are conspicuous geomorphic provinces that archive tectonic and climatic variations related to surface uplift. Their growth is associated with spatial and temporal variations of mode and rate of tectonics and surface processes. Those processes can be strongly linked to the evolution of margins and plateaus thorough time. As one of the major morpho-tectonic provinces of Turkey, the Central Pontides (coinciding with the northern margin of the Central Anatolian Plateau (CAP)) display a remarkable topography and present valuable geologic and geomorphic indicators to identify active tectonics. Morpho-tectonic analysis, geological cross-sections, seismic profiles, and geodetic analysis reveal continuous deformation characterized by brittle faults from Late Miocene to recent across the northern margin of the CAP. In the Sinop Peninsula and offshore in the southern Black Sea, pervasive faulting and folding and uplift of Late Miocene to Quaternary marine deposits is related to active margin tectonics of the offshore southern Black Sea thrust and the onshore Balifaki and Erikli faults. In the Kastamonu-Boyabat sedimentary basin, the Late Miocene to Quaternary continental equivalents are strongly deformed by the Ekinveren Fault. This vergent inverse and thrust fault with overstepping en echelon segments deforms not only Quaternary travertines and conglomerates, but also patterns of the Pleistocene to Holocene drainage systems. In the southern Kastamonu-Boyabat basin, an antithetic thrust fault of the Ekinveren Fault system deformed also Quaternary fluviatile terrace deposits. Farther south, a dextral transpressive splay of the North Anatolian Fault (NAF) deforms pediment surfaces and forms the northern flank of the Ilgaz active mountain range. The Ilgaz Range rises up to 2587 m.a.s.l and is delimited by active segments of the NAF.The Central Pontides are located at the apex of northward convex arc of the NAF. Geodetic analysis indicate a deviation of the slip vectors and strain partitioning in the Central Pontides due to the large restraining bend geometry of the NAF. DEM analysis and field observations reveal that the Central Pontides integrate an active bivergent wedge, indicating out-of sequence thrusting and topographical asymmetry, with a gentle pro-wedge northern slope and a steep retro-wedge southern slopes, and regional surface tilting from south to north. Uplifted presumably Late Pleistocene to Holocene marine terraces 4 to 40 m.a.s.l. along the coast and well developed pediment and fill and strath terrace surfaces ranging from 10 to 300 m above along the Gokirmak and Kizilirmak rivers will provide chronological constraints on the uplift and incision rates of the study area.

GLUT1 expression in pediatric adrenocortical tumors: a promising candidate to predict clinical behavior.

PubMed

Pinheiro, Céline; Granja, Sara; Longatto-Filho, Adhemar; Faria, André M; Fragoso, Maria C B V; Lovisolo, Silvana M; Bonatelli, Murilo; Costa, Ricardo F A; Lerário, Antonio M; Almeida, Madson Q; Baltazar, Fátima; Zerbini, Maria C N

2017-09-08

Discrimination between benign and malignant tumors is a challenging process in pediatric adrenocortical tumors. New insights in the metabolic profile of pediatric adrenocortical tumors may contribute to this distinction, predict prognosis, as well as identify new molecular targets for therapy. The aim of this work is to characterize the expression of the metabolism-related proteins MCT1, MCT2, MCT4, CD147, CD44, GLUT1 and CAIX in a series of pediatric adrenocortical tumors. A total of 50 pediatric patients presenting adrenocortical tumors, including 41 clinically benign and 9 clinically malignant tumors, were included. Protein expression was evaluated using immunohistochemistry in samples arranged in tissue microarrays. The immunohistochemical analysis showed a significant increase in plasma membrane expression of GLUT1 in malignant lesions, when compared to benign lesions ( p =0.004), being the expression of this protein associated with shorter overall and disease-free survival ( p =0.004 and p =0.001, respectively). Although significant differences were not observed for proteins other than GLUT1, MCT1, MCT4 and CD147 were highly expressed in pediatric adrenocortical neoplasias (around 90%). GLUT1 expression was differentially expressed in pediatric adrenocortical tumors, with higher expression in clinically malignant tumors, and associated with shorter survival, suggesting a metabolic remodeling towards a hyperglycolytic phenotype in this malignancy.

Characterization of acetate transport in colorectal cancer cells and potential therapeutic implications

PubMed Central

Ferro, Suellen; Azevedo-Silva, João; Casal, Margarida; Côrte-Real, Manuela; Baltazar, Fatima; Preto, Ana

2016-01-01

Acetate, together with other short chain fatty acids has been implicated in colorectal cancer (CRC) prevention/therapy. Acetate was shown to induce apoptosis in CRC cells. The precise mechanism underlying acetate transport across CRC cells membrane, that may be implicated in its selectivity towards CRC cells, is not fully understood and was addressed here. We also assessed the effect of acetate in CRC glycolytic metabolism and explored its use in combination with the glycolytic inhibitor 3-bromopyruvate (3BP). We provide evidence that acetate enters CRC cells by the secondary active transporters MCT1 and/or MCT2 and SMCT1 as well as by facilitated diffusion via aquaporins. CRC cell exposure to acetate upregulates the expression of MCT1, MCT4 and CD147, while promoting MCT1 plasma membrane localization. We also observed that acetate increases CRC cell glycolytic phenotype and that acetate-induced apoptosis and anti-proliferative effect was potentiated by 3BP. Our data suggest that acetate selectivity towards CRC cells might be explained by the fact that aquaporins and MCTs are found overexpressed in CRC clinical cases. Our work highlights the importance that acetate transport regulation has in the use of drugs such as 3BP as a new therapeutic strategy for CRC. PMID:28874966

Medium-chain triglyceride as an alternative of in-feed colistin sulfate to improve growth performance and intestinal microbial environment in newly weaned pigs.

PubMed

Yen, Hung-Che; Lai, Wei-Kang; Lin, Chuan-Shun; Chiang, Shu-Hsing

2015-01-01

Five hundred and twenty-eight newly weaned pigs were given four treatments, with eight replicates per treatment. Sixteen to 18 pigs were assigned per replicate and were fed diets supplemented with 0 or 3% medium-chain triglyceride (MCT) and 0 or 40 ppm colistin sulfate (CS) in a 2 × 2 factorial arrangement for 2 weeks. The results showed that dietary supplementation with MCT improved the gain-to-feed ratio during days 3-7 and in the overall period (P < 0.05). Dietary supplementation with MCT decreased coliforms counts (C) in colon and rectum content (P < 0.05). Dietary supplementation with CS decreased C and lactic acid bacteria plus C counts (L + C) in cecum (P < 0.05), and C, L + C (P < 0.01) and ratio of L and C (P < 0.05) in colon and rectum contents. The lack of interactions between MCT and CS indicates different modes of action and additive effects between the two supplementations. In conclusion, supplementation with MCT in diet with or without CS could improve the intestinal microbial environment and the feed utilization efficiency of newly weaned pigs. © 2014 Japanese Society of Animal Science.

Influence of the MCT1 rs1049434 on Indirect Muscle Disorders/Injuries in Elite Football Players.

PubMed

Massidda, Myosotis; Eynon, Nir; Bachis, Valeria; Corrias, Laura; Culigioni, Claudia; Piras, Francesco; Cugia, Paolo; Scorcu, Marco; Calò, Carla M

The aim of this study was to investigate the association between MCT1 rs1049434 polymorphism and indirect muscle injuries in elite football players. One hundred and seventy-three male elite Italian football players (age = 19.2 ± 5.3 years) were recruited from a first-league football club participating at the Official National Italian Football Championship (Serie A, Primavera, Allievi, Giovanissimi). The cohort was genotyped for the MCT1 rs1049434 polymorphism, and muscle injuries data were collected during the period of 2009-2014 (five football seasons). Genomic DNA was extracted using a buccal swab, and genotyping was performed using PCR method. Structural-mechanical injuries and functional muscle disorder were included in the acute indirect muscle injury group. Participants with the MCT1 AA (AA = 1.57 ± 3.07, n  = 69) genotype exhibit significantly higher injury incidents compared to participants with the TT genotype (TT = 0.09 ± 0.25, n  = 22, P  = 0.04). The MCT1 rs1049434 polymorphism is associated with the incidence of muscle injuries in elite football players. We anticipate that the knowledge of athletes' genetic predisposition to sports-related injuries might aid in individualizing training programs.

Monocrotaline: Histological Damage and Oxidant Activity in Brain Areas of Mice

PubMed Central

Honório Junior, José Eduardo Ribeiro; Vasconcelos, Germana Silva; Rodrigues, Francisca Taciana Sousa; Sena Filho, José Guedes; Barbosa-Filho, José Maria; Aguiar, Carlos Clayton Torres; Leal, Luzia Kalyne Almeida Moreira; Soares, Pedro Marcos Gomes; Woods, David John; Fonteles, Marta Maria de França; Vasconcelos, Silvânia Maria Mendes

2012-01-01

This work was designed to study MCT effect in histopathological analysis of hippocampus (HC) and parahippocampal cortex (PHC) and in oxidative stress (OS) parameters in brain areas such as hippocampus (HC), prefrontal cortex (PFC), and striatum (ST). Swiss mice (25–30 g) were administered a single i.p. dose of MCT (5, 50, or 100 mg/kg) or 4% Tween 80 in saline (control group). After 30 minutes, the animals were sacrificed by decapitation and the brain areas (HC, PHC, PFC, or ST) were removed for histopathological analysis or dissected and homogenized for measurement of OS parameters (lipid peroxidation, nitrite, and catalase) by spectrophotometry. Histological evaluation of brain structures of rats treated with MCT (50 and 100 mg/kg) revealed lesions in the hippocampus and parahippocampal cortex compared to control. Lipid peroxidation was evident in all brain areas after administration of MCT. Nitrite/nitrate content decreased in all doses administered in HC, PFC, and ST. Catalase activity was increased in the MCT group only in HC. In conclusion, monocrotaline caused cell lesions in the hippocampus and parahippocampal cortex regions and produced oxidative stress in the HC, PFC, and ST in mice. These findings may contribute to the neurological effects associated with this compound. PMID:23251721

Effect of medium/ω-6 long chain triglyceride-based emulsion on leucocyte death and inflammatory gene expression

PubMed Central

Cury-Boaventura, M F; Gorjão, R; Martins de Lima, T; Fiamoncini, J; Godoy, A B P; Deschamphs, F C; Soriano, F G; Curi, R

2011-01-01

Lipid emulsion (LE) containing medium/ω-6 long chain triglyceride-based emulsion (MCT/ω-6 LCT LE) has been recommended in the place of ω-6 LCT-based emulsion to prevent impairment of immune function. The impact of MCT/ω-6 LCT LE on lymphocyte and neutrophil death and expression of genes related to inflammation was investigated. Seven volunteers were recruited and infusion of MCT/ω-6 LCT LE was performed for 6 h. Four volunteers received saline and no change was found. Blood samples were collected before, immediately afterwards and 18 h after LE infusion. Lymphocytes and neutrophils were studied immediately after isolation and after 24 and 48 h in culture. The following determinations were carried out: plasma-free fatty acids, triacylglycerol and cholesterol concentrations, plasma fatty acid composition, neutral lipid accumulation in lymphocytes and neutrophils, signs of lymphocyte and neutrophil death and lymphocyte expression of genes related to inflammation. MCT/ω-6 LCT LE induced lymphocyte and neutrophil death. The mechanism for MCT/ω-6 LCT LE-dependent induction of leucocyte death may involve changes in neutral lipid content and modulation of expression of genes related to cell death, proteolysis, cell signalling, inflammatory response, oxidative stress and transcription. PMID:21682721

The role of monocarboxylate transporters in uptake of lactic acid in HeLa cells.

PubMed

Cheeti, Sravanthi; Warrier, Bharat K; Lee, Chi H

2006-11-15

This study was aimed to identify the monocarboxylate transporters (MCTs) in HeLa cells and to delineate their role in transportation of L-lactic acid. The functional role of MCTs in lactic acid transport was evaluated at various mucosal pHs (4.5-7.4) or in the presence of various loading doses (0.2-2mM) of lactic acid, MCT substrates (nicotinic acid, n-butyric acid, etc.) and inhibitors (alpha-cyano-4-hydroxycinnamate and para-chloromercuribenzoic acid). The molecular properties of MCTs were characterized using reverse transcription-polymerase chain reaction (RT-PCR). The uptake rate of lactic acid by HeLa cells significantly increased from 0.353+/-0.052 to 1.103+/-0.196 micromol/mg protein as the extra-cellular pH changed from 7.4 to 4.5, indicating that activities of MCT were mediated through H(+)-linked mechanism. The uptake profile of lactic acid followed the saturable process with the K(m) value of 0.53 mM. The uptake rate of lactic acid is concentration dependent and is reduced in the presence of MCT inhibitors. MCT isoforms 1, 5 and 6 in HeLa cells were identified by RT-PCR. HeLa cell line can be used as an effective screening tool for intravaginally administered drugs targeted toward MCT.

Boundary element analysis of active mountain building and stress heterogeneity proximal to the 2015 Nepal earthquake

NASA Astrophysics Data System (ADS)

Thompson, T. B.; Meade, B. J.

2015-12-01

The Himalayas are the tallest mountains on Earth with ten peaks exceeding 8000 meters, including Mt. Everest. The geometrically complex fault system at the Himalayan Range Front produces both great relief and great earthquakes, like the recent Mw=7.8 Nepal rupture. Here, we develop geometrically accurate elastic boundary element models of the fault system at the Himalayan Range Front including the Main Central Thrust, South Tibetan Detachment, Main Frontal Thrust, Main Boundary Thrust, the basal detachment, and surface topography. Using these models, we constrain the tectonic driving forces and frictional fault strength required to explain Quaternary fault slip rate estimates. These models provide a characterization of the heterogeneity of internal stress in the region surrounding the 2015 Nepal earthquake.

Geologic map of the Nelson quadrangle, Lewis and Clark County, Montana

USGS Publications Warehouse

Reynolds, Mitchell W.; Hays, William H.

2003-01-01

The geologic map of the Nelson quadrangle, scale 1:24,000, was prepared as part of the Montana Investigations Project to provide new information on the stratigraphy, structure, and geologic history of an area in the geologically complex southern part of the Montana disturbed belt. In the Nelson area, rocks ranging in age from Middle Proterozoic through Cretaceous are exposed on three major thrust plates in which rocks have been telescoped eastward. Rocks within the thrust plates are folded and broken by thrust faults of smaller displacement than the major bounding thrust faults. Middle and Late Tertiary sedimentary and volcaniclastic rocks unconformably overlie the pre-Tertiary rocks. A major normal fault displaces rocks of the western half of the quadrangle down on the west with respect to strata of the eastern part. Alluvial and terrace gravels and local landslide deposits are present in valley bottoms and on canyon walls in the deeply dissected terrain. Different stratigraphic successions are exposed at different structural levels across the quadrangle. In the northeastern part, strata of the Middle Cambrian Flathead Sandstone, Wolsey Shale, and Meagher Limestone, the Middle and Upper Cambrian Pilgrim Formation and Park Shale undivided, the Devonian Maywood, Jefferson, and lower part of the Three Forks Formation, and Lower and Upper Mississippian rocks assigned to the upper part of the Three Forks Formation and the overlying Lodgepole and Mission Canyon Limestones are complexly folded and faulted. These deformed strata are overlain structurally in the east-central part of the quadrangle by a succession of strata including the Middle Proterozoic Greyson Formation and the Paleozoic succession from the Flathead Sandstone upward through the Lodgepole Limestone. In the east-central area, the Flathead Sandstone rests unconformably on the middle part of the Greyson Formation. The north edge, northwest quarter, and south half of the quadrangle are underlain by a succession of rocks that includes not only strata equivalent to those of the remainder of the quadrangle, but also the Middle Proterozoic Newland, Greyson, and Spokane Formations, Pennsylvanian and Upper Mississippian Amsden Formation and Big Snowy Group undivided, the Permian and Pennsylvanian Phosphoria and Quadrant Formations undivided, the Jurassic Ellis Group and Lower Cretaceous Kootenai Formation. Hornblende diorite sills and irregular bodies of probable Late Cretaceous age intrude Middle Proterozoic, Cambrian and Devonian strata. No equivalent intrusive rocks are present in structurally underlying successions of strata. In this main part of the quadrangle, the Flathead Sandstone cuts unconformably downward from south to north across the Spokane Formation into the upper middle part of the Greyson Formation. Tertiary (Miocene?) strata including sandstone, pebble and cobble conglomerate, and vitric crystal tuff underlie, but are poorly exposed, in the southeastern part of the quadrangle where they are overlain by late Tertiary and Quaternary gravel. The structural complexity of the quadrangle decreases from northeast to southwest across the quadrangle. At the lowest structural level (Avalanche Butte thrust plate) exposed in the canyon of Beaver Creek, lower and middle Paleozoic rocks are folded in northwest-trending east-inclined disharmonic anticlines and synclines that are overlain by recumbently folded and thrust faulted Devonian and Mississippian rocks. The Mississippian strata are imbricated adjacent to the recumbent folds. In the east-central part of the quadrangle, a structurally overlying thrust plate, likely equivalent to the Hogback Mountain thrust plate of the Hogback Mountain quadrangle adjacent to the east (Reynolds, 20xx), juxtaposes recumbently folded Middle Proterozoic and unconformably overlying lower Paleozoic rocks on the complexly folded and faulted rocks of the Avalanche Butte thrust plate. The highest structural plate, bounded below

Permian deposition in the north central Brooks Range, Alaska Constraints for tectonic reconstructions

USGS Publications Warehouse

Adams, K.E.; Mull, C.G.; Crowder, R.K.

1997-01-01

Two opposing tectonic models have been offered to explain the regional structural relations in the north central Brooks Range fold-thrust belt of northern Alaska. The first suggests that rocks of the northern Endicott Mountains were thrust from south to north over the area of the present Mount Doonerak high and are therefore highly allochthonous. The second implies that the rocks of the northern Endicott Mountains were deposited in a basin that lay north of the Mount Doonerak high and later were thrust a short distance southward onto the northern flank of the high and are thus parautochthonous. To provide stratigraphic constraints for these models, this study examines Permian facies of the north central Brooks Range. Permian rocks in the north central Brooks Range comprise a thin (40 to 160 m thick), fining-upward succession of clastic, storm-influenced shelf deposits. When the rocks of the northern Endicott Mountains are restored south of the Mount Doonerak area, a minimum distance of 80 km, the Permian deposits grade systematically from distal facies (Siksikpuk Formation) in the southwest to proximal facies (Echooka Formation) in the northeast. Facies trends in the reconstructed Permian basin include, from southwest to northeast, (1) an increase in carbonate content and corresponding decrease in silica content, (2) a general darkening and thickening of shaley intervals, (3) an increase in proximal features of storm beds, including coarser, thicker, more abundant, and more closely spaced beds, and (4) an increase in abundance and diversity of the faunal assemblage with a corresponding decrease in age. These stratigraphic relations imply that rocks of the northern Endicott Mountains are allochthonous and structurally overlie a proximal stratigraphic succession similar to that exposed in the Mount Doonerak area and northeastern Brooks Range. Copyright 1997 by the American Geophysical Union.

Apatite Fission Track Constraints On The Denudational History Of The Bielsa And Millares Plutons, West-Central Pyrenees, Spain

NASA Astrophysics Data System (ADS)

Schwabe, E.; Fitzgerald, P. G.; Munoz, J. A.; Baldwin, S. L.

2006-12-01

The Pyreneean orogen extends for ~ 440 km from the Bay of Biscay to the Mediterranean Sea, forming a WNW-ESE topographic barrier between France and Spain. The mountain belt, formed by the Late Cretaceous-Early Miocene oblique collision and partial subduction of the Iberian Plate beneath the European Plate. Restored and balanced cross sections show a decrease in crustal shortening from ~165 km in the central Pyrenees to ~ 50 km in the Cantabrian margin, further to the west. The variation in shortening and crustal style is due to the decrease westward in convergence and differences in inherited geometry of pre- existing extensional faults. We propose the variation must also be reflected in the denudation record, with relative timing of the main denudational events younging to the west, as well as the magnitude and rates of denudation decreasing westward. In this study we analyze AFT data collected from vertical profiles on the southern flank of the mountains in the west-central Pyrenees. The results constrain the relative timing of structures between the central and west-central Pyrenees. AFTT data from the Bielsa and Millares massifs, located in the Bielsa and Millares thrust sheets on the southern flank of the axial zone, west-central Pyrenees yield AFT ages from 30 to 20 Ma. The data, including constraints from inverse thermal modeling, indicate denudation at rates ca. 300 m/my underway in the middle Oligocene, slowing in the Miocene. Denudation is likely related to erosion following thrusting during which the granites were transported within the south-vergent Bielsa and Millares thrust sheets. The Late Oligocene-Early Miocene AFT PAZ has since been exhumed to its present elevation. In form, results are similar to those from the central Pyrenees (Fitzgerald et al., 1999) but that Oligocene denudation in the west-central Pyrenees occurred later, was slower, and of reduced magnitude when compared to extremely rapid Oligocene denudation recorded ~50 km east in the central Pyrenees. There, as demonstrated in results from the Maladeta profile, denudation in the Early Oligocene is extremely rapid (km/my) followed by a slowing or cessation of exhumation. The Miocene PAZ preserved in both profiles suggests a similar post- orogenic history most likely related to filling and subsequent re-excavation of the Ebro Basin.

[Monocarboxylate transporter 1 enhances the sensitivity of breast cancer cells to 3-bromopyruvate in vitro].

PubMed

Li, Qi-Xiang; Zhang, Pei; Liu, Fang; Wang, Xian-Zhi; Li, Lu; Wang, Zhong-Kun; Jiang, Chen-Chen; Zheng, Hai-Lun; Liu, Hao

2017-05-20

To investigate the role of monocarboxylate transporter 1 (MCT1) in enhancing the sensitivity of breast cancer cells to 3-bromopyruvate (3-BrPA). The inhibitory effect of 3-BrPA on the proliferation of breast cancer cells was assessed with MTT assay, and brominated propidium bromide single staining flow cytometry was used for detecting the cell apoptosis. An ELISA kit was used to detect the intracellular levels of hexokinase II, lactate dehydrogenase, lactate, and adenosine triphosphate, and Western blotting was performed to detect the expression of MCT1. MDA-MB-231 cells were transiently transfected with MCT1 cDNA for over-expressing MCT1, and the effect of 3-BrPA on the cell proliferation and adenosine triphosphate level was deteced. 3-BrPA did not produce significant effects on the proliferation and apoptosis of MDA-MB-231 cells, and the cells treated with 200 µmol/L 3-BrPA for 24 h showed an inhibition rate and an apoptosis rate of only 8.72% and 7.8%, respectively. The same treatment, however, produced an inhibition rate and an apoptosis rate of 84.6% and 82.3% in MCF-7 cells, respectively. In MDA-MB-231 cells with MCT1 overexpression, 200 µmol/L 3-BrPA resulted in an inhibition rate of 72.44%, significantly higher than that in the control cells (P<0.05); treatment of the cells with 25, 50, 100, and 200 µmol/L 3-BrPA for 6 h resulted in intracellular adenosine triphosphate levels of 96.98%, 88.44%, 43.3% and 27.56% relative to the control level respectively. MCT1 can enhance the sensitivity of breast cancer cells to 3-BrPA possibly by transporting 3-BrPA into cells to inhibit cell glycolysis.

GLUT1, MCT1/4 and CD147 overexpression supports the metabolic reprogramming in papillary renal cell carcinoma.

PubMed

Almeida, L M C A; Silva, R; Cavadas, B; Lima, J; Pereira, L; Soares, P; Sobrinho-Simões, M; Lopes, J M; Máximo, V

2017-10-01

Papillary Renal Cell carcinoma (pRCC) is the second most common type of RCC, accounting for about 15% of all RCCs. Surgical excision is the main treatment option. Still, 10 - 15 % of clinically localized tumours will recur and/or develop metastasis early after surgery, and no reliable prognostic biomarkers are available to identify them. It is known that pRCC cells rely on high rates of aerobic glycolysis, characterized by the up-regulation of many proteins and enzymes related with the glycolytic pathway. However, a metabolic signature enabling the identification of advanced pRCC tumours remains to be discovered. The aim of this study was to characterize the metabolic phenotype of pRCCs (subtypes 1-pRCC1 and 2-pRCC2) by evaluating the expression pattern of the glucose transporters (GLUTs) 1 and 4 and the monocarboxylate transporters (MCTs) 1 and 4, as well as their chaperon CD147. We analysed the clinico-pathological data and the protein and mRNA expression of GLUT1, GLUT4 and MCT1, MCT4 and CD147 in tumours from Porto and TCGA series (http://cancergenome.nih.gov/), respectively. With the exception of GLUT4, plasma membrane expression of all proteins was frequently observed in pRCCs. GLUT1 and MCT1 membrane overexpression was significantly higher in pRCC2 and significantly associated with higher pN-stage and higher Fuhrman grade. Overexpression of GLUT1, MCT1/4 and CD147, supports the metabolic reprograming in pRCCs. MCT1 expression was associated with pRCC aggressiveness, regardless of the tumour histotype.

Hyperpalatable Diet and Physical Exercise Modulate the Expression of the Glial Monocarboxylate Transporters MCT1 and 4.

PubMed

Portela, Luis V; Brochier, Andressa W; Haas, Clarissa B; de Carvalho, Afonso Kopczynski; Gnoato, Jussania A; Zimmer, Eduardo R; Kalinine, Eduardo; Pellerin, Luc; Muller, Alexandre P

2017-10-01

Hyperpalatable diets (HP) impair brain metabolism, and regular physical exercise has an apparent opposite effect. Here, we combined a prior long-term exposure to HP diet followed by physical exercise and evaluated the impact on some neuroenergetic components and on cognitive performance. We assessed the extracellular lactate concentration, expression of monocarboxylate transporters (MCTs), pyruvate dehydrogenase (PDH), and mitochondrial function in the hippocampus. Male C57BL/6J mice were fed 4 months with HP or a control diet. Subsequently, they were divided in the following groups: control diet sedentary (CDS), control diet exercise (CDE), HP diet sedentary (HPS), and HP diet exercise (HPE) (n = 15 per group) and were engaged for an additional 30-day period of voluntary exercise and HP diet. Relative to the control situation, exercise increased MCT1, MCT4, and PDH protein levels, while the HP diet increased MCT1 and MCT4 protein levels. The production of hydrogen peroxide (H 2 O 2 ) and the mitochondrial membrane potential (∆Ѱ m ) stimulated by succinate in hippocampal homogenates were not significantly different between groups. ADP phosphorylation and the maximal respiratory rate induced by FCCP showed similar responses between groups, implying a normal mitochondrial function. Also, extracellular brain lactate levels were increased in the HPE group compared to other groups soon after performing the Y-maze task. However, such enhanced lactate levels were not associated with improved memory performance. In summary, hippocampal protein expression levels of MCT1 and 4 were increased by physical exercise and HP diet, whereas PDH was only increased by exercise. These observations indicate that a hippocampal metabolic reprogramming takes place in response to these environmental factors.

MCT1 A1470T: a novel polymorphism for sprint performance?

PubMed

Sawczuk, Marek; Banting, Lauren K; Cięszczyk, Paweł; Maciejewska-Karłowska, Agnieszka; Zarębska, Aleksandra; Leońska-Duniec, Agata; Jastrzębski, Zbigniew; Bishop, David J; Eynon, Nir

2015-01-01

The A1470T polymorphism (rs1049434) in the monocarboxylate (lactate/pyruvate) transporter 1 gene (MCT1) has been suggested to influence athletic performance in the general population. We compared genotype distributions and allele frequencies of the MCT1 gene A1470T polymorphism between endurance athletes, sprint/power athletes and matched controls. We also examined the association between the MCT1 A1470T and the athletes' competition level ('elite' and 'national' level). The study involved endurance athletes (n=112), sprint/power athletes (n=100), and unrelated sedentary controls (n=621), all Caucasians. Genomic DNA was extracted from buccal epithelium using a standard protocol. We conducted Fisher's exact tests and multinomial logistic regression analyses to assess the association between MCT1 genotype and athletic status/competition level. Sprint/power athletes were more likely than controls to possess the minor T allele (TT genotype compared to the AA [p<0.001]; TT or AT compared to the AA [p=0.007]; TT compared to both AA and AT genotypes [p<0.001]). Likewise, sprint/power athletes were more likely than endurance athletes to have the TT genotype compared to the AA (p=0.029) and the TT compared to both AA and AT genotypes (p=0.027). Furthermore, elite sprint/power athletes were more likely than national-level athletes to have the TT genotype compared to the AA (p=0.044), and more likely to have the TT genotype compared to both AA and AT genotypes (recessive model) (p=0.045). The MCT1 TT genotype is associated with elite sprint/power athletic status. Future studies are encouraged to replicate these findings in other elite athlete cohorts. Copyright © 2013 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

Measurement of macrocyclic trichothecene in floor dust of water-damaged buildings using gas chromatography/tandem mass spectrometry—dust matrix effects

PubMed Central

Saito, Rena; Park, Ju-Hyeong; LeBouf, Ryan; Green, Brett J.; Park, Yeonmi

2017-01-01

Gas chromatography-tandem mass spectrometry (GC-MS/MS) was used to detect fungal secondary metabolites. Detection of verrucarol, the hydrolysis product of Stachybotrys chartarum macrocyclic trichothecene (MCT), was confounded by matrix effects associated with heterogeneous indoor environmental samples. In this study, we examined the role of dust matrix effects associated with GC-MS/ MS to better quantify verrucarol in dust as a measure of total MCT. The efficiency of the internal standard (ISTD, 1,12-dodecanediol), and application of a matrix-matched standard correction method in measuring MCT in floor dust of water-damaged buildings was additionally examined. Compared to verrucarol, ISTD had substantially higher matrix effects in the dust extracts. The results of the ISTD evaluation showed that without ISTD adjustment, there was a 280% ion enhancement in the dust extracts compared to neat solvent. The recovery of verrucarol was 94% when the matrix-matched standard curve without the ISTD was used. Using traditional calibration curves with ISTD adjustment, none of the 21 dust samples collected from water damaged buildings were detectable. In contrast, when the matrix-matched calibration curves without ISTD adjustment were used, 38% of samples were detectable. The study results suggest that floor dust of water-damaged buildings may contain MCT. However, the measured levels of MCT in dust using the GC-MS/MS method could be significantly under- or overestimated, depending on the matrix effects, the inappropriate ISTD, or combination of the two. Our study further shows that the routine application of matrix-matched calibration may prove useful in obtaining accurate measurements of MCT in dust derived from damp indoor environments, while no isotopically labeled verrucarol is available. PMID:26853932

Measurement of macrocyclic trichothecene in floor dust of water-damaged buildings using gas chromatography/tandem mass spectrometry-dust matrix effects.

PubMed

Saito, Rena; Park, Ju-Hyeong; LeBouf, Ryan; Green, Brett J; Park, Yeonmi

2016-01-01

Gas chromatography-tandem mass spectrometry (GC-MS/MS) was used to detect fungal secondary metabolites. Detection of verrucarol, the hydrolysis product of Stachybotrys chartarum macrocyclic trichothecene (MCT), was confounded by matrix effects associated with heterogeneous indoor environmental samples. In this study, we examined the role of dust matrix effects associated with GC-MS/MS to better quantify verrucarol in dust as a measure of total MCT. The efficiency of the internal standard (ISTD, 1,12-dodecanediol), and application of a matrix-matched standard correction method in measuring MCT in floor dust of water-damaged buildings was additionally examined. Compared to verrucarol, ISTD had substantially higher matrix effects in the dust extracts. The results of the ISTD evaluation showed that without ISTD adjustment, there was a 280% ion enhancement in the dust extracts compared to neat solvent. The recovery of verrucarol was 94% when the matrix-matched standard curve without the ISTD was used. Using traditional calibration curves with ISTD adjustment, none of the 21 dust samples collected from water damaged buildings were detectable. In contrast, when the matrix-matched calibration curves without ISTD adjustment were used, 38% of samples were detectable. The study results suggest that floor dust of water-damaged buildings may contain MCT. However, the measured levels of MCT in dust using the GC-MS/MS method could be significantly under- or overestimated, depending on the matrix effects, the inappropriate ISTD, or combination of the two. Our study further shows that the routine application of matrix-matched calibration may prove useful in obtaining accurate measurements of MCT in dust derived from damp indoor environments, while no isotopically labeled verrucarol is available.

Gene Expressions of Nitric Oxide Synthase and Matrix Metalloproteinase-2 in Monocrotaline-Induced Pulmonary Hypertension in Rats After Bosentan Treatment

PubMed Central

Koo, Hee Sun; Kim, Kwan Chang

2011-01-01

Background and Objectives Nitric oxide (NO) is a major endothelium dependent vasomediator and growth inhibitor. NO synthesis is catalyzed by endothelial nitric oxide synthase (eNOS), and NO can also produce peroxynitrite, which activates matrix metalloproteinases (MMPs). The purpose of this study was to determine the gene expression of eNOS and MMP-2 in the lungs of a rat model of pulmonary hypertension after bosentan treatment. Materials and Methods Six-week-old male Sprague-Dawley rats were treated as follows: control group, subcutaneous (sc) injection of saline; monocrotaline (MCT) group, sc injection of MCT (60 mg/kg); and bosentan group, sc injection of MCT (60 mg/kg) plus 20 mg/day bosentan orally. The rats were sacrificed after 1, 5, 7, 14 and 28 days. Results The right ventricle/(left ventricle+septum) ratio significantly increased in the MCT group compared to the control group on day 14 and 28. The expression of eNOS messenger ribonucleic acid was significantly increased in the MCT group compared to the control group on day 28. MMP-2 gene expression was significantly increased in the MCT-treated rats compared to the control group on day 5 and 28. Following bosentan treatment to reduce pulmonary hypertension, the expression levels of MMP-2 gene were significantly decreased on day 7 and 28. eNOS and tissue inhibitor of MMPs genes were also significantly decreased on day 28 after bosentan treatment. Conclusion These results suggest that elevated eNOS expression may be responsible for MMP-2 activation. The causal relationship between eNOS and MMP-2 and their role in pulmonary hypertension require further investigations. PMID:21430993

Mct8 and trh co-expression throughout the hypothalamic paraventricular nucleus is modified by dehydration-induced anorexia in rats.

PubMed

Alvarez-Salas, Elena; Mengod, Guadalupe; García-Luna, Cinthia; Soberanes-Chávez, Paulina; Matamoros-Trejo, Gilberto; de Gortari, Patricia

2016-04-01

Thyrotropin-releasing hormone (TRH) is a neuropeptide with endocrine and neuromodulatory effects. TRH from the paraventricular hypothalamic nucleus (PVN) participates in the control of energy homeostasis; as a neuromodulator TRH has anorexigenic effects. Negative energy balance decreases PVN TRH expression and TSH concentration; in contrast, a particular model of anorexia (dehydration) induces in rats a paradoxical increase in TRH expression in hypophysiotropic cells from caudal PVN and high TSH serum levels, despite their apparent hypothalamic hyperthyroidism and low body weight. We compared here the mRNA co-expression pattern of one of the brain thyroid hormones' transporters, the monocarboxylate transporter-8 (MCT8) with that of TRH in PVN subdivisions of dehydration-induced anorexic (DIA) and control rats. Our aim was to identify whether a low MCT8 expression in anorexic rats could contribute to their high TRH mRNA content.We registered daily food intake and body weight of 7-day DIA and control rats and analyzed TRH and MCT8 mRNA co-expression throughout the PVN by double in situ hybridization assays. We found that DIA rats showed increased number of TRHergic cells in caudal PVN, as well as a decreased percentage of TRH-expressing neurons that co-expressed MCT8 mRNA signal. Results suggest that the reduced proportion of double TRH/MCT8 expressing cells may be limiting the entry of hypothalamic triiodothyronine to the greater number of TRH-expressing neurons from caudal PVN and be in part responsible for the high TRH expression in anorexia rats and for the lack of adaptation of their hypothalamic-pituitary-thyroid axis to their low food intake.