Levels of cyclic-2,3-diphosphoglycerate in Methanobacterium thermoautotrophicum during phosphate limitation.

PubMed Central

Seely, R J; Fahrney, D E

1984-01-01

Batch-grown Methanobacterium thermoautotrophicum cells grew nonexponentially in the absence of exogenous Pi until intracellular cyclic-2,3-diphosphoglycerate (cyclic DPG) had fallen below 2 mumol/g (dry weight), the limit of detection. Growth resumed immediately upon transfer to medium containing Pi Cyclic DPG levels were also below detection in Pi-limited chemostat cultures operating at a dilution rate of 0.173 h-1 (4-h doubling time), with reservoir Pi concentrations below 200 microM. At this dilution rate, the Pi concentration in the culture was 4 microM. An H2-limited steady state was achieved with 400 microM Pi in the inflowing medium (67 microM in the culture). The cyclic DPG content of these cells was 72 to 74 mumol/g, about one-third the amount in batch-grown cells. The specific growth rate accelerated immediately to 0.36 h-1 (1.9-h doubling time) under washout conditions at high dilution rate. The cellular content of cyclic DPG declined over a 2-h period, and then increased rapidly as the Pi level in the medium approached 200 microM. Expansion of the cyclic DPG pool coincided with a marked increase in Pi assimilation. These results indicated that M. thermoautotrophicum accumulated cyclic DPG only when Pi and H2 were readily available. PMID:6480564

Levels of cyclic-2,3-diphosphoglycerate in Methanobacterium thermoautotrophicum during phosphate limitation.

PubMed

Seely, R J; Fahrney, D E

1984-10-01

Batch-grown Methanobacterium thermoautotrophicum cells grew nonexponentially in the absence of exogenous Pi until intracellular cyclic-2,3-diphosphoglycerate (cyclic DPG) had fallen below 2 mumol/g (dry weight), the limit of detection. Growth resumed immediately upon transfer to medium containing Pi Cyclic DPG levels were also below detection in Pi-limited chemostat cultures operating at a dilution rate of 0.173 h-1 (4-h doubling time), with reservoir Pi concentrations below 200 microM. At this dilution rate, the Pi concentration in the culture was 4 microM. An H2-limited steady state was achieved with 400 microM Pi in the inflowing medium (67 microM in the culture). The cyclic DPG content of these cells was 72 to 74 mumol/g, about one-third the amount in batch-grown cells. The specific growth rate accelerated immediately to 0.36 h-1 (1.9-h doubling time) under washout conditions at high dilution rate. The cellular content of cyclic DPG declined over a 2-h period, and then increased rapidly as the Pi level in the medium approached 200 microM. Expansion of the cyclic DPG pool coincided with a marked increase in Pi assimilation. These results indicated that M. thermoautotrophicum accumulated cyclic DPG only when Pi and H2 were readily available.

Adaptation of the symbiotic Mesorhizobium-chickpea relationship to phosphate deficiency relies on reprogramming of whole-plant metabolism.

PubMed

Nasr Esfahani, Maryam; Kusano, Miyako; Nguyen, Kien Huu; Watanabe, Yasuko; Ha, Chien Van; Saito, Kazuki; Sulieman, Saad; Herrera-Estrella, Luis; Tran, L S

2016-08-09

Low inorganic phosphate (Pi) availability is a major constraint for efficient nitrogen fixation in legumes, including chickpea. To elucidate the mechanisms involved in nodule acclimation to low Pi availability, two Mesorhizobium-chickpea associations exhibiting differential symbiotic performances, Mesorhizobium ciceri CP-31 (McCP-31)-chickpea and Mesorhizobium mediterranum SWRI9 (MmSWRI9)-chickpea, were comprehensively studied under both control and low Pi conditions. MmSWRI9-chickpea showed a lower symbiotic efficiency under low Pi availability than McCP-31-chickpea as evidenced by reduced growth parameters and down-regulation of nifD and nifK These differences can be attributed to decline in Pi level in MmSWRI9-induced nodules under low Pi stress, which coincided with up-regulation of several key Pi starvation-responsive genes, and accumulation of asparagine in nodules and the levels of identified amino acids in Pi-deficient leaves of MmSWRI9-inoculated plants exceeding the shoot nitrogen requirement during Pi starvation, indicative of nitrogen feedback inhibition. Conversely, Pi levels increased in nodules of Pi-stressed McCP-31-inoculated plants, because these plants evolved various metabolic and biochemical strategies to maintain nodular Pi homeostasis under Pi deficiency. These adaptations involve the activation of alternative pathways of carbon metabolism, enhanced production and exudation of organic acids from roots into the rhizosphere, and the ability to protect nodule metabolism against Pi deficiency-induced oxidative stress. Collectively, the adaptation of symbiotic efficiency under Pi deficiency resulted from highly coordinated processes with an extensive reprogramming of whole-plant metabolism. The findings of this study will enable us to design effective breeding and genetic engineering strategies to enhance symbiotic efficiency in legume crops.

QTL mapping of downy and powdery mildew resistances in PI 197088 cucumber with genotyping-by-sequencing in RIL population

USDA-ARS?s Scientific Manuscript database

The downy mildew (DM) and powdery mildew (PM) are the two most important foliar diseases of cucurbit crops worldwide. The cucumber accession PI 197088 exhibits high level resistances to both pathogens. We conducted QTL mapping to identified genes underlying host resistance for DM and PM in PI 197088...

Icaritin requires Phosphatidylinositol 3 kinase (PI3K)/Akt signaling to counteract skeletal muscle atrophy following mechanical unloading

PubMed Central

ZHANG, Zong-Kang; LI, Jie; LIU, Jin; GUO, Baosheng; LEUNG, Albert; ZHANG, Ge; ZHANG, Bao-Ting

2016-01-01

Counteracting muscle atrophy induced by mechanical unloading/inactivity is of great clinical need and challenge. A therapeutic agent that could counteract muscle atrophy following mechanical unloading in safety is desired. This study showed that natural product Icaritin (ICT) could increase the phosphorylation level of Phosphatidylinositol 3 kinase (PI3K) at p110 catalytic subunit and promote PI3K/Akt signaling markers in C2C12 cells. This study further showed that the high dose ICT treatment could significantly attenuate the decreases in the phosphorylation level of PI3K at p110 catalytic subunit and its downstream markers related to protein synthesis, and inhibit the increases in protein degradation markers at mRNA and protein levels in rat soleus muscle following 28-day hindlimb unloading. In addition, the decreases in soleus muscle mass, muscle fiber cross-sectional area, twitch force, specific force, contraction time and half relaxation time could be significantly attenuated by the high dose ICT treatment. The low dose ICT treatment could moderately attenuate the above changes induced by unloading. Wortmannin, a specific inhibitor of PI3K at p110 catalytic subunit, could abolish the above effects of ICT in vitro and in vivo, indicating that PI3K/Akt signaling could be required by ICT to counteract skeletal muscle atrophy following mechanical unloading. PMID:26831566

Characterization of pi-Conjugated Polymers for Transistor and Photovoltaic Applications

NASA Astrophysics Data System (ADS)

Paulsen, Bryan D.

pi-Conjugated polymers represent a unique class of optoelectronic materials. Being polymers, they are solution processable and inherently "soft" materials. This makes them attractive candidates for the production of roll-to-roll printed electronic devices on flexible substrates. The optical and electronic properties of pi-conjugated polymers are synthetically tunable allowing material sets to be tailored to specific applications. Two of the most heavily researched applications are the thin film transistor, the building block of electronic circuits, and the bulk heterojunction solar cell, which holds great potential as a renewable energy source. Key to developing commercially feasible pi-conjugated polymer devices is a thorough understanding of the electronic structure and charge transport behavior of these materials in relationship with polymer structure. Here this structure property relationship has been investigated through electrical and electrochemical means in concert with a variety of other characterization techniques and device test beds. The tunability of polymer optical band gap and frontier molecular orbital energy level was investigated in systems of vinyl incorporating statistical copolymers. Energy levels and band gaps are crucial parameters in developing efficient photovoltaic devices, with control of these parameters being highly desirable. Additionally, charge transport and density of electronic states were investigated in pi-conjugated polymers at extremely high electrochemically induced charge density. Finally, the effects of molecular weight on pi-conjugated polymer optical properties, energy levels, charge transport, morphology, and photovoltaic device performance was examined.

Vasculogenic Mimicry in Prostate Cancer: The Roles of EphA2 and PI3K.

PubMed

Wang, Hua; Lin, Hao; Pan, Jincheng; Mo, Chengqiang; Zhang, Faming; Huang, Bin; Wang, Zongren; Chen, Xu; Zhuang, Jintao; Wang, Daohu; Qiu, Shaopeng

2016-01-01

Aggressive tumor cells can form perfusable networks that mimic normal vasculature and enhance tumor growth and metastasis. A number of molecular players have been implicated in such vasculogenic mimicry, among them the receptor tyrosine kinase EphA2, which is aberrantly expressed in aggressive tumors. Here we study the role and regulation of EphA2 in vasculogenic mimicry in prostate cancer where this phenomenon is still poorly understood. Vasculogenic mimicry was characterized by tubules whose cellular lining was negative for the endothelial cell marker CD34 but positive for periodic acid-Schiff staining, and/or contained red blood cells. Vasculogenic mimicry was assessed in 92 clinical samples of prostate cancer and analyzed in more detail in three prostate cancer cell lines kept in three-dimensional culture. Tissue samples and cell lines were also assessed for total and phosphorylated levels of EphA2 and its potential regulator, Phosphoinositide 3-Kinase (PI3K). In addition, the role of EphA2 in vasculogenic mimicry and in cell migration and invasion were investigated by manipulating the levels of EphA2 through specific siRNAs. Furthermore, the role of PI3K in vasculogenic mimicry and in regulating EphA2 was tested by application of an inhibitor, LY294002. Immunohistochemistry of prostate cancers showed a significant correlation between vasculogenic mimicry and high expression levels of EphA2, high Gleason scores, advanced TNM stage, and the presence of lymph node and distant metastases. Likewise, two prostate cancer cell lines (PC3 and DU-145) formed vasculogenic networks on Matrigel and expressed high EphA2 levels, while one line (LNCaP) showed no vasculogenic networks and lower EphA2 levels. Specific silencing of EphA2 in PC3 and DU-145 cells decreased vasculogenic mimicry as well as cell migration and invasion. Furthermore, high expression levels of PI3K and EphA2 phosphorylation at Ser897 significantly correlated with the presence of vasculogenic mimicry and in vitro inhibition of PI3K by LY294002 disrupted vasculogenic mimicry, potentially through a reduction of EphA2 phosphorylation at Ser897. The expression levels of PI3K and EphA2 are positively correlated with vasculogenic mimicry both in vivo and in vitro. Moreover, phosphorylation levels of EphA2 regulated by PI3K are also significantly associated with vasculogenic mimicry in vivo. Based on its functional implication in vasculogenic mimicry in vitro, EphA2 signaling may be a potential therapeutic target in advanced prostate cancer.

Mapping of Yr62 and a small effect QTL for high-temperature adult-plant resistance to stripe rust in spring wheat PI 192252

USDA-ARS?s Scientific Manuscript database

Stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), is a devastating disease of wheat worldwide. Spring wheat germplasm PI 192252 showed a high level of high-temperature adult-plant (HTAP) resistance to stripe rust in germplasm evaluation over eight years in the State of Washington. ...

High-spin states in {sup 188}Au: Further evidence for nonaxial shape

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

Fang, Y. D.; Zhang, Y. H.; Zhou, X. H.

2010-12-15

The high-spin level structure of {sup 188}Au has been investigated via the {sup 173}Yb({sup 19}F,4n{gamma}) reaction at beam energies of 86 and 90 MeV. The previously reported level scheme has been modified and extended significantly. A new I{sup {pi}}=20{sup +} state associated with {pi}h{sub 11/2}{sup -1} x {nu}i{sub 13/2}{sup -2}h{sub 9/2}{sup -1} configuration and two new rotational bands, one of which is built on the {pi}h{sub 9/2} x {nu}i{sub 13/2} configuration, have been identified. The prolate-to-oblate shape transition through triaxial shape has been proposed to occur around {sup 188}Au for the {pi}h{sub 9/2} x {nu}i{sub 13/2} bands in odd-odd Aumore » isotopes. Evidence for {pi}h{sub 11/2}{sup -1} x {nu}i{sub 13/2}{sup -1} structure of nonaxial shape with {gamma}<-70 deg. has been obtained by comparison with total Routhian surface and cranked-shell-model calculations.« less

Pi-CO₂ aqueous post-combustion CO₂ capture: Proof of concept through thermodynamic, hydrodynamic, and gas-lift pump modeling

DOE PAGES

Blount, G.; Gorensek, M.; Hamm, L.; ...

2014-12-31

Partnering in Innovation, Inc. (Pi-Innovation) introduces an aqueous post-combustion carbon dioxide (CO₂) capture system (Pi-CO₂) that offers high market value by directly addressing the primary constraints limiting beneficial re-use markets (lowering parasitic energy costs, reducing delivered cost of capture, eliminating the need for special solvents, etc.). A highly experienced team has completed initial design, modeling, manufacturing verification, and financial analysis for commercial market entry. Coupled thermodynamic and thermal-hydraulic mass transfer modeling results fully support proof of concept. Pi-CO₂ has the potential to lower total cost and risk to levels sufficient to stimulate global demand for CO₂ from local industrial sources.

Revised NEO Personality Inventory normative data for police officer selection.

PubMed

Detrick, Paul; Chibnall, John T

2013-11-01

The Revised NEO Personality Inventory (NEO PI-R) has demonstrated utility in the personnel selection context. Its use in police officer selection has been relatively limited, in part, because there are no published normative data for the NEO PI-R for police officer applicants. The authors present normative data on NEO PI-R domain and facet scores for a large sample (N = 288) of police officer applicants in a large, urban, Midwestern police department who completed the NEO PI-R as part of a preemployment psychological evaluation. Applicants reported low levels of Neuroticism and high levels of Extraversion and Conscientiousness. Neuroticism and Conscientiousness scores were strongly and consistently correlated with the Positive Presentation Management (PPM) research validity scale of the NEO PI-R. Extraversion and Agreeableness scores were moderately and less consistently correlated with PPM. These data may serve as a normative comparison group for professionals and researchers who use or may want to use the NEO PI-R in the police officer selection context.

Pancake π–π Bonding Goes Double: Unexpected 4e/All-Sites Bonding in Boron- and Nitrogen-Doped Phenalenyls

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

Tian, Yong-Hui; Sumpter, Bobby G.; Du, Shiyu

Phenalenyl is an important neutral pi-radical due to its capability to form unconventional pancake pi-pi bonding interactions, whereas its analogues with graphitic boron (B) or nitrogen (N)-doping have been regarded as closed-shell systems and therefore received much less attention. By using high-level quantum chemistry calculations, we also show that the B- and N-doped closed-shell phenalenyls unexpectedly form open-shell singlet pi-dimers with diradicaloid character featuring 2e/all-sites double pi-pi bonding. Moreover, by proper substitutions, the doped phenalenyl derivatives can be made open-shell species that form closed shell singlet pi-dimers bound by stronger 4e/all-sites double pi-pi bonding. Moreover, covalent pi-pi bonding overlap ismore » distributed on all of the atomic sites giving robust and genuine pancake-shaped pi-dimers which, depending on the number of electrons available in the bonding interactions, are equally or more stable than the pi-dimers of the pristine phenalenyl.« less

Pancake π–π Bonding Goes Double: Unexpected 4e/All-Sites Bonding in Boron- and Nitrogen-Doped Phenalenyls

DOE PAGES

Tian, Yong-Hui; Sumpter, Bobby G.; Du, Shiyu; ...

2015-06-03

Phenalenyl is an important neutral pi-radical due to its capability to form unconventional pancake pi-pi bonding interactions, whereas its analogues with graphitic boron (B) or nitrogen (N)-doping have been regarded as closed-shell systems and therefore received much less attention. By using high-level quantum chemistry calculations, we also show that the B- and N-doped closed-shell phenalenyls unexpectedly form open-shell singlet pi-dimers with diradicaloid character featuring 2e/all-sites double pi-pi bonding. Moreover, by proper substitutions, the doped phenalenyl derivatives can be made open-shell species that form closed shell singlet pi-dimers bound by stronger 4e/all-sites double pi-pi bonding. Moreover, covalent pi-pi bonding overlap ismore » distributed on all of the atomic sites giving robust and genuine pancake-shaped pi-dimers which, depending on the number of electrons available in the bonding interactions, are equally or more stable than the pi-dimers of the pristine phenalenyl.« less

Rab27a controls HIV-1 assembly by regulating plasma membrane levels of phosphatidylinositol 4,5-bisphosphate

PubMed Central

Gerber, Pehuén Pereyra; Cabrini, Mercedes; Jancic, Carolina; Paoletti, Luciana; Banchio, Claudia; von Bilderling, Catalina; Sigaut, Lorena; Pietrasanta, Lía I.; Duette, Gabriel; Freed, Eric O.; de Saint Basile, Genevieve; Moita, Catarina Ferreira; Moita, Luis Ferreira; Amigorena, Sebastian; Benaroch, Philippe; Geffner, Jorge

2015-01-01

During the late stages of the HIV-1 replication cycle, the viral polyprotein Pr55Gag is recruited to the plasma membrane (PM), where it binds phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and directs HIV-1 assembly. We show that Rab27a controls the trafficking of late endosomes carrying phosphatidylinositol 4-kinase type 2 α (PI4KIIα) toward the PM of CD4+ T cells. Hence, Rab27a promotes high levels of PM phosphatidylinositol 4-phosphate and the localized production of PI(4,5)P2, therefore controlling Pr55Gag membrane association. Rab27a also controls PI(4,5)P2 levels at the virus-containing compartments of macrophages. By screening Rab27a effectors, we identified that Slp2a, Slp3, and Slac2b are required for the association of Pr55Gag with the PM and that Slp2a cooperates with Rab27a in the recruitment of PI4KIIα to the PM. We conclude that by directing the trafficking of PI4KIIα-positive endosomes toward the PM, Rab27a controls PI(4,5)P2 production and, consequently, HIV-1 replication. PMID:25940347

Mapping QTL for resistance to stripe rust in spring wheat PI 192252 and winter wheat Druchamp

USDA-ARS?s Scientific Manuscript database

Stripe rust, caused by Puccinia striiformis f. sp. tritici, is an important disease of wheat worldwide. High-temperature adult-plant (HTAP) resistance has proven to be durable, but may not be adequate. Spring wheat PI 192252 and winter wheat Druchamp have high-levels of HTAP resistance. To elucidate...

Comparison and correlation of pelvic parameters between low-grade and high-grade spondylolisthesis.

PubMed

Min, Woo-Kie; Lee, Chang-Hwa

2014-05-01

This study was retrospectively conducted on 51 patients with L5-S1 spondylolisthesis. This study was conducted to compare a total of 11 pelvic parameters, such as the level of displacement by Meyerding method, lumbar lordosis, sacral inclination, lumbosacral angle, slip angle, S2 inclination, pelvic incidence (PI), L5 inclination, L5 slope, pelvic tilt (PT), and sacral slope (SS) between low-grade and high-grade spondylolisthesis, and to investigate a correlation of the level of displacement by Meyerding method with other pelvic parameters. Pelvic parameters were measured using preoperational erect lateral spinal simple radiographs. The patients were divided into 39 patients with low-grade spondylolisthesis and 12 patients with high-grade spondylolisthesis before analysis. In all patients of both groups, 11 radiographic measurements including the level of displacement by Meyerding method, lumbar lordosis, sacral inclination, lumbosacral angle, slip angle, S2 inclination, PI, L5 inclination, L5 slope, PT, and SS were performed. T test and Pearson correlation analysis were conducted to compare and analyze each measurement. As for the comparison between the 2 groups, a statistically great significance in the level of displacement by Meyerding method, lumbosacral angle, slip angle, L5 incidence, PI, and L5 slope (P≤0.001) was shown. Meanwhile, a statistical significance in the sacral inclination and PT (P<0.05) was also shown. However, no statistical significance in the S2 incidence and SS was shown. A correlation of the level of displacement by Meyerding method with each parameter was analyzed in the both the groups. A high correlation was observed in the lumbar lordosis, lumbosacral angle, slip angle, L5 incidence, and L5 slope (Pearson correlation coefficient, P=0.01), as well as the sacral inclination, PI, and PT (Pearson correlation coefficient, P=0.05). Meanwhile, no correlation was shown in the S2 incidence and SS. A significant difference in the lumbosacral angle, slip angle, L5 incidence, PI, L5 slope, sacral inclination, and PT was shown between the patients with high-grade spondylolisthesis and patients with low-grade spondylolisthesis. Among the aforementioned measurements, the PI showed a significant difference between the 2 groups and also had a significant correlation with the dislocation level in all the patients.

Spermatozoa Expression of piR-31704, piR-39888, and piR-40349 and Their Correlation to Sperm Concentration and Fertilization Rate After ICSI.

PubMed

Cui, Long; Fang, Li; Shi, Biwei; Qiu, Sunquan; Ye, Yinghui

2018-05-01

To investigate the relationship between spermatozoa PIWI-interacting RNAs (piRNAs) levels and semen parameters and to evaluate the role of expression of piRNAs on fertilization and embryo development after intracytoplasmic sperm injection (ICSI) treatment. One hundred and eighty-six patients with idiopathic male infertility who had undergone first ICSI cycles were enrolled in our study. The levels of piRNAs in spermatozoa were measured by real-time polymerase chain reaction. Semen parameters, including sperm concentration, motility, and morphology, were evaluated. The rates of fertilization, early cleavage, and day 3 good-quality embryo were calculated to assess embryo development potential. Spermatozoa levels of piR-31704 and piR-39888 were decreased in male factor infertility group as compared with control group (for piR-31704, P = .027 and for piR-39888, P = .041, respectively). And these 2 piRNAs were expressed at higher levels in patients with normal sperm concentration compared with subnormal sperm concentration group (for piR-31704, P = .042; for piR-39888, P = .047, respectively), while there were no correlation between the 3 piRNAs expression levels in spermatozoa and the rates of sperm progressive motility and normal sperm morphology. There were significant increases in the levels of all 3 piRNAs in spermatozoa from the group with higher 2PN rates (for piR-31704, P = .002; for piR-39888, P < .001; for piR-40349, P < .001; respectively), but there was no correlation between spermatozoa levels of these 3 piRNAs and the rates of embryo early cleavage, day 3 good-quality embryos and pregnancy. Spermatozoa piRNA levels correlate with sperm concentration and fertilization rate after ICSI. Paternal piRNAs may play a role in fertilization process.

Identification of yrast high-K intrinsic states in {sup 188}Os

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

Modamio, V.; Jungclaus, A.; Instituto de Estructura de la Materia, CSIC, Serrano 113bis, E-28006 Madrid

2009-02-15

The high-spin structure of the Z=76 nucleus {sup 188}Os has been studied using the incomplete fusion reaction {sup 7}Li+{sup 186}W. A K{sup {pi}}=10{sup +} band has been established up to spin (24{sup +}) and its crossing with the ground-state band has been studied. In addition, intrinsic high-K states have been identified and on top of two of them, K{sup {pi}}=7{sup -} and K{sup {pi}}=10{sup -}, regular bands have been observed. The K{sup {pi}}=16{sup +} and K{sup {pi}}=18{sup +} states are yrast whereas the K{sup {pi}}=14{sup +} level lies only 33 keV above the yrast line and decays with a lowmore » reduced hindrance of f{sub {nu}}<1.3 to the ground-state band ({delta}K=14). The results are discussed by means of a systematic comparison with the even-even neighboring nucleus {sup 186}Os. Configuration-constrained multiquasiparticle potential-energy-surface calculations have been performed to identify the configurations of multiquasiparticle states.« less

Search for Exotic Baryons in 800 GeV pp{yields}p{xi}{sup {+-}}{pi}{sup {+-}}X Reactions

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

Christian, D.C.; Gottschalk, E.E.; Gutierrez, G.

We report the results of a high-statistics, sensitive search for narrow baryon resonances decaying to {xi}{sup -}{pi}{sup -}, {xi}{sup -}{pi}{sup +}, {xi}{sup +}{pi}{sup -}, and {xi}{sup +}{pi}{sup +}. The only resonances observed are the well known {xi}{sup 0}(1530) and {xi}{sup 0}(1530). No evidence is found for the states near 1862 MeV, previously reported by NA49 [Phys. Rev. Lett. 92, 042003 (2003)]. At the 95% confidence level, we find the upper limit for the production of a Gaussian enhancement with {sigma}=7.6 MeV in the {xi}{sup -}{pi}{sup -} effective mass spectrum to be 0.3% of the number of observed {xi}{sup 0}(1530){yields}{xi}{sup -}{pi}{supmore » +}. We find similarly restrictive upper limits for an enhancement at 1862 MeV in the {xi}{sup -}{pi}{sup +}, {xi}{sup +}{pi}{sup -}, and {xi}{sup +}{pi}{sup +} mass spectra.« less

Comparison of theoretical proteomes: identification of COGs with conserved and variable pI within the multimodal pI distribution.

PubMed

Nandi, Soumyadeep; Mehra, Nipun; Lynn, Andrew M; Bhattacharya, Alok

2005-09-09

Theoretical proteome analysis, generated by plotting theoretical isoelectric points (pI) against molecular masses of all proteins encoded by the genome show a multimodal distribution for pI. This multimodal distribution is an effect of allowed combinations of the charged amino acids, and not due to evolutionary causes. The variation in this distribution can be correlated to the organisms ecological niche. Contributions to this variation maybe mapped to individual proteins by studying the variation in pI of orthologs across microorganism genomes. The distribution of ortholog pI values showed trimodal distributions for all prokaryotic genomes analyzed, similar to whole proteome plots. Pairwise analysis of pI variation show that a few COGs are conserved within, but most vary between, the acidic and basic regions of the distribution, while molecular mass is more highly conserved. At the level of functional grouping of orthologs, five groups vary significantly from the population of orthologs, which is attributed to either conservation at the level of sequences or a bias for either positively or negatively charged residues contributing to the function. Individual COGs conserved in both the acidic and basic regions of the trimodal distribution are identified, and orthologs that best represent the variation in levels of the acidic and basic regions are listed. The analysis of pI distribution by using orthologs provides a basis for resolution of theoretical proteome comparison at the level of individual proteins. Orthologs identified that significantly vary between the major acidic and basic regions maybe used as representative of the variation of the entire proteome.

Loss of PiT-1 Results in Abnormal Endocytosis in the Yolk Sac Visceral Endoderm

PubMed Central

Wallingford, Mary C.; Giachelli, Cecilia M.

2014-01-01

PiT-1 protein is a transmembrane sodium-dependent phosphate (Pi) transporter. PiT-1 knock out (KO) embryos die from largely unknown causes by embryonic day (E) 12.5. We tested the hypothesis that PiT-1 is required for endocytosis in the embryonic yolk sac (YS) visceral endoderm (VE). Here we present data supporting that PiT-1 KO results in a YS remodeling defect and decreased endocytosis in the YS VE. The remodeling defect is not due to an upstream cardiomyocyte requirement for PiT-1, as SM22αCre-specific KO of PiT-1 in the developing heart and the YS mesodermal layer (ME) does not recapitulate the PiT-1 global KO phenotype. Furthermore, we find that high levels of PiT-1 protein localize to the YS VE apical membrane. Together these data support that PiT-1 is likely required in YS VE. During normal development maternal immunoglobulin (IgG) is endocytosed into YS VE and accumulates in the apical side of the VE in a specialized lysosome termed the apical vacuole (AV). We have identified a reduction in PiT-1 KO VE cell height and a striking loss of IgG accumulation in the PiT-1 KO VE. The endocytosis genes Tfeb, Lamtor2 and Snx2 are increased at the RNA level. Lysotracker Red staining reveals a loss of distinct AVs, and yolk sacs incubated ex vivo with phRODO Green Dextran for Endocytosis demonstrate a functional loss of endocytosis. As yolk sac endocytosis is controlled in part by microautophagy, but expression of LC3 had not been examined, we investigated LC3 expression during yolk sac development and found stage-specific LC3 RNA expression that is predominantly from the YS VE layer at E9.5. Normalized LC3-II protein levels are decreased in the PiT-1 KO YS, supporting a requirement for PiT-1 in autophagy in the YS. Therefore, we propose the novel idea that PiT-1 is central to the regulation of endocytosis and autophagy in the YS VE. PMID:25138534

Extremely High Phosphate Sorption Capacity in Cu-Pb-Zn Mine Tailings.

PubMed

Huang, Longbin; Li, Xiaofang; Nguyen, Tuan A H

2015-01-01

Elevated inorganic phosphate (Pi) concentrations in pore water of amended tailings under direct revegetation may cause toxicity in some native woody species but not native forbs or herb species, all of which are key constituents in target native plant communities for phytostabilizing base metal mine tailings. As a result, Pi sorption capacity has been quantified by a conventional batch procedure in three types of base metal mine tailings sampled from two copper (Cu)-lead (Pb)-zinc (Zn) mines, as the basis for Pi-fertiliser addition. It was found that the Pi-sorption capacity in the tailings and local soil was extremely high, far higher than highly weathered agricultural soils in literature, but similar to those of volcanic ash soils. The Langmuir P-sorption maximum was up to 7.72, 4.12, 4.02 and 3.62 mg P g-1 tailings, in the fresh tailings of mixed Cu-Pb-Zn streams (MIMTD7), the weathered tailings of mixed Cu-Pb-Zn streams (MIMTD5), EHM-TD (fresh Cu-stream, high magnetite content) and local soil (weathered shale and schist), respectively. Physicochemical factors highly correlated with the high Pi-sorption in the tailings were fine particle distribution, oxalate and dithionite-citrate-bicarbonate extractable Fe (FeO and Fed), oxalate-extractable Al and Mn, and the levels of soluble Cd and Zn, and total S and Fe. Large amounts of amorphous Fe oxides and oxyhydroxides may have been formed from the oxidation of pyritic materials and redox cycles of Fe-minerals (such as pyrite (FeS2), ankerite (Ca(Fe Mg)(CO3)2 and siderite (FeCO3), as indicated by the extractable FeO values. The likely formation of sparingly soluble Zn-phosphate in the Pb-Zn tailings containing high levels of Zn (from sphalerite ((Zn,Fe)S, ZnS, (Zn,Cd)S)) may substantially lower soluble Zn levels in the tailings through high rates of Pi-fertiliser addition. As a result, the possibility of P-toxicity in native plant species caused by the addition of soluble phosphate fertilizers would be minimal.

Extremely High Phosphate Sorption Capacity in Cu-Pb-Zn Mine Tailings

PubMed Central

Huang, Longbin; Li, Xiaofang; Nguyen, Tuan A. H.

2015-01-01

Elevated inorganic phosphate (Pi) concentrations in pore water of amended tailings under direct revegetation may cause toxicity in some native woody species but not native forbs or herb species, all of which are key constituents in target native plant communities for phytostabilizing base metal mine tailings. As a result, Pi sorption capacity has been quantified by a conventional batch procedure in three types of base metal mine tailings sampled from two copper (Cu)-lead (Pb)-zinc (Zn) mines, as the basis for Pi-fertiliser addition. It was found that the Pi-sorption capacity in the tailings and local soil was extremely high, far higher than highly weathered agricultural soils in literature, but similar to those of volcanic ash soils. The Langmuir P-sorption maximum was up to 7.72, 4.12, 4.02 and 3.62 mg P g-1 tailings, in the fresh tailings of mixed Cu-Pb-Zn streams (MIMTD7), the weathered tailings of mixed Cu-Pb-Zn streams (MIMTD5), EHM-TD (fresh Cu-stream, high magnetite content) and local soil (weathered shale and schist), respectively. Physicochemical factors highly correlated with the high Pi-sorption in the tailings were fine particle distribution, oxalate and dithionite-citrate-bicarbonate extractable Fe (FeO and Fed), oxalate-extractable Al and Mn, and the levels of soluble Cd and Zn, and total S and Fe. Large amounts of amorphous Fe oxides and oxyhydroxides may have been formed from the oxidation of pyritic materials and redox cycles of Fe-minerals (such as pyrite (FeS2), ankerite (Ca(Fe Mg)(CO3)2 and siderite (FeCO3), as indicated by the extractable FeO values. The likely formation of sparingly soluble Zn-phosphate in the Pb-Zn tailings containing high levels of Zn (from sphalerite ((Zn,Fe)S, ZnS, (Zn,Cd)S)) may substantially lower soluble Zn levels in the tailings through high rates of Pi-fertiliser addition. As a result, the possibility of P-toxicity in native plant species caused by the addition of soluble phosphate fertilizers would be minimal. PMID:26295582

Using the prostate imaging reporting and data system version 2 (PI-RIDS v2) to detect prostate cancer can prevent unnecessary biopsies and invasive treatment.

PubMed

Liu, Chang; Liu, Shi-Liang; Wang, Zhi-Xian; Yu, Kai; Feng, Chun-Xiang; Ke, Zan; Wang, Liang; Zeng, Xiao-Yong

2018-04-13

Prostate cancer (PCa) is one of the most common cancers among men globally. The authors aimed to evaluate the ability of the Prostate Imaging Reporting and Data System version 2 (PI-RADS v2) to classify men with PCa, clinically significant PCa (CSPCa), or no PCa, especially among those with serum total prostate-specific antigen (tPSA) levels in the "gray zone" (4-10 ng ml -1 ). A total of 308 patients (355 lesions) were enrolled in this study. Diagnostic efficiency was determined. Univariate and multivariate analyses, receiver operating characteristic curve analysis, and decision curve analysis were performed to determine and compare the predictors of PCa and CSPCa. The results suggested that PI-RADS v2, tPSA, and prostate-specific antigen density (PSAD) were independent predictors of PCa and CSPCa. A PI-RADS v2 score ≥4 provided high negative predictive values (91.39% for PCa and 95.69% for CSPCa). A model of PI-RADS combined with PSA and PSAD helped to define a high-risk group (PI-RADS score = 5 and PSAD ≥0.15 ng ml -1 cm -3 , with tPSA in the gray zone, or PI-RADS score ≥4 with high tPSA level) with a detection rate of 96.1% for PCa and 93.0% for CSPCa while a low-risk group with a detection rate of 6.1% for PCa and 2.2% for CSPCa. It was concluded that the PI-RADS v2 could be used as a reliable and independent predictor of PCa and CSPCa. The combination of PI-RADS v2 score with PSA and PSAD could be helpful in the prediction and diagnosis of PCa and CSPCa and, thus, may help in preventing unnecessary invasive procedures.

Vasculogenic Mimicry in Prostate Cancer: The Roles of EphA2 and PI3K

PubMed Central

Wang, Hua; Lin, Hao; Pan, Jincheng; Mo, Chengqiang; Zhang, Faming; Huang, Bin; Wang, Zongren; Chen, Xu; Zhuang, Jintao; Wang, Daohu; Qiu, Shaopeng

2016-01-01

BACKGROUND. Aggressive tumor cells can form perfusable networks that mimic normal vasculature and enhance tumor growth and metastasis. A number of molecular players have been implicated in such vasculogenic mimicry, among them the receptor tyrosine kinase EphA2, which is aberrantly expressed in aggressive tumors. Here we study the role and regulation of EphA2 in vasculogenic mimicry in prostate cancer where this phenomenon is still poorly understood. METHODS. Vasculogenic mimicry was characterized by tubules whose cellular lining was negative for the endothelial cell marker CD34 but positive for periodic acid-Schiff staining, and/or contained red blood cells. Vasculogenic mimicry was assessed in 92 clinical samples of prostate cancer and analyzed in more detail in three prostate cancer cell lines kept in three-dimensional culture. Tissue samples and cell lines were also assessed for total and phosphorylated levels of EphA2 and its potential regulator, Phosphoinositide 3-Kinase (PI3K). In addition, the role of EphA2 in vasculogenic mimicry and in cell migration and invasion were investigated by manipulating the levels of EphA2 through specific siRNAs. Furthermore, the role of PI3K in vasculogenic mimicry and in regulating EphA2 was tested by application of an inhibitor, LY294002. RESULTS. Immunohistochemistry of prostate cancers showed a significant correlation between vasculogenic mimicry and high expression levels of EphA2, high Gleason scores, advanced TNM stage, and the presence of lymph node and distant metastases. Likewise, two prostate cancer cell lines (PC3 and DU-145) formed vasculogenic networks on Matrigel and expressed high EphA2 levels, while one line (LNCaP) showed no vasculogenic networks and lower EphA2 levels. Specific silencing of EphA2 in PC3 and DU-145 cells decreased vasculogenic mimicry as well as cell migration and invasion. Furthermore, high expression levels of PI3K and EphA2 phosphorylation at Ser897 significantly correlated with the presence of vasculogenic mimicry and in vitro inhibition of PI3K by LY294002 disrupted vasculogenic mimicry, potentially through a reduction of EphA2 phosphorylation at Ser897. CONCLUSIONS. The expression levels of PI3K and EphA2 are positively correlated with vasculogenic mimicry both in vivo and in vitro. Moreover, phosphorylation levels of EphA2 regulated by PI3K are also significantly associated with vasculogenic mimicry in vivo. Based on its functional implication in vasculogenic mimicry in vitro, EphA2 signaling may be a potential therapeutic target in advanced prostate cancer. PMID:27326255

Novel phosphate-activated macrophages prevent ectopic calcification by increasing extracellular ATP and pyrophosphate

PubMed Central

Villa-Bellosta, Ricardo; Hamczyk, Magda R.; Andrés, Vicente

2017-01-01

Purpose Phosphorus is an essential nutrient involved in many pathobiological processes. Less than 1% of phosphorus is found in extracellular fluids as inorganic phosphate ion (Pi) in solution. High serum Pi level promotes ectopic calcification in many tissues, including blood vessels. Here, we studied the effect of elevated Pi concentration on macrophage polarization and calcification. Macrophages, present in virtually all tissues, play key roles in health and disease and display remarkable plasticity, being able to change their physiology in response to environmental cues. Methods and results High-throughput transcriptomic analysis and functional studies demonstrated that Pi induces unpolarized macrophages to adopt a phenotype closely resembling that of alternatively-activated M2 macrophages, as revealed by arginine hydrolysis and energetic and antioxidant profiles. Pi-induced macrophages showed an anti-calcifying action mediated by increased availability of extracellular ATP and pyrophosphate. Conclusion We conclude that the ability of Pi-activated macrophages to prevent calcium-phosphate deposition is a compensatory mechanism protecting tissues from hyperphosphatemia-induced pathologic calcification. PMID:28362852

Inhibitory effect of leonurine on the formation of advanced glycation end products.

PubMed

Huang, Lianqi; Yang, Xin; Peng, Anlin; Wang, Hui; Lei, Xiang; Zheng, Ling; Huang, Kun

2015-02-01

Long-term hyperglycemia is a typical symptom of diabetes mellitus (DM) which can cause a high level of protein glycation and lead to the formation of advanced glycation end products (AGEs). The accumulation of AGEs in turn deteriorates DM and its complications. Insulin, the only hormone that directly decreases blood sugar in vivo, is vulnerable to glycation which causes the loss of its biological activity. In this study, we used a porcine insulin (PI)-methylglyoxal (MGO) model to investigate the inhibitory effect of leonurine (LN), a natural alkaloid extracted from Herba leonuri, on AGE formation. Assays including AGE-specific fluorescence, and fructosamine level and carbonyl group content determination showed that LN can dose-dependently suppress PI glycation. A significantly decreased cross-linking level on the glycated PI was also proven by SDS-PAGE electrophoresis. A further liquid chromatography-mass spectrometry study suggested that LN may inhibit PI glycation through trapping MGO and keeping it from reacting with PI. Our results thus indicate that LN is a promising anti-glycation agent for the prevention of diabetes and its complications via inhibiting AGE formation.

Application of Prostate Imaging Reporting and Data System Version 2 (PI-RADS v2): Interobserver Agreement and Positive Predictive Value for Localization of Intermediate- and High-Grade Prostate Cancers on Multiparametric Magnetic Resonance Imaging.

PubMed

Chen, Frank; Cen, Steven; Palmer, Suzanne

2017-09-01

To evaluate interobserver agreement with the use of and the positive predictive value (PPV) of Prostate Imaging Reporting and Data System version 2 (PI-RADS v2) for the localization of intermediate- and high-grade prostate cancers on multiparametric magnetic resonance imaging (mpMRI). In this retrospective, institutional review board-approved study, 131 consecutive patients who had mpMRI followed by transrectal ultrasound-MR imaging fusion-guided biopsy of the prostate were included. Two readers who were blinded to initial mpMRI reports, clinical data, and pathologic outcomes reviewed the MR images, identified all prostate lesions, and scored each lesion based on the PI-RADS v2. Interobserver agreement was assessed by intraclass correlation coefficient (ICC), and PPV was calculated for each PI-RADS category. PI-RADS v2 was found to have a moderate level of interobserver agreement between two readers of varying experience, with ICC of 0.74, 0.72, and 0.67 for all lesions, peripheral zone lesions, and transitional zone lesions, respectively. Despite only moderate interobserver agreement, the calculated PPV in the detection of intermediate- and high-grade prostate cancers for each PI-RADS category was very similar between the two readers, with approximate PPV of 0%, 12%, 64%, and 87% for PI-RADS categories 2, 3, 4, and 5, respectively. In our study, PI-RADS v2 has only moderate interobserver agreement, a similar finding in studies of the original PI-RADS and in initial studies of PI-RADS v2. Despite this, PI-RADS v2 appears to be a useful system to predict significant prostate cancer, with PI-RADS scores correlating well with the likelihood of intermediate- and high-grade cancers. Copyright © 2017 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.

Part II. Initial molecular and cellular characterization of high nitric oxide-adapted human tongue squamous cell carcinoma cell lines.

PubMed

Tarjan, Gabor; Haines, G Kenneth; Vesper, Benjamin J; Xue, Jiaping; Altman, Michael B; Yarmolyuk, Yaroslav R; Khurram, Huma; Elseth, Kim M; Roeske, John C; Aydogan, Bulent; Radosevich, James A

2011-02-01

It is not understood why some head and neck squamous cell carcinomas, despite having identical morphology, demonstrate different tumor aggressiveness, including radioresistance. High levels of the free radical nitric oxide (NO) and increased expression of the NO-producing enzyme nitric oxide synthase (NOS) have been implicated in tumor progression. We previously adapted three human tongue cancer cell lines to high NO (HNO) levels by gradually exposing them to increasing concentrations of an NO donor; the HNO cells grew faster than their corresponding untreated ("parent") cells, despite being morphologically identical. Herein we initially characterize the HNO cells and compare the biological properties of the HNO and parent cells. HNO/parent cell line pairs were analyzed for cell cycle distribution, DNA damage, X-ray and ultraviolet radiation response, and expression of key cellular enzymes, including NOS, p53, glutathione S-transferase-pi (GST-pi), apurinic/apyrimidinic endonuclease-1 (APE1), and checkpoint kinases (Chk1, Chk2). While some of these properties were cell line-specific, the HNO cells typically exhibited properties associated with a more aggressive behavior profile than the parent cells (greater S-phase percentage, radioresistance, and elevated expression of GST-pi/APE1/Chk1/Chk2). To correlate these findings with conditions in primary tumors, we examined the NOS, GST-pi, and APE1 expression in human tongue squamous cell carcinomas. A majority of the clinical samples exhibited elevated expression levels of these enzymes. Together, the results herein suggest cancer cells exposed to HNO levels can develop resistance to free radicals by upregulating protective mechanisms, such as GST-pi and APE1. These upregulated defense mechanisms may contribute to their aggressive expression profile.

Arsenic-phosphorus interactions in the soil-plant-microbe system: Dynamics of uptake, suppression and toxicity to plants.

PubMed

Anawar, Hossain M; Rengel, Zed; Damon, Paul; Tibbett, Mark

2018-02-01

High arsenic (As) concentrations in the soil, water and plant systems can pose a direct health risk to humans and ecosystems. Phosphate (Pi) ions strongly influence As availability in soil, its uptake and toxicity to plants. Better understanding of As(V)-Pi interactions in soils and plants will facilitate a potential remediation strategy for As contaminated soils, reducing As uptake by crop plants and toxicity to human populations via manipulation of soil Pi content. However, the As(V)-Pi interactions in soil-plant systems are complex, leading to contradictory findings among different studies. Therefore, this review investigates the role of soil type, soil properties, minerals, Pi levels in soil and plant, Pi transporters, mycorrhizal association and microbial activities on As-Pi interactions in soils and hydroponics, and uptake by plants, elucidate the key mechanisms, identify key knowledge gaps and recommend new research directions. Although Pi suppresses As uptake by plants in hydroponic systems, in soils it could either increase or decrease As availability and toxicity to plants depending on the soil types, properties and charge characteristics. In soil, As(V) availability is typically increased by the addition of Pi. At the root surface, the Pi transport system has high affinity for Pi over As(V). However, Pi concentration in plant influences the As transport from roots to shoots. Mycorrhizal association may reduce As uptake via a physiological shift to the mycorrhizal uptake pathway, which has a greater affinity for Pi over As(V) than the root epidermal uptake pathway. Copyright © 2017 Elsevier Ltd. All rights reserved.

Kinetics of PTEN-mediated PI(3,4,5)P3 hydrolysis on solid supported membranes

PubMed Central

Liu, Chun; Deb, Sanghamitra; Ferreira, Vinicius S.; Xu, Eric; Baumgart, Tobias

2018-01-01

Phosphatidylinositides play important roles in cellular signaling and migration. Phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3) is an important phosphatidylinositide because it acts as a secondary messenger to trigger cell movement and proliferation. A high level of PI(3,4,5)P3 at the plasma membrane is known to contribute to tumorigenesis. One key enzyme that regulates PI(3,4,5)P3 levels at the plasma membrane is phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which dephosphorylates PI(3,4,5)P3 through hydrolysis to form phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2). It has been reported that PI(4,5)P2 is involved in positive feedback in the PI(3,4,5)P3 hydrolysis by PTEN. However, how PI(3,4,5)P3 dephosphorylation by PTEN is regulated, is still under debate. How other PI(3,4,5)P3-binding proteins affect the dephosphorylation kinetics catalyzed by PTEN also remains unclear. Here, we develop a fluorescent-protein biosensor approach to study how PI(3,4,5)P3 dephosphorylation is regulated by PTEN as well as its membrane-mediated feedback mechanisms. Our observation of sigmoidal kinetics of the PI(3,4,5)P3 hydrolysis reaction supports the notion of autocatalysis in PTEN function. We developed a kinetic model to describe the observed reaction kinetics, which allowed us to i) distinguish between membrane-recruitment and allosteric activation of PTEN by PI(4,5)P2, ii) account for the influence of the biosensor on the observed reaction kinetics, and iii) demonstrate that all of these mechanisms contribute to the kinetics of PTEN-mediated catalysis. PMID:29447222

Kinetics of PTEN-mediated PI(3,4,5)P3 hydrolysis on solid supported membranes.

PubMed

Liu, Chun; Deb, Sanghamitra; Ferreira, Vinicius S; Xu, Eric; Baumgart, Tobias

2018-01-01

Phosphatidylinositides play important roles in cellular signaling and migration. Phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3) is an important phosphatidylinositide because it acts as a secondary messenger to trigger cell movement and proliferation. A high level of PI(3,4,5)P3 at the plasma membrane is known to contribute to tumorigenesis. One key enzyme that regulates PI(3,4,5)P3 levels at the plasma membrane is phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which dephosphorylates PI(3,4,5)P3 through hydrolysis to form phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2). It has been reported that PI(4,5)P2 is involved in positive feedback in the PI(3,4,5)P3 hydrolysis by PTEN. However, how PI(3,4,5)P3 dephosphorylation by PTEN is regulated, is still under debate. How other PI(3,4,5)P3-binding proteins affect the dephosphorylation kinetics catalyzed by PTEN also remains unclear. Here, we develop a fluorescent-protein biosensor approach to study how PI(3,4,5)P3 dephosphorylation is regulated by PTEN as well as its membrane-mediated feedback mechanisms. Our observation of sigmoidal kinetics of the PI(3,4,5)P3 hydrolysis reaction supports the notion of autocatalysis in PTEN function. We developed a kinetic model to describe the observed reaction kinetics, which allowed us to i) distinguish between membrane-recruitment and allosteric activation of PTEN by PI(4,5)P2, ii) account for the influence of the biosensor on the observed reaction kinetics, and iii) demonstrate that all of these mechanisms contribute to the kinetics of PTEN-mediated catalysis.

Comparison of theoretical proteomes: Identification of COGs with conserved and variable pI within the multimodal pI distribution

PubMed Central

Nandi, Soumyadeep; Mehra, Nipun; Lynn, Andrew M; Bhattacharya, Alok

2005-01-01

Background Theoretical proteome analysis, generated by plotting theoretical isoelectric points (pI) against molecular masses of all proteins encoded by the genome show a multimodal distribution for pI. This multimodal distribution is an effect of allowed combinations of the charged amino acids, and not due to evolutionary causes. The variation in this distribution can be correlated to the organisms ecological niche. Contributions to this variation maybe mapped to individual proteins by studying the variation in pI of orthologs across microorganism genomes. Results The distribution of ortholog pI values showed trimodal distributions for all prokaryotic genomes analyzed, similar to whole proteome plots. Pairwise analysis of pI variation show that a few COGs are conserved within, but most vary between, the acidic and basic regions of the distribution, while molecular mass is more highly conserved. At the level of functional grouping of orthologs, five groups vary significantly from the population of orthologs, which is attributed to either conservation at the level of sequences or a bias for either positively or negatively charged residues contributing to the function. Individual COGs conserved in both the acidic and basic regions of the trimodal distribution are identified, and orthologs that best represent the variation in levels of the acidic and basic regions are listed. Conclusion The analysis of pI distribution by using orthologs provides a basis for resolution of theoretical proteome comparison at the level of individual proteins. Orthologs identified that significantly vary between the major acidic and basic regions maybe used as representative of the variation of the entire proteome. PMID:16150155

The role of the PI3K-Akt signaling pathway in the developmental competence of bovine oocytes.

PubMed

Andrade, Gabriella Mamede; da Silveira, Juliano Coelho; Perrini, Claudia; Del Collado, Maite; Gebremedhn, Samuel; Tesfaye, Dawit; Meirelles, Flávio Vieira; Perecin, Felipe

2017-01-01

The ovarian follicle encloses oocytes in a microenvironment throughout their growth and acquisition of competence. Evidence suggests a dynamic interplay among follicular cells and oocytes, since they are constantly exchanging "messages". We dissected bovine ovarian follicles and recovered follicular cells (FCs-granulosa and cumulus cells) and cumulus-oocyte complexes (COCs) to investigate whether the PI3K-Akt signaling pathway impacted oocyte quality. Following follicle rupture, COCs were individually selected for in vitro cultures to track the follicular cells based on oocyte competence to reach the blastocyst stage after parthenogenetic activation. Levels of PI3K-Akt signaling pathway components in FCs correlated with oocyte competence. This pathway is upregulated in FCs from follicles with high-quality oocytes that are able to reach the blastocyst stage, as indicated by decreased levels of PTEN and increased levels of the PTEN regulators bta-miR-494 and bta-miR-20a. Using PI3K-Akt responsive genes, we showed decreased FOXO3a levels and BAX levels in lower quality groups, indicating changes in cell cycle progression, oxidative response and apoptosis. Based on these results, the measurement of levels of PI3K-Akt pathway components in FCs from ovarian follicles carrying oocytes with distinct developmental competences is a useful tool to identify putative molecular pathways involved in the acquisition of oocyte competence.

Ectopic expression of a Catalpa bungei (Bignoniaceae) PISTILLATA homologue rescues the petal and stamen identities in Arabidopsis pi-1 mutant.

PubMed

Jing, Danlong; Xia, Yan; Chen, Faju; Wang, Zhi; Zhang, Shougong; Wang, Junhui

2015-02-01

PISTILLATA (PI) plays crucial roles in Arabidopsis flower development by specifying petal and stamen identities. To investigate the molecular mechanisms underlying organ development of woody angiosperm in Catalpa, we isolated and identified a PI homologue, referred to as CabuPI (C. bungei PISTILLATA), from two genetically cognate C. bungei (Bignoniaceae) bearing single and double flowers. Sequence and phylogenetic analyses revealed that the gene is closest related to the eudicot PI homologues. Moreover, a highly conserved PI-motif is found in the C-terminal regions of CabuPI. Semi-quantitative and quantitative real time PCR analyses showed that the expression of CabuPI was restricted to petals and stamens. However, CabuPI expression in the petals and stamens persisted throughout all floral development stages, but the expression levels were different. In 35S::CabuPI transgenic homozygous pi-1 mutant Arabidopsis, the second and the third whorl floral organs produced normal petals and a different number of stamens, respectively. Furthermore, ectopic expression of the CabuPI in transgenic wild-type or heterozygote pi-1 mutant Arabidopsis caused the first whorl sepal partially converted into a petal-like structure. These results clearly reveal the functional conservation of PI homologues between C. bungei and Arabidopsis. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Cloning, identification and functional characterization of a pi-class glutathione-S-transferase from the freshwater mussel Cristaria plicata.

PubMed

Hu, Baoqing; Deng, Lirong; Wen, Chungen; Yang, Xilan; Pei, Pengzu; Xie, Yanhai; Luo, Shaoqing

2012-01-01

Glutathione-S-transferases (GSTs) are multifunctional phase II detoxification enzymes that catalyze the attachment of electrophilic substrates to glutathione and play an important role in protecting organisms against the toxicity of reactive oxygen species (ROS). The piGST cDNA was cloned and sequenced after rapid amplification of cDNA ends (RACE) from the freshwater mussel Cristaria plicata. The comparison of the deduced amino acid sequences with GSTs from other species showed that the enzymes belonged to the pi-class and the amino acids defining the binding sites of glutathione (G-site) and for xenobiotic substrates (H-site) were highly conserved. The Cp-piGST cDNA is 816 nucleotides (nt) in length and contained a 615 nt open reading frame (ORF) encoding 205 amino acid residues, and has 19 nt of 5' untranslated region (UTR) and a 3' UTR of 182 nt including a tailing signal (AATAAA) and a poly (A) tail. The molecular weight of the predicted piGST is 23.4 kDa, with the calculated PI being 5.2. The mRNA transcript of Cp-piGST could be detected in all the examined tissues with highest expression level in hepatopancreas. The expression level of Cp-piGST in hepatopancreas and gill showed similar trend that were significantly increased after bacterial challenge compared to the control group at 12 h. Furthermore, the recombinant Cp-piGST with high enzyme activity was induced to be expressed as a soluble form by IPTG at 20°C for 8 h, and then was purified by using the native Ni(2+) affinity chromatography. The specific activity of the purified soluble Cp-piGST enzyme into pET30 was 2.396 μmol/min/mg, and which into pET32 was 1.706 μmol/min/mg. The recombinant Cp-piGST had a maximum activity at approximately pH 8.0, and its optimum temperature was 37°C. The recombinant Cp-piGST enzyme activity became lower gradually with the denaturant concentration increasing. Copyright © 2011 Elsevier Ltd. All rights reserved.

Increasing contextual demand modulates anterior and lateral prefrontal brain regions associated with proactive interference.

PubMed

Wolf, Robert Christian; Walter, Henrik; Vasic, Nenad

2010-01-01

Using a parametric version of a modified item-recognition paradigm with three different load levels and by means of event-related functional magnetic resonance imaging, this study tested the hypothesis that cerebral activation associated with intratrial proactive interference (PI) during working memory retrieval is influenced by increased context processing. We found activation of left BA 45 during interference trials across all levels of cognitive processing, and left lateralized activation of the dorsolateral prefrontal cortex (DLPFC, BA 9/46) and the frontopolar cortex (FPC, BA 10) with increasing contextual load. Compared with high susceptibility to PI, low susceptibility was associated with activation of the left DLPFC. These results suggest that an intratrial PI effect can be modulated by increasing context processing of a transiently relevant stimulus set. Moreover, PI resolution associated with increasing context load involves multiple prefrontal regions including the ventro- and dorsolateral prefrontal cortex as well as frontopolar brain areas. Furthermore, low susceptibility to PI might be influenced by increased executive control exerted by the DLPFC.

Regulation of renal NaPi-2 expression and tubular phosphate reabsorption by growth hormone in the juvenile rat.

PubMed

Woda, Craig B; Halaihel, Nabil; Wilson, Paul V; Haramati, Aviad; Levi, Moshe; Mulroney, Susan E

2004-07-01

Growth hormone (GH) is an important factor in the developmental adaptation to enhance P(i) reabsorption; however, the nephron sites and mechanisms by which GH regulates renal P(i) uptake remain unclear and are the focus of the present study. Micropuncture experiments were performed after acute thyroparathyroidectomy in the presence and absence of parathyroid hormone (PTH) in adult (14- to 17-wk old), juvenile (4-wk old), and GH-suppressed juvenile male rats. While the phosphaturic effect of PTH was blunted in the juvenile rat compared with the adult, suppression of GH in the juvenile restored fractional P(i) excretion to adult levels. In the presence or absence of PTH, GH suppression in the juvenile rat caused a significant increase in the fractional P(i) delivery to the late proximal convoluted (PCT) and early distal tubule, so that delivery was not different from that in adults. These data were confirmed by P(i) uptake studies into brush-border membrane (BBM) vesicles. Immunofluorescence studies indicate increased BBM type IIa NaP(i) cotransporter (NaPi-2) expression in the juvenile compared with adult rat, and GH suppression reduced NaPi-2 expression to levels observed in the adult. GH replacement in the [N-acetyl-Tyr(1)-d-Arg(2)]-GRF-(1-29)-NH(2)-treated juveniles restored high NaPi-2 expression and P(i) uptake. Together, these novel results demonstrate that the presence of GH in the juvenile animal is crucial for the early developmental upregulation of BBM NaPi-2 and, most importantly, describe the enhanced P(i) reabsorption along the PCT and proximal straight nephron segments in the juvenile rat.

Monitoring of unfractionated heparin with rotational thrombelastometry using the prothrombinase-induced clotting time reagent (PiCT®).

PubMed

Schaden, E; Jilch, S; Hacker, S; Schober, A; Kozek-Langenecker, S

2012-12-24

To achieve sufficient and safe anticoagulation with unfractionated heparin (UFH) a close and reliable drug monitoring is necessary. In general, the activated partial thromboplastin time (APTT) is used for this purpose. In acute phase response, however, the APTT test procedure might be unreliable e.g. with false low results in the presence of elevated factor VIII. In this so called heparin resistance, measurement of anti-Xa activity is recommended over APTT to avoid potentially harmful dose escalation. A combination of anti-Xa measurement and global hemostatic testing with ROTEM® employing the anti-Xa sensitive PiCT® reagent showed high correlation with enoxaparin levels. This test modification could also be suitable for monitoring UFH. Aim of the study was to evaluate the correlation between PiCT®-ROTEM® and levels of UFH. In this in-vitro study blood samples from healthy volunteers were spiked with UFH and subjected to different ROTEM® tests. There was a linear correlation between UFH level and clotting time (CT) in the PiCT®-ROTEM® test with an excellent correlation coefficient of 0.92. Additional endpoints showed similar results (PiCT®-ROTEM® MaxVel r = -0.85 and PiCT®-ROTEM® t_MaxVel r = 0.88). As a point-of-care applicable tool ROTEM® is immediately at hand. If further clinical studies confirm sensitivity in heparin resistance, PiCT®-ROTEM® could permit rapid UFH dose adjustments especially required in critical illness with acute phase response. Copyright © 2012 Elsevier B.V. All rights reserved.

Genetic regulation by NLA and microRNA827 for maintaining nitrate-dependent phosphate homeostasis in arabidopsis.

PubMed

Kant, Surya; Peng, Mingsheng; Rothstein, Steven J

2011-03-01

Plants need abundant nitrogen and phosphorus for higher yield. Improving plant genetics for higher nitrogen and phosphorus use efficiency would save potentially billions of dollars annually on fertilizers and reduce global environmental pollution. This will require knowledge of molecular regulators for maintaining homeostasis of these nutrients in plants. Previously, we reported that the NITROGEN LIMITATION ADAPTATION (NLA) gene is involved in adaptive responses to low-nitrogen conditions in Arabidopsis, where nla mutant plants display abrupt early senescence. To understand the molecular mechanisms underlying NLA function, two suppressors of the nla mutation were isolated that recover the nla mutant phenotype to wild type. Map-based cloning identified these suppressors as the phosphate (Pi) transport-related genes PHF1 and PHT1.1. In addition, NLA expression is shown to be regulated by the low-Pi induced microRNA miR827. Pi analysis revealed that the early senescence in nla mutant plants was due to Pi toxicity. These plants accumulated over five times the normal Pi content in shoots specifically under low nitrate and high Pi but not under high nitrate conditions. Also the Pi overaccumulator pho2 mutant shows Pi toxicity in a nitrate-dependent manner similar to the nla mutant. Further, the nitrate and Pi levels are shown to have an antagonistic crosstalk as displayed by their differential effects on flowering time. The results demonstrate that NLA and miR827 have pivotal roles in regulating Pi homeostasis in plants in a nitrate-dependent fashion.

How Nurse Gender Influences Patient Priority Assignments in U.S. Emergency Departments

PubMed Central

Vigil, Jacob Miguel; Coulombe, Patrick; Alcock, Joe; Stith, Sarah See; Kruger, Eric; Cichowski, Sara

2016-01-01

The goals of this study were to compare whether emergency department (ED) patients’ pain intensity (PI) is measured differently by male and female nurses and to determine whether PI, heart rate (HR) and respiratory rate (RR) we’re used to prioritize patient urgency differently by male and female nurses. The associations between patients’ PI|HR|RR and the Emergency Severity Index (ESI) scores they were assigned by attending nurses were analyzed using a national database of electronic medical records of U.S. Veterans Affairs ED patients from 2008 to 2012. A total of 129,991 patients presenting for emergency care (Mage = 59.5, 92% males) and their triage nurses (n = 774, Mage = 47.5, 18% males) were analyzed, resulting in a total of 359,642 patient/provider interactions. Patients’ PI did not differ by nurse’s gender; however a cross-classified mixed-effects model showed that nurse gender influenced how PI and RR measurements informed the ESI levels that male patients received. Higher PI levels were associated with more urgent (higher priority) ESI levels by female nurses, yet less urgent ESI levels by male nurses. In contrast, male patients with high RR received more urgent ESI levels by male nurses, while nurse gender did not influence ESI assignments for female patients. These findings show that ED patients receive disparate treatment based on inherent characteristics of their triage nurses, and more standardized (e.g., automated) protocols that can account for implicit social factors on healthcare practice for reliably assessing and prioritizing ED patients may be currently warranted. PMID:28187101

Two differentially regulated phosphate transporters from the symbiotic fungus Hebeloma cylindrosporum and phosphorus acquisition by ectomycorrhizal Pinus pinaster.

PubMed

Tatry, Marie-Violaine; El Kassis, Elie; Lambilliotte, Raphaël; Corratgé, Claire; van Aarle, Ingrid; Amenc, Laurie K; Alary, Rémi; Zimmermann, Sabine; Sentenac, Hervé; Plassard, Claude

2009-03-01

Ectomycorrhizal symbiosis markedly improves plant phosphate uptake, but the molecular mechanisms underlying this benefit are still poorly understood. We identified two ESTs in a cDNA library prepared from the ectomycorrhizal basidiomycete Hebeloma cylindrosporum with significant similarities to phosphate transporters from the endomycorrhizal fungus Glomus versiforme and from non-mycorrhizal fungi. The full-length cDNAs corresponding to these two ESTs complemented a yeast phosphate transport mutant (Deltapho84). Measurements of (33)P-phosphate influx into yeast expressing either cDNA demonstrated that the encoded proteins, named HcPT1 and HcPT2, were able to mediate Pi:H(+) symport with different affinities for Pi (K(m) values of 55 and 4 mum, respectively). Real-time RT-PCR showed that Pi starvation increased the levels of HcPT1 transcripts in H. cylindrosporum hyphae grown in pure culture. Transcript levels of HcPT2 were less dependent on Pi availability. The two transporters were expressed in H. cylindrosporum associated with its natural host plant, Pinus pinaster, grown under low or high P conditions. The presence of ectomycorrhizae increased net Pi uptake rates into intact Pinus pinaster roots at low or high soil P levels. The expression patterns of HcPT1 and HcPT2 indicate that the two fungal phosphate transporters may be involved in uptake of phosphate from the soil solution under the two soil P availability conditions used.

The Chinese herbal medicine FTZ attenuates insulin resistance via IRS1 and PI3K in vitro and in rats with metabolic syndrome

PubMed Central

2014-01-01

Background Insulin resistance plays an important role in the development of metabolic syndrome (MS). Fu Fang Zhen Zhu Tiao Zhi formula (FTZ), a Chinese medicinal decoction, has been used to relieve hyperlipidemia, atherosclerosis and other symptoms associated with metabolic disorders in the clinic. Methods To evaluate the effect of FTZ on insulin resistance, HepG2 cells were induced with high insulin as a model of insulin resistance and treated with FTZ at one of three dosages. Next, the levels of glucose content, insulin receptor substrate1 (IRS1) protein expression and phosphatidylinositol 3-kinase (PI3K) subunit p85 mRNA expression were measured. Alternatively, MS was induced in rats via gavage feeding of a high-fat diet for four consecutive weeks followed by administration of FTZ for eight consecutive weeks. Body weight and the plasma levels of lipids, insulin and glucose were evaluated. Finally, the expression of PI3K p85 mRNA in adipose tissue of rats was measured. Results Our results revealed that FTZ attenuated glucose content and up-regulated the expression of PI3K p85 mRNA and IRS1 protein in insulin-resistant HepG2 cells in vitro. Moreover, FTZ reduced body weight and the plasma concentrations of triacylglycerol, cholesterol, fasting glucose and insulin in insulin resistant MS rats. FTZ also elevated the expression of PI3K p85 mRNA in the adipose tissues of MS rats. Conclusion FTZ attenuated MS symptoms by decreasing the plasma levels of glucose and lipids. The underlying mechanism was attenuation of the reduced expression of PI3K p85 mRNA and IRS1 protein in both insulin-resistant HepG2 cells and MS rats. PMID:24555840

Ursolic acid improves podocyte injury caused by high glucose.

PubMed

Xu, Li; Fan, Qiuling; Wang, Xu; Li, Lin; Lu, Xinxing; Yue, Yuan; Cao, Xu; Liu, Jia; Zhao, Xue; Wang, Lining

2017-08-01

Autophagy plays an important role in the maintenance of podocyte homeostasis. Reduced autophagy may result in limited renal cell function during exposure to high glucose conditions. In this study we investigated the effects of ursolic acid (UA) on autophagy and podocyte injury, which were induced by high glucose. Conditionally immortalized murine podocytes were cultured in media supplemented with high glucose and the effects of the PI3K inhibitor LY294002 and UA on protein expression were determined. miR-21 expression was detected by real-time RT-PCR. Activation of the PTEN-PI3K/Akt/mTOR pathway, expression of autophagy-related proteins and expression of podocyte marker proteins were determined by western blot. Immunofluorescence was used to monitor the accumulation of LC3 puncta. Autophagosomes were also observed by transmission electron microscopy. During exposure to high glucose conditions, the normal level of autophagy was reduced in podocytes, and this defective autophagy induced podocyte injury. Increased miR-21 expression, decreased PTEN expression and abnormal activation of the PI3K/Akt/mTOR pathway were observed in cells that were cultured in high glucose conditions. UA and LY294002 reduced podocyte injury through the restoration of defective autophagy. Our data suggest that UA inhibits miR-21 expression and increases PTEN expression, which in turn inhibits Akt and mTOR and restores normal levels of autophagy. Our data suggest that podocyte injury is associated with reduced levels of autophagy during exposure to high glucose conditions, UA attenuated podocyte injury via an increase in autophagy through miR-21 inhibition and PTEN expression, which inhibit the abnormal activation of the PI3K/Akt/mTOR pathway. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Functional pools of oxidative and glycolytic fibers in human muscle observed by 31P magnetic resonance spectroscopy during exercise.

PubMed Central

Park, J H; Brown, R L; Park, C R; McCully, K; Cohn, M; Haselgrove, J; Chance, B

1987-01-01

Quantitative probing of heterogeneous regions in muscle is feasible with phosphorus-31 magnetic resonance spectroscopy because of the differentiation of metabolic patterns of glycolytic and oxidative fibers. A differential recruitment of oxidative and glycolytic fibers during exercise was demonstrated in 4 of 10 untrained young men by following changes in phosphate metabolites. Concentrations of inorganic phosphate (Pi), phosphocreatine, and ATP were estimated in the wrist flexor muscles of the forearm at rest, during two cycles of three grades of exercise, and in recovery. At high work levels (40% of maximum strength), two distinct Pi peaks were observed and identified with Pi pools at pH 6.9 and pH 5.9-6.4, respectively. These could be accounted for as follows. At the lowest level of work (using 20% of maximum strength), early recruitment primarily of oxidative (type I) and possibly some intermediate (type IIA) muscle fibers occurs with relatively little net lactate production and consequently little decrease in pH. At higher work loads, however, primarily glycolytic (type IIB) muscle fibers are recruited, which have relatively high net lactate production and therefore generate a second pool of Pi at low pH. ATP depletion (35-54%) and Pi losses accompanied the reduction in ability to perform during the first exercise cycle. When the cycle of graded exercise was repeated immediately, the total Pi remained high but gave rise to only one peak at pH 6.8-7.0. These observations indicated exhaustion of glycolytic type IIB fibers, removal of lactate by high local blood flow, and sustained contractions largely by oxidative type I and IIA fibers. A functional differentiation of fiber types could also be demonstrated during recovery if exercise was stopped while two pools of Pi were still apparent. In the first 3 min of recovery, the Pi peak at pH 6.8-6.9 disappeared almost entirely, whereas the Pi peak at pH 6.0 remained unaltered, reflecting the faster recovery of oxidative type I fibers. The potential of magnetic resonance spectroscopy to characterize oxidative and glycolytic fibers, predict capacity for aerobic performance, and signal the presence of muscle pathology is discussed. PMID:3480522

Metallothionein expression is suppressed in primary human hepatocellular carcinomas and is mediated through inactivation of CCAAT/enhancer binding protein alpha by phosphatidylinositol 3-kinase signaling cascade.

PubMed

Datta, Jharna; Majumder, Sarmila; Kutay, Huban; Motiwala, Tasneem; Frankel, Wendy; Costa, Robert; Cha, Hyuk C; MacDougald, Ormond A; Jacob, Samson T; Ghoshal, Kalpana

2007-03-15

Reactive oxygen species (ROS) resulting from chronic inflammation cause liver injury leading to transformation of regenerating hepatocytes. Metallothioneins (MT), induced at high levels by oxidative stress, are potent scavengers of ROS. Here, we report that the levels of MT-1 and MT-2A are drastically reduced in primary human hepatocellular carcinomas (HCCs) and in diethylnitrosamine-induced liver tumors in mice, which is primarily due to transcriptional repression. Expression of the transcription factor, MTF-1, essential for MT expression, and its target gene Zn-T1 that encodes the zinc transporter-1 was not significantly altered in HCCs. Inhibitors of both phosphatidylinositol 3-kinase (PI3K) and its downstream target AKT increased expression of MT genes in HCC cells but not in liver epithelial cells. Suppression of MT-1 and MT-2A by ectopic expression of the constitutively active PI3K or AKT and their up-regulation by dominant-negative PI3K or AKT mutant confirmed negative regulation of MT expression by PI3K/AKT signaling pathway. Further, treatment of cells with a specific inhibitor of glycogen synthase kinase-3 (GSK-3), a downstream effector of PI3K/AKT, inhibited MT expression specifically in HCC cells. Short interfering RNA-mediated depletion of CCAAT/enhancer binding protein alpha (C/EBPalpha), a target of GSK-3, impeded MT expression, which could not be reversed by PI3K inhibitors. DNA binding activity of C/EBPalpha and its phosphorylation at T222 and T226 by GSK-3 are required for MT expression. MTF-1 and C/EBPalpha act in concert to increase MT-2A expression, which probably explains the high level of MT expression in the liver. This study shows the role of PI3K/AKT signaling pathway and C/EBPalpha in regulation of MT expression in hepatocarcinogenesis.

Prebiopsy biparametric MRI: differences of PI-RADS version 2 in patients with different PSA levels.

PubMed

Choi, M H; Lee, Y J; Jung, S E; Rha, S E; Byun, J Y

2018-06-09

To validate the diagnostic accuracy of Prostate Imaging-Reporting and Data System (PI-RADS) version 2 in detecting clinically significant prostate cancer (csPCa, Gleason score ≥7) on prebiopsy biparametric MRI (bpMRI) in patients with different prostate-specific antigen (PSA) levels. This retrospective study included 184 patients who underwent prebiopsy bpMRI followed by transrectal ultrasonography-guided biopsy between June 2015 and February 2017. Reader 1 performed a combination of systematic and targeted biopsy with cognitive fusion after reviewing bpMRI and reader 2 reviewed the bpMRIs retrospectively. PI-RADS categories 4 and 5 were considered positive, and the results of the biopsy were considered the reference standard. Diagnostic performance of PI-RADS of bpMRI was evaluated in two PSA groups with a PSA cut-off level of 10 ng/ml and compared to PSA and the PSA density using receiver operating characteristics (ROC) curve analysis. csPCa was diagnosed in 24 of 123 patients (19.5%) and 26 of 61 patients (42.6%) in the low and high PSA groups, respectively. A PI-RADS v2 category by either readers 1 or 2 had a significantly better performance to detect csPCa than PSA in both PSA groups. In the high PSA group, only one csPCa was missed by reader 2, but none by reader 1. In the low PSA group, readers 1 and 2 were unable to detect seven and five of the 24 csPCas, respectively. Prebiopsy bpMRI has good performance for detecting csPCa in the high PSA group but may miss small-volume csPCa in the low PSA group. Copyright © 2018 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Low Prolactin and High 20-α-Hydroxysteroid Dehydrogenase Levels Contribute to Lower Progesterone Levels in HIV-Infected Pregnant Women Exposed to Protease Inhibitor-Based Combination Antiretroviral Therapy.

PubMed

Papp, Eszter; Balogun, Kayode; Banko, Nicole; Mohammadi, Hakimeh; Loutfy, Mona; Yudin, Mark H; Shah, Rajiv; MacGillivray, Jay; Murphy, Kellie E; Walmsley, Sharon L; Silverman, Michael; Serghides, Lena

2016-05-15

It has been reported that pregnant women receiving protease inhibitor (PI)-based combination antiretroviral therapy (cART) have lower levels of progesterone, which put them at risk of adverse birth outcomes, such as low birth weight. We sought to understand the mechanisms involved in this decline in progesterone level. We assessed plasma levels of progesterone, prolactin, and lipids and placental expression of genes involved in progesterone metabolism in 42 human immunodeficiency virus (HIV)-infected and 31 HIV-uninfected pregnant women. In vitro studies and a mouse pregnancy model were used to delineate the effect of HIV from that of PI-based cART on progesterone metabolism. HIV-infected pregnant women receiving PI-based cART showed a reduction in plasma progesterone levels (P= .026) and an elevation in placental expression of the progesterone inactivating enzyme 20-α-hydroxysteroid dehydrogenase (20α-HSD; median, 2.5 arbitrary units [AU]; interquartile range [IQR], 1.00-4.10 AU), compared with controls (median, 0.89 AU; IQR, 0.66-1.26 AU;P= .002). Prolactin, a key regulator of 20α-HSD, was lower (P= .012) in HIV-infected pregnant women. We observed similar data in pregnant mice exposed to PI-based cART. In vitro inhibition of 20α-HSD activity in trophoblast cells reversed PI-based cART-induced decreases in progesterone levels. Our data suggest that the decrease in progesterone levels observed in HIV-infected pregnant women exposed to PI-based cART is caused, at least in part, by an increase in placental expression of 20α-HSD, which may be due to lower prolactin levels observed in these women. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Low Prolactin and High 20-α-Hydroxysteroid Dehydrogenase Levels Contribute to Lower Progesterone Levels in HIV-Infected Pregnant Women Exposed to Protease Inhibitor–Based Combination Antiretroviral Therapy

PubMed Central

Papp, Eszter; Balogun, Kayode; Banko, Nicole; Mohammadi, Hakimeh; Loutfy, Mona; Yudin, Mark H.; Shah, Rajiv; MacGillivray, Jay; Murphy, Kellie E.; Walmsley, Sharon L.; Silverman, Michael; Serghides, Lena

2016-01-01

Background. It has been reported that pregnant women receiving protease inhibitor (PI)–based combination antiretroviral therapy (cART) have lower levels of progesterone, which put them at risk of adverse birth outcomes, such as low birth weight. We sought to understand the mechanisms involved in this decline in progesterone level. Methods. We assessed plasma levels of progesterone, prolactin, and lipids and placental expression of genes involved in progesterone metabolism in 42 human immunodeficiency virus (HIV)–infected and 31 HIV-uninfected pregnant women. In vitro studies and a mouse pregnancy model were used to delineate the effect of HIV from that of PI-based cART on progesterone metabolism. Results. HIV-infected pregnant women receiving PI-based cART showed a reduction in plasma progesterone levels (P = .026) and an elevation in placental expression of the progesterone inactivating enzyme 20-α-hydroxysteroid dehydrogenase (20α-HSD; median, 2.5 arbitrary units [AU]; interquartile range [IQR], 1.00–4.10 AU), compared with controls (median, 0.89 AU; IQR, 0.66–1.26 AU; P = .002). Prolactin, a key regulator of 20α-HSD, was lower (P = .012) in HIV-infected pregnant women. We observed similar data in pregnant mice exposed to PI-based cART. In vitro inhibition of 20α-HSD activity in trophoblast cells reversed PI-based cART–induced decreases in progesterone levels. Conclusions. Our data suggest that the decrease in progesterone levels observed in HIV-infected pregnant women exposed to PI-based cART is caused, at least in part, by an increase in placental expression of 20α-HSD, which may be due to lower prolactin levels observed in these women. PMID:26740274

Ion channel regulation by phosphoinositides analyzed with VSPs—PI(4,5)P2 affinity, phosphoinositide selectivity, and PI(4,5)P2 pool accessibility

PubMed Central

Rjasanow, Alexandra; Leitner, Michael G.; Thallmair, Veronika; Halaszovich, Christian R.; Oliver, Dominik

2015-01-01

The activity of many proteins depends on the phosphoinositide (PI) content of the membrane. E.g., dynamic changes of the concentration of PI(4,5)P2 are cellular signals that regulate ion channels. The susceptibility of a channel to such dynamics depends on its affinity for PI(4,5)P2. Yet, measuring affinities for endogenous PIs has not been possible directly, but has relied largely on the response to soluble analogs, which may not quantitatively reflect binding to native lipids. Voltage-sensitive phosphatases (VSPs) turn over PI(4,5)P2 to PI(4)P when activated by depolarization. In combination with voltage-clamp electrophysiology VSPs are useful tools for rapid and reversible depletion of PI(4,5)P2. Because cellular PI(4,5)P2 is resynthesized rapidly, steady state PI(4,5)P2 changes with the degree of VSP activation and thus depends on membrane potential. Here we show that titration of endogenous PI(4,5)P2 with Ci-VSP allows for the quantification of relative PI(4,5)P2 affinities of ion channels. The sensitivity of inward rectifier and voltage-gated K+ channels to Ci-VSP allowed for comparison of PI(4,5)P2 affinities within and across channel subfamilies and detected changes of affinity in mutant channels. The results also reveal that VSPs are useful only for PI effectors with high binding specificity among PI isoforms, because PI(4,5)P2 depletion occurs at constant overall PI level. Thus, Kir6.2, a channel activated by PI(4,5)P2 and PI(4)P was insensitive to VSP. Surprisingly, despite comparable PI(4,5)P2 affinity as determined by Ci-VSP, the Kv7 and Kir channel families strongly differed in their sensitivity to receptor-mediated depletion of PI(4,5)P2. While Kv7 members were highly sensitive to activation of PLC by Gq-coupled receptors, Kir channels were insensitive even when PI(4,5)P2 affinity was lowered by mutation. We hypothesize that different channels may be associated with distinct pools of PI(4,5)P2 that differ in their accessibility to PLC and VSPs. PMID:26150791

Progress in video immersion using Panospheric imaging

NASA Astrophysics Data System (ADS)

Bogner, Stephen L.; Southwell, David T.; Penzes, Steven G.; Brosinsky, Chris A.; Anderson, Ron; Hanna, Doug M.

1998-09-01

Having demonstrated significant technical and marketplace advantages over other modalities for video immersion, PanosphericTM Imaging (PI) continues to evolve rapidly. This paper reports on progress achieved since AeroSense 97. The first practical field deployment of the technology occurred in June-August 1997 during the NASA-CMU 'Atacama Desert Trek' activity, where the Nomad mobile robot was teleoperated via immersive PanosphericTM imagery from a distance of several thousand kilometers. Research using teleoperated vehicles at DRES has also verified the exceptional utility of the PI technology for achieving high levels of situational awareness, operator confidence, and mission effectiveness. Important performance enhancements have been achieved with the completion of the 4th Generation PI DSP-based array processor system. The system is now able to provide dynamic full video-rate generation of spatial and computational transformations, resulting in a programmable and fully interactive immersive video telepresence. A new multi- CCD camera architecture has been created to exploit the bandwidth of this processor, yielding a well-matched PI system with greatly improved resolution. While the initial commercial application for this technology is expected to be video tele- conferencing, it also appears to have excellent potential for application in the 'Immersive Cockpit' concept. Additional progress is reported in the areas of Long Wave Infrared PI Imaging, Stereo PI concepts, PI based Video-Servoing concepts, PI based Video Navigation concepts, and Foveation concepts (to merge localized high-resolution views with immersive views).

Nineteen-month stability of Revised NEO Personality Inventory domain and facet scores in patients with personality disorders.

PubMed

Wilberg, Theresa; Karterud, Sigmund; Pedersen, Geir; Urnes, Øyvind; Costa, Paul T

2009-03-01

We lack knowledge of the temporal stability of major personality dimensions in patients with personality disorders (PDs). The Revised NEO Personality Inventory (NEO-PI-R) is a self-report instrument that operationalizes the Five-Factor Model of personality. This study investigated the relative stability, mean level stability, and individual level stability of the NEO-PI-R scores in patients with PDs (n = 393) and patients with symptom disorders only (n = 131). The NEO-PI-R was administered at admission to short-term day treatment and after an average of 19 months. The results showed a moderate to high degree of stability of NEO-PI-R scale scores with no substantial difference in stability between patients with and without PD. Changes in NEO-PI-R scores were associated with changes in symptom distress. Neuroticism was the least stable domain. The study indicates that the Five-Factor Model of personality dimensions and traits are fairly stable in patients with PDs. The lower stability of Neuroticism may partly be explained by its inherent state aspects.

Fabrication of polyimide based microfluidic channels for biosensor devices

NASA Astrophysics Data System (ADS)

Zulfiqar, Azeem; Pfreundt, Andrea; Svendsen, Winnie Edith; Dimaki, Maria

2015-03-01

The ever-increasing complexity of the fabrication process of Point-of-care (POC) devices, due to high demand of functional versatility, compact size and ease-of-use, emphasizes the need of multifunctional materials that can be used to simplify this process. Polymers, currently in use for the fabrication of the often needed microfluidic channels, have limitations in terms of their physicochemical properties. Therefore, the use of a multipurpose biocompatible material with better resistance to the chemical, thermal and electrical environment, along with capability of forming closed channel microfluidics is inevitable. This paper demonstrates a novel technique of fabricating microfluidic devices using polyimide (PI) which fulfills the aforementioned properties criteria. A fabrication process to pattern microfluidic channels, using partially cured PI, has been developed by using a dry etching method. The etching parameters are optimized and compared to those used for fully cured PI. Moreover, the formation of closed microfluidic channel on wafer level by bonding two partially cured PI layers or a partially cured PI to glass with high bond strength has been demonstrated. The reproducibility in uniformity of PI is also compared to the most commonly used SU8 polymer, which is a near UV sensitive epoxy resin. The potential applications of PI processing are POC and biosensor devices integrated with microelectronics.

Genetic Regulation by NLA and MicroRNA827 for Maintaining Nitrate-Dependent Phosphate Homeostasis in Arabidopsis

PubMed Central

Kant, Surya; Peng, Mingsheng; Rothstein, Steven J.

2011-01-01

Plants need abundant nitrogen and phosphorus for higher yield. Improving plant genetics for higher nitrogen and phosphorus use efficiency would save potentially billions of dollars annually on fertilizers and reduce global environmental pollution. This will require knowledge of molecular regulators for maintaining homeostasis of these nutrients in plants. Previously, we reported that the NITROGEN LIMITATION ADAPTATION (NLA) gene is involved in adaptive responses to low-nitrogen conditions in Arabidopsis, where nla mutant plants display abrupt early senescence. To understand the molecular mechanisms underlying NLA function, two suppressors of the nla mutation were isolated that recover the nla mutant phenotype to wild type. Map-based cloning identified these suppressors as the phosphate (Pi) transport-related genes PHF1 and PHT1.1. In addition, NLA expression is shown to be regulated by the low-Pi induced microRNA miR827. Pi analysis revealed that the early senescence in nla mutant plants was due to Pi toxicity. These plants accumulated over five times the normal Pi content in shoots specifically under low nitrate and high Pi but not under high nitrate conditions. Also the Pi overaccumulator pho2 mutant shows Pi toxicity in a nitrate-dependent manner similar to the nla mutant. Further, the nitrate and Pi levels are shown to have an antagonistic crosstalk as displayed by their differential effects on flowering time. The results demonstrate that NLA and miR827 have pivotal roles in regulating Pi homeostasis in plants in a nitrate-dependent fashion. PMID:21455488

Local and distal effects of arbuscular mycorrhizal colonization on direct pathway Pi uptake and root growth in Medicago truncatula

PubMed Central

Watts-Williams, Stephanie J.; Jakobsen, Iver; Cavagnaro, Timothy R.; Grønlund, Mette

2015-01-01

Two pathways exist for plant Pi uptake from soil: via root epidermal cells (direct pathway) or via associations with arbuscular mycorrhizal (AM) fungi, and the two pathways interact in a complex manner. This study investigated distal and local effects of AM colonization on direct root Pi uptake and root growth, at different soil P levels. Medicago truncatula was grown at three soil P levels in split-pots with or without AM fungal inoculation and where one root half grew into soil labelled with 33P. Plant genotypes included the A17 wild type and the mtpt4 mutant. The mtpt4 mutant, colonized by AM fungi, but with no functional mycorrhizal pathway for Pi uptake, was included to better understand effects of AM colonization per se. Colonization by AM fungi decreased expression of direct Pi transporter genes locally, but not distally in the wild type. In mtpt4 mutant plants, direct Pi transporter genes and the Pi starvation-induced gene Mt4 were more highly expressed than in wild-type roots. In wild-type plants, less Pi was taken up via the direct pathway by non-colonized roots when the other root half was colonized by AM fungi, compared with non-mycorrhizal plants. Colonization by AM fungi strongly influenced root growth locally and distally, and direct root Pi uptake activity locally, but had only a weak influence on distal direct pathway activity. The responses to AM colonization in the mtpt4 mutant suggested that in the wild type, the increased P concentration of colonized roots was a major factor driving the effects of AM colonization on direct root Pi uptake. PMID:25944927

Effect of proteolysis index level on instrumental adhesiveness, free amino acids content and volatile compounds profile of dry-cured ham.

PubMed

Pérez-Santaescolástica, C; Carballo, J; Fulladosa, E; Garcia-Perez, José V; Benedito, J; Lorenzo, J M

2018-05-01

Defective textures in dry-cured ham are a common problem that causes important economic losses in the ham industry. An increase of proteolysis during the dry-cured ham processing may lead to high adhesiveness and consumer rejection of the product. Therefore, the influence of proteolysis index (PI) on instrumental adhesiveness, free amino acids and volatile profile of dry-cured ham was assessed. Two hundred Spanish dry-cured ham units were firstly classified according to their PI: low PI (<32%), medium PI (32-36%) and high PI (>36%). Instrumental adhesiveness was affected by PI, showing the lowest values in the batch with low PI. Significant differences (P < 0.05) among groups were found in six amino acids: serine, taurine, cysteine, methionine, isoleucine and leucine. The content of leucine, serine, methionine, and isoleucine significantly (P < 0.05) increased as the proteolysis index rose. However, taurine and cysteine content showed an opposite behaviour, reaching the highest values in the dry-cured hams with low PI. Significant differences (P < 0.001) in the total content of volatile compounds among ham groups were observed, with the highest concentration in the batch with low PI, and decreasing the concentration as the PI increased. Regarding the different chemical families of volatiles, the hydrocarbons (the main family), alcohols, aldehydes, ketones and acids were more abundant in the hams showing the lowest PI. Esters did not show significant differences among the three batches of hams studied. The present study demonstrated that, apart from the effect on the adhesiveness, an excessive proteolysis seems to be associated with negative effects on the taste and aroma of the dry-cured ham. Copyright © 2018 Elsevier Ltd. All rights reserved.

The Molecular Mechanism of Ethylene-Mediated Root Hair Development Induced by Phosphate Starvation

PubMed Central

Song, Li; Yu, Haopeng; Dong, Jinsong; Liu, Dong

2016-01-01

Enhanced root hair production, which increases the root surface area for nutrient uptake, is a typical adaptive response of plants to phosphate (Pi) starvation. Although previous studies have shown that ethylene plays an important role in root hair development induced by Pi starvation, the underlying molecular mechanism is not understood. In this work, we characterized an Arabidopsis mutant, hps5, that displays constitutive ethylene responses and increased sensitivity to Pi starvation due to a mutation in the ethylene receptor ERS1. hps5 accumulates high levels of EIN3 protein, a key transcription factor involved in the ethylene signaling pathway, under both Pi sufficiency and deficiency. Pi starvation also increases the accumulation of EIN3 protein. Combined molecular, genetic, and genomic analyses identified a group of genes that affect root hair development by regulating cell wall modifications. The expression of these genes is induced by Pi starvation and is enhanced in the EIN3-overexpressing line. In contrast, the induction of these genes by Pi starvation is suppressed in ein3 and ein3eil1 mutants. EIN3 protein can directly bind to the promoter of these genes, some of which are also the immediate targets of RSL4, a key transcription factor that regulates root hair development. Based on these results, we propose that under normal growth conditions, the level of ethylene is low in root cells; a group of key transcription factors, including RSL4 and its homologs, trigger the transcription of their target genes to promote root hair development; Pi starvation increases the levels of the protein EIN3, which directly binds to the promoters of the genes targeted by RSL4 and its homologs and further increase their transcription, resulting in the enhanced production of root hairs. This model not only explains how ethylene mediates root hair responses to Pi starvation, but may provide a general mechanism for how ethylene regulates root hair development under both stress and non-stress conditions. PMID:27427911

Chiral anomalies and effective vector meson Lagrangian beyond the tree level

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

Dominguez, C.A.

1987-12-01

The decays ..pi../sup O/ ..-->.. ..gamma gamma.., rho ..-->.. ..pi gamma.., ..omega.. ..-->.. ..pi gamma.., ..omega.. ..-->.. 3..pi.. and ..gamma.. ..-->.. 3..pi.. are studied in the framework of the chiral invariant effective Vector Meson Lagrangian beyond the tree level. The standard Lagrangian is enlarged by including an infinite number of radial excitations which are summed according to the dual model. As a result tree level diagrams are modified by a universal form factor at each vertex containing off-mass-shell mesons, but still respecting chiral anomaly low energy theorems. These vertex corrections bring the tree level predictions into better agreement with experiment.more » The presence of the ..omega.. ..-->.. 3..pi.. contact term is confirmed but its strength is considerably smaller than at tree level.« less

Notoginsenoside R1 attenuates glucose-induced podocyte injury via the inhibition of apoptosis and the activation of autophagy through the PI3K/Akt/mTOR signaling pathway

PubMed Central

Huang, Guodong; Zou, Bingyu; Lv, Jianzhen; Li, Tongyu; Huai, Guoli; Xiang, Shaowei; Lu, Shilong; Luo, Huan; Zhang, Yaping; Jin, Yi; Wang, Yi

2017-01-01

Injury to terminally differentiated podocytes contributes ignificantly to proteinuria and glomerulosclerosis. The aim of this study was to examine the protective effects of notoginsenoside R1 (NR1) on the maintenance of podocyte number and foot process architecture via the inhibition of apoptosis, the induction of autophagy and the maintenance pf podocyte biology in target cells. The effects of NR1 on conditionally immortalized human podocytes under high glucose conditions were evaluated by determining the percentage apoptosis, the percentage autophagy and the expression levels of slit diaphragm proteins. Our results revealed that NR1 protected the podocytes against high glucose-induced injury by decreasing apoptosis, increasing autophagy and by promoting cytoskeletal recovery. The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway was further investigated in order to elucidate the mechanisms responsible for the protective effects of NR1 on podocytes. Our data indicated that treatment with NR increased the phosphorylation levels of PI3K, Akt and mTOR, leading to the activation of the PI3K/Akt/mTOR signaling pathway in podocytes. To the best of our knowledge, this is the first in vitro study to demonstrate that NR1 protects podocytes by activating the PI3K/Akt/mTOR pathway. PMID:28112381

Probing Combustion Chemistry in a Miniature Shock Tube with Synchrotron VUV Photo Ionization Mass Spectrometry

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

Lynch, Patrick T.; Troy, Tyler P.; Ahmed, Musahid

2015-01-29

Tunable synchrotron-sourced photoionization time-of-flight mass spectrometry (PI-TOF-MS) is an important technique in combustion chemistry, complementing lab-scale electron impact and laser photoionization studies for a wide variety of reactors, typically at low pressure. For high-temperature and high-pressure chemical kinetics studies, the shock tube is the reactor of choice. Extending the benefits of shock tube/TOF-MS research to include synchrotron sourced PI-TOF-MS required a radical reconception of the shock tube. An automated, miniature, high-repetition-rate shock tube was developed and can be used to study high-pressure reactive systems (T > 600 K, P < 100 bar) behind reflected shock waves. In this paper, wemore » present results of a PI-TOF-MS study at the Advanced Light Source at Lawrence Berkeley National Laboratory. Dimethyl ether pyrolysis (2% CH3OCH3/Ar) was observed behind the reflected shock (1400 < T-5 < 1700 K, 3 < P-5 < 16 bar) with ionization energies between 10 and 13 eV. Individual experiments have extremely low signal levels. However, product species and radical intermediates are well-resolved when averaging over hundreds of shots, which is ordinarily impractical in conventional shock tube studies. The signal levels attained and data throughput rates with this technique are comparable to those with other synchrotron-based PI-TOF-MS reactors, and it is anticipated that this high pressure technique will greatly complement those lower pressure techniques.« less

Lack of phosphoinositide 3-kinase-gamma attenuates ventilator-induced lung injury.

PubMed

Lionetti, Vincenzo; Lisi, Alberto; Patrucco, Enrico; De Giuli, Paolo; Milazzo, Maria Giovanna; Ceci, Simone; Wymann, Matthias; Lena, Annalisa; Gremigni, Vittorio; Fanelli, Vito; Hirsch, Emilio; Ranieri, V Marco

2006-01-01

G protein-coupled receptors may up-regulate the inflammatory response elicited by ventilator-induced lung injury but also regulate cell survival via protein kinase B (Akt) and extracellular signal regulated kinases 1/2 (ERK1/2). The G protein-sensitive phosphoinositide-3-kinase gamma (PI3Kgamma) regulates several cellular functions including inflammation and cell survival. We explored the role of PI3Kgamma on ventilator-induced lung injury. Prospective, randomized, experimental study. University animal research laboratory. Wild-type (PI3Kgamma), knock-out (PI3Kgamma ), and kinase-dead (PI3Kgamma) mice. Three ventilatory strategies (no stretch, low stretch, high stretch) were studied in an isolated, nonperfused model of acute lung injury (lung lavage) in PI3Kgamma, PI3Kgamma, and PI3Kgamma mice. Reduction in lung compliance, hyaline membrane formation, and epithelial detachment with high stretch were more pronounced in PI3Kgamma than in PI3Kgamma and PI3Kgamma (p < .01). Inflammatory cytokines and IkBalpha phosphorylation with high stretch did not differ among PI3Kgamma, PI3Kgamma, and PI3Kgamma. Apoptotic index (terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick-end labeling) and caspase-3 (immunohistochemistry) with high stretch were larger (p < .01) in PI3Kgamma and PI3Kgamma than in PI3Kgamma. Electron microscopy showed that high stretch caused apoptotic changes in alveolar cells of PI3Kgamma mice whereas PI3Kgamma mice showed necrosis. Phosphorylation of Akt and ERK1/2 with high stretch was more pronounced in PI3Kgamma than in PI3Kgamma and PI3Kgamma (p < .01). Silencing PI3Kgamma seems to attenuate functional and morphological consequences of ventilator-induced lung injury independently of inhibitory effects on cytokines release but through the enhancement of pulmonary apoptosis.

Addressing the Health Concerns of VA Women with Sexual Trauma

DTIC Science & Technology

2015-10-01

high school boys Role Co-I NIDA R34DA038770-01A1 (Zlotnick) 4/01/2015-3/31/2018 2.04 calendar Computer-Based Intervention for Battered...School Boys 1U01CE002531-01 (Orchowski: PI) 9/1/14 – 8/31/18 4.56 CM National Center for Injury Prevention and Control Preventing sexual...aggression among high school boys Role: PI Community-Level Primary Prevention of Dating and Sexual Violence in Middle Schools 1U01CE002651-01

Anti-hepatitis C virus activity and toxicity of type III phosphatidylinositol-4-kinase beta inhibitors.

PubMed

Lamarche, M J; Borawski, J; Bose, A; Capacci-Daniel, C; Colvin, R; Dennehy, M; Ding, J; Dobler, M; Drumm, J; Gaither, L A; Gao, J; Jiang, X; Lin, K; McKeever, U; Puyang, X; Raman, P; Thohan, S; Tommasi, R; Wagner, K; Xiong, X; Zabawa, T; Zhu, S; Wiedmann, B

2012-10-01

Type III phosphatidylinositol-4-kinase beta (PI4KIIIβ) was previously implicated in hepatitis C virus (HCV) replication by small interfering RNA (siRNA) depletion and was therefore proposed as a novel cellular target for the treatment of hepatitis C. Medicinal chemistry efforts identified highly selective PI4KIIIβ inhibitors that potently inhibited the replication of genotype 1a and 1b HCV replicons and genotype 2a virus in vitro. Replicon cells required more than 5 weeks to reach low levels of 3- to 5-fold resistance, suggesting a high resistance barrier to these cellular targets. Extensive in vitro profiling of the compounds revealed a role of PI4KIIIβ in lymphocyte proliferation. Previously proposed functions of PI4KIIIβ in insulin secretion and the regulation of several ion channels were not perturbed with these inhibitors. Moreover, PI4KIIIβ inhibitors were not generally cytotoxic as demonstrated across hundreds of cell lines and primary cells. However, an unexpected antiproliferative effect in lymphocytes precluded their further development for the treatment of hepatitis C.

Anti-Hepatitis C Virus Activity and Toxicity of Type III Phosphatidylinositol-4-Kinase Beta Inhibitors

PubMed Central

LaMarche, M. J.; Borawski, J.; Bose, A.; Capacci-Daniel, C.; Colvin, R.; Dennehy, M.; Ding, J.; Dobler, M.; Drumm, J.; Gaither, L. A.; Gao, J.; Jiang, X.; Lin, K.; McKeever, U.; Puyang, X.; Raman, P.; Thohan, S.; Tommasi, R.; Wagner, K.; Xiong, X.; Zabawa, T.; Zhu, S.

2012-01-01

Type III phosphatidylinositol-4-kinase beta (PI4KIIIβ) was previously implicated in hepatitis C virus (HCV) replication by small interfering RNA (siRNA) depletion and was therefore proposed as a novel cellular target for the treatment of hepatitis C. Medicinal chemistry efforts identified highly selective PI4KIIIβ inhibitors that potently inhibited the replication of genotype 1a and 1b HCV replicons and genotype 2a virus in vitro. Replicon cells required more than 5 weeks to reach low levels of 3- to 5-fold resistance, suggesting a high resistance barrier to these cellular targets. Extensive in vitro profiling of the compounds revealed a role of PI4KIIIβ in lymphocyte proliferation. Previously proposed functions of PI4KIIIβ in insulin secretion and the regulation of several ion channels were not perturbed with these inhibitors. Moreover, PI4KIIIβ inhibitors were not generally cytotoxic as demonstrated across hundreds of cell lines and primary cells. However, an unexpected antiproliferative effect in lymphocytes precluded their further development for the treatment of hepatitis C. PMID:22825118

Distinct effects of thrombopoietin depending on a threshold level of activated Mpl in BaF-3 cells.

PubMed

Millot, Gaël A; Vainchenker, William; Duménil, Dominique; Svinarchuk, Fédor

2002-06-01

Thrombopoietin (TPO) plays a critical role in megakaryopoiesis through binding to its receptor Mpl. This involves activation of various intracellular signaling pathways, including phosphoinositide 3-kinase (PI3K) and the mitogen-activated protein kinase (MAPK) pathways. Their precise role in TPO-mediated proliferation, survival and differentiation is not fully understood. In the present study, we show that TPO induces different biological responses in Mpl-transduced BaF-3 cells, depending on the cell surface density of Mpl and the resulting activation level of signaling pathways. TPO mediates cell proliferation in cells expressing high levels of Mpl but only mediates survival without proliferation in cells expressing low levels of the receptor. By using the kinase inhibitors PD98059 and LY294002, we further showed that the activation level of the PI3K and MAPK p42/44 pathways is a determining factor for the proliferative effect. In cells expressing low levels of Mpl, the survival effect was strongly dependent on the activation level of the PI3K/AKT, but not the MAPK p42/44 pathway. Moreover, this effect was correlated with the phosphorylation level of BAD but not with the expression level of Bcl-X(L). However, PI3K pathway inhibition did not increase apoptosis when BaF-3 cells proliferated in response to TPO, indicating a compensating mechanism from other Mpl signaling pathways in this case.

Physical inactivity as a policy problem: applying a concept from policy analysis to a public health issue.

PubMed

Rütten, Alfred; Abu-Omar, Karim; Gelius, Peter; Schow, Diana

2013-03-07

Despite the recent rapid development of policies to counteract physical inactivity (PI), only a small number of systematic analyses on the evolution of these policies exists. In this article we analyze how PI, as a public health issue, "translates" into a policy-making issue. First, we discuss why PI has become an increasingly important public health issue during the last two decades. We then follow Guy Peters and conceptualize PI as a "policy problem" that has the potential to be linked to policy instruments and policy impact. Analysis indicates that PI is a policy problem that i) is chronic in nature; ii) involves a high degree of political complexity; iii) can be disaggregated into smaller scales; iv) is addressed through interventions that can be difficult to "sell" to the public when their benefits are not highly divisible; v) cannot be solved by government spending alone; vi) must be addressed through a broad scope of activities; and vii) involves interdependencies among both multiple sectors and levels of government.We conclude that the new perspective on PI proposed in this article might be useful and important for i) describing and mapping policies to counteract PI in different contexts; ii) evaluating whether or not existing policy instruments are appropriate to the policy problem of PI, and iii) explaining the factors and processes that underlie policy development and implementation. More research is warranted in all these areas. In particular, we propose to focus on comparative analyses of how the problem of PI is defined and tackled in different contexts, and on the identification of truly effective policy instruments that are designed to "solve" the PI policy problem.

Regulation of root morphogenesis in arbuscular mycorrhizae: what role do fungal exudates, phosphate, sugars and hormones play in lateral root formation?

PubMed Central

Fusconi, Anna

2014-01-01

Background Arbuscular mycorrhizae (AMs) form a widespread root–fungus symbiosis that improves plant phosphate (Pi) acquisition and modifies the physiology and development of host plants. Increased branching is recognized as a general feature of AM roots, and has been interpreted as a means of increasing suitable sites for colonization. Fungal exudates, which are involved in the dialogue between AM fungi and their host during the pre-colonization phase, play a well-documented role in lateral root (LR) formation. In addition, the increased Pi content of AM plants, in relation to Pi-starved controls, as well as changes in the delivery of carbohydrates to the roots and modulation of phytohormone concentration, transport and sensitivity, are probably involved in increasing root system branching. Scope This review discusses the possible causes of increased branching in AM plants. The differential root responses to Pi, sugars and hormones of potential AM host species are also highlighted and discussed in comparison with those of the non-host Arabidopsis thaliana. Conclusions Fungal exudates are probably the main compounds regulating AM root morphogenesis during the first colonization steps, while a complex network of interactions governs root development in established AMs. Colonization and high Pi act synergistically to increase root branching, and sugar transport towards the arbusculated cells may contribute to LR formation. In addition, AM colonization and high Pi generally increase auxin and cytokinin and decrease ethylene and strigolactone levels. With the exception of cytokinins, which seem to regulate mainly the root:shoot biomass ratio, these hormones play a leading role in governing root morphogenesis, with strigolactones and ethylene blocking LR formation in the non-colonized, Pi-starved plants, and auxin inducing them in colonized plants, or in plants grown under high Pi conditions. PMID:24227446

Genetic and Genomic Evidence That Sucrose Is a Global Regulator of Plant Responses to Phosphate Starvation in Arabidopsis1[W][OA

PubMed Central

Lei, Mingguang; Liu, Yidan; Zhang, Baocai; Zhao, Yingtao; Wang, Xiujie; Zhou, Yihua; Raghothama, Kashchandra G.; Liu, Dong

2011-01-01

Plants respond to phosphate (Pi) starvation by exhibiting a suite of developmental, biochemical, and physiological changes to cope with this nutritional stress. To understand the molecular mechanism underlying these responses, we isolated an Arabidopsis (Arabidopsis thaliana) mutant, hypersensitive to phosphate starvation1 (hps1), which has enhanced sensitivity in almost all aspects of plant responses to Pi starvation. Molecular and genetic analyses indicated that the mutant phenotype is caused by overexpression of the SUCROSE TRANSPORTER2 (SUC2) gene. As a consequence, hps1 has a high level of sucrose (Suc) in both its shoot and root tissues. Overexpression of SUC2 or its closely related family members SUC1 and SUC5 in wild-type plants recapitulates the phenotype of hps1. In contrast, the disruption of SUC2 functions greatly inhibits plant responses to Pi starvation. Microarray analysis further indicated that 73% of the genes that are induced by Pi starvation in wild-type plants can be induced by elevated levels of Suc in hps1 mutants, even when they are grown under Pi-sufficient conditions. These genes include several important Pi signaling components and those that are directly involved in Pi transport, mobilization, and distribution between shoot and root. Interestingly, Suc and low-Pi signals appear to interact with each other both synergistically and antagonistically in regulating gene expression. Our genetic and genomic studies provide compelling evidence that Suc is a global regulator of plant responses to Pi starvation. This finding will help to further elucidate the signaling mechanism that controls plant responses to this particular nutritional stress. PMID:21346170

piRNA pathway targets active LINE1 elements to establish the repressive H3K9me3 mark in germ cells

PubMed Central

Pezic, Dubravka; Manakov, Sergei A.; Sachidanandam, Ravi; Aravin, Alexei A.

2014-01-01

Transposable elements (TEs) occupy a large fraction of metazoan genomes and pose a constant threat to genomic integrity. This threat is particularly critical in germ cells, as changes in the genome that are induced by TEs will be transmitted to the next generation. Small noncoding piwi-interacting RNAs (piRNAs) recognize and silence a diverse set of TEs in germ cells. In mice, piRNA-guided transposon repression correlates with establishment of CpG DNA methylation on their sequences, yet the mechanism and the spectrum of genomic targets of piRNA silencing are unknown. Here we show that in addition to DNA methylation, the piRNA pathway is required to maintain a high level of the repressive H3K9me3 histone modification on long interspersed nuclear elements (LINEs) in germ cells. piRNA-dependent chromatin repression targets exclusively full-length elements of actively transposing LINE families, demonstrating the remarkable ability of the piRNA pathway to recognize active elements among the large number of genomic transposon fragments. PMID:24939875

Enhanced Secondary- and Hormone Metabolism in Leaves of Arbuscular Mycorrhizal Medicago truncatula1[OPEN

PubMed Central

Adolfsson, Lisa; Šimura, Jan; Beebo, Azeez; Aboalizadeh, Jila; Široká, Jitka

2017-01-01

Arbuscular mycorrhizas (AM) are the most common symbiotic associations between a plant’s root compartment and fungi. They provide nutritional benefit (mostly inorganic phosphate [Pi]), leading to improved growth, and nonnutritional benefits, including defense responses to environmental cues throughout the host plant, which, in return, delivers carbohydrates to the symbiont. However, how transcriptional and metabolic changes occurring in leaves of AM plants differ from those induced by Pi fertilization is poorly understood. We investigated systemic changes in the leaves of mycorrhized Medicago truncatula in conditions with no improved Pi status and compared them with those induced by high-Pi treatment in nonmycorrhized plants. Microarray-based genome-wide profiling indicated up-regulation by mycorrhization of genes involved in flavonoid, terpenoid, jasmonic acid (JA), and abscisic acid (ABA) biosynthesis as well as enhanced expression of MYC2, the master regulator of JA-dependent responses. Accordingly, total anthocyanins and flavonoids increased, and most flavonoid species were enriched in AM leaves. Both the AM and Pi treatments corepressed iron homeostasis genes, resulting in lower levels of available iron in leaves. In addition, higher levels of cytokinins were found in leaves of AM- and Pi-treated plants, whereas the level of ABA was increased specifically in AM leaves. Foliar treatment of nonmycorrhized plants with either ABA or JA induced the up-regulation of MYC2, but only JA also induced the up-regulation of flavonoid and terpenoid biosynthetic genes. Based on these results, we propose that mycorrhization and Pi fertilization share cytokinin-mediated improved shoot growth, whereas enhanced ABA biosynthesis and JA-regulated flavonoid and terpenoid biosynthesis in leaves are specific to mycorrhization. PMID:28698354

MiR-374b Promotes Proliferation and Inhibits Apoptosis of Human GIST Cells by Inhibiting PTEN through Activation of the PI3K/Akt Pathway.

PubMed

Long, Zi-Wen; Wu, Jiang-Hong; Hong, Cai-; Wang, Ya-Nong; Zhou, Ye

2018-06-14

Gastrointestinal stromal tumours (GIST) are the most common mesenchymal tumors of the gastrointestinal (GI) tract. In order to investigate a new treatment fot GIST, we hypothesized the effect of miR-374b targeting PTEN gene-mediated PI3K/Akt signal transduction pathway on proliferation and apoptosis of human gastrointestinal stromal tumor (GIST) cells. We obtained GIST tissues and adjacent normal tissues from 143 patients with GIST to measure the levels of miR- 374b, PTEN, PI3K, Akt, caspase9, Bax, MMP2, MMP9, ki67, PCNA, P53 and cyclinD1. Finally, cell viability, cell cycle and apoptosis were detected. According to the KFGG analysis of DEGs, PTEN was involved in a variety of signaling pathways and miRs were associated with cancer development. The results showed that MiR-374b was highly expressed, while PTEN was downregulated in the GIST tissues. The levels of miR-374b, PI3K, AKT and PTEN were related to tumor diameter and pathological stage. Additionally, miR-374b increased the mRNA and protein levels of PI3K, Akt, MMP2, MMP9, P53 and cyclinD1, suggesting that miR-374b activates PI3K/Akt signaling pathway in GIST-T1 cells. Moreover, MiR- 374b promoted cell viability, migration, invasion, and cell cycle entry, and inhibited apoptosis in GIST cells. Taken together, the results indicated that miR-374b promotes viability and inhibits apoptosis of human GIST cells by targeting PTEN gene through the PI3K/Akt signaling pathway. Thus, this study provides a new potential target for GIST treatment.

Biogenesis pathways of piRNAs loaded onto AGO3 in the Drosophila testis.

PubMed

Nagao, Akihiro; Mituyama, Toutai; Huang, Haidong; Chen, Dahua; Siomi, Mikiko C; Siomi, Haruhiko

2010-12-01

PIWI-interacting RNAs (piRNAs) silence transposable elements in animal germ cells. In Drosophila ovaries, piRNAs are produced by two distinct pathways: the "ping-pong" amplification cycle that operates in germ cells and a ping-pong-independent pathway termed the primary pathway that mainly operates in somatic cells. AGO3, one of three PIWI proteins in flies, is involved in the ping-pong cycle in ovaries. We characterized AGO3-associated piRNAs in fly testes and found that like in ovaries, AGO3 functions in the ping-pong cycle with Aubergine (Aub) for piRNA production from transposon transcripts. In contrast, most AGO3-associated piRNAs corresponding to Suppressor of Stellate [Su(Ste)] genes are antisense-oriented and bound to Aub. In addition, the vast majority of AGO3-bound piRNAs derived from the AT-chX locus on chromosome X are antisense-oriented and are also found among Aub-associated piRNAs. The presence of very few sense Su(Ste) and AT-chX piRNAs suggests that biogenesis of both Su(Ste) and AT-chX piRNAs by a ping-pong mechanism only is highly unlikely. Nevertheless, the mutual interdependence of AGO3 and Aub for the accumulation of these piRNAs shows that their production relies on both AGO3 and Aub. Analysis of piRNA pathway mutants revealed that although the requirements for piRNA factors for Su(Ste)- and AT-chX-piRNA levels mostly overlap and resemble those for the ping-pong mechanism in the ovaries, Armitage (armi) is not required for the accumulation of AT-chX-1 piRNA. These findings suggest that the impacts of armi mutants on the operation of the piRNA pathway are variable in germ cells of fly testes.

Phosphite, an analog of phosphate, suppresses the coordinated expression of genes under phosphate starvation.

PubMed

Varadarajan, Deepa K; Karthikeyan, Athikkattuvalasu S; Matilda, Paino Durzo; Raghothama, Kashchandra G

2002-07-01

Phosphate (Pi) and its analog phosphite (Phi) are acquired by plants via Pi transporters. Although the uptake and mobility of Phi and Pi are similar, there is no evidence suggesting that plants can utilize Phi as a sole source of phosphorus. Phi is also known to interfere with many of the Pi starvation responses in plants and yeast (Saccharomyces cerevisiae). In this study, effects of Phi on plant growth and coordinated expression of genes induced by Pi starvation were analyzed. Phi suppressed many of the Pi starvation responses that are commonly observed in plants. Enhanced root growth and root to shoot ratio, a hallmark of Pi stress response, was strongly inhibited by Phi. The negative effects of Phi were not obvious in plants supplemented with Pi. The expression of Pi starvation-induced genes such as LePT1, LePT2, AtPT1, and AtPT2 (high-affinity Pi transporters); LePS2 (a novel acid phosphatase); LePS3 and TPSI1 (novel genes); and PAP1 (purple acid phosphatase) was suppressed by Phi in plants and cell cultures. Expression of luciferase reporter gene driven by the Pi starvation-induced AtPT2 promoter was also suppressed by Phi. These analyses showed that suppression of Pi starvation-induced genes is an early response to addition of Phi. These data also provide evidence that Phi interferes with gene expression at the level of transcription. Synchronized suppression of multiple Pi starvation-induced genes by Phi points to its action on the early molecular events, probably signal transduction, in Pi starvation response.

Cancer Associated Fibroblast-Derived Hepatocyte Growth Factor Inhibits the Paclitaxel-Induced Apoptosis of Lung Cancer A549 Cells by Up-Regulating the PI3K/Akt and GRP78 Signaling on a Microfluidic Platform

PubMed Central

Xu, Zhiyun; He, Tianrui; Li, Encheng; Guo, Zhe; Liu, Fen; Jiang, Chunmeng; Wang, Qi

2015-01-01

Tumor stroma and growth factors provide a survival environment to tumor cells and can modulate their chemoresistance by dysregulating several signal pathways. In this study, we fabricated a three-dimensional (3D) microfluidic chip using polydimethylsiloxane (PDMS) to investigate the impact of hepatocyte growth factor (HGF) from cancer-associated fibroblasts (CAF) on the Met/PI3K/AKT activation, glucose regulatory protein (GRP78) expression and the paclitaxel-induced A549 cell apoptosis. With a concentration gradient generator, the assembled chip was able to reconstruct a tumor microenvironment in vitro. We found high levels of HGF in the supernatants of CAF and the CAF matrix from the supernatants of activated HFL1 fibroblasts or HGF enhanced the levels of Met, PI3K and AKT phosphorylation and GRP78 expression in A549 cells cultured in a 3D cell chamber, which was abrogated by anti-HGF. Inhibition of Met attenuated the CAF matrix-enhanced PI3K/AKT phosphorylation and GRP78 expression while inhibition of PI3K reduced GRP78 expression, but not Met phosphorylation in A549 cells. Inhibition of GRP78 failed to modulate the CAF matrix-enhanced Met/PI3K/AKT phosphorylation in A549 cells. Furthermore, inhibition of PI3K or GRP78 enhanced spontaneous and paclitaxel-induced A549 cell apoptosis. Moreover, treatment with the CAF matrix inhibited spontaneous and medium or high dose of paclitaxel-induced A549 cell apoptosis. Inhibition of PI3K or GRP78 attenuated the CAF matrix-mediated inhibition on paclitaxel-induced A549 cell apoptosis. Our data indicated that HGF in the CAF matrix activated the Met/PI3K/AKT and up-regulated GRP78 expression, promoting chemoresistance to paclitaxel-mediated apoptosis in A549 cells. Our findings suggest that the microfluidic system may represent an ideal platform for signaling research and drug screening. PMID:26115510

Phosphatidylinositol (4,5)Bisphosphate Inhibits K+-Efflux Channel Activity in NT1 Tobacco Cultured Cells1[W][OA

PubMed Central

Ma, Xiaohong; Shor, Oded; Diminshtein, Sofia; Yu, Ling; Im, Yang Ju; Perera, Imara; Lomax, Aaron; Boss, Wendy F.; Moran, Nava

2009-01-01

In the animal world, the regulation of ion channels by phosphoinositides (PIs) has been investigated extensively, demonstrating a wide range of channels controlled by phosphatidylinositol (4,5)bisphosphate (PtdInsP2). To understand PI regulation of plant ion channels, we examined the in planta effect of PtdInsP2 on the K+-efflux channel of tobacco (Nicotiana tabacum), NtORK (outward-rectifying K channel). We applied a patch clamp in the whole-cell configuration (with fixed “cytosolic” Ca2+ concentration and pH) to protoplasts isolated from cultured tobacco cells with genetically manipulated plasma membrane levels of PtdInsP2 and cellular inositol (1,4,5)trisphosphate: “Low PIs” had depressed levels of these PIs, and “High PIs” had elevated levels relative to controls. In all of these cells, K channel activity, reflected in the net, steady-state outward K+ currents (IK), was inversely related to the plasma membrane PtdInsP2 level. Consistent with this, short-term manipulations decreasing PtdInsP2 levels in the High PIs, such as pretreatment with the phytohormone abscisic acid (25 μm) or neutralizing the bath solution from pH 5.6 to pH 7, increased IK (i.e. NtORK activity). Moreover, increasing PtdInsP2 levels in controls or in abscisic acid-treated high-PI cells, using the specific PI-phospholipase C inhibitor U73122 (2.5–4 μm), decreased NtORK activity. In all cases, IK decreases stemmed largely from decreased maximum attainable NtORK channel conductance and partly from shifted voltage dependence of channel gating to more positive potentials, making it more difficult to activate the channels. These results are consistent with NtORK inhibition by the negatively charged PtdInsP2 in the internal plasma membrane leaflet. Such effects are likely to underlie PI signaling in intact plant cells. PMID:19052153

Phosphatidylinositol (4,5)bisphosphate inhibits K+-efflux channel activity in NT1 tobacco cultured cells.

PubMed

Ma, Xiaohong; Shor, Oded; Diminshtein, Sofia; Yu, Ling; Im, Yang Ju; Perera, Imara; Lomax, Aaron; Boss, Wendy F; Moran, Nava

2009-02-01

In the animal world, the regulation of ion channels by phosphoinositides (PIs) has been investigated extensively, demonstrating a wide range of channels controlled by phosphatidylinositol (4,5)bisphosphate (PtdInsP2). To understand PI regulation of plant ion channels, we examined the in planta effect of PtdInsP2 on the K+-efflux channel of tobacco (Nicotiana tabacum), NtORK (outward-rectifying K channel). We applied a patch clamp in the whole-cell configuration (with fixed "cytosolic" Ca2+ concentration and pH) to protoplasts isolated from cultured tobacco cells with genetically manipulated plasma membrane levels of PtdInsP2 and cellular inositol (1,4,5)trisphosphate: "Low PIs" had depressed levels of these PIs, and "High PIs" had elevated levels relative to controls. In all of these cells, K channel activity, reflected in the net, steady-state outward K+ currents (IK), was inversely related to the plasma membrane PtdInsP2 level. Consistent with this, short-term manipulations decreasing PtdInsP2 levels in the High PIs, such as pretreatment with the phytohormone abscisic acid (25 microM) or neutralizing the bath solution from pH 5.6 to pH 7, increased IK (i.e. NtORK activity). Moreover, increasing PtdInsP2 levels in controls or in abscisic acid-treated high-PI cells, using the specific PI-phospholipase C inhibitor U73122 (2.5-4 microM), decreased NtORK activity. In all cases, IK decreases stemmed largely from decreased maximum attainable NtORK channel conductance and partly from shifted voltage dependence of channel gating to more positive potentials, making it more difficult to activate the channels. These results are consistent with NtORK inhibition by the negatively charged PtdInsP2 in the internal plasma membrane leaflet. Such effects are likely to underlie PI signaling in intact plant cells.

Heat Stress Affects Pi-related Genes Expression and Inorganic Phosphate Deposition/Accumulation in Barley

PubMed Central

Pacak, Andrzej; Barciszewska-Pacak, Maria; Swida-Barteczka, Aleksandra; Kruszka, Katarzyna; Sega, Pawel; Milanowska, Kaja; Jakobsen, Iver; Jarmolowski, Artur; Szweykowska-Kulinska, Zofia

2016-01-01

Phosphorus (P) in plants is taken from soil as an inorganic phosphate (Pi) and is one of the most important macroelements in growth and development. Plants actively react to Pi starvation by the induced expression of Pi transporters, MIR399, MIR827, and miR399 molecular sponge – IPS1 genes and by the decreased expression of the ubiquitin-conjugating enzyme E2 (PHOSPHATE2 – PHO2) and Pi sensing and transport SPX-MFS genes. The PHO2 protein is involved in the degradation of Pi transporters PHT1;1 (from soil to roots) and PHO1 (from roots to shoots). The decreased expression of PHO2 leads to Pi accumulation in shoots. In contrast, the pho1 mutant shows a decreased level of Pi concentration in shoots. Finally, Pi starvation leads to decreased Pi concentration in all plant tissues. Little is known about plant Pi homeostasis in other abiotic stress conditions. We found that, during the first hour of heat stress, Pi accumulated in barley shoots but not in the roots, and transcriptomic data analysis as well as RT-qPCR led us to propose an explanation for this phenomenon. Pi transport inhibition from soil to roots is balanced by lower Pi efflux from roots to shoots directed by the PHO1 transporter. In shoots, the PHO2 mRNA level is decreased, leading to an increased Pi level. We concluded that Pi homeostasis in barley during heat stress is maintained by dynamic changes in Pi-related genes expression. PMID:27446155

Metabolic biomarkers for response to PI3K inhibition in basal-like breast cancer

PubMed Central

2013-01-01

Introduction The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in cancer cells through numerous mutations and epigenetic changes. The recent development of inhibitors targeting different components of the PI3K pathway may represent a valuable treatment alternative. However, predicting efficacy of these drugs is challenging, and methods for therapy monitoring are needed. Basal-like breast cancer (BLBC) is an aggressive breast cancer subtype, frequently associated with PI3K pathway activation. The objectives of this study were to quantify the PI3K pathway activity in tissue sections from xenografts representing basal-like and luminal-like breast cancer before and immediately after treatment with PI3K inhibitors, and to identify metabolic biomarkers for treatment response. Methods Tumor-bearing animals (n = 8 per treatment group) received MK-2206 (120 mg/kg/day) or BEZ235 (50 mg/kg/day) for 3 days. Activity in the PI3K/Akt/mammalian target of rapamycin pathway in xenografts and human biopsies was evaluated using a novel method for semiquantitative assessment of Aktser473 phosphorylation. Metabolic changes were assessed by ex vivo high-resolution magic angle spinning magnetic resonance spectroscopy. Results Using a novel dual near-infrared immunofluorescent imaging method, basal-like xenografts had a 4.5-fold higher baseline level of pAktser473 than luminal-like xenografts. Following treatment, basal-like xenografts demonstrated reduced levels of pAktser473 and decreased proliferation. This correlated with metabolic changes, as both MK-2206 and BEZ235 reduced lactate concentration and increased phosphocholine concentration in the basal-like tumors. BEZ235 also caused increased glucose and glycerophosphocholine concentrations. No response to treatment or change in metabolic profile was seen in luminal-like xenografts. Analyzing tumor sections from five patients with BLBC demonstrated that two of these patients had an elevated pAktser473 level. Conclusion The activity of the PI3K pathway can be determined in tissue sections by quantitative imaging using an antibody towards pAktser473. Long-term treatment with MK-2206 or BEZ235 resulted in significant growth inhibition in basal-like, but not luminal-like, xenografts. This indicates that PI3K inhibitors may have selective efficacy in basal-like breast cancer with increased PI3K signaling, and identifies lactate, phosphocholine and glycerophosphocholine as potential metabolic biomarkers for early therapy monitoring. In human biopsies, variable pAktser473 levels were observed, suggesting heterogeneous PI3K signaling activity in BLBC. PMID:23448424

Assessing adolescents' personality with the NEO PI-R.

PubMed

De Fruyt, F; Mervielde, I; Hoekstra, H A; Rolland, J P

2000-12-01

The suitability of the Revised NEO Personality Inventory (NEO PI-R) to assess adolescents' personality traits was investigated in an unselected heterogeneous sample of 469 adolescents aged 12 to 17 years. They were further administered the Hierarchical Personality Inventory for Children (HiPIC) to allow an examination of convergent and discriminant validity. The adult NEO PI-R factor structure proved to be highly replicable in the sample of adolescents, with all facet scales primarily loading on the expected factors, independent of the age group. Domain and facet internal consistency coefficients were comparable to those obtained in adult samples, with less than 12% of the items showing corrected item-facet correlations below absolute value .20. Although, in general, adolescents reported few difficulties with the comprehensibility of the items, they tend to report more problems with the Openness to Ideas (05) and Openness to Values (06) items. Correlations between NEO PI-R and HiPIC scales underscored the convergent and discriminant validity of the NEO facets and HiPIC scales. It was concluded that the NEO PI-R in its present form is useful for assessing adolescents' traits at the primary level, but additional research is necessary to infer the most appropriate facet level structure.

The Two-Component System PhoPR of Clostridium acetobutylicum Is Involved in Phosphate-Dependent Gene Regulation ▿

PubMed Central

Fiedler, Tomas; Mix, Maren; Meyer, Uta; Mikkat, Stefan; Glocker, Michael O.; Bahl, Hubert; Fischer, Ralf-Jörg

2008-01-01

The phoPR gene locus of Clostridium acetobutylicum ATCC 824 comprises two genes, phoP and phoR. Deduced proteins are predicted to represent a response regulator and sensor kinase of a phosphate-dependent two-component regulatory system. We analyzed the expression patterns of phoPR in Pi-limited chemostat cultures and in response to Pi pulses. A basic transcription level under high-phosphate conditions was shown, and a significant increase in mRNA transcript levels was found when external Pi concentrations dropped below 0.3 mM. In two-dimensional gel electrophoresis experiments, a 2.5-fold increase in PhoP was observed under Pi-limiting growth conditions compared to growth with an excess of Pi. At least three different transcription start points for phoP were determined by primer extension analyses. Proteins PhoP and an N-terminally truncated *PhoR were individually expressed heterologously in Escherichia coli and purified. Autophosphorylation of *PhoR and phosphorylation of PhoP were shown in vitro. Electromobility shift assays proved that there was a specific binding of PhoP to the promoter region of the phosphate-regulated pst operon of C. acetobutylicum. PMID:18689481

Sodium-dependent phosphate cotransporters and phosphate-induced calcification of vascular smooth muscle cells: Redundant roles for PiT-1 and PiT-2

PubMed Central

Crouthamel, Matthew H.; Lau, Wei Ling; Leaf, Elizabeth M.; Chavkin, Nick; Wallingford, Mary C.; Peterson, Danielle F.; Li, Xianwu; Liu, Yonggang; Chin, Michael T.; Levi, Moshe; Giachelli, Cecilia M.

2014-01-01

Objective Elevated serum phosphate has emerged as a major risk factor for vascular calcification. The sodium-dependent phosphate cotransporter, PiT-1, was previously shown to be required for phosphate-induced osteogenic differentiation and calcification of cultured human VSMCs, but its importance in vascular calcification in vivo, as well as the potential role of its homologue, PiT-2, have not been determined. We investigated the in vivo requirement for PiT-1 in vascular calcification using a mouse model of chronic kidney disease, and the potential compensatory role of PiT-2 using in vitro knockdown and over-expression strategies. Approach and Results Mice with targeted deletion of PiT-1 in VSMCs were generated (PiT-1Δsm). PiT-1 mRNA levels were undetectable whereas PiT-2 mRNA levels were increased 2 fold in the vascular aortic media of PiT-1Δsm compared to PiT-1flox/flox control. When arterial medial calcification was induced in PiT-1Δsm and PiT-1flox/flox by chronic kidney disease followed by dietary phosphate loading, the degree of aortic calcification was not different between genotypes, suggesting compensation by PiT-2. Consistent with this possibility, VSMCs isolated from PiT-1Δsm mice had no PiT-1 mRNA expression, increased PiT-2 mRNA levels, and no difference in sodium-dependent phosphate uptake or phosphate-induced matrix calcification compared to PiT-1flox/flox VSMCs. Knockdown of PiT-2 decreased phosphate uptake and phosphate-induced calcification of PiT-1Δsm VSMCs. Furthermore, over-expression of PiT-2 restored these parameters in human PiT-1-deficient VSMCs. Conclusions PiT-2 can mediate phosphate uptake and calcification of VSMCs in the absence of PiT-1. Mechanistically, PiT-1 and PiT-2 appear to serve redundant roles in phosphate-induced calcification of vascular smooth muscle cells. PMID:23968976

Mutation of genes of the PI3K/AKT pathway in breast cancer supports their potential importance as biomarker for breast cancer aggressiveness.

PubMed

Tserga, Aggeliki; Chatziandreou, Ilenia; Michalopoulos, Nicolaos V; Patsouris, Efstratios; Saetta, Angelica A

2016-07-01

Deregulation of phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is closely associated with cancer development and cancer progression. PIK3CA, AKT1, and PTEN are the fundamental molecules of the PI3K/AKT pathway with increased mutation rates in cancer cases leading to aberrant regulation of the pathway. Even though molecular alterations of the PI3K/AKT pathway have been studied in breast cancer, correlations between specific molecular alterations and clinicopathological features remain contradictory. In this study, we examined mutations of the PI3K/AKT pathway in 75 breast carcinomas using high-resolution melting analysis and pyrosequencing, in parallel with analysis of relative expression of PIK3CA and AKT2 genes. Mutations of PIK3CA were found in our cohort in 21 cases (28 %), 10 (13 %) in exon 9 and 11(15 %) in exon 20. Mutation frequency of AKT1 and PTEN genes was 4 and 3 %, respectively. Overall, alterations in the PI3K/AKT signaling cascade were detected in 35 % of the cases. Furthermore, comparison of 50 breast carcinomas with adjacent normal tissues showed elevated PIK3CA messenger RNA (mRNA) levels in 18 % of tumor cases and elevated AKT2 mRNA levels in 14 %. Our findings, along with those of previous studies, underline the importance of the PI3K/AKT pathway components as potential biomarkers for breast carcinogenesis.

Clinical impact of (11)C-Pittsburgh compound-B positron emission tomography carried out in addition to magnetic resonance imaging and single-photon emission computed tomography on the diagnosis of Alzheimer's disease in patients with dementia and mild cognitive impairment.

PubMed

Omachi, Yoshie; Ito, Kimiteru; Arima, Kunimasa; Matsuda, Hiroshi; Nakata, Yasuhiro; Sakata, Masuhiro; Sato, Noriko; Nakagome, Kazuyuki; Motohashi, Nobutaka

2015-12-01

The purpose of this study was to evaluate the clinical impact of addition of [(11)C]Pittsburgh compound-B positron emission tomography ((11)C-PiB PET) on routine clinical diagnosis of Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI), and to assess diagnostic agreement between clinical criteria and research criteria of the National Institute on Aging-Alzheimer's Association. The diagnosis in 85 patients was made according to clinical criteria. Imaging examinations, including both magnetic resonance imaging and single-photon emission computed tomography/computed tomography to identify neuronal injury (NI), and (11)C-PiB PET to identify amyloid were performed, and all subjects were re-categorized according to the research criteria. Among 40 patients with probable AD dementia (ProAD), 37 were NI-positive, 29 were (11)C-PiB-positive, and 27 who were both NI- and (11C-PiB-positive were categorized as having 'ProAD dementia with a high level of evidence of the AD pathophysiological process'. Among 20 patients with possible AD dementia (PosAD), 17 were NI-positive, and six who were both NI- and (11)C-PiB-positive were categorized as having 'PosAD with evidence of the AD pathophysiological process'. Among 25 patients with MCI, 18 were NI-positive, 13 were (11)C-PiB-positive, and 10 who were both NI- and (11)C-PiB-positive were categorized as having 'MCI due to AD-high likelihood'. Diagnostic concordance between clinical criteria and research criteria may not be high in this study. (11)C-PiB PET may be of value in making the diagnosis of dementia and MCI in cases with high diagnostic uncertainty. © 2015 The Authors. Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology.

Characterization of Novel Gene Yr79 and Four Additional Quantitative Trait Loci for All-Stage and High-Temperature Adult-Plant Resistance to Stripe Rust in Spring Wheat PI 182103.

PubMed

Feng, Junyan; Wang, Meinan; See, Deven R; Chao, Shiaoman; Zheng, Youliang; Chen, Xianming

2018-06-01

Stripe rust, caused by Puccinia striiformis f. sp. tritici, is an important disease of wheat worldwide. Exploring new resistance genes is essential for breeding resistant wheat cultivars. PI 182103, a spring wheat landrace originally from Pakistan, has shown a high level of resistance to stripe rust in fields for many years, but genes for resistance to stripe rust in the variety have not been studied. To map the resistance gene(s) in PI 182103, 185 recombinant inbred lines (RILs) were developed from a cross with Avocet Susceptible (AvS). The RIL population was genotyped with simple sequence repeat (SSR) and single nucleotide polymorphism markers and tested with races PST-100 and PST-114 at the seedling stage under controlled greenhouse conditions and at the adult-plant stage in fields at Pullman and Mt. Vernon, Washington under natural infection by the stripe rust pathogen in 2011, 2012, and 2013. A total of five quantitative trait loci (QTL) were detected. QyrPI182103.wgp-2AS and QyrPI182103.wgp-3AL were detected at the seedling stage, QyrPI182103.wgp-4DL was detected only in Mt. Vernon field tests, and QyrPI182103.wgp-5BS was detected in both seedling and field tests. QyrPI182103.wgp-7BL was identified as a high-temperature adult-plant resistance gene and detected in all field tests. Interactions among the QTL were mostly additive, but some negative interactions were detected. The 7BL QTL was mapped in chromosomal bin 7BL 0.40 to 0.45 and identified as a new gene, permanently designated as Yr79. SSR markers Xbarc72 and Xwmc335 flanking the Yr79 locus were highly polymorphic in various wheat genotypes, indicating that the molecular markers are useful for incorporating the new gene for potentially durable stripe rust resistance into new wheat cultivars.

Distinctive changes in plasma membrane phosphoinositides underlie differential regulation of TRPV1 in nociceptive neurons.

PubMed

Lukacs, Viktor; Yudin, Yevgen; Hammond, Gerald R; Sharma, Esseim; Fukami, Kiyoko; Rohacs, Tibor

2013-07-10

Transient Receptor Potential Vanilloid 1 (TRPV1) is a polymodal, Ca(2+)-permeable cation channel crucial to regulation of nociceptor responsiveness. Sensitization of TRPV1 by G-protein coupled receptor (GPCR) agonists to its endogenous activators, such as low pH and noxious heat, is a key factor in hyperalgesia during tissue injury as well as pathological pain syndromes. Conversely, chronic pharmacological activation of TRPV1 by capsaicin leads to calcium influx-induced adaptation of the channel. Paradoxically, both conditions entail activation of phospholipase C (PLC) enzymes, which hydrolyze phosphoinositides. We found that in sensory neurons PLCβ activation by bradykinin led to a moderate decrease in phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2), but no sustained change in the levels of its precursor PI(4)P. Preventing this selective decrease in PI(4,5)P2 inhibited TRPV1 sensitization, while selectively decreasing PI(4,5)P2 independently of PLC potentiated the sensitizing effect of protein kinase C (PKC) on the channel, thereby inducing increased TRPV1 responsiveness. Maximal pharmacological TRPV1 stimulation led to a robust decrease of both PI(4,5)P2 and its precursor PI(4)P in sensory neurons. Attenuating the decrease of either lipid significantly reduced desensitization, and simultaneous reduction of PI(4,5)P2 and PI(4)P independently of PLC inhibited TRPV1. We found that, on the mRNA level, the dominant highly Ca(2+)-sensitive PLC isoform in dorsal root ganglia is PLCδ4. Capsaicin-induced desensitization of TRPV1 currents was significantly reduced, whereas capsaicin-induced nerve impulses in the skin-nerve preparation increased in mice lacking this isoform. We propose a comprehensive model in which differential changes in phosphoinositide levels mediated by distinct PLC isoforms result in opposing changes in TRPV1 activity.

Distinctive Changes in Plasma Membrane Phosphoinositides Underlie Differential Regulation of TRPV1 in Nociceptive Neurons

PubMed Central

Lukacs, Viktor; Yudin, Yevgen; Hammond, Gerald R.; Sharma, Esseim; Fukami, Kiyoko

2013-01-01

Transient Receptor Potential Vanilloid 1 (TRPV1) is a polymodal, Ca2+-permeable cation channel crucial to regulation of nociceptor responsiveness. Sensitization of TRPV1 by G-protein coupled receptor (GPCR) agonists to its endogenous activators, such as low pH and noxious heat, is a key factor in hyperalgesia during tissue injury as well as pathological pain syndromes. Conversely, chronic pharmacological activation of TRPV1 by capsaicin leads to calcium influx-induced adaptation of the channel. Paradoxically, both conditions entail activation of phospholipase C (PLC) enzymes, which hydrolyze phosphoinositides. We found that in sensory neurons PLCβ activation by bradykinin led to a moderate decrease in phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2), but no sustained change in the levels of its precursor PI(4)P. Preventing this selective decrease in PI(4,5)P2 inhibited TRPV1 sensitization, while selectively decreasing PI(4,5)P2 independently of PLC potentiated the sensitizing effect of protein kinase C (PKC) on the channel, thereby inducing increased TRPV1 responsiveness. Maximal pharmacological TRPV1 stimulation led to a robust decrease of both PI(4,5)P2 and its precursor PI(4)P in sensory neurons. Attenuating the decrease of either lipid significantly reduced desensitization, and simultaneous reduction of PI(4,5)P2 and PI(4)P independently of PLC inhibited TRPV1. We found that, on the mRNA level, the dominant highly Ca2+-sensitive PLC isoform in dorsal root ganglia is PLCδ4. Capsaicin-induced desensitization of TRPV1 currents was significantly reduced, whereas capsaicin-induced nerve impulses in the skin–nerve preparation increased in mice lacking this isoform. We propose a comprehensive model in which differential changes in phosphoinositide levels mediated by distinct PLC isoforms result in opposing changes in TRPV1 activity. PMID:23843517

Acclimation of the crucifer Eutrema salsugineum to phosphate limitation is associated with constitutively high expression of phosphate-starvation genes.

PubMed

Velasco, Vera Marjorie Elauria; Mansbridge, John; Bremner, Samantha; Carruthers, Kimberley; Summers, Peter S; Sung, Wilson W L; Champigny, Marc J; Weretilnyk, Elizabeth A

2016-08-01

Eutrema salsugineum, a halophytic relative of Arabidopsis thaliana, was subjected to varying phosphate (Pi) treatments. Arabidopsis seedlings grown on 0.05 mm Pi displayed shortened primary roots, higher lateral root density and reduced shoot biomass allocation relative to those on 0.5 mm Pi, whereas Eutrema seedlings showed no difference in lateral root density and shoot biomass allocation. While a low Fe concentration mitigated the Pi deficiency response for Arabidopsis, Eutrema root architecture was unaltered, but adding NaCl increased Eutrema lateral root density almost 2-fold. Eutrema and Arabidopsis plants grown on soil without added Pi for 4 weeks had low shoot and root Pi content. Pi-deprived, soil-grown Arabidopsis plants were stunted with senescing older leaves, whereas Eutrema plants were visually indistinguishable from 2.5 mm Pi-supplemented plants. Genes associated with Pi starvation were analysed by RT-qPCR. EsIPS2, EsPHT1;4 and EsPAP17 showed up-regulated expression in Pi-deprived Eutrema plants, while EsPHR1, EsWRKY75 and EsRNS1 showed no induction. Absolute quantification of transcripts indicated that PHR1, WRKY75 and RNS1 were expressed at higher levels in Eutrema plants relative to those in Arabidopsis regardless of external Pi. The low phenotypic plasticity Eutrema displays to Pi supply is consistent with adaptation to chronic Pi deprivation in its extreme natural habitat. © 2016 The Authors. Plant, Cell & Environment published by John Wiley & Sons Ltd.

Elevated fibroblast growth factor 23 levels as a cause of early post-renal transplantation hypophosphatemia.

PubMed

Han, S Y; Hwang, E A; Park, S B; Kim, H C; Kim, H T

2012-04-01

Hypophosphatemia is a common complication after renal transplantation. Hyperparathyroidism has long been thought to be the cause, but hypophosphatemia can persist after high parathyroid hormone (PTH) levels normalize. Furthermore, calcitriol levels remain inappropriately low after transplantation, suggesting that mechanisms other than PTH contribute. Fibroblast growth factor 23 (FGF-23) induces phosphaturia, inhibits calcitriol synthesis, and accumulates in chronic kidney disease. We performed prospective study to investigate if FGF-23 early after renal transplantation contributes to hypophosphatemia. We measured FGF-23 levels before and at 1, 2, 4, and 12 weeks after transplantation in 20 renal transplant recipients. Serum creatinine, calcium (Ca), phosphate (Pi), intact PTH (PTH), and 1,25-dihydroxy vitamin D (1,25(OH)(2)VitD) were measured at the same time. FGF-23 levels decreased by 97% at 4 weeks after renal transplantation (PRT) (7,471 ± 11,746 vs 225 ± 295 pg/mL; P < .05) but were still above normal. PTH and Pi levels also decreased significantly after renal transplantation, and Ca and 1,25(OH)(2)VitD slightly increased. PRT hypophosphatemia of <2.5 mg/dL developed in 15 (75%) and 12 (60%) patients at 4 weeks and 12 weeks respectively. Compared with nonhypophosphatemic patients, the levels of FGF-23 of hypophosphatemic patients were higher (303 ± 311 vs 10 ± 6.9 pg/mL; P = .02) at 4 weeks PRT. FGF-23 levels were inversely correlated with Pi (r(2) = 0.406; P = .011); PTH was not independently associated with Pi (r(2) = 0.132; P = .151). FGF-23 levels decrease dramatically after renal transplantation. During the early PRT period, Pi rapidly decreased, suggesting that FGF-23 is cleared by the kidney, but residual FGF-23 may contribute to the PRT hypophosphatemia. FGF-23, but not PTH levels, was independently associated with PRT hypophosphatemia. Copyright © 2012 Elsevier Inc. All rights reserved.

Studies of molecular physics in sodium-potassium: An analysis of the 4(3)Sigma+ state and interactions between the 2(A)(1)Sigma+ and 1(b)(3)Pi states

NASA Astrophysics Data System (ADS)

Burns, Patrick

2004-12-01

In this dissertation we report the results of three experiments designed to provide new information on the structure and interactions of the NaK molecule. Specifically these experiments investigate 2(A)1Sigma +(upsilonA, J) + M → 1(b)3 pi0(upsilonb, J) + M collisional excitation transfers (where M is a collision partner), hyperfine structure of the NaK 1(b)3pi and 1(b)3pi0 ˜ 2(A)1Sigma+ spin-orbit interactions, and the structure and spectra of the NaK 43Sigma+ state, respectively. In this first experiment, populations of collisionally populated levels were recorded near the NaK 1(b)3pi0(upsilon =18, J = 44) ˜ 2(A)1Sigma+ (upsilon = 20, J = 44) center of spin-orbit perturbation. Our data indicate that population is transferred from the pumped level, 2(A) 1Sigma+(upsilon = 20, J = 49), directly to the surrounding "daughter" levels [1(b)3Sigma 0(upsilon =18, J = 45--48) and 2(A)1Sigma +(upsilon = 20, J = 45--48)]. The relative populations of the daughter levels appear anomalous, as their populations do not monotonically decrease for levels further away in energy from the pumped level. We have measured the hyperfine structure of mutually perturbing ro-vibrational levels of the 1(b)3pi0 and 2(A)1Sigma + states of the NaK molecule, using the PFOODR method with co-propagating lasers. Unperturbed 1(b)3pi0 levels are split into four hyperfine components by the Fermi contact interaction b FI·S. Mixing between the 1(b)3pi0 and 2(A)1Sigma + levels imparts hyperfine structure to the nominally singlet component, and reduces the hyperfine splitting of the nominally triplet component, of the perturbed levels. We determined a value for the Fermi constant, bF= (0.00989 +/- 0.00027) cm-1, and the magnitude of the electronic part of the 1(b)3pi 0 ˜ 2(A)1Sigma+ spin-orbit coupling, |Hel| = (15.65 +/- 0.14) cm-1 , from an analysis of the measured hyperfine splittings of the mixed singlet-triplet levels. High-resolution spectra have been observed for numerous vibrational-rotational levels (upsilon, N) of the 43Sigma + state of NaK. A potential curve was obtained from the data using the inverse perturbation approximation method. Measured bound-free emission, 43Sigma+ → 1(a)3Sigma +, was used to determine both the absolute vibrational numbering and the transition dipole moment function M(R). Each (upsilon, N) level is typically split into three sets of sublevels by the Fermi contact interaction bFI·S. Further splitting (of order 0.004 cm-1) has been attributed to the spin-rotation interaction gammaN·S. The values of bF that fit the data best are ˜(0.99 +/- 0.04) x 10-2 cm-1, with weak dependence on upsilon. The best fit values of gamma are in the range 1--6 x 10-4 cm-1 and depend strongly on upsilon.

Programmable digital memory devices based on nanoscale thin films of a thermally dimensionally stable polyimide

NASA Astrophysics Data System (ADS)

Lee, Taek Joon; Chang, Cha-Wen; Hahm, Suk Gyu; Kim, Kyungtae; Park, Samdae; Kim, Dong Min; Kim, Jinchul; Kwon, Won-Sang; Liou, Guey-Sheng; Ree, Moonhor

2009-04-01

We have fabricated electrically programmable memory devices with thermally and dimensionally stable poly(N-(N',N'-diphenyl-N'-1,4-phenyl)-N,N-4,4'-diphenylene hexafluoroisopropylidene-diphthalimide) (6F-2TPA PI) films and investigated their switching characteristics and reliability. 6F-2TPA PI films were found to reveal a conductivity of 1.0 × 10-13-1.0 × 10-14 S cm-1. The 6F-2TPA PI films exhibit versatile memory characteristics that depend on the film thickness. All the PI films are initially present in the OFF state. The PI films with a thickness of >15 to <100 nm exhibit excellent write-once-read-many-times (WORM) (i.e. fuse-type) memory characteristics with and without polarity depending on the thickness. The WORM memory devices are electrically stable, even in air ambient, for a very long time. The devices' ON/OFF current ratio is high, up to 1010. Therefore, these WORM memory devices can provide an efficient, low-cost means of permanent data storage. On the other hand, the 100 nm thick PI films exhibit excellent dynamic random access memory (DRAM) characteristics with polarity. The ON/OFF current ratio of the DRAM devices is as high as 1011. The observed electrical switching behaviors were found to be governed by trap-limited space-charge-limited conduction and local filament formation and further dependent on the differences between the highest occupied molecular orbital and the lowest unoccupied molecular orbital energy levels of the PI film and the work functions of the top and bottom electrodes as well as the PI film thickness. In summary, the excellent memory properties of 6F-2TPA PI make it a promising candidate material for the low-cost mass production of high density and very stable digital nonvolatile WORM and volatile DRAM memory devices.

Programmable digital memory devices based on nanoscale thin films of a thermally dimensionally stable polyimide.

PubMed

Lee, Taek Joon; Chang, Cha-Wen; Hahm, Suk Gyu; Kim, Kyungtae; Park, Samdae; Kim, Dong Min; Kim, Jinchul; Kwon, Won-Sang; Liou, Guey-Sheng; Ree, Moonhor

2009-04-01

We have fabricated electrically programmable memory devices with thermally and dimensionally stable poly(N-(N',N'-diphenyl-N'-1,4-phenyl)-N,N-4,4'-diphenylene hexafluoroisopropylidene-diphthalimide) (6F-2TPA PI) films and investigated their switching characteristics and reliability. 6F-2TPA PI films were found to reveal a conductivity of 1.0 x 10(-13)-1.0 x 10(-14) S cm(-1). The 6F-2TPA PI films exhibit versatile memory characteristics that depend on the film thickness. All the PI films are initially present in the OFF state. The PI films with a thickness of >15 to <100 nm exhibit excellent write-once-read-many-times (WORM) (i.e. fuse-type) memory characteristics with and without polarity depending on the thickness. The WORM memory devices are electrically stable, even in air ambient, for a very long time. The devices' ON/OFF current ratio is high, up to 10(10). Therefore, these WORM memory devices can provide an efficient, low-cost means of permanent data storage. On the other hand, the 100 nm thick PI films exhibit excellent dynamic random access memory (DRAM) characteristics with polarity. The ON/OFF current ratio of the DRAM devices is as high as 10(11). The observed electrical switching behaviors were found to be governed by trap-limited space-charge-limited conduction and local filament formation and further dependent on the differences between the highest occupied molecular orbital and the lowest unoccupied molecular orbital energy levels of the PI film and the work functions of the top and bottom electrodes as well as the PI film thickness. In summary, the excellent memory properties of 6F-2TPA PI make it a promising candidate material for the low-cost mass production of high density and very stable digital nonvolatile WORM and volatile DRAM memory devices.

Antibiosis in Soybean Genotypes and the Resistance Levels to Spodoptera eridania (Cramer) (Lepidoptera: Noctuidae).

PubMed

Souza, B H S; Silva, A G; Janini, J C; Boica Júnior, A L

2014-12-01

The southern armyworm (SAW) Spodoptera eridania (Cramer) is one of the most common armyworm species defoliating soybeans. Preliminary screening trials have indicated that some soybean genotypes exhibit resistance to SAW. Therefore, in this study, we evaluated the development of SAW larvae fed on ten soybean genotypes in order to identify genotypes with antibiosis-type resistance. Neonate SAW larvae were daily fed with young leaves collected from plants at the vegetative growth stages V4-V5. Larval development and survival were recorded. Genotypes PI 227687 and PI 227682 delayed larval, pupal, and larva-adult development and yielded larvae with the lowest weight and survival and pupae with the lowest weight. Genotypes IAC 100 and DM 339 also negatively affected larval and pupal development and larval survival but at a lower level. Based on our results, the soybean lines PI 227687 and PI 227682 could be used as sources of genes for soybean breeding programs aiming to develop high yield, SAW-resistant cultivars. Moreover, further trials must be carried out under field conditions to validate if the commercial cultivars IAC 100 and DM 339, which expressed moderate levels of antibiosis-type resistance in the laboratory, are effective in suppressing SAW larvae populations.

Basal expression of insulin-like growth factor 1 receptor determines intrinsic resistance of cancer cells to a phosphatidylinositol 3-kinase inhibitor ZSTK474

PubMed Central

Isoyama, Sho; Kajiwara, Gensei; Tamaki, Naomi; Okamura, Mutsumi; Yoshimi, Hisashi; Nakamura, Naoki; Kawamura, Kento; Nishimura, Yumiko; Namatame, Nachi; Yamori, Takao; Dan, Shingo

2015-01-01

Drug resistance often critically limits the efficacy of molecular targeted drugs. Although pharmacological inhibition of phosphatidylinositol 3-kinase (PI3K) is an attractive therapeutic strategy for cancer therapy, molecular determinants for efficacy of PI3K inhibitors (PI3Kis) remain unclear. We previously identified that overexpression of insulin-like growth factor 1 receptor (IGF1R) contributed to the development of drug resistance after long-term exposure to PI3Kis. In this study, we examined the involvement of basal IGF1R expression in intrinsic resistance of drug-naïve cancer cells to PI3Kis and whether inhibition of IGF1R overcomes the resistance. We found that cancer cells highly expressing IGF1R showed resistance to dephosphorylation of Akt and subsequent antitumor effect by ZSTK474 treatment. Knockdown of IGF1R by siRNAs facilitated the dephosphorylation and enhanced the drug efficacy. These cells expressed tyrosine-phosphorylated insulin receptor substrate 1 at high levels, which was dependent on basal IGF1R expression. In these cells, the efficacy of ZSTK474 in vitro and in vivo was improved by its combination with the IGF1R inhibitor OSI-906. Finally, we found a significant correlation between the basal expression level of IGF1R and the inefficacy of ZSTK474 in an in vivo human cancer panel, as well as in vitro. These results suggest that basal IGF1R expression affects intrinsic resistance of cancer cells to ZSTK474, and IGF1R is a promising target to improve the therapeutic efficacy. The current results provide evidence of combination therapy of PI3Kis with IGF1R inhibitors for treating IGF1R-positive human cancers. PMID:25483727

Level and potential social-ecological factors associated with physical inactivity and sedentary behavior among Moroccan school-age adolescents: a cross-sectional study.

PubMed

El-Ammari, Abdelghaffar; El Kazdouh, Hicham; Bouftini, Siham; El Fakir, Samira; El Achhab, Youness

2017-05-18

Creating a successful intervention that supports an active lifestyle and prevents sedentary one requires a better understanding of the factors associated with physical inactivity (PI) and sedentary behavior (SB). However, these factors have not been assessed among Moroccan adolescents. This study aimed to determine prevalence of PI and SB and to explore their potential social-ecological associated factors in school-age adolescents. In this cross-sectional study, 764 students (age range, 14-19 years) were enrolled from six schools in Taza city, Morocco. The Global School-based Student Health Survey was used to collect data about variables. We used bivariate and multivariate analyses to assess relations between dependent and independent variables. Overall, the prevalence of PI was 79.5% and SB was 36.5%. Among girls, these rates were higher (87.0 and 39.1%, respectively) than rates shown in boys (70.9 and 33.6%, respectively). In the multivariate logistic regression analysis, PI was associated with the following variables: illiterate father, hunger, suicidal ideation, inadequate vegetable consumption, and absence from physical education classes. Age, inadequate vegetable consumption, and absenteeism were associated with SB. The prevalence of PI and SB is high, especially among girls. Thus, there is an urgent need to implement appropriate interventions to reduce PI and SB levels in secondary school-age adolescents and the associated factors identified can be useful.

Kinetics of phosphate uptake, growth, and accumulation of cyclic diphosphoglycerate in a phosphate-limited continuous culture of Methanobacterium thermoautotrophicum.

PubMed Central

Krueger, R D; Harper, S H; Campbell, J W; Fahrney, D E

1986-01-01

The archaebacterium Methanobacterium thermoautotrophicum was grown in continuous culture at 65 degrees C in a phosphate-limited medium at specific growth rates from 0.06 to 0.28 h-1 (maximum growth rate [mu max] = 0.36 h-1). Cyclic-2,3-diphosphoglycerate (cyclic DPG) levels ranged from 2 to 20 mM in Pi-limited cells, compared with about 30 mM in batch-grown cells. The Monod constant for Pi-limited growth was 5 nM. Pi uptake rates were determined by following the disappearance of 32Pi from the medium. Interrupting the H2 supply stopped the uptake of Pi and the release of organic phosphates. Little or no efflux of Pi occurred in the presence or absence of H2. Pi uptake of cells adapted to nanomolar Pi concentrations could be accounted for by the operation of one uptake system with an apparent Km of about 25 nM and a Vmax of 58 nmol of Pi per min per g (dry weight). Uptake curves at 30 microM Pi or above were biphasic due to a sevenfold decrease in Vmax after an initial phase of rapid movement of Pi into the cell. Under these conditions the growth rate slowed to zero and the cyclic DPG pool expanded before growth resumed. Thus, three properties of M. thermoautotrophicum make it well adapted to live in a low-P environment: the presence of a low-Km, high-Vmax uptake system for Pi; the ability to accumulate cyclic DPG rapidly; and a growth strategy in which accumulation of Pi and cyclic DPG takes precedence over a shift-up in growth rate when excess Pi becomes available. PMID:3722128

Kinetics of phosphate uptake, growth, and accumulation of cyclic diphosphoglycerate in a phosphate-limited continuous culture of Methanobacterium thermoautotrophicum.

PubMed

Krueger, R D; Harper, S H; Campbell, J W; Fahrney, D E

1986-07-01

The archaebacterium Methanobacterium thermoautotrophicum was grown in continuous culture at 65 degrees C in a phosphate-limited medium at specific growth rates from 0.06 to 0.28 h-1 (maximum growth rate [mu max] = 0.36 h-1). Cyclic-2,3-diphosphoglycerate (cyclic DPG) levels ranged from 2 to 20 mM in Pi-limited cells, compared with about 30 mM in batch-grown cells. The Monod constant for Pi-limited growth was 5 nM. Pi uptake rates were determined by following the disappearance of 32Pi from the medium. Interrupting the H2 supply stopped the uptake of Pi and the release of organic phosphates. Little or no efflux of Pi occurred in the presence or absence of H2. Pi uptake of cells adapted to nanomolar Pi concentrations could be accounted for by the operation of one uptake system with an apparent Km of about 25 nM and a Vmax of 58 nmol of Pi per min per g (dry weight). Uptake curves at 30 microM Pi or above were biphasic due to a sevenfold decrease in Vmax after an initial phase of rapid movement of Pi into the cell. Under these conditions the growth rate slowed to zero and the cyclic DPG pool expanded before growth resumed. Thus, three properties of M. thermoautotrophicum make it well adapted to live in a low-P environment: the presence of a low-Km, high-Vmax uptake system for Pi; the ability to accumulate cyclic DPG rapidly; and a growth strategy in which accumulation of Pi and cyclic DPG takes precedence over a shift-up in growth rate when excess Pi becomes available.

Electron transport through rectifying self-assembled monolayer diodes on silicon: Fermi-level pinning at the molecule-metal interface.

PubMed

Lenfant, S; Guerin, D; Tran Van, F; Chevrot, C; Palacin, S; Bourgoin, J P; Bouloussa, O; Rondelez, F; Vuillaume, D

2006-07-20

We report the synthesis and characterization of molecular rectifying diodes on silicon using sequential grafting of self-assembled monolayers of alkyl chains bearing a pi group at their outer end (Si/sigma-pi/metal junctions). We investigate the structure-performance relationships of these molecular devices, and we examine the extent to which the nature of the pi end group (change in the energy position of their molecular orbitals) drives the properties of these molecular diodes. Self-assembled monolayers of alkyl chains (different chain lengths from 6 to 15 methylene groups) functionalized by phenyl, anthracene, pyrene, ethylene dioxythiophene, ethylene dioxyphenyl, thiophene, terthiophene, and quaterthiophene were synthesized and characterized by contact angle measurements, ellipsometry, Fourier transform infrared spectroscopy, and atomic force microscopy. We demonstrate that reasonably well-packed monolayers are obtained in all cases. Their electrical properties were assessed by dc current-voltage characteristics and high-frequency (1-MHz) capacitance measurements. For all of the pi groups investigated here, we observed rectification behavior. These results extend our preliminary work using phenyl and thiophene groups (Lenfant et al., Nano Lett. 2003, 3, 741). The experimental current-voltage curves were analyzed with a simple analytical model, from which we extracted the energy position of the molecular orbital of the pi group in resonance with the Fermi energy of the electrodes. We report experimental studies of the band lineup in these silicon/alkyl pi-conjugated molecule/metal junctions. We conclude that Fermi-level pinning at the pi group/metal interface is mainly responsible for the observed absence of a dependence of the rectification effect on the nature of the pi groups, even though the groups examined were selected to have significant variations in their electronic molecular orbitals.

Phosphoinositide 5-phosphatase Fig 4p is required for both acute rise and subsequent fall in stress-induced phosphatidylinositol 3,5-bisphosphate levels.

PubMed

Duex, Jason E; Nau, Johnathan J; Kauffman, Emily J; Weisman, Lois S

2006-04-01

Phosphoinositide lipids regulate complex events via the recruitment of proteins to a specialized region of the membrane at a specific time. Precise control of both the synthesis and turnover of phosphoinositide lipids is integral to membrane trafficking, signal transduction, and cytoskeletal rearrangements. Little is known about the acute regulation of the levels of these signaling lipids. When Saccharomyces cerevisiae cells are treated with hyperosmotic medium the levels of phosphatidylinositol 3,5-bisphosphate (PI3,5P(2)) increase 20-fold. Here we show that this 20-fold increase is rapid and occurs within 5 min. Surprisingly, these elevated levels are transient. Fifteen minutes following hyperosmotic shock they decrease at a rapid rate, even though the cells remain in hyperosmotic medium. In parallel with the rapid increase in the levels of PI3,5P(2), vacuole volume decreases rapidly. Furthermore, concomitant with a return to basal levels of PI3,5P(2) vacuole volume is restored. We show that Fig 4p, consistent with its proposed role as a PI3,5P(2) 5-phosphatase, is required in vivo for this rapid return to basal levels of PI3,5P(2). Surprisingly, we find that Fig 4p is also required for the hyperosmotic shock-induced increase in PI3,5P(2) levels. These findings demonstrate that following hyperosmotic shock, large, transient changes occur in the levels of PI3,5P(2) and further suggest that Fig 4p is important in regulating both the acute rise and subsequent fall in PI3,5P(2) levels.

Reproducibility of a novel model of murine asthma-like pulmonary inflammation

PubMed Central

MCKINLEY, L; KIM, J; BOLGOS, G L; SIDDIQUI, J; REMICK, D G

2004-01-01

Sensitization to cockroach allergens (CRA) has been implicated as a major cause of asthma, especially among inner-city populations. Endotoxin from Gram-negative bacteria has also been investigated for its role in attenuating or exacerbating the asthmatic response. We have created a novel model utilizing house dust extract (HDE) containing high levels of both CRA and endotoxin to induce pulmonary inflammation (PI) and airway hyperresponsiveness (AHR). A potential drawback of this model is that the HDE is in limited supply and preparation of new HDE will not contain the exact components of the HDE used to define our model system. The present study involved testing HDEs collected from various homes for their ability to cause PI and AHR. Dust collected from five homes was extracted in phosphate buffered saline overnight. The levels of CRA and endotoxin in the supernatants varied from 7·1 to 49·5 mg/ml of CRA and 1·7–6 µg/ml of endotoxin in the HDEs. Following immunization and two pulmonary exposures to HDE all five HDEs induced AHR, PI and plasma IgE levels substantially higher than normal mice. This study shows that HDE containing high levels of cockroach allergens and endotoxin collected from different sources can induce an asthma-like response in our murine model. PMID:15086384

The effect of Liuwei Dihuang decoction on PI3K/Akt signaling pathway in liver of type 2 diabetes mellitus (T2DM) rats with insulin resistance.

PubMed

Dai, Bing; Wu, Qinxuan; Zeng, Chengxi; Zhang, Jiani; Cao, Luting; Xiao, Zizeng; Yang, Menglin

2016-11-04

Liuwei Dihaung decoction (LWDHT) is a well-known classic traditional Chinese medicine formula, consists of six herbs including Rehmannia glutinosa Libosch.(family: Scrophulariaceae), Cornus officinalis Sieb.(family: Cornaceae), Dioscorea opposite Thunb.(family: Dioscoreaceae), Alisma orientale(G. Samuelsson) Juz (family: Alismataceae), Poria cocos (Schw.) Wolf (family: Polyporaceae) and Paeonia suffruticosa Andrews (family: Paeoniaceae). It has been used in the treatment of many types of diseases with signs of deficiency of Yin in the kidneys in China clinically. This study is aimed at investigating the effect of Liuwei dihuang decoction on PI3K/Akt signaling pathway in liver of T2DM rats with insulin resistance. T2DM model was induced in male Sprague-Dawley (SD) rats by high sugar and high fat diets combined with small dose of streptozocin (STZ) injection. The successful T2DM rats were randomly allocated three group--vehicle group, positive control group and Liuwei Dihuang decoction group. After 12-weeks treatment with distilled water, rosiglitazone and LWDHT by intragastric administration respectively, the rats were put to death in batches. The variance of fasting blood glucose (FBG) and fasting insulin (FINS) in serum were determined, the pathological changes of each rats' liver were observed by hematoxylin-eosin (HE) staining, the expression of insulin receptor substrate 2(IRS2), phosphatidylinositol 3-kinase (PI3K) and protein kinas B (Akt) involving the canonical PI3K/Akt signaling pathway were detected by Real-time fluorescent quantitative PCR (RT-PCR), and the expression level of IRS2, PI3K, Akt protein and phosphorylated IRS2, PI3K, Akt protein were evaluated by Western Blot. All the data were analyzed by SPSS 17.0. Four weeks of treatment with LWDHT could significantly decrease the level of FBG and FINS in serum, improve the cellular morphology of liver, kidney, pancreas tissue, and the expression of IRS2, PI3K, Akt mRNA and phosphorylated IRS2, PI3K, Akt protein involved in the canonical PI3K/Akt signaling pathway of T2DM rats in liver were significantly up-regulated, while the total IRS2, PI3K, and Akt protein had no obvious changes. The results suggest that Liuwei Dihuang decoction could intervene insulin resistance of T2DM, in part, through regulation of canonical PI3K/Akt signaling pathway of T2DM rats in liver. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Effect of Npt2b deletion on intestinal and renal inorganic phosphate (Pi) handling.

PubMed

Ikuta, Kayo; Segawa, Hiroko; Sasaki, Shohei; Hanazaki, Ai; Fujii, Toru; Kushi, Aoi; Kawabata, Yuka; Kirino, Ruri; Sasaki, Sumire; Noguchi, Miwa; Kaneko, Ichiro; Tatsumi, Sawako; Ueda, Otoya; Wada, Naoko A; Tateishi, Hiromi; Kakefuda, Mami; Kawase, Yosuke; Ohtomo, Shuichi; Ichida, Yasuhiro; Maeda, Akira; Jishage, Kou-Ichi; Horiba, Naoshi; Miyamoto, Ken-Ichi

2018-06-01

Hyperphosphatemia is common in chronic kidney disease and is associated with morbidity and mortality. The intestinal Na + -dependent phosphate transporter Npt2b is thought to be an important molecular target for the prevention of hyperphosphatemia. The role of Npt2b in the net absorption of inorganic phosphate (Pi), however, is controversial. In the present study, we made tamoxifen-inducible Npt2b conditional knockout (CKO) mice to analyze systemic Pi metabolism, including intestinal Pi absorption. Although the Na + -dependent Pi transport in brush-border membrane vesicle uptake levels was significantly decreased in the distal intestine of Npt2b CKO mice compared with control mice, plasma Pi and fecal Pi excretion levels were not significantly different. Data obtained using the intestinal loop technique showed that Pi uptake in Npt2b CKO mice was not affected at a Pi concentration of 4 mM, which is considered the typical luminal Pi concentration after meals in mice. Claudin, which may be involved in paracellular pathways, as well as claudin-2, 12, and 15 protein levels were significantly decreased in the Npt2b CKO mice. Thus, Npt2b deficiency did not affect Pi absorption within the range of Pi concentrations that normally occurs after meals. These findings indicate that abnormal Pi metabolism may also be involved in tight junction molecules such as Cldns that are affected by Npt2b deficiency.

The Influence of Pelvic Incidence and Lumbar Lordosis Mismatch on Development of Symptomatic Adjacent Level Disease Following Single-Level Transforaminal Lumbar Interbody Fusion.

PubMed

Tempel, Zachary J; Gandhoke, Gurpreet S; Bolinger, Bryan D; Khattar, Nicolas K; Parry, Philip V; Chang, Yue-Fang; Okonkwo, David O; Kanter, Adam S

2017-06-01

Annual incidence of symptomatic adjacent level disease (ALD) following lumbar fusion surgery ranges from 0.6% to 3.9% per year. Sagittal malalignment may contribute to the development of ALD. To describe the relationship between pelvic incidence-lumbar lordosis (PI-LL) mismatch and the development of symptomatic ALD requiring revision surgery following single-level transforaminal lumbar interbody fusion for degenerative lumbar spondylosis and/or low-grade spondylolisthesis. All patients who underwent a single-level transforaminal lumbar interbody fusion at either L4/5 or L5/S1 between July 2006 and December 2012 were analyzed for pre- and postoperative spinopelvic parameters. Using univariate and logistic regression analysis, we compared the spinopelvic parameters of those patients who required revision surgery against those patients who did not develop symptomatic ALD. We calculated the predictive value of PI-LL mismatch. One hundred fifty-nine patients met the inclusion criteria. The results noted that, for a 1° increase in PI-LL mismatch (preop and postop), the odds of developing ALD requiring surgery increased by 1.3 and 1.4 fold, respectively, which were statistically significant increases. Based on our analysis, a PI-LL mismatch of >11° had a positive predictive value of 75% for the development of symptomatic ALD requiring revision surgery. A high PI-LL mismatch is strongly associated with the development of symptomatic ALD requiring revision lumbar spine surgery. The development of ALD may represent a global disease process as opposed to a focal condition. Spine surgeons may wish to consider assessment of spinopelvic parameters in the evaluation of degenerative lumbar spine pathology. Copyright © 2017 by the Congress of Neurological Surgeons

Hepatectomy-Related Hypophosphatemia: A Novel Phosphaturic Factor in the Liver-Kidney Axis

PubMed Central

Nomura, Kengo; Miyagawa, Atsumi; Shiozaki, Yuji; Sasaki, Shohei; Kaneko, Ichiro; Ito, Mikiko; Kido, Shinsuke; Segawa, Hiroko; Sano, Mitsue; Fukuwatari, Tsutomu; Shibata, Katsumi

2014-01-01

Marked hypophosphatemia is common after major hepatic resection, but the pathophysiologic mechanism remains unknown. We used a partial hepatectomy (PH) rat model to investigate the molecular basis of hypophosphatemia. PH rats exhibited hypophosphatemia and hyperphosphaturia. In renal and intestinal brush-border membrane vesicles isolated from PH rats, Na+-dependent phosphate (Pi) uptake decreased by 50%–60%. PH rats also exhibited significantly decreased levels of renal and intestinal Na+-dependent Pi transporter proteins (NaPi-IIa [NaPi-4], NaPi-IIb, and NaPi-IIc). Parathyroid hormone was elevated at 6 hours after PH. Hyperphosphaturia persisted, however, even after thyroparathyroidectomy in PH rats. Moreover, DNA microarray data revealed elevated levels of nicotinamide phosphoribosyltransferase (Nampt) mRNA in the kidney after PH, and Nampt protein levels and total NAD concentration increased significantly in the proximal tubules. PH rats also exhibited markedly increased levels of the Nampt substrate, urinary nicotinamide (NAM), and NAM catabolites. In vitro analyses using opossum kidney cells revealed that NAM alone did not affect endogenous NaPi-4 levels. However, in cells overexpressing Nampt, the addition of NAM led to a marked decrease in cell surface expression of NaPi-4 that was blocked by treatment with FK866, a specific Nampt inhibitor. Furthermore, FK866-treated mice showed elevated renal Pi reabsorption and hypophosphaturia. These findings indicate that hepatectomy-induced hypophosphatemia is due to abnormal NAM metabolism, including Nampt activation in renal proximal tubular cells. PMID:24262791

In vivo, Pikfyve generates PI(3,5)P2, which serves as both a signaling lipid and the major precursor for PI5P

PubMed Central

Zolov, Sergey N.; Bridges, Dave; Zhang, Yanling; Lee, Wei-Wei; Riehle, Ellen; Verma, Rakesh; Lenk, Guy M.; Converso-Baran, Kimber; Weide, Thomas; Albin, Roger L.; Saltiel, Alan R.; Meisler, Miriam H.; Russell, Mark W.; Weisman, Lois S.

2012-01-01

Mutations that cause defects in levels of the signaling lipid phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] lead to profound neurodegeneration in mice. Moreover, mutations in human FIG4 predicted to lower PI(3,5)P2 levels underlie Charcot–Marie–Tooth type 4J neuropathy and are present in selected cases of amyotrophic lateral sclerosis. In yeast and mammals, PI(3,5)P2 is generated by a protein complex that includes the lipid kinase Fab1/Pikfyve, the scaffolding protein Vac14, and the lipid phosphatase Fig4. Fibroblasts cultured from Vac14−/− and Fig4−/− mouse mutants have a 50% reduction in the levels of PI(3,5)P2, suggesting that there may be PIKfyve-independent pathways that generate this lipid. Here, we characterize a Pikfyve gene-trap mouse (Pikfyveβ-geo/β-geo), a hypomorph with ∼10% of the normal level of Pikfyve protein. shRNA silencing of the residual Pikfyve transcript in fibroblasts demonstrated that Pikfyve is required to generate all of the PI(3,5)P2 pool. Surprisingly, Pikfyve also is responsible for nearly all of the phosphatidylinositol-5-phosphate (PI5P) pool. We show that PI5P is generated directly from PI(3,5)P2, likely via 3′-phosphatase activity. Analysis of tissues from the Pikfyveβ-geo/β-geo mouse mutants reveals that Pikfyve is critical in neural tissues, heart, lung, kidney, thymus, and spleen. Thus, PI(3,5)P2 and PI5P have major roles in multiple organs. Understanding the regulation of these lipids may provide insights into therapies for multiple diseases. PMID:23047693

PI3K-AKT signaling pathway is involved in hypoxia/thermal-induced immunosuppression of small abalone Haliotis diversicolor.

PubMed

Sun, Yulong; Zhang, Xin; Wang, Guodong; Lin, Shi; Zeng, Xinyang; Wang, Yilei; Zhang, Ziping

2016-12-01

The PI3K-AKT signal pathway has been found to be involved in many important physiological and pathological processes of the innate immune system of vertebrates and invertebrates. In this study, the AKT (HdAKT) and PI3K (HdPI3K) gene of small abalone Haliotis diversicolor were cloned and characterized for the important status of PI3K and AKT protein in PI3K-AKT signaling pathway. The full length cDNAs of HdAKT and HdPI3K are 2126 bp and 6052 bp respectively, encoding proteins of 479 amino acids and 1097 amino acids, respectively. The mRNA expression level of fourteen genes in the PI3K-AKT signaling pathway were detected by quantitative real-time PCR. The results showed that all these fourteen genes were ubiquitously expressed in seven selected tissues. Meanwhile, HdAKT was expressed in haemocytes with the highest expression level (p < 0.05) next in hepatopancreas (p < 0.05). On the other hand, the expression level of HdPI3K in haemocytes was higher than other tissues. Under normal condition, the gene expression level of HdAKT, HdPI3K, and other PI3K-AKT signaling pathway members were significantly up-regulated by Vibrio parahaemolyticus infection which demonstrated that HdAKT, HdPI3K, and other PI3K-AKT signaling pathway members play a role in the innate immune system of abalone. The mRNA expression of these genes in gills, haemocytes and hepatopancreas was significantly down-regulated after the Vibrio parahaemolyticus stimulation with environment stimulation (thermal, hypoxia and thermal & hypoxia). These results indicate that the dual/multiple stresses defeat the immune system and lead to immunosuppression in abalone. PI3K-AKT signaling pathway may be involved in hypoxia/thermal-induced immunosuppression of small abalone Haliotis diversicolor. Copyright © 2016 Elsevier Ltd. All rights reserved.

Role of rat sodium/phosphate cotransporters in the cell membrane transport of arsenate

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

Villa-Bellosta, Ricardo; Sorribas, Victor

2008-10-01

Inorganic arsenate (As{sup V}) is a common contaminant of underground water. Following oral exposure, it is assumed that As{sup V} is distributed and crosses cell membranes through inorganic phosphate (Pi) transporters. We have tested this hypothesis by studying the inhibition of rat Na/Pi cotransporters by As{sup V} in Xenopus laevis oocytes and in several rat tissues. The ubiquitously expressed type III Pi transporters (PiT-1 and PiT-2) showed a low affinity for As{sup V} (K{sub i} {approx} 3.8 mM), similar to the Pi transport system in aortic vascular smooth muscle cells (K{sub i} 1.5 mM). The type II renal isoforms, NaPi-IIamore » and NaPi-IIc, were also poorly inhibited by As{sup V} (K{sub i} {approx} 1 mM), similar to the Pi transport from kidney cortex brush-border membrane (BBM) vesicles. Conversely, the high-affinity intestinal transporter, NaPi-IIb, was very efficiently inhibited with a K{sub i} of 51 {mu}M, similar to the Pi transport from intestinal BBM vesicles. Taking into account the 1.1 mM Pi in blood and renal ultrafiltrate, and the nanomolar range of As{sup V} exposures, we have determined that the contribution by Na/Pi cotransporters to As{sup V} membrane transport is negligible, given that 10-15 mM As{sup V} would be necessary in these fluids to be significantly transported. Intestinal transport is an exception, because Pi competition is weak, thereby considering that its concentration in lumen mainly depends on low Pi levels from ingested fresh water, and because As{sup V} very efficiently inhibits Pi intestinal transport. Our data agree with current toxicokinetic knowledge, and they explain the asymmetric excretion of trivalent and pentavalent arsenic species into bile and urine.« less

The Heart Protection Effect of Alcalase Potato Protein Hydrolysate Is through IGF1R-PI3K-Akt Compensatory Reactivation in Aging Rats on High Fat Diets

PubMed Central

Hu, Wei-Syun; Ting, Wei-Jen; Chiang, Wen-Dee; Pai, Peiying; Yeh, Yu-Lan; Chang, Chung-Ho; Lin, Wan-Teng; Huang, Chih-Yang

2015-01-01

The prevalence of obesity is high in older adults. Alcalase potato protein hydrolysate (APPH), a nutraceutical food, might have greater benefits and be more economical than hypolipidemic drugs. In this study, serum lipid profiles and heart protective effects were evaluated in high fat diet (HFD) induced hyperlipidemia in aging rats treated with APPH (15, 45 and 75 mg/kg/day) and probucol (500 mg/kg/day). APPH treatments reduced serum triacylglycerol (TG), total cholesterol (TC), and low density lipoprotein (LDL) levels to the normal levels expressed in the control group. Additionally, the IGF1R-PI3K-Akt survival pathway was reactivated, and Fas-FADD (Fas-associated death domain) induced apoptosis was inhibited by APPH treatments (15 and 45 mg/kg/day) in HFD aging rat hearts. APPH (75 mg/kg/day) rather than probucol (500 mg/kg/day) treatment could reduce serum lipids without affecting HDL expression. The heart protective effect of APPH in aging rats with hyperlipidemia was through lowering serum lipids and enhancing the activation of the compensatory IGF1R-PI3K-Akt survival pathway. PMID:25950762

The Heart Protection Effect of Alcalase Potato Protein Hydrolysate Is through IGF1R-PI3K-Akt Compensatory Reactivation in Aging Rats on High Fat Diets.

PubMed

Hu, Wei-Syun; Ting, Wei-Jen; Chiang, Wen-Dee; Pai, Peiying; Yeh, Yu-Lan; Chang, Chung-Ho; Lin, Wan-Teng; Huang, Chih-Yang

2015-05-05

The prevalence of obesity is high in older adults. Alcalase potato protein hydrolysate (APPH), a nutraceutical food, might have greater benefits and be more economical than hypolipidemic drugs. In this study, serum lipid profiles and heart protective effects were evaluated in high fat diet (HFD) induced hyperlipidemia in aging rats treated with APPH (15, 45 and 75 mg/kg/day) and probucol (500 mg/kg/day). APPH treatments reduced serum triacylglycerol (TG), total cholesterol (TC), and low density lipoprotein (LDL) levels to the normal levels expressed in the control group. Additionally, the IGF1R-PI3K-Akt survival pathway was reactivated, and Fas-FADD (Fas-associated death domain) induced apoptosis was inhibited by APPH treatments (15 and 45 mg/kg/day) in HFD aging rat hearts. APPH (75 mg/kg/day) rather than probucol (500 mg/kg/day) treatment could reduce serum lipids without affecting HDL expression. The heart protective effect of APPH in aging rats with hyperlipidemia was through lowering serum lipids and enhancing the activation of the compensatory IGF1R-PI3K-Akt survival pathway.

Harnessing the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia: Eliminating activity by targeting at different levels

PubMed Central

Ricci, Francesca; Tabellini, Giovanna; Chiarini, Francesca; Tazzari, Pier Luigi; Melchionda, Fraia; Buontempo, Francesca; Pagliaro, Pasqualepaolo; Pession, Andrea; McCubrey, James A.; Martelli, Alberto M.

2012-01-01

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignant hematological disorder arising in the thymus from T-cell progenitors. T-ALL mainly affects children and young adults, and remains fatal in 20% of adolescents and 50% of adults, despite progress in polychemotherapy protocols. Therefore, innovative targeted therapies are desperately needed for patients with a dismal prognosis. Aberrant activation of PI3K/Akt/mTOR signaling is a common event in T-ALL patients and portends a poor prognosis. Preclinical studies have highlighted that modulators of PI3K/Akt/mTOR signaling could have a therapeutic relevance in T-ALL. However, the best strategy for inhibiting this highly complex signal transduction pathway is still unclear, as the pharmaceutical companies have disclosed an impressive array of small molecules targeting this signaling network at different levels. Here, we demonstrate that a dual PI3K/PDK1 inhibitor, NVP-BAG956, displayed the most powerful cytotoxic effects against T-ALL cell lines and primary patients samples, when compared with a pan class I PI3K inhibitor (GDC-0941), an allosteric Akt inhibitor (MK-2206), an mTORC1 allosteric inhibitor (RAD-001), or an ATP-competitive mTORC1/mTORC2 inhibitor (KU-63794). Moreover, we also document that combinations of some of the aforementioned drugs strongly synergized against T-ALL cells at concentrations well below their respective IC50. This observation indicates that vertical inhibition at different levels of the PI3K/Akt/mTOR network could be considered as a future innovative strategy for treating T-ALL patients. PMID:22885370

Harnessing the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia: eliminating activity by targeting at different levels.

PubMed

Bressanin, Daniela; Evangelisti, Camilla; Ricci, Francesca; Tabellini, Giovanna; Chiarini, Francesca; Tazzari, Pier Luigi; Melchionda, Fraia; Buontempo, Francesca; Pagliaro, Pasqualepaolo; Pession, Andrea; McCubrey, James A; Martelli, Alberto M

2012-08-01

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignant hematological disorder arising in the thymus from T-cell progenitors. T-ALL mainly affects children and young adults, and remains fatal in 20% of adolescents and 50% of adults, despite progress in polychemotherapy protocols. Therefore, innovative targeted therapies are desperately needed for patients with a dismal prognosis. Aberrant activation of PI3K/Akt/mTOR signaling is a common event in T-ALL patients and portends a poor prognosis. Preclinical studies have highlighted that modulators of PI3K/Akt/mTOR signaling could have a therapeutic relevance in T-ALL. However, the best strategy for inhibiting this highly complex signal transduction pathway is still unclear, as the pharmaceutical companies have disclosed an impressive array of small molecules targeting this signaling network at different levels. Here, we demonstrate that a dual PI3K/PDK1 inhibitor, NVP-BAG956, displayed the most powerful cytotoxic affects against T-ALL cell lines and primary patients samples, when compared with a pan class I PI3K inhibitor (GDC-0941), an allosteric Akt inhibitor (MK-2206), an mTORC1 allosteric inhibitor (RAD-001), or an ATP-competitive mTORC1/mTORC2 inhibitor (KU63794). Moreover, we also document that combinations of some of the aforementioned drugs strongly synergized against T-ALL cells at concentrations well below their respective IC50. This observation indicates that vertical inhibition at different levels of the PI3K/Akt/mTOR network could be considered as a future innovative strategy for treating T-ALL patients.

Potent therapeutic effects of shouwu jiangqi decoction on polycystic ovary syndrome with insulin resistance in rats.

PubMed

Wang, Li-hong; Wang, Xu; Yu, Xi-zhong; Xu, Wen-ting

2016-02-01

To investigate the effect of Shouwu Jiangqi Decoction (SJD) on polycystic ovary syndrome (PCOS) with insulin resistance (IR) in rats and to explore the underlining molecular mechanisms. A total of 51 female Sprague-Dawley rats were randomly divided into 6 groups: control group (n=7), model group (n=8), SJD high-dose group (n=9), SJD medium-dose group (n=9), SJD low-dose group (n=9) and DMBG group (n=9). Radioimmunoassay was used to measure serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone concentrations and qRT-PCR and western blot were used to examine the expression levels of mRNA and protein respectively of insulin receptor substrate 1 (IRS-1) and phosphatidylinositide 3-kinases (PI3K) p85α in different groups. FSH level significantly decreased in the model group compared with the normal control (P<0.01), and high-dose SJD and DMBG can significantly increase FSH level (P<0.01). LH level showed a mild increase without statistic significance in the model group compared with the control and different dosages of SJD had no significance effect on LH level, while DMBG can significantly decrease LH level (P<0.01). Testosterone level significantly increased in the model group compared with the control group (P<0.01), and high-dose SJD and DMBG can significantly decrease testosterone level (P<0.01). The expression of IRS-1 as well as PI3Kp85α were significantly decreased in the model group compared with the normal control group at both mRNA (P<0.001) and protein (P<0.01) level, and both high-dose SJD and DMBG can enhance IRS-1 and PI3K expression (P<0.05). SJD has potent therapeutic effects on PCOS with IR in rats. The therapeutic effects of SJD on IR and ovulatory dysfunction are probably achieved through correcting the defective insulin signaling transduction.

Combined chirp coded tissue harmonic and fundamental ultrasound imaging for intravascular ultrasound: 20–60 MHz phantom and ex vivo results

PubMed Central

Park, Jinhyoung; Li, Xiang; Zhou, Qifa; Shung, K. Kirk

2013-01-01

The application of chirp coded excitation to pulse inversion tissue harmonic imaging can increase signal to noise ratio. On the other hand, the elevation of range side lobe level, caused by leakages of the fundamental signal, has been problematic in mechanical scanners which are still the most prevalent in high frequency intravascular ultrasound imaging. Fundamental chirp coded excitation imaging can achieve range side lobe levels lower than –60 dB with Hanning window, but it yields higher side lobes level than pulse inversion chirp coded tissue harmonic imaging (PI-CTHI). Therefore, in this paper a combined pulse inversion chirp coded tissue harmonic and fundamental imaging mode (CPI-CTHI) is proposed to retain the advantages of both chirp coded harmonic and fundamental imaging modes by demonstrating 20–60 MHz phantom and ex vivo results. A simulation study shows that the range side lobe level of CPI-CTHI is 16 dB lower than PI-CTHI, assuming that the transducer translates incident positions by 50 μm when two beamlines of pulse inversion pair are acquired. CPI-CTHI is implemented for a proto-typed intravascular ultrasound scanner capable of combined data acquisition in real-time. A wire phantom study shows that CPI-CTHI has a 12 dB lower range side lobe level and a 7 dB higher echo signal to noise ratio than PI-CTHI, while the lateral resolution and side lobe level are 50 μm finer and –3 dB less than fundamental chirp coded excitation imaging respectively. Ex vivo scanning of a rabbit trachea demonstrates that CPI-CTHI is capable of visualizing blood vessels as small as 200 μm in diameter with 6 dB better tissue contrast than either PI-CTHI or fundamental chirp coded excitation imaging. These results clearly indicate that CPI-CTHI may enhance tissue contrast with less range side lobe level than PI-CTHI. PMID:22871273

Economic evaluation of a psychological intervention for high distress cancer patients and carers: costs and quality-adjusted life years.

PubMed

Chatterton, Mary Lou; Chambers, Suzanne; Occhipinti, Stefano; Girgis, Afaf; Dunn, Jeffrey; Carter, Rob; Shih, Sophy; Mihalopoulos, Cathrine

2016-07-01

This study compared the cost-effectiveness of a psychologist-led, individualised cognitive behavioural intervention (PI) to a nurse-led, minimal contact self-management condition for highly distressed cancer patients and carers. This was an economic evaluation conducted alongside a randomised trial of highly distressed adult cancer patients and carers calling cancer helplines. Services used by participants were measured using a resource use questionnaire, and quality-adjusted life years were measured using the assessment of quality of life - eight-dimension - instrument collected through a computer-assisted telephone interview. The base case analysis stratified participants based on the baseline score on the Brief Symptom Inventory. Incremental cost-effectiveness ratio confidence intervals were calculated with a nonparametric bootstrap to reflect sampling uncertainty. The results were subjected to sensitivity analysis by varying unit costs for resource use and the method for handling missing data. No significant differences were found in overall total costs or quality-adjusted life years (QALYs) between intervention groups. Bootstrapped data suggest the PI had a higher probability of lower cost and greater QALYs for both carers and patients with high distress at baseline. For patients with low levels of distress at baseline, the PI had a higher probability of greater QALYs but at additional cost. Sensitivity analysis showed the results were robust. The PI may be cost-effective compared with the nurse-led, minimal contact self-management condition for highly distressed cancer patients and carers. More intensive psychological intervention for patients with greater levels of distress appears warranted. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

HIV Protease Inhibitor Use During Pregnancy Is Associated With Decreased Progesterone Levels, Suggesting a Potential Mechanism Contributing to Fetal Growth Restriction

PubMed Central

Papp, Eszter; Mohammadi, Hakimeh; Loutfy, Mona R.; Yudin, Mark H.; Murphy, Kellie E.; Walmsley, Sharon L.; Shah, Rajiv; MacGillivray, Jay; Silverman, Michael; Serghides, Lena

2015-01-01

Background. Protease inhibitor (PI)–based combination antiretroviral therapy (cART) is administered during pregnancy to prevent perinatal human immunodeficiency virus (HIV) transmission. However, PI use has been associated with adverse birth outcomes, including preterm delivery and small-for-gestational-age (SGA) births. The mechanisms underlying these outcomes are unknown. We hypothesized that PIs contribute to these adverse events by altering progesterone levels. Methods. PI effects on trophoblast progesterone production were assessed in vitro. A mouse pregnancy model was used to assess the impact of PI-based cART on pregnancy outcomes and progesterone levels in vivo. Progesterone levels were assessed in plasma specimens from 27 HIV-infected and 17 HIV-uninfected pregnant women. Results. PIs (ritonavir, lopinavir, and atazanavir) but not nucleoside reverse transcriptase inhibitors (NRTIs) or nonnucleoside reverse transcriptase inhibitors reduced trophoblast progesterone production in vitro. In pregnant mice, PI-based cART but not dual-NRTI therapy was associated with significantly lower progesterone levels that directly correlated with fetal weight. Progesterone supplementation resulted in a significant improvement in fetal weight. We observed lower progesterone levels and smaller infants in HIV-infected women receiving PI-based cART, compared with the control group. In HIV-infected women, progesterone levels correlated significantly with birth weight percentile. Conclusions. Our data suggest that PI use in pregnancy may lead to lower progesterone levels that could contribute to adverse birth outcomes. PMID:25030058

HIV protease inhibitor use during pregnancy is associated with decreased progesterone levels, suggesting a potential mechanism contributing to fetal growth restriction.

PubMed

Papp, Eszter; Mohammadi, Hakimeh; Loutfy, Mona R; Yudin, Mark H; Murphy, Kellie E; Walmsley, Sharon L; Shah, Rajiv; MacGillivray, Jay; Silverman, Michael; Serghides, Lena

2015-01-01

Protease inhibitor (PI)-based combination antiretroviral therapy (cART) is administered during pregnancy to prevent perinatal human immunodeficiency virus (HIV) transmission. However, PI use has been associated with adverse birth outcomes, including preterm delivery and small-for-gestational-age (SGA) births. The mechanisms underlying these outcomes are unknown. We hypothesized that PIs contribute to these adverse events by altering progesterone levels. PI effects on trophoblast progesterone production were assessed in vitro. A mouse pregnancy model was used to assess the impact of PI-based cART on pregnancy outcomes and progesterone levels in vivo. Progesterone levels were assessed in plasma specimens from 27 HIV-infected and 17 HIV-uninfected pregnant women. PIs (ritonavir, lopinavir, and atazanavir) but not nucleoside reverse transcriptase inhibitors (NRTIs) or nonnucleoside reverse transcriptase inhibitors reduced trophoblast progesterone production in vitro. In pregnant mice, PI-based cART but not dual-NRTI therapy was associated with significantly lower progesterone levels that directly correlated with fetal weight. Progesterone supplementation resulted in a significant improvement in fetal weight. We observed lower progesterone levels and smaller infants in HIV-infected women receiving PI-based cART, compared with the control group. In HIV-infected women, progesterone levels correlated significantly with birth weight percentile. Our data suggest that PI use in pregnancy may lead to lower progesterone levels that could contribute to adverse birth outcomes. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

The Second-Generation Maturation Inhibitor GSK3532795 Maintains Potent Activity Toward HIV Protease Inhibitor-Resistant Clinical Isolates.

PubMed

Ray, Neelanjana; Li, Tianbo; Lin, Zeyu; Protack, Tricia; van Ham, Petronella Maria; Hwang, Carey; Krystal, Mark; Nijhuis, Monique; Lataillade, Max; Dicker, Ira

2017-05-01

Protease inhibitor (PI)-resistant HIV-1 isolates with primary substitutions in protease (PR) and secondary substitutions in Gag could potentially exhibit cross-resistance to maturation inhibitors. We evaluated the second-generation maturation inhibitor, GSK3532795, for activity toward clinical isolates with genotypic and phenotypic characteristics associated with PI resistance (longitudinal). Longitudinal clinical isolates from 15 PI-treated patients and 7 highly PI-resistant (nonlongitudinal) viruses containing major and minor PI resistance-associated mutations were evaluated for GSK3532795 sensitivity. Phenotypic sensitivity was determined using the PhenoSense Gag/PR assay (Monogram Biosciences) or in-house single- and multiple-cycle assays. Changes from baseline [CFB; ratio of post- to pre-treatment FC-IC50 (fold-change in IC50 versus wild-type virus)] <3 were considered to be within the no-effect level. All nonlongitudinal viruses tested were sensitive to GSK3532795 (FC-IC50 range 0.16-0.68). Among longitudinal isolates, all post-PI treatment samples had major PI resistance-associated mutations in PR and 17/21 had PI resistance-associated changes in Gag. Nineteen of the 21 post-PI treatment samples had GSK3532795 CFB <3. Median (range) CFB was 0.83 (0.05-27.4) [Monogram (11 patients)] and 1.5 (1.0-2.2) [single-cycle (4 patients)]. The 2 post-PI treatment samples showing GSK3532795 CFB >3 (Monogram) were retested using single- and multiple-cycle assays. Neither sample had meaningful sensitivity changes in the multiple-cycle assay. Gag changes were not associated with an increased GSK3532795 CFB. GSK3532795 maintained antiviral activity against PI-resistant isolates with emergent PR and/or Gag mutations. This finding supports continued development of GSK3532795 in treatment-experienced patients with or without previous PI therapy.

Protective effects of 6-Gingerol on vascular endothelial cell injury induced by high glucose via activation of PI3K-AKT-eNOS pathway in human umbilical vein endothelial cells.

PubMed

Liu, Dan; Wu, Mengqing; Lu, Yi; Xian, Tao; Wang, Yupeng; Huang, Bowei; Zeng, Guohua; Huang, Qiren

2017-09-01

6-Gingerol (6-Gin), an active constituent of Zingiber officinale, has been reported to have anti-inflammatory, anti-oxidative, anti-cancerous etc. bioactivities. However, little is known about its endothelial protective effects and the underlying mechanisms. In this study, our purpose was to investigate the protective effects of 6-Gin and its underlying mechanisms. HUVECs were exposed to high glucose (HG, 33mM glucose) for 48h, followed by 50μM 6-Gin with or without LY294002 (10μM), AKT inhibitor IV (0.5μM) or L-NAME (5mM) for another 24h. Cell viability, levels of NO, LDH and ROS were detected. In addition, the expression levels of IKK, IRS-1, PI3K, AKT, eNOS and their phosphorylated proteins were measured by western blots. Compared with the control, HUVECs were significantly impaired by HG, characterized by decreased levels of the cell viability, NO, pY458-PI3K, pS473-AKT and pS1177-eNOS while increased levels of LDH, pS176-IKK, and p-S312-IRS-1. Conversely, 6-Gin remarkably protected HUVECs against HG-induced injury in a concentration- and time-dependent manner. However, the protective effects of 6-Gin were abolished by co-treatment with LY294002, AKT inhibitor IV or L-NAME at the HG state. Collectively, 6-Gin attenuated the injury of HUVECs induced by HG through the activation of PI3K-AKT-eNOS signal pathway. The findings provide a novel potential for 6-Gin to prevent and treat the angiopathy resulting from diabetes mellitus. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Isoform-selective induction of human p110δ PI3K expression by TNFα: identification of a new and inducible PIK3CD promoter

PubMed Central

Whitehead, Maria A.; Bombardieri, Michele; Pitzalis, Costantino; Vanhaesebroeck, Bart

2012-01-01

PI3Ks (phosphoinositide 3-kinases) are signalling molecules and drug targets with important biological functions, yet the regulation of PI3K gene expression is poorly understood. Key PI3Ks are the class IA PI3Ks that consist of a catalytic subunit (p110α, p110β and p110δ) in complex with a p85 regulatory subunit. Whereas p110α and p110β are ubiquitously expressed, high levels of p110δ are mainly found in white blood cells, with most non-leucocytes expressing low levels of p110δ. In the present paper we report that TNFα (tumour necrosis factor α) stimulation induces p110δ expression in human ECs (endothelial cells) and synovial fibroblasts, but not in leucocytes, through transcription start sites located in a novel promoter region in the p110δ gene (PIK3CD). This promoter is used in all cell types, including solid tumour cell lines that express p110δ, and is activated by TNFα in ECs and synovial fibroblasts. We further present a detailed biochemical and bioinformatic characterization of p110δ gene regulation, demonstrating that PIK3CD has distinct promoters, some of which can be dynamically activated by pro-inflammatory mediators. This is the first molecular identification of a PI3K promoter under the control of acute extracellular stimulation. PMID:22375552

PTEN Regulates PI(3,4)P2 Signaling Downstream of Class I PI3K.

PubMed

Malek, Mouhannad; Kielkowska, Anna; Chessa, Tamara; Anderson, Karen E; Barneda, David; Pir, Pınar; Nakanishi, Hiroki; Eguchi, Satoshi; Koizumi, Atsushi; Sasaki, Junko; Juvin, Véronique; Kiselev, Vladimir Y; Niewczas, Izabella; Gray, Alexander; Valayer, Alexandre; Spensberger, Dominik; Imbert, Marine; Felisbino, Sergio; Habuchi, Tomonori; Beinke, Soren; Cosulich, Sabina; Le Novère, Nicolas; Sasaki, Takehiko; Clark, Jonathan; Hawkins, Phillip T; Stephens, Len R

2017-11-02

The PI3K signaling pathway regulates cell growth and movement and is heavily mutated in cancer. Class I PI3Ks synthesize the lipid messenger PI(3,4,5)P 3 . PI(3,4,5)P 3 can be dephosphorylated by 3- or 5-phosphatases, the latter producing PI(3,4)P 2 . The PTEN tumor suppressor is thought to function primarily as a PI(3,4,5)P 3 3-phosphatase, limiting activation of this pathway. Here we show that PTEN also functions as a PI(3,4)P 2 3-phosphatase, both in vitro and in vivo. PTEN is a major PI(3,4)P 2 phosphatase in Mcf10a cytosol, and loss of PTEN and INPP4B, a known PI(3,4)P 2 4-phosphatase, leads to synergistic accumulation of PI(3,4)P 2 , which correlated with increased invadopodia in epidermal growth factor (EGF)-stimulated cells. PTEN deletion increased PI(3,4)P 2 levels in a mouse model of prostate cancer, and it inversely correlated with PI(3,4)P 2 levels across several EGF-stimulated prostate and breast cancer lines. These results point to a role for PI(3,4)P 2 in the phenotype caused by loss-of-function mutations or deletions in PTEN. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Exploring perceived barriers, drivers, impacts and the need for evaluation of public involvement in health and social care research: a modified Delphi study

PubMed Central

Snape, D; Kirkham, J; Britten, N; Froggatt, K; Gradinger, F; Lobban, F; Popay, Jennie; Wyatt, K; Jacoby, Ann

2014-01-01

Objective To explore areas of consensus and conflict in relation to perceived public involvement (PI) barriers and drivers, perceived impacts of PI and ways of evaluating PI approaches in health and social care research. Background Internationally and within the UK the recognition of potential benefits of PI in health and social care research is gathering momentum and PI is increasingly identified by organisations as a prerequisite for funding. However, there is relatively little examination of the impacts of PI and how those impacts might be measured. Design Mixed method, three-phase, modified Delphi technique, conducted as part of a larger MRC multiphase project. Sample Clinical and non-clinical academics, members of the public, research managers, commissioners and funders. Findings This study found high levels of consensus about the most important barriers and drivers to PI. There was acknowledgement that tokenism was common in relation to PI; and strong support for the view that demonstrating the impacts and value of PI was made more difficult by tokenistic practice. PI was seen as having intrinsic value; nonetheless, there was clear support for the importance of evaluating its impact. Research team cohesion and appropriate resources were considered essential to effective PI implementation. Panellists agreed that PI can be challenging, but can be facilitated by clear guidance, together with models of good practice and measurable standards. Conclusions This study is the first to present empirical evidence of the opinions voiced by key stakeholders on areas of consensus and conflict in relation to perceived PI barriers and drivers, perceived impacts of PI and the need to evaluate PI. As such it further contributes to debate around best practice in PI, the potential for tokenism and how best to evaluate the impacts of PI. These findings have been used in the development of the Public Involvement Impact Assessment Framework (PiiAF), an online resource which offers guidance to researchers and members of the public involved in the PI process. PMID:24939808

Correlation Between Iron and alpha and pi Glutathione-S-Transferase Levels in Humans

DTIC Science & Technology

2012-09-01

assays were performed as described in the Biotrin High Sensitivity Alpha GST EIA kit protocol. First, serum samples were diluted 1:10 with wash solution...immunosorbent assays were performed as described in the Biotrin Pi GST EIA kit protocol. First, plasma samples were diluted 1:5 with sample diluent...immunosorbent assays were performed as described in the AssayMax Human Transferrin ELISA kit protocol. First, serum samples were diluted 1:2000 with MIX

Preserved Proactive Interference in Autism Spectrum Disorder.

PubMed

Carmo, Joana C; Duarte, Elsa; Pinho, Sandra; Filipe, Carlos N; Marques, J Frederico

2016-01-01

In this study, we aimed to evaluate further the functioning and structuring of the semantic system in autism spectrum disorders (ASD). We analyzed the performance of 19 high-functioning young adults with ASD and a group of 20 age-, verbal IQ- and education-matched individuals with the Proactive Interference (PI) Paradigm to evaluate semantic functioning in ASD (Experiment 1). In Experiment 2, we analyzed the performances of both groups in a PI paradigm with manipulation of the level of typicality. In both experiments, we observed significant effects of trial and group but no trial by group interactions, which we interpreted as robust evidence of preserved PI (build up effect) that indicated the preservation of semantic mechanisms of encoding and retrieval.

Influence of infection by Toxoplasma gondii on purine levels and E-ADA activity in the brain of mice experimentally infected mice.

PubMed

Tonin, Alexandre A; Da Silva, Aleksandro S; Casali, Emerson A; Silveira, Stephanie S; Moritz, Cesar E J; Camillo, Giovana; Flores, Mariana M; Fighera, Rafael; Thomé, Gustavo R; Morsch, Vera M; Schetinger, Maria Rosa C; Rue, Mario De La; Vogel, Fernanda S F; Lopes, Sonia T A

2014-07-01

The aim of this study was to assess the purine levels and E-ADA activity in the brain of mice (BALB/c) experimentally infected with Toxoplasma gondii. In experiment I (n=24) the mice were infected with RH strain of T. gondii, while in experiment II (n=36) they were infected with strain ME-49 of T. gondii. Our results showed that, for RH strain (acute phase), an increase in both periods in the levels of ATP, ADP, AMP, adenosine, hypoxanthine, xanthine (only on day 6 PI) and uric acid (only on day 6 PI). By the other hand, the RH strain led, on days 4 and 6 PI, to a reduction in the concentration of inosine. ME-49, a cystogenic strain, showed some differences in acute and chronic phase, since on day 6 PI the levels of ATP and ADP were increased, while on day 30 these same nucleotides were reduced. On day 60 PI, ME-49 induced a reduction in the levels of ATP, ADP, AMP, adenosine, inosine and xanthine, while uric acid was increased. A decrease of E-ADA activity was observed in brain on days 4 and 6 PI (RH), and 30 PI (ME-49); however on day 60 PI E-ADA activity was increased for infection by ME-49 strain. Therefore, it was possible to conclude that infection with T. gondii changes the purine levels and the activity of E-ADA in brain, which may be associated with neurological signs commonly observed in this disease. Copyright © 2014 Elsevier Inc. All rights reserved.

Effect of aniracetam on phosphatidylinositol transfer protein alpha in cytosolic and plasma membrane fractions of astrocytes subjected to simulated ischemia in vitro.

PubMed

Gabryel, Bozena; Chalimoniuk, Małgorzata; Małecki, Andrzej; Strosznajder, Joanna B

2005-01-01

Brain ischemia affects phosphoinositide metabolism and the level of lipid-derived second messengers. Phosphatidylinositol transfer proteins (PI-PTs) are responsible for the transport of phosphatidylinositol (PI) and other phospholipids through membranes. Isoform of PI-TPs (PI-TPalpha) is an essential component in ensuring substrate supply for phospholipase C (PLC). The current study was conducted to examine potential effect of aniracetam on PI-TPalpha expression and to characterize the PI-TPalpha isoform distribution between membrane and cytosol fractions of astrocytes exposed to simulated ischemia in vitro. After 8 h period of ischemia, the level of PI-TPalpha was significantly higher in cytosol (by about 28%) as well as in membrane fraction (by about 80%) in comparison with control. We have found that aniracetam treatment of astrocytes in normoxia significantly increased the level of PI-TPalpha in membrane fraction with a maximal effect at 0.1 microM concentration of aniracetam (by about 195% of control). In membrane fractions of ischemic cells, aniracetam increased PI-TPalpha expression in a concentration-dependent manner. In ischemic cells, aniracetam (10 microM) has elevated PI-TPalpha expression up to 155% and 428% in cytosolic and membrane fractions in comparison with ischemic untreated cells, respectively. The study has shown that aniracetam significantly activates PI-TPalpha in cell membrane fraction and this effect might be connected with previously described activation of MAP kinase cascade.

Impacts of strigolactone on shoot branching under phosphate starvation in chrysanthemum (Dendranthema grandiflorum cv. Jinba)

PubMed Central

Xi, Lin; Wen, Chao; Fang, Shuang; Chen, Xiaoli; Nie, Jing; Chu, JinFang; Yuan, Cunquan; Yan, Cunyu; Ma, Nan; Zhao, Liangjun

2015-01-01

Chrysanthemum (Dendranthema grandiflorum cv. Jinba) shoot branching is determined by bud outgrowth during the vegetative growth stage. The degree of axillary bud outgrowth is highly influenced by environmental conditions, such as nutrient availability. Here, we demonstrated that phosphorus (Pi) starvation significantly reduces axillary bud outgrowth in chrysanthemum. A strigolactone (SL) biosynthesis gene, DgCCD7, was isolated and characterized as an ortholog of MAX3/DAD3/RMS5/D17. By using ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS), three putative SLs were identified and levels of all three SLs showed strong increase under Pi starvation conditions. Determinations of the distribution of SLs and regulation of DgCCD7/8 in response to Pi changes in root indicate that SL acts systemically. However, temporal expression patterns of biosynthesis and signaling genes in nodes revealed that Pi starvation causes a local response of SL pathway. Treatment of node segments with or without auxin and Pi revealed that in the absence of exogenous auxin, Pi delayed axillary buds outgrowth and up-regulated local SL pathway genes. These data indicated that an auxin-SL regulatory loop responded to Pi starvation for delaying bud outgrowth locally, root biosynthesized SLs were transported acropetally and functioned in shoot branching inhibition under Pi starvation. We proposed that SLs contributed to chrysanthemum shoot branching control in response to Pi-limiting conditions in a systemic way. PMID:26442011

Targeting the Renin–Angiotensin System Combined With an Antioxidant Is Highly Effective in Mitigating Radiation-Induced Lung Damage

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

Mahmood, Javed; Radiation Medicine Program, STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, Ontario; Jelveh, Salomeh

Purpose: To investigate the outcome of suppression of the renin angiotensin system using captopril combined with an antioxidant (Eukarion [EUK]-207) for mitigation of radiation-induced lung damage in rats. Methods and Materials: The thoracic cavity of female Sprague-Dawley rats was irradiated with a single dose of 11 Gy. Treatment with captopril at a dose of 40 mg/kg/d in drinking water and EUK-207 given by subcutaneous injection (8 mg/kg daily) was started 1 week after irradiation (PI) and continuing until 14 weeks PI. Breathing rate was monitored until the rats were killed at 32 weeks PI, when lung fibrosis was assessed by lung hydroxyproline content. Lung levels ofmore » the cytokine transforming growth factor-β1 and macrophage activation were analyzed by immunohistochemistry. Oxidative DNA damage was assessed by 8-hydroxy-2-deoxyguanosine levels, and lipid peroxidation was measured by a T-BARS assay. Results: The increase in breathing rate in the irradiated rats was significantly reduced by the drug treatments. The drug treatment also significantly decreased the hydroxyproline content, 8-hydroxy-2-deoxyguanosine and malondialdehyde levels, and levels of activated macrophages and the cytokine transforming growth factor-β1 at 32 weeks. Almost complete mitigation of these radiation effects was observed by combining captopril and EUK-207. Conclusion: Captopril and EUK-207 can provide mitigation of radiation-induced lung damage out to at least 32 weeks PI after treatment given 1-14 weeks PI. Overall the combination of captopril and EUK-207 was more effective than the individual drugs used alone.« less

Exploring areas of consensus and conflict around values underpinning public involvement in health and social care research: a modified Delphi study

PubMed Central

Snape, D; Kirkham, J; Preston, J; Popay, J; Britten, N; Collins, M; Froggatt, K; Gibson, A; Lobban, F; Wyatt, K; Jacoby, A

2014-01-01

Objective There is growing interest in the potential benefits of public involvement (PI) in health and social care research. However, there has been little examination of values underpinning PI or how these values might differ for different groups with an interest in PI in the research process. We aimed to explore areas of consensus and conflict around normative, substantive and process-related values underpinning PI. Design Mixed method, three-phase, modified Delphi study, conducted as part of a larger multiphase project. Setting The UK health and social care research community. Participants Stakeholders in PI in research, defined as: clinical and non-clinical academics, members of the public, research managers, commissioners and funders; identified via research networks, online searches and a literature review. Results We identified high levels of consensus for many normative, substantive and process-related issues. However, there were also areas of conflict in relation to issues of bias and representativeness, and around whether the purpose of PI in health and social care research is to bring about service change or generate new knowledge. There were large differences by group in the percentages endorsing the ethical justification for PI and the argument that PI equalises power imbalances. With regard to practical implementation of PI, research support infrastructures were reported as lacking. Participants reported shortcomings in the uptake and practice of PI. Embedding PI practice and evaluation in research study designs was seen as fundamental to strengthening the evidence base. Conclusions Our findings highlight the extent to which PI is already embedded in research. However, they also highlight a need for ‘best practice’ standards to assist research teams to understand, implement and evaluate PI. These findings have been used in developing a Public Involvement Impact Assessment Framework (PiiAF), which offers guidance to researchers and members of the public involved in the PI process. PMID:24413356

Molecular Cloning and Optimization for High Level Expression of Cold-Adapted Serine Protease from Antarctic Yeast Glaciozyma antarctica PI12

PubMed Central

Ahmad Mazian, Mu'adz; Salleh, Abu Bakar; Basri, Mahiran; Rahman, Raja Noor Zaliha Raja Abd.

2014-01-01

Psychrophilic basidiomycete yeast, Glaciozyma antarctica strain PI12, was shown to be a protease-producer. Isolation of the PI12 protease gene from genomic and mRNA sequences allowed determination of 19 exons and 18 introns. Full-length cDNA of PI12 protease gene was amplified by rapid amplification of cDNA ends (RACE) strategy with an open reading frame (ORF) of 2892 bp, coded for 963 amino acids. PI12 protease showed low homology with the subtilisin-like protease from fungus Rhodosporidium toruloides (42% identity) and no homology to other psychrophilic proteases. The gene encoding mature PI12 protease was cloned into Pichia pastoris expression vector, pPIC9, and positioned under the induction of methanol-alcohol oxidase (AOX) promoter. The recombinant PI12 protease was efficiently secreted into the culture medium driven by the Saccharomyces cerevisiae α-factor signal sequence. The highest protease production (28.3 U/ml) was obtained from P. pastoris GS115 host (GpPro2) at 20°C after 72 hours of postinduction time with 0.5% (v/v) of methanol inducer. The expressed protein was detected by SDS-PAGE and activity staining with a molecular weight of 99 kDa. PMID:25093119

Faster and stronger manifestation of mitochondrial diseases in skeletal muscle than in heart related to cytosolic inorganic phosphate (Pi) accumulation

PubMed Central

2016-01-01

A model of the cell bioenergetic system was used to compare the effect of oxidative phosphorylation (OXPHOS) deficiencies in a broad range of moderate ATP demand in skeletal muscle and heart. Computer simulations revealed that kinetic properties of the system are similar in both cases despite the much higher mitochondria content and “basic” OXPHOS activity in heart than in skeletal muscle, because of a much higher each-step activation (ESA) of OXPHOS in skeletal muscle than in heart. Large OXPHOS deficiencies lead in both tissues to a significant decrease in oxygen consumption (V̇o2) and phosphocreatine (PCr) and increase in cytosolic ADP, Pi, and H+. The main difference between skeletal muscle and heart is a much higher cytosolic Pi concentration in healthy tissue and much higher cytosolic Pi accumulation (level) at low OXPHOS activities in the former, caused by a higher PCr level in healthy tissue (and higher total phosphate pool) and smaller Pi redistribution between cytosol and mitochondria at OXPHOS deficiency. This difference does not depend on ATP demand in a broad range. A much greater Pi increase and PCr decrease during rest-to-moderate work transition in skeletal muscle at OXPHOS deficiencies than at normal OXPHOS activity significantly slows down the V̇o2 on-kinetics. Because high cytosolic Pi concentrations cause fatigue in skeletal muscle and can compromise force generation in skeletal muscle and heart, this system property can contribute to the faster and stronger manifestation of mitochondrial diseases in skeletal muscle than in heart. Shortly, skeletal muscle with large OXPHOS deficiencies becomes fatigued already during low/moderate exercise. PMID:27283913

Faster and stronger manifestation of mitochondrial diseases in skeletal muscle than in heart related to cytosolic inorganic phosphate (Pi) accumulation.

PubMed

Korzeniewski, Bernard

2016-08-01

A model of the cell bioenergetic system was used to compare the effect of oxidative phosphorylation (OXPHOS) deficiencies in a broad range of moderate ATP demand in skeletal muscle and heart. Computer simulations revealed that kinetic properties of the system are similar in both cases despite the much higher mitochondria content and "basic" OXPHOS activity in heart than in skeletal muscle, because of a much higher each-step activation (ESA) of OXPHOS in skeletal muscle than in heart. Large OXPHOS deficiencies lead in both tissues to a significant decrease in oxygen consumption (V̇o2) and phosphocreatine (PCr) and increase in cytosolic ADP, Pi, and H(+) The main difference between skeletal muscle and heart is a much higher cytosolic Pi concentration in healthy tissue and much higher cytosolic Pi accumulation (level) at low OXPHOS activities in the former, caused by a higher PCr level in healthy tissue (and higher total phosphate pool) and smaller Pi redistribution between cytosol and mitochondria at OXPHOS deficiency. This difference does not depend on ATP demand in a broad range. A much greater Pi increase and PCr decrease during rest-to-moderate work transition in skeletal muscle at OXPHOS deficiencies than at normal OXPHOS activity significantly slows down the V̇o2 on-kinetics. Because high cytosolic Pi concentrations cause fatigue in skeletal muscle and can compromise force generation in skeletal muscle and heart, this system property can contribute to the faster and stronger manifestation of mitochondrial diseases in skeletal muscle than in heart. Shortly, skeletal muscle with large OXPHOS deficiencies becomes fatigued already during low/moderate exercise. Copyright © 2016 the American Physiological Society.

The PI3K inhibitor GDC-0941 displays promising in vitro and in vivo efficacy for targeted medulloblastoma therapy.

PubMed

Ehrhardt, Michael; Craveiro, Rogerio B; Holst, Martin I; Pietsch, Torsten; Dilloo, Dagmar

2015-01-20

Deregulation of the Phosphoinositide 3-kinase (PI3K)/AKT signalling network is a hallmark of oncogenesis. Also medulloblastoma, the most common malignant brain tumor in children, is characterized by high levels of AKT phosphorylation and activated PI3K signalling in medulloblastoma is associated with enhanced cellular motility, survival and chemoresistency underscoring its role of as a potential therapeutic target. Here we demonstrate that GDC-0941, a highly specific PI3K inhibitor with good clinical tolerability and promising anti-neoplastic activity in adult cancer, also displays anti-proliferative and pro-apoptotic effects in pediatric human medulloblastoma cell lines. Loss in cell viability is accompanied by reduced phosphorylation of AKT, a downstream target of PI3K. Furthermore, we show that GDC-0941 attenuates the migratory capacity of medulloblastoma cells and targets subpopulations expressing the stem cell marker CD133. GDC-0941 also synergizes with the standard medulloblastoma chemotherapeutic etoposide. In an orthotopic xenograft model of the most aggressive human medulloblastoma variant we document that oral adminstration of GDC-0941 impairs tumor growth and significantly prolongs survival. These findings provide a rational to further investigate GDC-0941 alone and in combination with standard chemotherapeutics for medulloblastoma treatment.

The PI3K inhibitor GDC-0941 displays promising in vitro and in vivo efficacy for targeted medulloblastoma therapy

PubMed Central

Holst, Martin I.; Pietsch, Torsten; Dilloo, Dagmar

2015-01-01

Deregulation of the Phosphoinositide 3-kinase (PI3K)/AKT signalling network is a hallmark of oncogenesis. Also medulloblastoma, the most common malignant brain tumor in children, is characterized by high levels of AKT phosphorylation and activated PI3K signalling in medulloblastoma is associated with enhanced cellular motility, survival and chemoresistency underscoring its role of as a potential therapeutic target. Here we demonstrate that GDC-0941, a highly specific PI3K inhibitor with good clinical tolerability and promising anti-neoplastic activity in adult cancer, also displays anti-proliferative and pro-apoptotic effects in pediatric human medulloblastoma cell lines. Loss in cell viability is accompanied by reduced phosphorylation of AKT, a downstream target of PI3K. Furthermore, we show that GDC-0941 attenuates the migratory capacity of medulloblastoma cells and targets subpopulations expressing the stem cell marker CD133. GDC-0941 also synergizes with the standard medulloblastoma chemotherapeutic etoposide. In an orthotopic xenograft model of the most aggressive human medulloblastoma variant we document that oral adminstration of GDC-0941 impairs tumor growth and significantly prolongs survival. These findings provide a rational to further investigate GDC-0941 alone and in combination with standard chemotherapeutics for medulloblastoma treatment. PMID:25596739

A novel blast resistance gene, Pi54rh cloned from wild species of rice, Oryza rhizomatis confers broad spectrum resistance to Magnaporthe oryzae.

PubMed

Das, Alok; Soubam, D; Singh, P K; Thakur, S; Singh, N K; Sharma, T R

2012-06-01

The dominant rice blast resistance gene, Pi54 confers resistance to Magnaporthe oryzae in different parts of India. In our effort to identify more effective forms of this gene, we isolated an orthologue of Pi54 named as Pi54rh from the blast-resistant wild species of rice, Oryza rhizomatis, using allele mining approach and validated by complementation. The Pi54rh belongs to CC-NBS-LRR family of disease resistance genes with a unique Zinc finger (C(3)H type) domain. The 1,447 bp Pi54rh transcript comprises of 101 bp 5'-UTR, 1,083 bp coding region and 263 bp 3'-UTR, driven by pathogen inducible promoter. We showed the extracellular localization of Pi54rh protein and the presence of glycosylation, myristoylation and phosphorylation sites which implicates its role in signal transduction process. This is in contrast to other blast resistance genes that are predicted to be intracellular NBS-LRR-type resistance proteins. The Pi54rh was found to express constitutively at basal level in the leaves, but upregulates 3.8-fold at 96 h post-inoculation with the pathogen. Functional validation of cloned Pi54rh gene using complementation test showed high degree of resistance to seven isolates of M. oryzae collected from different geographical locations of India. In this study, for the first time, we demonstrated that a rice blast resistance gene Pi54rh cloned from wild species of rice provides broad spectrum resistance to M. oryzae hence can be used in rice improvement breeding programme.

Measurement of CP--violating asymmetries in $$D^0\\to\\pi^+\\pi^-$$ and $$D^0\\to K^+K^-$$ decays at CDF

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

Aaltonen, T.; /Helsinki Inst. of Phys.; Alvarez Gonzalez, B.

2011-11-01

We report on a measurement of CP-violating asymmetries (A{sub CP}) in the Cabibbo-suppressed D{sup 0} {yields} {pi}{sup +}{pi}{sup -} and D{sup 0} {yields} K{sup +}K{sup -} decays reconstructed in a data sample corresponding to 5.9 fb{sup -1} of integrated luminosity collected by the upgraded Collider Detector at Fermilab. We use the strong decay D*{sup +} {yields} D{sup 0}{pi}{sup +} to identify the flavor of the charmed meson at production and exploit CP-conserving strong c{bar c} pair-production in p{bar p} collisions. High-statistics samples of Cabibbo-favored D{sup 0} {yields} K{sup -}{pi}{sup +} decays with and without a D*{sup {+-}} tag are usedmore » to correct for instrumental effects and significantly reduce systematic uncertainties. We measure A{sub CP}(D{sup 0} {yields} {pi}{sup +}{pi}{sup -}) = (+0.22 {+-} 0.24(stat) {+-} 0.11 (syst))% and A{sub CP}(D{sup 0} {yields} K{sup +}K{sup -}) = (-0.24 {+-} 0.22 (stat) {+-} 0.09 (syst))%, in agreement with CP conservation. These are the most precise determinations from a single experiment to date. Under the assumption of negligible direct CP violation in D{sup 0} {yields} {pi}{sup +}{pi}{sup -} and D{sup 0} {yields} K{sup +}K{sup -} decays, the results provide an upper limit to the CP-violating asymmetry in D{sup 0} mixing, |A{sub CP}{sup ind}(D{sup 0})| < 0.13% at the 90% confidence level.« less

Effect of unitarization on the amplitudes for the decays K{sub 1}{sup 0} {sup {yields} {pi}+{pi}-} and K{sup +} {sup {yields} {pi}+{pi}+{pi}-}

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

Shabalin, E. P., E-mail: shabalin@itep.r

The unitarization of the amplitude for the decay process K{sub 1}{sup 0} {sup {yields} {pi}+{pi}-} and allowance for the rescattering of final-state pions in the decay process K{sup +} {sup {yields} {pi}+{pi}+{pi}-} make it possible to evaluate, by using the parameters extracted from data on K {sup {yields}}2{pi} decays, the K{sup +} {sup {yields} {pi}+{pi}+{pi}-} decay width. The result agrees with the experimental width value at a level of a few percent. Allowance for corrections for higher order terms of the momentum expansion of the amplitude for the decay process K{sup +} {sup {yields} {pi}+{pi}+{pi}-} leads to the slope-parameter valuemore » of g{sub ++-}{sup th} = 0.2182, which agrees with its experimental counterpart, g{sub ++-}{sup exp} = 0.2154 {+-} 0.0035.« less

Characterization of Uranium Tolerance and Biomineralization Potential of Caulobacter crescentus

NASA Astrophysics Data System (ADS)

Park, D.

2015-12-01

Due to its high toxicity and mobility, U(VI) poses a major environmental threat to ecosystems. The ubiquitous aerobic bacterium Caulobacter cresecentus is an attractive candidate for U(VI) bioremediation because of its ability to survive in low-nutrient environments (5, 6), tolerate high U concentrations and mineralize U(VI) aerobically through the formation of uranyl phosphate (U-Pi) precipitates. Despite these attractive environmental properties, both a systems level understanding of the adaptive response pathways involved in U tolerance and the environmental conditions affecting the biomineralization process and stability of biogenic U-Pi minerals remain limited. By measuring changes in both mRNA and protein expression during exposure to high U levels, we have identified the core stress response pathways involved in U tolerance. Pathways associated with heat shock, lipospolysaccharide biosynthesis and transport, outer membrane lipoprotein transport and outermembrane assembly were highly induced at both the RNA and protein levels. Correspondingly, removal of integral components of proteolysis pathways including clpA, clpS and degP significantly reduced U tolerance under biomineralization conditions. Surprisingly, in contrast to many other heavy metals, U did not cause oxidative stress or DNA damage. Together, these analyses indicate that U predominately targets the outermembrane and causes mis-folding of both cytoplasmic and extracytoplasmic proteins. Efforts are currently underway to characterize the morphological and structural properties of biogenic U-Pi minerals and the environmental factors that influence their production and stability. Preliminary AFM studies suggest that U-Pi minerals formed under biomineralization conditions appear morphologically distinct from those formed abiotically between U(VI) and inorganic phosphate. Additionally, we observed that biomineralization tolerates a wide pH range (pH 6-9). Our long-range goal is the development of a conceptual model of the role of microbes in U cycling under oxidizing conditions across the DOE complex, and ultimately, provide DOE with the scientific basis to support decisions for the remediation of legacy sites.

PI(4)P Promotes Phosphorylation and Conformational Change of Smoothened through Interaction with Its C-terminal Tail

PubMed Central

Zhang, Jie; Li, Xiang-An; Evers, B. Mark; Zhu, Haining; Jia, Jianhang

2016-01-01

In Hedgehog (Hh) signaling, binding of Hh to the Patched-Interference Hh (Ptc-Ihog) receptor complex relieves Ptc inhibition on Smoothened (Smo). A longstanding question is how Ptc inhibits Smo and how such inhibition is relieved by Hh stimulation. In this study, we found that Hh elevates production of phosphatidylinositol 4-phosphate (PI(4)P). Increased levels of PI(4)P promote, whereas decreased levels of PI(4)P inhibit, Hh signaling activity. We further found that PI(4)P directly binds Smo through an arginine motif, which then triggers Smo phosphorylation and activation. Moreover, we identified the pleckstrin homology (PH) domain of G protein-coupled receptor kinase 2 (Gprk2) as an essential component for enriching PI(4)P and facilitating Smo activation. PI(4)P also binds mouse Smo (mSmo) and promotes its phosphorylation and ciliary accumulation. Finally, Hh treatment increases the interaction between Smo and PI(4)P but decreases the interaction between Ptc and PI(4)P, indicating that, in addition to promoting PI(4)P production, Hh regulates the pool of PI(4)P associated with Ptc and Smo. PMID:26863604

Age differences in behavioral and neural correlates of proactive interference: Disentangling the role of overall working memory performance.

PubMed

Loosli, Sandra V; Rahm, Benjamin; Unterrainer, Josef M; Mader, Irina; Weiller, Cornelius; Kaller, Christoph P

2016-02-15

Reliable performance in working memory (WM) critically depends on the ability to resist proactive interference (PI) from previously relevant WM contents. Both WM performance and PI susceptibility are subject to cognitive decline at older adult age. However, the behavioral and neural processes underlying these co-evolving developmental changes and their potential interdependencies are not yet understood. Here, we investigated PI using a recent-probes WM paradigm and functional MRI in a cross-sectional sample of younger (n=18, 10 female, 23.4 ± 2.7 years) and older adults (n=18, 10 female, 70.2 ± 2.7 years). As expected, older adults showed lower WM performance and higher PI susceptibility than younger adults. Resolution of PI activated a mainly bilateral frontal network across all participants. Significant interactions with age indicated reduced neural activation in older adults for PI resolution. A second analysis in a selection of younger and older adults (n=12 each) with matched WM performance also revealed significant differences in PI between both age groups and - on a descriptive level - again a hypo-activation of the older adults' PI network. But the differential effect of age on the neural PI effects did not reach significance in this smaller sample most likely to the reduced statistical power. However, given the highly similar patterns in both the overall and the WM-matched samples, we propose that the hypo-activation of the PI network in the older adults may not be attributable to age-related differences in overall WM performance, hence suggesting that higher PI susceptibility in older adult age does not directly depend on their lower WM performance. Copyright © 2015 Elsevier Inc. All rights reserved.

Sensitivity of jarrah (Eucalyptus marginata) to phosphate, phosphite, and arsenate pulses as influenced by fungal symbiotic associations.

PubMed

Kariman, Khalil; Barker, Susan J; Jost, Ricarda; Finnegan, Patrick M; Tibbett, Mark

2016-07-01

Many plant species adapted to P-impoverished soils, including jarrah (Eucalyptus marginata), develop toxicity symptoms when exposed to high doses of phosphate (Pi) and its analogs such as phosphite (Phi) and arsenate (AsV). The present study was undertaken to investigate the effects of fungal symbionts Scutellospora calospora, Scleroderma sp., and Austroboletus occidentalis on the response of jarrah to highly toxic pulses (1.5 mmol kg(-1) soil) of Pi, Phi, and AsV. S. calospora formed an arbuscular mycorrhizal (AM) symbiosis while both Scleroderma sp. and A. occidentalis established a non-colonizing symbiosis with jarrah plants. All these interactions significantly improved jarrah growth and Pi uptake under P-limiting conditions. The AM fungal colonization naturally declines in AM-eucalypt symbioses after 2-3 months; however, in the present study, the high Pi pulse inhibited the decline of AM fungal colonization in jarrah. Four weeks after exposure to the Pi pulse, plants inoculated with S. calospora had significantly lower toxicity symptoms compared to non-mycorrhizal (NM) plants, and all fungal treatments induced tolerance against Phi toxicity in jarrah. However, no tolerance was observed for AsV-treated plants even though all inoculated plants had significantly lower shoot As concentrations than the NM plants. The transcript profile of five jarrah high-affinity phosphate transporter (PHT1 family) genes in roots was not altered in response to any of the fungal species tested. Interestingly, plants exposed to high Pi supplies for 1 day did not have reduced transcript levels for any of the five PHT1 genes in roots, and transcript abundance of four PHT1 genes actually increased. It is therefore suggested that jarrah, and perhaps other P-sensitive perennial species, respond positively to Pi available in the soil solution through increasing rather than decreasing the expression of selected PHT1 genes. Furthermore, Scleroderma sp. can be considered as a fungus with dual functional capacity capable of forming both ectomycorrhizal and non-colonizing associations, where both pathways are always accompanied by evident growth and nutritional benefits.

The combination of lanthanum chloride and the calcimimetic calindol delays the progression of vascular smooth muscle cells calcification

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

Ciceri, Paola; Volpi, Elisa; Brenna, Irene

2012-02-24

Highlights: Black-Right-Pointing-Pointer Lanthanum reduces the progression of high phosphate-induced calcium deposition. Black-Right-Pointing-Pointer Calcium receptor agonists and the calcimimetic calindol reduce calcium deposition. Black-Right-Pointing-Pointer Lanthanum and calindol cooperate on reducing calcium deposition. Black-Right-Pointing-Pointer Lanthanum and calindol may interact with the same receptor. -- Abstract: Phosphate (Pi)-binders are commonly used in dialysis patients to control high Pi levels, that associated with vascular calcification (VC). The aim of this study was to investigate the effects of lanthanum chloride (LaCl{sub 3}) on the progression of high Pi-induced VC, in rat vascular smooth muscle cells (VSMCs). Pi-induced Ca deposition was inhibited by LaCl{sub 3}, withmore » a maximal effect at 100 {mu}M (59.0 {+-} 2.5% inhibition). Furthermore, we studied the effects on VC of calcium sensing receptor (CaSR) agonists. Gadolinium chloride, neomycin, spermine, and the calcimimetic calindol significantly inhibited Pi-induced VC (55.9 {+-} 2.2%, 37.3 {+-} 4.7%, 30.2 {+-} 5.7%, and 63.8 {+-} 5.7%, respectively). To investigate the hypothesis that LaCl{sub 3} reduces the progression of VC by interacting with the CaSR, we performed a concentration-response curve of LaCl{sub 3} in presence of a sub-effective concentration of calindol (10 nM). Interestingly, this curve was shifted to the left (IC{sub 50} 9.6 {+-} 2.6 {mu}M), compared to the curve in the presence of LaCl{sub 3} alone (IC{sub 50} 19.0 {+-} 4.8 {mu}M). In conclusion, we demonstrated that lanthanum chloride effectively reduces the progression of high phosphate-induced vascular calcification. In addition, LaCl{sub 3} cooperates with the calcimimetic calindol in decreasing Ca deposition in this in vitro model. These results suggest the potential role of lanthanum in the treatment of VC induced by high Pi.« less

Assessment of selected biochemical parameters and humoral immune response of Nile crocodiles (Crocodylus niloticus) experimentally infected with Trichinella zimbabwensis.

PubMed

La Grange, Louis J; Mukaratirwa, Samson

2014-08-21

Fifteen crocodiles were randomly divided into three groups of five animals. They represented high-infection, medium-infection and low-infection groups of 642 larvae/kg, 414 larvae/kg and 134 larvae/kg bodyweight, respectively. The parameters assessed were blood glucose, creatine phosphokinase (CPK), lactate dehydrogenase (LDH), aspartate transaminase (AST) and alanine transaminase (ALT). The humoral immune response to Trichinella zimbabwensis infection was evaluated in all three groups by an indirect ELISA method. The results showed deviations from normal parameters of blood glucose, CPK, LDH, AST and ALT when compared with reported levels in uninfected reptiles. Contrary to studies involving mammals, hypoglycaemia was not observed in the infected groups in this study. Peak values of blood glucose were reached on post-infection (PI) Day 49, Day 42 and Day 35 in the high-infection, medium-infection and low-infection groups, respectively. Peak values of LDH and AST were observed on PI Day 56, Day 49 and Day 42 in the high-infection, medium-infection and low-infection groups, respectively. Peak values of CPK were observed on Day 35 PI in all three groups. Peak ALT values were reached on Day 56 in the high-infection group and on Day 28 PI in both the medium-infection and low-infection groups. No correlations between the biochemical parameters and infection intensity were observed. Peak antibody titres were reached on Day 49 PI in the medium-infection group, and on Day 42 PI in both the high-infection and low-infection groups. Infection intensity could not be correlated with the magnitude of the humoral immune response or time to sero-conversion. Results from this study were in agreement with results reported in mammals infected with other Trichinella species and showed that antibody titres could not be detected indefinitely.

Elevations in the Fasting Serum Proinsulin-to-C-Peptide Ratio Precede the Onset of Type 1 Diabetes.

PubMed

Sims, Emily K; Chaudhry, Zunaira; Watkins, Renecia; Syed, Farooq; Blum, Janice; Ouyang, Fangqian; Perkins, Susan M; Mirmira, Raghavendra G; Sosenko, Jay; DiMeglio, Linda A; Evans-Molina, Carmella

2016-09-01

We tested whether an elevation in the serum proinsulin-to-C-peptide ratio (PI:C), a biomarker of β-cell endoplasmic reticulum (ER) dysfunction, was associated with progression to type 1 diabetes. Fasting total PI and C levels were measured in banked serum samples obtained from TrialNet Pathway to Prevention (PTP) participants, a cohort of autoantibody-positive relatives without diabetes of individuals with type 1 diabetes. Samples were obtained ∼12 months before diabetes onset from PTP progressors in whom diabetes developed (n = 60), and were compared with age-, sex-, and BMI-matched nonprogressors who remained normoglycemic (n = 58). PI:C ratios were calculated as molar ratios and were multiplied by 100% to obtain PI levels as a percentage of C levels. Although absolute PI levels did not differ between groups, PI:C ratios were significantly increased in antibody-positive subjects in whom there was progression to diabetes compared with nonprogressors (median 1.81% vs. 1.17%, P = 0.03). The difference between groups was most pronounced in subjects who were ≤10 years old, where the median progressor PI:C ratio was nearly triple that of nonprogressors; 90.0% of subjects in this age group within the upper PI:C quartile progressed to the development of diabetes. Logistic regression analysis, adjusted for age and BMI, demonstrated increased odds of progression for higher natural log PI:C ratio values (odds ratio 1.44, 95% CI 1.02, 2.05). These data suggest that β-cell ER dysfunction precedes type 1 diabetes onset, especially in younger children. Elevations in the serum PI:C ratio may have utility in predicting the onset of type 1 diabetes in the presymptomatic phase. © 2016 by the American Diabetes Association.

Elevations in the Fasting Serum Proinsulin–to–C-Peptide Ratio Precede the Onset of Type 1 Diabetes

PubMed Central

Sims, Emily K.; Chaudhry, Zunaira; Watkins, Renecia; Syed, Farooq; Blum, Janice; Ouyang, Fangqian; Perkins, Susan M.; Mirmira, Raghavendra G.; Sosenko, Jay; DiMeglio, Linda A.

2016-01-01

OBJECTIVE We tested whether an elevation in the serum proinsulin–to–C-peptide ratio (PI:C), a biomarker of β-cell endoplasmic reticulum (ER) dysfunction, was associated with progression to type 1 diabetes. RESEARCH DESIGN AND METHODS Fasting total PI and C levels were measured in banked serum samples obtained from TrialNet Pathway to Prevention (PTP) participants, a cohort of autoantibody-positive relatives without diabetes of individuals with type 1 diabetes. Samples were obtained ∼12 months before diabetes onset from PTP progressors in whom diabetes developed (n = 60), and were compared with age-, sex-, and BMI-matched nonprogressors who remained normoglycemic (n = 58). PI:C ratios were calculated as molar ratios and were multiplied by 100% to obtain PI levels as a percentage of C levels. RESULTS Although absolute PI levels did not differ between groups, PI:C ratios were significantly increased in antibody-positive subjects in whom there was progression to diabetes compared with nonprogressors (median 1.81% vs. 1.17%, P = 0.03). The difference between groups was most pronounced in subjects who were ≤10 years old, where the median progressor PI:C ratio was nearly triple that of nonprogressors; 90.0% of subjects in this age group within the upper PI:C quartile progressed to the development of diabetes. Logistic regression analysis, adjusted for age and BMI, demonstrated increased odds of progression for higher natural log PI:C ratio values (odds ratio 1.44, 95% CI 1.02, 2.05). CONCLUSIONS These data suggest that β-cell ER dysfunction precedes type 1 diabetes onset, especially in younger children. Elevations in the serum PI:C ratio may have utility in predicting the onset of type 1 diabetes in the presymptomatic phase. PMID:27385327

IMPACT: Imaging and Molecular Markers for Patients with Lung Cancer: Approaches with Molecular Targets, Complementary/Innovative Treatments, and Therapeutic Modalities

DTIC Science & Technology

2014-02-01

DRP-1: Treatment of Malignant Pleural Effusion with ZD6474, a Novel VEGFR and EGFR TK Inhibitor (PI and co-PI: Roy Herbst, M.D., Ph.D., Carlos...Jimenez, M.D.) Recurrent malignant pleural effusion is a debilitating clinical problem that requires palliation with repeated therapeutic...thoracentesis or pleurodesis (Putnam, J Surg Clin North Am 2002). Malignant pleural effusions have been associated with high levels of VEGF. Treatment with a

Does the Loss of Stromal Caveolin-1 Remodel the Tumor Microenvironment by Activating Src-Mediated PEAK1 and PI3K Pathways

DTIC Science & Technology

2017-11-01

and PI3K Pathways? PRINCIPAL INVESTIGATOR: MARIANA REIS SOBREIRO PhD CONTRACTING ORGANIZATION: Cedars-Sinai Medical Center Los Angeles, CA 90048...BEVERLY BLVD LOS ANGELES CA 90048-1804 9. SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR’S ACRONYM(S) U.S. Army Medical...oncosomes ( LO ). LO internalization induces reprogramming of human normal prostate fibroblasts, as reflected by high levels of α-SMA, IL6, and MMP9. In

MicroRNA399 is a long-distance signal for the regulation of plant phosphate homeostasis

PubMed Central

Pant, Bikram Datt; Buhtz, Anja; Kehr, Julia; Scheible, Wolf-Rüdiger

2008-01-01

The presence of microRNA species in plant phloem sap suggests potential signaling roles by long-distance regulation of gene expression. Proof for such a role for a phloem-mobile microRNA is lacking. Here we show that phosphate (Pi) starvation-induced microRNA399 (miR399) is present in the phloem sap of two diverse plant species, rapeseed and pumpkin, and levels are strongly and specifically increased in phloem sap during Pi deprivation. By performing micro-grafting experiments using Arabidopsis, we further show that chimeric plants constitutively over-expressing miR399 in the shoot accumulate mature miR399 species to very high levels in their wild-type roots, while corresponding primary transcripts are virtually absent in roots, demonstrating shoot-to-root transport. The chimeric plants exhibit (i) down-regulation of the miR399 target transcript (PHO2), which encodes a critical component for maintenance of Pi homeostasis, in the wild-type root, and (ii) Pi accumulation in the shoot, which is the phenotype of pho2 mutants, miR399 over-expressers or chimeric plants with a genetic knock-out of PHO2 in the root. Hence the transported miR399 molecules retain biological activity. This is a demonstration of systemic control of a biological process, i.e. maintenance of plant Pi homeostasis, by a phloem-mobile microRNA. PMID:17988220

Development of perceived instrumentality for mathematics, reading and science curricula

NASA Astrophysics Data System (ADS)

Garcia, Steve L.

Perceptions of instrumentality (PI) are the connections one sees between a current activity and a future goal. With high PI, one is motivated to persist with quality effort because the current activity, even when difficult, is perceived as aligned with, and progress toward, the goal. Conversely, with low PI, one is motivated to relinquish effort in pursuit of other, more meaningful goals. In view of the alarming dropout rates in this country, it appears that PI research has much to offer in understanding students' motivations to stay in school and hence to become employed in their field of choice. Because academic achievement motivation can be affected by gender and ethnicity, particularly for specific components of the curriculum, and because curricular content varies across grade levels and school settings, this line of research offers significant potential for understanding and improving student outcomes. This research examined the development of PI among suburban 6th, 8th, 10th and 12th graders from a school district in the southwestern United States. Twelve hundred students completed a one-time paper and pencil survey measuring the perceived instrumentality of mathematics, literacy and science courses in terms of the students' occupational choices. MANOVA was used to determine factors that may affect students' overall PI and individual subject PI. Grade, gender, ethnicity, occupational choice, expectancy and value were the independent variables. A school setting variable was examined for effects on 12th graders. For the 8th through 12th grade sample, significant main effects were observed for grade, gender, minority status, occupational choice and expectancy on PI. Results show that PI is highest in the 6 th grade. Males reported higher Math PI than females. Females reported higher Reading PI and Science PI than males. Minority students reported lower overall PI and Science PI than non-minority students. Students who aspire to professional careers report the highest PI; and students who expect to achieve their occupational choice score higher than those who do not. Among 12th graders, significant two-way interaction effects on PI were observed between school type and gender; school type and occupational value; and, occupational expectancy and value.

Characterization of porcine partially reprogrammed iPSCs from adipose-derived stem cells.

PubMed

Wei, Chao; Li, Xia; Zhang, Pengfei; Zhang, Yu; Liu, Tong; Jiang, Shaoshuai; Han, Fei; Zhang, Yunhai

2015-05-01

Partially reprogrammed induced pluripotent stem cells (PiPSCs) have great potential for investigating reprogramming mechanisms and represent an alternative potential material for making genetically modified animals and regenerative medicine. To date, PiPSCs have scarcely been reported in detail when compared with mice and humans. In this study, we obtained PiPSCs from porcine adipose-derived stem cells (pADSCs) by ectopic expression of human transcription factors (OCT4, SOX2, c-MYC, and KLF4) in feeder-free condition. The morphology and proliferation activity of porcine PiPSCs (pPiPSCs) were similar to those of porcine fully reprogrammed iPSCs (pFiPSCs); furthermore, pPiPSCs expressed higher levels of the typical surface molecules (CD29) found in pADSCs. However, pPiPSCs were negative for key proteins (NANOG) connected with stemness and possessed lower differentiation ability in vivo and in vitro. When differentiation-inhibiting factors were withdrawn, pPiPSCs-derived cells (pPiPSC-DCs) showed similar features to pADSCs in many aspects, including proliferation, differentiation, and immunosuppression. When both types of cells were used to produce cloned embryos, we found that the blastocyst formation rate of 19DC (one of the pPiPSC-DC cell lines)-derived cloned embryos was obviously higher than that of others. The total cell number of 19DC-derived blastocysts was significantly higher than the 30DC (one pFiPSC-DC cell line)-derived blastocysts. In all, through limited differentiation ability, the proliferation activity of pPiPSCs is similar to that of pFiPSCs, and pPiPSCs can retain several of the features of pADSCs, which are beneficial to cell therapy. Furthermore, the differentiation of pPiPSCs is more favorable for producing high-quality reconstructed embryos. © 2015 Society for Reproduction and Fertility.

Cardio-Metabolic Effects of HIV Protease Inhibitors (Lopinavir/Ritonavir)

PubMed Central

Reyskens, Kathleen M. S. E.; Fisher, Tarryn-Lee; Schisler, Jonathan C.; O'Connor, Wendi G.; Rogers, Arlin B.; Willis, Monte S.; Planesse, Cynthia; Boyer, Florence; Rondeau, Philippe; Bourdon, Emmanuel; Essop, M. Faadiel

2013-01-01

Although antiretroviral treatment decreases HIV-AIDS morbidity/mortality, long-term side effects may include the onset of insulin resistance and cardiovascular diseases. However, the underlying molecular mechanisms responsible for highly active antiretroviral therapy (HAART)-induced cardio-metabolic effects are poorly understood. In light of this, we hypothesized that HIV protease inhibitor (PI) treatment (Lopinavir/Ritonavir) elevates myocardial oxidative stress and concomitantly inhibits the ubiquitin proteasome system (UPS), thereby attenuating cardiac function. Lopinavir/Ritonavir was dissolved in 1% ethanol (vehicle) and injected into mini-osmotic pumps that were surgically implanted into Wistar rats for 8 weeks vs. vehicle and sham controls. We subsequently evaluated metabolic parameters, gene/protein markers and heart function (ex vivo Langendorff perfusions). PI-treated rats exhibited increased serum LDL-cholesterol, higher tissue triglycerides (heart, liver), but no evidence of insulin resistance. In parallel, there was upregulation of hepatic gene expression, i.e. acetyl-CoA carboxylase β and 3-hydroxy-3-methylglutaryl-CoA-reductase, key regulators of fatty acid oxidation and cholesterol synthesis, respectively. PI-treated hearts displayed impaired cardiac contractile function together with attenuated UPS activity. However, there was no significant remodeling of hearts exposed to PIs, i.e. lack of ultrastructural changes, fibrosis, cardiac hypertrophic response, and oxidative stress. Western blot analysis of PI-treated hearts revealed that perturbed calcium handling may contribute to the PI-mediated contractile dysfunction. Here chronic PI administration led to elevated myocardial calcineurin, nuclear factor of activated T-cells 3 (NFAT3), connexin 43, and phosphorylated phospholamban, together with decreased calmodulin expression levels. This study demonstrates that early changes triggered by PI treatment include increased serum LDL-cholesterol levels together with attenuated cardiac function. Furthermore, PI exposure inhibits the myocardial UPS and leads to elevated calcineurin and connexin 43 expression that may be associated with the future onset of cardiac contractile dysfunction. PMID:24098634

Phosphatidyl Inositol 3 Kinase-Gamma Balances Antiviral and Inflammatory Responses During Influenza A H1N1 Infection: From Murine Model to Genetic Association in Patients

PubMed Central

Garcia, Cristiana C.; Tavares, Luciana P.; Dias, Ana Carolina F.; Kehdy, Fernanda; Alvarado-Arnez, Lucia Elena; Queiroz-Junior, Celso M.; Galvão, Izabela; Lima, Braulio H.; Matos, Aline R.; Gonçalves, Ana Paula F.; Soriani, Frederico M.; Moraes, Milton O.; Marques, João T.; Siqueira, Marilda M.; Machado, Alexandre M. V.; Sousa, Lirlândia P.; Russo, Remo C.; Teixeira, Mauro M.

2018-01-01

Influenza A virus (IAV) infection causes severe pulmonary disease characterized by intense leukocyte infiltration. Phosphoinositide-3 kinases (PI3Ks) are central signaling enzymes, involved in cell growth, survival, and migration. Class IB PI3K or phosphatidyl inositol 3 kinase-gamma (PI3Kγ), mainly expressed by leukocytes, is involved in cell migration during inflammation. Here, we investigated the contribution of PI3Kγ for the inflammatory and antiviral responses to IAV. PI3Kγ knockout (KO) mice were highly susceptible to lethality following infection with influenza A/WSN/33 H1N1. In the early time points of infection, infiltration of neutrophils was higher than WT mice whereas type-I and type-III IFN expression and p38 activation were reduced in PI3Kγ KO mice resulting in higher viral loads when compared with WT mice. Blockade of p38 in WT macrophages infected with IAV reduced levels of interferon-stimulated gene 15 protein to those induced in PI3Kγ KO macrophages, suggesting that p38 is downstream of antiviral responses mediated by PI3Kγ. PI3Kγ KO-derived fibroblasts or macrophages showed reduced type-I IFN transcription and altered pro-inflammatory cytokines suggesting a cell autonomous imbalance between inflammatory and antiviral responses. Seven days after IAV infection, there were reduced infiltration of natural killer cells and CD8+ T lymphocytes, increased concentration of inflammatory cytokines in bronchoalveolar fluid, reduced numbers of resolving macrophages, and IL-10 levels in PI3Kγ KO. This imbalanced environment in PI3Kγ KO-infected mice culminated in enhanced lung neutrophil infiltration, reactive oxygen species release, and lung damage that together with the increased viral loads, contributed to higher mortality in PI3Kγ KO mice compared with WT mice. In humans, we tested the genetic association of disease severity in influenza A/H1N1pdm09-infected patients with three potentially functional PIK3CG single-nucleotide polymorphisms (SNPs), rs1129293, rs17847825, and rs2230460. We observed that SNPs rs17847825 and rs2230460 (A and T alleles, respectively) were significantly associated with protection from severe disease using the recessive model in patients infected with influenza A(H1N1)pdm09. Altogether, our results suggest that PI3Kγ is crucial in balancing antiviral and inflammatory responses to IAV infection.

Dietary choline deficiency and excess induced intestinal inflammation and alteration of intestinal tight junction protein transcription potentially by modulating NF-κB, STAT and p38 MAPK signaling molecules in juvenile Jian carp.

PubMed

Wu, Pei; Jiang, Wei-Dan; Jiang, Jun; Zhao, Juan; Liu, Yang; Zhang, Yong-An; Zhou, Xiao-Qiu; Feng, Lin

2016-11-01

This study investigated the effects of choline on intestinal mucosal immune and the possible mechanisms in fish by feeding juvenile Jian carp (Cyprinus carpio var. Jian) with graded levels of dietary choline (165-1820 mg/kg diet) for 65 days. The results firstly showed that choline deficiency induced inflammatory infiltration in the proximal intestine (PI), mid intestine (MI) and distal intestine (DI) of fish. Meanwhile, compared with the optimal choline group, choline deficiency decreased the activities of lysozyme and acid phosphatase, contents of complement 3 and IgM in the intestine, downregulated the mRNA levels of antimicrobial peptides (liver-expressed antimicrobial peptide (LEAP) 2A and defensin-3 in the PI and MI, LEAP-2B and hepcidin in the PI, MI and DI), anti-inflammatory cytokines (interleukin (IL) 10 and transforming growth factor β2 in the PI, MI and DI), and signaling molecule IκB in the PI, MI and DI; while upregulated the mRNA levels of pro-inflammatory cytokines (IL-6a and tumor necrosis factor α in the MI and DI, interferon γ2b in the PI and MI, IL-1β and IL-6b in the PI, MI and DI), and signaling molecules (Toll-like receptor 4 in the MI, myeloid differentiation primary response 88 in the PI and MI, Janus kinase 3 and tyrosine kinase 2 in the MI and DI, nuclear factor kappa B (NF-κB), signal transducers and activators of transcription (STAT) 4 and STAT5 in the PI, MI and DI) of juvenile Jian carp, further indicating that choline deficiency caused inflammation and immunity depression in the intestine of fish. But choline deficiency decreased the PI IL-6a mRNA level, and increased the DI LEAP-2A and defensin-3 mRNA levels with unknown reasons. Furthermore, dietary choline deficiency downregulated mRNA levels of tight junction (TJ) proteins (claudin 3c in the PI and MI, claudin 7, claudin 11 and occludin in the PI, MI and DI) and signaling molecule mitogen-activated protein kinases p38 in the PI, MI and DI of juvenile Jian carp, whereas upregulated the mRNA levels of claudin 3b in the MI and DI, and claudin 3c in the DI. Moreover, the excessive choline exhibited negative effects on intestinal immunity and TJ proteins that were similar to the choline deficiency. In summary, dietary choline deficiency or excess caused the depression of intestinal mucosal immune by inducing inflammation and dysfunction of the intestinal physical barrier, and regulating related signaling molecules of fish. Copyright © 2016 Elsevier Ltd. All rights reserved.

Association of serum inorganic phosphate with sex steroid hormones and vitamin D in a nationally representative sample of men.

PubMed

Wulaningsih, W; Van Hemelrijck, M; Michaelsson, K; Kanarek, N; Nelson, W G; Ix, J H; Platz, E A; Rohrmann, S

2014-11-01

Defects in bone regulatory pathways have been linked to chronic diseases including cardiovascular disease and cancer. In men, a link between bone metabolism and gonadal hormones has been suggested. However, to date, there is lack of evidence on the association between serum inorganic phosphate (Pi) and sex steroid hormones. The objective of this study was to investigate the association between Pi, sex steroid hormones and a known Pi metabolic regulator, vitamin D, in men in the National Health and Nutrition Examination Survey III (NHANES III). From NHANES III, we selected 1412 men aged 20+ who participated in the morning session of Phase I (1988-1991) with serum measurements of Pi, sex hormones, and vitamin D. Multivariable linear regression was used to calculate crude and geometric mean Pi by total and estimated free testosterone and estradiol, sex hormone-binding globulin, androstanediol glucuronide (AAG), and vitamin D. Similar analyses were performed while stratifying by race/ethnicity and vitamin D levels. We found a lack of statistically significant difference in geometric means of Pi across quintiles of concentrations of sex hormones, indicating a tight regulation of Pi. However, Pi levels were inversely associated with calculated free testosterone in non-Hispanic black men, with geometric mean levels of Pi of 1.16 and 1.02 ng/mL for those in the lowest and highest quintiles of free testosterone, respectively (p-trend < 0.05). A similar but weaker pattern was seen between total testosterone and Pi. An inverse association was also seen between AAG and Pi in men with vitamin D concentration below the median (<24.2 ng/mL). No associations were observed among men with vitamin D levels at or above the median. Our findings suggest a weak link among sex hormones, vitamin D, and Pi in men. The observed effects of race/ethnicity and vitamin D indicate a complex association involving various regulators of Pi homeostasis. © 2014 American Society of Andrology and European Academy of Andrology.

Functional pools of fast and slow twitch fibers observed by /sup 31/P-NMR during exercise of flexor wrist muscles in man

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

Park, J.H.; Park, C.R.; Brown, R.L.

Functional compartments of fast and slow twitch fibers have been observed by /sup 31/P-NMR spectroscopy during exercise of the wrist flexor muscles in a sedentary, young male subject. Values of Pi, phosphocreatine (PCr) and adenine nucleotides were determined at rest and during an exercise protocol. The subject flexed his wrist muscles at 20% of maximum strength every 5 sec for 6 min and then increased his effort in the next two 6 min intervals to 40% and 60% of maximum. With exercise, the Pi/PCr rose rapidly to the exceptionally high value of 2.2 at 60% effort. As the Pi increased,more » the initial single peak (pH 7.0-6.9) split into two distinct components with pH values of 6.8 and 6.3. Quantitatively, distribution of the Pi was 40% in the pH 6.8 peak and 60% in the pH 6.3 peak as determined by area estimation following curve fitting. This presumably reflects two pools of Pi corresponding to the oxidative (slow twitch, high pH) and glycolytic (fast twitch, low pH) fibers. In the second identical exercise sequence which followed immediately, only one Pi peak (pH 6.8-6.9) appeared. This suggested that the glycolytic contribution to energy production was largely exhausted and the residual energy was derived from oxidative metabolism. During exercise at high levels, total phosphate decreased due primarily to loss of NMR visible adenine nucleotides. Similar phenomena have been observed in three other sedentary individuals, but not in trained athletes.« less

Diversity of P-element piRNA production among M' and Q strains and its association with P-M hybrid dysgenesis in Drosophila melanogaster.

PubMed

Wakisaka, Keiko Tsuji; Ichiyanagi, Kenji; Ohno, Seiko; Itoh, Masanobu

2017-01-01

Transposition of P elements in the genome causes P-M hybrid dysgenesis in Drosophila melanogaster . For the P strain, the P-M phenotypes are associated with the ability to express a class of small RNAs, called piwi-interacting small RNAs (piRNAs), that suppress the P elements in female gonads. However, little is known about the extent to which piRNAs are involved in the P-M hybrid dysgenesis in M' and Q strains, which show different abilities to regulate the P elements from P strains. To elucidate the molecular basis of the suppression of paternally inherited P elements, we analyzed the mRNA and piRNA levels of P elements in the F1 progeny between males of a P strain and nine-line females of M' or Q strains (M' or Q progenies). M' progenies showed the hybrid dysgenesis phenotype, while Q progenies did not. Consistently, the levels of P -element mRNA in both the ovaries and F1 embryos were higher in M' progenies than in Q progenies, indicating that the M' progenies have a weaker ability to suppress P -element expression. The level of P -element mRNA was inversely correlated to the level of piRNAs in F1 embryos. Importantly, the M' progenies were characterized by a lower abundance of P -element piRNAs in both young ovaries and F1 embryonic bodies. The Q progenies showed various levels of piRNAs in both young ovaries and F1 embryonic bodies despite all of the Q progenies suppressing P -element transposition in their gonad. Our results are consistent with an idea that the level of P -element piRNAs is a determinant for dividing strain types between M' and Q and that the suppression mechanisms of transposable elements, including piRNAs, are varied between natural populations.

Preinduced intestinal HSP70 improves visceral hypersensitivity and abnormal intestinal motility in PI-IBS mouse model.

PubMed

Lan, Cheng; Sun, Xiao-Ning; Zhou, Xu-Chun; Yang, Bo; Huang, Bai-Li; Deng, Tao-Zhi; He, Zhou-Tao; Han, Xiang-Yang

2016-03-01

To investigate the impact of the preinduced intestinal heat shock protein 70 (HSP70) on the visceral hypersensitivity and abnormal intestinal motility in a post-infectious irritable bowel syndrome (PI-IBS) mouse model. Eighty-four female C57BL/6 mice were randomly assigned to four groups: control group (n = 21) and induction + PI-IBS group (n = 21), PI-IBS group (n = 21) and induction group (n = 21). The mice in PI-IBS group were infected in vivo with Trichinella spiralis by oral administration. The visceral hypersensitivity and intestinal motility were evaluated respectively with abdominal withdrawal reflex and colon transportation test. The intestinal HSP70 protein and mRNA level was measured by Western blot and real-time PCR. Meanwhile, the intestinal proinflammatory cytokines IL-10 and TNF-α level was detected by ELISA. Compared with their counterparts in PI-IBS group, the animals in the Induction + PI-IBS group show significantly increased intestinal level of HSP70 and obviously ameliorative clinical figures, including abdominal withdrawal reflex score, intestine transportation time and Bristol scores (P < 0.05). Meanwhile, the intestinal post-inflammatory cytokines remarkably changed, including increased IL-10 level and decreased TNF-α level (P < 0.05). Intestinal HSP70 may play a potential protective role through improving the imbalance between the intestinal post-inflammatory and anti-inflammatory cytokines in PI-IBS. Copyright © 2016 Hainan Medical College. Production and hosting by Elsevier B.V. All rights reserved.

Pharmacological inhibition of PI3K reduces adiposity and metabolic syndrome in obese mice and rhesus monkeys.

PubMed

Ortega-Molina, Ana; Lopez-Guadamillas, Elena; Mattison, Julie A; Mitchell, Sarah J; Muñoz-Martin, Maribel; Iglesias, Gema; Gutierrez, Vincent M; Vaughan, Kelli L; Szarowicz, Mark D; González-García, Ismael; López, Miguel; Cebrián, David; Martinez, Sonia; Pastor, Joaquin; de Cabo, Rafael; Serrano, Manuel

2015-04-07

Genetic inhibition of PI3K signaling increases energy expenditure, protects from obesity and metabolic syndrome, and extends longevity. Here, we show that two pharmacological inhibitors of PI3K, CNIO-PI3Ki and GDC-0941, decrease the adiposity of obese mice without affecting their lean mass. Long-term treatment of obese mice with low doses of CNIO-PI3Ki reduces body weight until reaching a balance that is stable for months as long as the treatment continues. CNIO-PI3Ki treatment also ameliorates liver steatosis and decreases glucose serum levels. The above observations have been recapitulated in independent laboratories and using different oral formulations of CNIO-PI3Ki. Finally, daily oral treatment of obese rhesus monkeys for 3 months with low doses of CNIO-PI3Ki decreased their adiposity and lowered their serum glucose levels, in the absence of detectable toxicities. Therefore, pharmacological inhibition of PI3K is an effective and safe anti-obesity intervention that could reverse the negative effects of metabolic syndrome in humans. Copyright © 2015 Elsevier Inc. All rights reserved.

PI(5)P Regulates Autophagosome Biogenesis

PubMed Central

Vicinanza, Mariella; Korolchuk, Viktor I.; Ashkenazi, Avraham; Puri, Claudia; Menzies, Fiona M.; Clarke, Jonathan H.; Rubinsztein, David C.

2015-01-01

Summary Phosphatidylinositol 3-phosphate (PI(3)P), the product of class III PI3K VPS34, recruits specific autophagic effectors, like WIPI2, during the initial steps of autophagosome biogenesis and thereby regulates canonical autophagy. However, mammalian cells can produce autophagosomes through enigmatic noncanonical VPS34-independent pathways. Here we show that PI(5)P can regulate autophagy via PI(3)P effectors and thereby identify a mechanistic explanation for forms of noncanonical autophagy. PI(5)P synthesis by the phosphatidylinositol 5-kinase PIKfyve was required for autophagosome biogenesis, and it increased levels of PI(5)P, stimulated autophagy, and reduced the levels of autophagic substrates. Inactivation of VPS34 impaired recruitment of WIPI2 and DFCP1 to autophagic precursors, reduced ATG5-ATG12 conjugation, and compromised autophagosome formation. However, these phenotypes were rescued by PI(5)P in VPS34-inactivated cells. These findings provide a mechanistic framework for alternative VPS34-independent autophagy-initiating pathways, like glucose starvation, and unravel a cytoplasmic function for PI(5)P, which previously has been linked predominantly to nuclear roles. PMID:25578879

Search for technicolor particles produced in association with a W Boson at CDF.

PubMed

Aaltonen, T; Adelman, J; Alvarez González, B; Amerio, S; Amidei, D; Anastassov, A; Annovi, A; Antos, J; Apollinari, G; Apresyan, A; Arisawa, T; Artikov, A; Asaadi, J; Ashmanskas, W; Attal, A; Aurisano, A; Azfar, F; Badgett, W; Barbaro-Galtieri, A; Barnes, V E; Barnett, B A; Barria, P; Bartos, P; Bauer, G; Beauchemin, P-H; Bedeschi, F; Beecher, D; Behari, S; Bellettini, G; Bellinger, J; Benjamin, D; Beretvas, A; Bhatti, A; Binkley, M; Bisello, D; Bizjak, I; Blair, R E; Blocker, C; Blumenfeld, B; Bocci, A; Bodek, A; Boisvert, V; Bortoletto, D; Boudreau, J; Boveia, A; Brau, B; Bridgeman, A; Brigliadori, L; Bromberg, C; Brubaker, E; Budagov, J; Budd, H S; Budd, S; Burkett, K; Busetto, G; Bussey, P; Buzatu, A; Byrum, K L; Cabrera, S; Calancha, C; Camarda, S; Campanelli, M; Campbell, M; Canelli, F; Canepa, A; Carls, B; Carlsmith, D; Carosi, R; Carrillo, S; Carron, S; Casal, B; Casarsa, M; Castro, A; Catastini, P; Cauz, D; Cavaliere, V; Cavalli-Sforza, M; Cerri, A; Cerrito, L; Chang, S H; Chen, Y C; Chertok, M; Chiarelli, G; Chlachidze, G; Chlebana, F; Cho, K; Chokheli, D; Chou, J P; Chung, K; Chung, W H; Chung, Y S; Chwalek, T; Ciobanu, C I; Ciocci, M A; Clark, A; Clark, D; Compostella, G; Convery, M E; Conway, J; Corbo, M; Cordelli, M; Cox, C A; Cox, D J; Crescioli, F; Cuenca Almenar, C; Cuevas, J; Culbertson, R; Cully, J C; Dagenhart, D; Datta, M; Davies, T; de Barbaro, P; De Cecco, S; Deisher, A; De Lorenzo, G; Dell'orso, M; Deluca, C; Demortier, L; Deng, J; Deninno, M; d'Errico, M; Di Canto, A; di Giovanni, G P; Di Ruzza, B; Dittmann, J R; D'Onofrio, M; Donati, S; Dong, P; Dorigo, T; Dube, S; Ebina, K; Elagin, A; Erbacher, R; Errede, D; Errede, S; Ershaidat, N; Eusebi, R; Fang, H C; Farrington, S; Fedorko, W T; Feild, R G; Feindt, M; Fernandez, J P; Ferrazza, C; Field, R; Flanagan, G; Forrest, R; Frank, M J; Franklin, M; Freeman, J C; Furic, I; Gallinaro, M; Galyardt, J; Garberson, F; Garcia, J E; Garfinkel, A F; Garosi, P; Gerberich, H; Gerdes, D; Gessler, A; Giagu, S; Giakoumopoulou, V; Giannetti, P; Gibson, K; Gimmell, J L; Ginsburg, C M; Giokaris, N; Giordani, M; Giromini, P; Giunta, M; Giurgiu, G; Glagolev, V; Glenzinski, D; Gold, M; Goldschmidt, N; Golossanov, A; Gomez, G; Gomez-Ceballos, G; Goncharov, M; González, O; Gorelov, I; Goshaw, A T; Goulianos, K; Gresele, A; Grinstein, S; Grosso-Pilcher, C; Grundler, U; Guimaraes da Costa, J; Gunay-Unalan, Z; Haber, C; Hahn, S R; Halkiadakis, E; Han, B-Y; Han, J Y; Happacher, F; Hara, K; Hare, D; Hare, M; Harr, R F; Hartz, M; Hatakeyama, K; Hays, C; Heck, M; Heijboer, A; Heinrich, J; Henderson, C; Herndon, M; Heuser, J; Hewamanage, S; Hidas, D; Hill, C S; Hirschbuehl, D; Hocker, A; Hou, S; Houlden, M; Hsu, S-C; Hughes, R E; Hurwitz, M; Husemann, U; Hussein, M; Huston, J; Incandela, J; Introzzi, G; Iori, M; Ivanov, A; James, E; Jang, D; Jayatilaka, B; Jeon, E J; Jha, M K; Jindariani, S; Johnson, W; Jones, M; Joo, K K; Jun, S Y; Jung, J E; Junk, T R; Kamon, T; Kar, D; Karchin, P E; Kato, Y; Kephart, R; Ketchum, W; Keung, J; Khotilovich, V; Kilminster, B; Kim, D H; Kim, H S; Kim, H W; Kim, J E; Kim, M J; Kim, S B; Kim, S H; Kim, Y K; Kimura, N; Kirsch, L; Klimenko, S; Kondo, K; Kong, D J; Konigsberg, J; Korytov, A; Kotwal, A V; Kreps, M; Kroll, J; Krop, D; Krumnack, N; Kruse, M; Krutelyov, V; Kuhr, T; Kulkarni, N P; Kurata, M; Kwang, S; Laasanen, A T; Lami, S; Lammel, S; Lancaster, M; Lander, R L; Lannon, K; Lath, A; Latino, G; Lazzizzera, I; Lecompte, T; Lee, E; Lee, H S; Lee, J S; Lee, S W; Leone, S; Lewis, J D; Lin, C-J; Linacre, J; Lindgren, M; Lipeles, E; Lister, A; Litvintsev, D O; Liu, C; Liu, T; Lockyer, N S; Loginov, A; Lovas, L; Lucchesi, D; Lueck, J; Lujan, P; Lukens, P; Lungu, G; Lys, J; Lysak, R; Macqueen, D; Madrak, R; Maeshima, K; Makhoul, K; Maksimovic, P; Malde, S; Malik, S; Manca, G; Manousakis-Katsikakis, A; Margaroli, F; Marino, C; Marino, C P; Martin, A; Martin, V; Martínez, M; Martínez-Ballarín, R; Mastrandrea, P; Mathis, M; Mattson, M E; Mazzanti, P; McFarland, K S; McIntyre, P; McNulty, R; Mehta, A; Mehtala, P; Menzione, A; Mesropian, C; Miao, T; Mietlicki, D; Miladinovic, N; Miller, R; Mills, C; Milnik, M; Mitra, A; Mitselmakher, G; Miyake, H; Moed, S; Moggi, N; Mondragon, M N; Moon, C S; Moore, R; Morello, M J; Morlock, J; Movilla Fernandez, P; Mülmenstädt, J; Mukherjee, A; Muller, Th; Murat, P; Mussini, M; Nachtman, J; Nagai, Y; Naganoma, J; Nakamura, K; Nakano, I; Napier, A; Nett, J; Neu, C; Neubauer, M S; Neubauer, S; Nielsen, J; Nodulman, L; Norman, M; Norniella, O; Nurse, E; Oakes, L; Oh, S H; Oh, Y D; Oksuzian, I; Okusawa, T; Orava, R; Osterberg, K; Pagan Griso, S; Pagliarone, C; Palencia, E; Papadimitriou, V; Papaikonomou, A; Paramanov, A A; Parks, B; Pashapour, S; Patrick, J; Pauletta, G; Paulini, M; Paus, C; Peiffer, T; Pellett, D E; Penzo, A; Phillips, T J; Piacentino, G; Pianori, E; Pinera, L; Pitts, K; Plager, C; Pondrom, L; Potamianos, K; Poukhov, O; Prokoshin, F; Pronko, A; Ptohos, F; Pueschel, E; Punzi, G; Pursley, J; Rademacker, J; Rahaman, A; Ramakrishnan, V; Ranjan, N; Redondo, I; Renton, P; Renz, M; Rescigno, M; Richter, S; Rimondi, F; Ristori, L; Robson, A; Rodrigo, T; Rodriguez, T; Rogers, E; Rolli, S; Roser, R; Rossi, M; Rossin, R; Roy, P; Ruiz, A; Russ, J; Rusu, V; Rutherford, B; Saarikko, H; Safonov, A; Sakumoto, W K; Santi, L; Sartori, L; Sato, K; Savoy-Navarro, A; Schlabach, P; Schmidt, A; Schmidt, E E; Schmidt, M A; Schmidt, M P; Schmitt, M; Schwarz, T; Scodellaro, L; Scribano, A; Scuri, F; Sedov, A; Seidel, S; Seiya, Y; Semenov, A; Sexton-Kennedy, L; Sforza, F; Sfyrla, A; Shalhout, S Z; Shears, T; Shepard, P F; Shimojima, M; Shiraishi, S; Shochet, M; Shon, Y; Shreyber, I; Simonenko, A; Sinervo, P; Sisakyan, A; Slaughter, A J; Slaunwhite, J; Sliwa, K; Smith, J R; Snider, F D; Snihur, R; Soha, A; Somalwar, S; Sorin, V; Squillacioti, P; Stanitzki, M; St Denis, R; Stelzer, B; Stelzer-Chilton, O; Stentz, D; Strologas, J; Strycker, G L; Suh, J S; Sukhanov, A; Suslov, I; Taffard, A; Takashima, R; Takeuchi, Y; Tanaka, R; Tang, J; Tecchio, M; Teng, P K; Thom, J; Thome, J; Thompson, G A; Thomson, E; Tipton, P; Ttito-Guzmán, P; Tkaczyk, S; Toback, D; Tokar, S; Tollefson, K; Tomura, T; Tonelli, D; Torre, S; Torretta, D; Totaro, P; Tourneur, S; Trovato, M; Tsai, S-Y; Tu, Y; Turini, N; Ukegawa, F; Uozumi, S; van Remortel, N; Varganov, A; Vataga, E; Vázquez, F; Velev, G; Vellidis, C; Vidal, M; Vila, I; Vilar, R; Vogel, M; Volobouev, I; Volpi, G; Wagner, P; Wagner, R G; Wagner, R L; Wagner, W; Wagner-Kuhr, J; Wakisaka, T; Wallny, R; Wang, S M; Warburton, A; Waters, D; Weinberger, M; Weinelt, J; Wester, W C; Whitehouse, B; Whiteson, D; Wicklund, A B; Wicklund, E; Wilbur, S; Williams, G; Williams, H H; Wilson, P; Winer, B L; Wittich, P; Wolbers, S; Wolfe, C; Wolfe, H; Wright, T; Wu, X; Würthwein, F; Yagil, A; Yamamoto, K; Yamaoka, J; Yang, U K; Yang, Y C; Yao, W M; Yeh, G P; Yi, K; Yoh, J; Yorita, K; Yoshida, T; Yu, G B; Yu, I; Yu, S S; Yun, J C; Zanetti, A; Zeng, Y; Zhang, X; Zheng, Y; Zucchelli, S

2010-03-19

We present a search for the technicolor particles rho{T} and pi_{T} in the process pp-->rho{T}-->Wpi{T} at a center of mass energy of sqrt[s]=1.96 TeV. The search uses a data sample corresponding to approximately 1.9 fb{-1} of integrated luminosity accumulated by the CDF II detector at the Fermilab Tevatron. The event signature we consider is W-->lnu and pi{T}-->bb, bc or bu depending on the pi{T} charge. We select events with a single high-p{T} electron or muon, large missing transverse energy, and two jets. Jets corresponding to bottom quarks are identified with multiple b-tagging algorithms. The observed number of events and the invariant mass distributions are consistent with the standard model background expectations, and we exclude a region at 95% confidence level in the rho{T}-pi{T} mass plane. As a result, a large fraction of the region m(rho{T})=180-250 GeV/c{2} and m(pi{T})=95-145 GeV/c{2} is excluded.

Higher Dietary Fructose Is Associated with Impaired Hepatic ATP Homeostasis in Obese Individuals with Type 2 Diabetes

PubMed Central

Abdelmalek, Manal F.; Lazo, Mariana; Horska, Alena; Bonekamp, Susanne; Lipkin, Edward W.; Balasubramanyam, Ashok; Bantle, John P.; Johnson, Richard J.; Diehl, Anna Mae; Clark, Jeanne M.

2012-01-01

Fructose consumption predicts increased hepatic fibrosis in those with nonalcoholic fatty liver disease (NAFLD). Due to its ability to lower hepatic adenosine triphosphate (ATP) levels, habitual fructose consumption could result in more hepatic ATP depletion and impaired ATP recovery. The degree of ATP depletion following an intravenous fructose challenge test in low versus high fructose consumers was assessed. We evaluated diabetic adults enrolled in the Look AHEAD Fatty Liver Ancillary Study (n=244) for whom dietary fructose consumption estimated by a 130-item Food Frequency questionnaire, hepatic ATP measured by phosphorus MRS (31P MRS) and uric acid (UA) levels were performed (n=105). In a subset of participants (n=25), an intravenous fructose challenge was utilized to assess change in hepatic ATP content. The relationships between dietary fructose, UA and hepatic ATP depletion at baseline and following intravenous fructose challenge was evaluated in low (<15 g/d) vs. high (≥15 g/d) fructose consumers. High dietary fructose consumers had slightly lower baseline hepatic ATP levels and a greater absolute change in hepatic α-ATP/Pi ratio (0.08 vs. 0.03, p=0.05) and γ-ATP /Pi ratio following an intravenous fructose challenge (0.03 vs. 0.06, p=0.06). Patients with high UA (≥5.5 mg/dl) showed a lower minimum liver ATP/Pi ratio post-fructose challenge (4.5 vs. 7.0, p = 0.04). Conclusions High fructose consumption depletes hepatic ATP and impairs recovery from ATP depletion following an intravenous fructose challenge. Subjects with high UA show a greater nadir in hepatic ATP in response to fructose. Both high dietary fructose intake and elevated UA level may predict more severe hepatic ATP depletion in response to fructose and hence may be risk factors for the development and progression of NAFLD. PMID:22467259

High-spin terminating states in the N = 88 Ho 155 and Er 156 isotones

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

Rees, J. M.; Paul, E. S.; Simpson, J.

2015-05-01

The Sn-124(Cl-37, 6n gamma) fusion-evaporation reaction at a bombarding energy of 180 MeV has been used to significantly extend the excitation level scheme of Ho-155(67)88. The collective rotational behavior of this nucleus breaks down above spin I similar to 30 and a fully aligned noncollective (band terminating) state has been identified at I-pi = 79/2(-). Comparison with cranked Nilsson-Strutinsky calculations also provides evidence for core-excited noncollective states at I-pi = 87/2(-) and (89/2(+)) involving particle-hole excitations across the Z = 64 shell gap. A similar core-excited state in Er-156(68)88 at I-pi = (46(+)) is also presented.

Why CO bonds side-on at low coverage and both side-on and upright at high coverage on the Cr(110) surface

NASA Technical Reports Server (NTRS)

Mehandru, S. P.; Anderson, A. B.

1985-01-01

An atom superposition and electron delocalization molecular orbital study of CO adsorption on the Cr(110) surface shows a high coordinate lying down orientation is favored. This is a result of the large number of empty d-band energy levels in chromium, which allows the antibonding counterparts to sigma and pi donation bonds to the surface to be empty. When lying down, backbonding to CO pi sup * orbitals is enhanced. Repulsive interactions cause additional CO to stand upright at 1/4 monolyer coverage. The results confirm the recent experimental study of Shinn and Madey.

Phosphatidylinositol 4,5-bisphosphate optical uncaging potentiates exocytosis

PubMed Central

Wierda, Keimpe DB; Pinheiro, Paulo S; Nadler, André; McCarthy, Anthony W; Ziomkiewicz, Iwona; Kruse, Martin; Reither, Gregor; Rettig, Jens; Lehmann, Martin; Haucke, Volker; Hille, Bertil

2017-01-01

Phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] is essential for exocytosis. Classical ways of manipulating PI(4,5)P2 levels are slower than its metabolism, making it difficult to distinguish effects of PI(4,5)P2 from those of its metabolites. We developed a membrane-permeant, photoactivatable PI(4,5)P2, which is loaded into cells in an inactive form and activated by light, allowing sub-second increases in PI(4,5)P2 levels. By combining this compound with electrophysiological measurements in mouse adrenal chromaffin cells, we show that PI(4,5)P2 uncaging potentiates exocytosis and identify synaptotagmin-1 (the Ca2+ sensor for exocytosis) and Munc13-2 (a vesicle priming protein) as the relevant effector proteins. PI(4,5)P2 activation of exocytosis did not depend on the PI(4,5)P2-binding CAPS-proteins, suggesting that PI(4,5)P2 uncaging may bypass CAPS-function. Finally, PI(4,5)P2 uncaging triggered the rapid fusion of a subset of readily-releasable vesicles, revealing a rapid role of PI(4,5)P2 in fusion triggering. Thus, optical uncaging of signaling lipids can uncover their rapid effects on cellular processes and identify lipid effectors. PMID:29068313

Neotectonic and Geomorphological Characteristics of the Ma Pi Leng Area (Ha Giang Province, North Vietnam): Implications for Improving the Worth of Vietnamese Geological Heritage

NASA Astrophysics Data System (ADS)

Van Bui, Thom; Huy Nguyen, Thinh; Duc Nguyen, Tung

2018-03-01

Ma Pi Leng area is the core part of Dong Van karst plateau geopark, and is a region of high diversity of geology and tectonics in Vietnam. This region has experienced strong uplift motions that have created three grades of regional relief: 1400-1600 m; 1100-1200 m and 500-600 m. This geomorphology is in turn strongly eroded by the stream systems and divided into different structural blocks controlled by the faults. During the neotectonic stage, several modes of faulting have occurred in Ma Pi Leng such as strikeslip, normal, extension, riverse faults. The NW-SE fault system had a decisive role in determining the structural pattern of the region. The tectonic fractures, at the largest scale, are hundreds of meters high and up to a kilometer long. Tectonic activities, together with exogenic processes, have made regional relief strongly diverse with strips of horsts and grabens as well as laddersteps-shaped escarpments, inverse topography, high cliffs and deep canyons. Besides that there are also the caves at varying levels of height, chains of sinkholes, and pyramidal mountainous peaks. Ma Pi Leng area is truly majestic and worthy of tourist attractions both in terms of scientific value and natural landscape.

Spleen transcriptome response to infection with avian pathogenic Escherichia coli in broiler chickens

PubMed Central

2011-01-01

Background Avian pathogenic Escherichia coli (APEC) is detrimental to poultry health and its zoonotic potential is a food safety concern. Regulation of antimicrobials in food-production animals has put greater focus on enhancing host resistance to bacterial infections through genetics. To better define effective mechanism of host resistance, global gene expression in the spleen of chickens, harvested at two times post-infection (PI) with APEC, was measured using microarray technology, in a design that will enable investigation of effects of vaccination, challenge, and pathology level. Results There were 1,101 genes significantly differentially expressed between severely infected and non-infected groups on day 1 PI and 1,723 on day 5 PI. Very little difference was seen between mildly infected and non-infected groups on either time point. Between birds exhibiting mild and severe pathology, there were 2 significantly differentially expressed genes on day 1 PI and 799 on day 5 PI. Groups with greater pathology had more genes with increased expression than decreased expression levels. Several predominate immune pathways, Toll-like receptor, Jak-STAT, and cytokine signaling, were represented between challenged and non-challenged groups. Vaccination had, surprisingly, no detectible effect on gene expression, although it significantly protected the birds from observable gross lesions. Functional characterization of significantly expressed genes revealed unique gene ontology classifications during each time point, with many unique to a particular treatment or class contrast. Conclusions More severe pathology caused by APEC infection was associated with a high level of gene expression differences and increase in gene expression levels. Many of the significantly differentially expressed genes were unique to a particular treatment, pathology level or time point. The present study not only investigates the transcriptomic regulations of APEC infection, but also the degree of pathology associated with that infection. This study will allow for greater discovery into host mechanisms for disease resistance, providing targets for marker assisted selection and advanced drug development. PMID:21951686

Spleen transcriptome response to infection with avian pathogenic Escherichia coli in broiler chickens.

PubMed

Sandford, Erin E; Orr, Megan; Balfanz, Emma; Bowerman, Nate; Li, Xianyao; Zhou, Huaijun; Johnson, Timothy J; Kariyawasam, Subhashinie; Liu, Peng; Nolan, Lisa K; Lamont, Susan J

2011-09-27

Avian pathogenic Escherichia coli (APEC) is detrimental to poultry health and its zoonotic potential is a food safety concern. Regulation of antimicrobials in food-production animals has put greater focus on enhancing host resistance to bacterial infections through genetics. To better define effective mechanism of host resistance, global gene expression in the spleen of chickens, harvested at two times post-infection (PI) with APEC, was measured using microarray technology, in a design that will enable investigation of effects of vaccination, challenge, and pathology level. There were 1,101 genes significantly differentially expressed between severely infected and non-infected groups on day 1 PI and 1,723 on day 5 PI. Very little difference was seen between mildly infected and non-infected groups on either time point. Between birds exhibiting mild and severe pathology, there were 2 significantly differentially expressed genes on day 1 PI and 799 on day 5 PI. Groups with greater pathology had more genes with increased expression than decreased expression levels. Several predominate immune pathways, Toll-like receptor, Jak-STAT, and cytokine signaling, were represented between challenged and non-challenged groups. Vaccination had, surprisingly, no detectible effect on gene expression, although it significantly protected the birds from observable gross lesions. Functional characterization of significantly expressed genes revealed unique gene ontology classifications during each time point, with many unique to a particular treatment or class contrast. More severe pathology caused by APEC infection was associated with a high level of gene expression differences and increase in gene expression levels. Many of the significantly differentially expressed genes were unique to a particular treatment, pathology level or time point. The present study not only investigates the transcriptomic regulations of APEC infection, but also the degree of pathology associated with that infection. This study will allow for greater discovery into host mechanisms for disease resistance, providing targets for marker assisted selection and advanced drug development.

Prototypical Recombinant Multi-Protease-Inhibitor-Resistant Infectious Molecular Clones of Human Immunodeficiency Virus Type 1

PubMed Central

Varghese, Vici; Mitsuya, Yumi; Fessel, W. Jeffrey; Liu, Tommy F.; Melikian, George L.; Katzenstein, David A.; Schiffer, Celia A.; Holmes, Susan P.

2013-01-01

The many genetic manifestations of HIV-1 protease inhibitor (PI) resistance present challenges to research into the mechanisms of PI resistance and the assessment of new PIs. To address these challenges, we created a panel of recombinant multi-PI-resistant infectious molecular clones designed to represent the spectrum of clinically relevant multi-PI-resistant viruses. To assess the representativeness of this panel, we examined the sequences of the panel's viruses in the context of a correlation network of PI resistance amino acid substitutions in sequences from more than 10,000 patients. The panel of recombinant infectious molecular clones comprised 29 of 41 study-defined PI resistance amino acid substitutions and 23 of the 27 tightest amino acid substitution clusters. Based on their phenotypic properties, the clones were classified into four groups with increasing cross-resistance to the PIs most commonly used for salvage therapy: lopinavir (LPV), tipranavir (TPV), and darunavir (DRV). The panel of recombinant infectious molecular clones has been made available without restriction through the NIH AIDS Research and Reference Reagent Program. The public availability of the panel makes it possible to compare the inhibitory activities of different PIs with one another. The diversity of the panel and the high-level PI resistance of its clones suggest that investigational PIs active against the clones in this panel will retain antiviral activity against most if not all clinically relevant PI-resistant viruses. PMID:23796938

Temporal pattern changes in duodenal protein tyrosine nitration events in response to Eimeria acervulina infection in chickens.

PubMed

Elsasser, Ted H; Miska, Kate; Kahl, Stanislaw; Fetterer, Raymond H; Martínez Ramirez, Alfredo

2018-06-04

Intracellular generation of nitric oxide (NO) and superoxide anion (SOA) can result in the formation of 3'-nitrotyrosine proteins (NTp). Nitrated proteins usually are associated with significant perturbation in protein function, apoptosis, autophagy, and cell death. We undertook the present study to establish the temporal dynamics of NTp generation in cytokeratin-18-positive epithelial cells (ETCs) of broiler chickens in response to infection with Eimeria acervulina. Duodenal tissue was harvested from noninfected (NOI) and infected (INF) broilers on days (d) 1, 3, 6, 7, and 10 postinfection (PI) and fixed, embedded, and sectioned for quantitative image analysis, immunohistochemistry with antibodies specific to NTp and the SOA-generating enzyme xanthine oxidase (XO). The pixel density characteristics for NTp and XO representative of ETCs demonstrated that NTp and XO increased in intestinal villi as early as d1 PI (P < 0.05 vs. NOI). Progressive increases in NTp were evident in ETCs through d6 PI. For XO, increases in cell content increased only through d3. On d6 and d7 PI, high levels of NTp were present in immune infiltrating cells (IIC) where no XO was detected. The increases in ETC NTp occurred in a defined pattern, significant by villus-to-crypt location for day of infection, initiating in the distal villus and progressing down into the crypts. Two NTp patterns were observed for ETCs: a high level associated with ETCs harboring parasites and a low-level increase in ETCs not containing Eimeria but in proximity to such. The data suggest that NTp and XO responses may mediate some of the processes through which ETCs respond to Eimeria to limit the extent of infection by this pathogen.

The Second-Generation Maturation Inhibitor GSK3532795 Maintains Potent Activity Toward HIV Protease Inhibitor–Resistant Clinical Isolates

PubMed Central

Ray, Neelanjana; Li, Tianbo; Lin, Zeyu; Protack, Tricia; van Ham, Petronella Maria; Hwang, Carey; Krystal, Mark; Nijhuis, Monique; Lataillade, Max

2017-01-01

Background: Protease inhibitor (PI)-resistant HIV-1 isolates with primary substitutions in protease (PR) and secondary substitutions in Gag could potentially exhibit cross-resistance to maturation inhibitors. We evaluated the second-generation maturation inhibitor, GSK3532795, for activity toward clinical isolates with genotypic and phenotypic characteristics associated with PI resistance (longitudinal). Methods: Longitudinal clinical isolates from 15 PI-treated patients and 7 highly PI-resistant (nonlongitudinal) viruses containing major and minor PI resistance-associated mutations were evaluated for GSK3532795 sensitivity. Phenotypic sensitivity was determined using the PhenoSense Gag/PR assay (Monogram Biosciences) or in-house single- and multiple-cycle assays. Changes from baseline [CFB; ratio of post- to pre-treatment FC-IC50 (fold-change in IC50 versus wild-type virus)] <3 were considered to be within the no-effect level. Results: All nonlongitudinal viruses tested were sensitive to GSK3532795 (FC-IC50 range 0.16–0.68). Among longitudinal isolates, all post-PI treatment samples had major PI resistance-associated mutations in PR and 17/21 had PI resistance-associated changes in Gag. Nineteen of the 21 post-PI treatment samples had GSK3532795 CFB <3. Median (range) CFB was 0.83 (0.05–27.4) [Monogram (11 patients)] and 1.5 (1.0–2.2) [single-cycle (4 patients)]. The 2 post-PI treatment samples showing GSK3532795 CFB >3 (Monogram) were retested using single- and multiple-cycle assays. Neither sample had meaningful sensitivity changes in the multiple-cycle assay. Gag changes were not associated with an increased GSK3532795 CFB. Conclusions: GSK3532795 maintained antiviral activity against PI-resistant isolates with emergent PR and/or Gag mutations. This finding supports continued development of GSK3532795 in treatment-experienced patients with or without previous PI therapy. PMID:28234686

Identification of amino acid residues of mammalian mitochondrial phosphate carrier important for its functional expression in yeast cells, as achieved by PCR-mediated random mutation and gap-repair cloning.

PubMed

Yamagoshi, Ryohei; Yamamoto, Takenori; Hashimoto, Mitsuru; Sugahara, Ryohei; Shiotsuki, Takahiro; Miyoshi, Hideto; Terada, Hiroshi; Shinohara, Yasuo

2017-01-01

The mitochondrial phosphate carrier (PiC) of mammals, but not the yeast one, is synthesized with a presequence. The deletion of this presequence of the mammalian PiC was reported to facilitate the import of the carrier into yeast mitochondria, but the question as to whether or not mammalian PiC could be functionally expressed in yeast mitochondria was not addressed. In the present study, we first examined whether the defective growth on a glycerol plate of yeast cells lacking the yeast PiC gene could be reversed by the introduction of expression vectors of rat PiCs. The introduction of expression vectors encoding full-length rat PiC (rPiC) or rPiC lacking the presequence (ΔNrPiC) was ineffective in restoring growth on the glycerol plates. When we examined the expression levels of individual rPiCs in yeast mitochondria, ΔNrPiC was expressed at a level similar to that of yeast PiC, but that of rPiC was very low. These results indicated that ΔNrPiC expressed in yeast mitochondria is inert. Next, we sought to isolate "revertants" viable on the glycerol plate by expressing randomly mutated ΔNrPiC, and obtained two clones. These clones carried either of two mutations, F267S or F282S; and these mutations restored the transport function of ΔNrPiC in yeast mitochondria. These two Phe residues were conserved in human carrier (hPiC), and the transport function of ΔNhPiC expressed in yeast mitochondria was also markedly improved by their substitutions. Thus, substitution of F267S or F282S was concluded to be important for functional expression of mammalian PiCs in yeast mitochondria. Copyright © 2016 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

Community-Based Participatory Research Approach to Evidence-Based Research: Lessons From the Pacific Islander American Health Study

PubMed Central

Panapasa, Sela; Jackson, James; Caldwell, Cleopatra; Heeringa, Steve; McNally, James; Williams, David; Coral, Debra; Taumoepeau, Leafa; Young, Louisa; Young, Setafano; Fa'asisila, Saia

2013-01-01

Objectives Reports on the challenges and lessons learned from the Pacific Island American Health Study engagement with community-based organizations (CBOs) and faith-based organizations (FBOs) in Pacific Islander (PI) communities and mechanisms to facilitate the collection of robust data. Methods Academic–community partnership building was achieved with PI CBOs and FBOs. Focus group meetings were organized to plan various aspects of the study, develop questionnaire themes and protocols for survey, assist with the interviewer recruitment process, and strategize data dissemination plan. Lessons Learned The PIA-HS represents a model for overcoming challenges in data collection among small understudied populations. FBOs represent a valuable resource for community-based participatory research (CBPR) data collection and for effective interventions. Conclusion The study methodology can be replicated for other racial/ethnic groups with high levels of religiosity combined with concentrated levels of residential clustering. Expansion of the Pacific Islander American Health Study (PIA-HS) to include other PI subgroups is encouraged. PMID:22643788

Selective Loss of Cysteine Residues and Disulphide Bonds in a Potato Proteinase Inhibitor II Family

PubMed Central

Li, Xiu-Qing; Zhang, Tieling; Donnelly, Danielle

2011-01-01

Disulphide bonds between cysteine residues in proteins play a key role in protein folding, stability, and function. Loss of a disulphide bond is often associated with functional differentiation of the protein. The evolution of disulphide bonds is still actively debated; analysis of naturally occurring variants can promote understanding of the protein evolutionary process. One of the disulphide bond-containing protein families is the potato proteinase inhibitor II (PI-II, or Pin2, for short) superfamily, which is found in most solanaceous plants and participates in plant development, stress response, and defence. Each PI-II domain contains eight cysteine residues (8C), and two similar PI-II domains form a functional protein that has eight disulphide bonds and two non-identical reaction centres. It is still unclear which patterns and processes affect cysteine residue loss in PI-II. Through cDNA sequencing and data mining, we found six natural variants missing cysteine residues involved in one or two disulphide bonds at the first reaction centre. We named these variants Pi7C and Pi6C for the proteins missing one or two pairs of cysteine residues, respectively. This PI-II-7C/6C family was found exclusively in potato. The missing cysteine residues were in bonding pairs but distant from one another at the nucleotide/protein sequence level. The non-synonymous/synonymous substitution (Ka/Ks) ratio analysis suggested a positive evolutionary gene selection for Pi6C and various Pi7C. The selective deletion of the first reaction centre cysteine residues that are structure-level-paired but sequence-level-distant in PI-II illustrates the flexibility of PI-II domains and suggests the functionality of their transient gene versions during evolution. PMID:21494600

Let’s Move for Pacific Islander Communities: An Evidence-Based Intervention to Increase Physical Activity

PubMed Central

LaBreche, Mandy; Cheri, Ashley; Custodio, Harold; Fex, Cleo Carlos; Foo, Mary Anne; Lepule, Jonathan Tana; May, Vanessa Tui’one; Orne, Annette; Pang, Jane Ka’ala; Pang, Victor Kaiwi; Sablan-Santos, Lola; Schmidt-Vaivao, Dorothy; Surani, Zul; Talavou, Melevesi Fifita; Toilolo, Tupou; Palmer, Paula Healani; Tanjasiri, Sora Park

2015-01-01

Pacific Islander (PI) populations of Southern California experience high obesity and low physical activity levels. Given PI’s rich cultural ties, efforts to increase physical activity using a community tailored strategy may motivate members in a more sustainable manner. In this paper, we: 1) detail the program adaptation methodology that was utilized to develop the Weaving an Islander Network for Cancer Awareness, Research and Training (WINCART) Center’s PI Let’s Move Program, a culturally-tailored program aimed to increase physical activity levels among members of PI organizations in Southern California, and 2) share the program’s pilot evaluation results on individual and organizational changes. The WINCART Center applied the National Cancer Institute’s program adaptation guidelines to tailor the evidence-based Instant Recess program to fit the needs of PIs. The end product, the PI Let’s Move Program, was piloted in 2012 with eight PI organizations, reaching 106 PI adults. At baseline, 52% of participants reported that they were not physically active, with the average number of days engaged in medium-intensity physical activity at 2.09 days/week. After the 2-month program, participants increased the number of days that they engaged in medium-intensity physical activity from 2.09 to 2.90 days/week. Post-pilot results found that 82% of participants reported intentions to engage in physical activity for at least the next six months. At baseline, only one organization was currently implementing a physical activity program, and none had implemented an evidence-based physical activity program tailored for PIs. After the 2-month timeframe, despite varying levels of capacity, all eight organizations were able to successfully implement the program. In conclusion, results from our program provide evidence that disparity populations, such as PIs, can be successfully reached through programs that are culturally tailored to both individuals and their community organizations. PMID:26153489

Reverse-D-4F Increases the Number of Endothelial Progenitor Cells and Improves Endothelial Progenitor Cell Dysfunctions in High Fat Diet Mice.

PubMed

Nana, Yang; Peng, Jiao; Jianlin, Zhang; Xiangjian, Zhang; Shutong, Yao; Enxin, Zhan; Bin, Li; Chuanlong, Zong; Hua, Tian; Yanhong, Si; Yunsai, Du; Shucun, Qin; Hui, Wang

2015-01-01

Although high density lipoprotein (HDL) improves the functions of endothelial progenitor cells (EPCs), the effect of HDL ApoAI mimetic peptide reverse-D-4F (Rev-D4F) on EPC mobilization and repair of EPC dysfunctions remains to be studied. In this study, we investigated the effects of Rev-D4F on peripheral blood cell subpopulations in C57 mice treated with a high fat diet and the mechanism of Rev-D4F in improving the function of EPCs impaired by tumor necrosis factor-α (TNF-α). The high fat diet significantly decreased the number of EPCs, EPC migratory functions, and the percentage of lymphocytes in the white blood cells. However, it significantly increased the number of white blood cells, the percentage of monocytes in the white blood cells, and the level of vascular endothelial growth factor (VEGF) and TNF-α in the plasma. Rev-D4F clearly inhibited the effect of the high fat diet on the quantification of peripheral blood cell subpopulations and cytokine levels, and increased stromal cell derived factor 1α (SDF-1α) in the plasma. We provided in vitro evidence that TNF-α impaired EPC proliferation, migration, and tube formation through inactive AKT and eNOS, which was restored by Rev-D4F treatment. In contrast, both the PI3-kinase (PI3K) inhibitor (LY294002) and AKT inhibitor (perifosine) obviously inhibited the restoration of Rev-4F on EPCs impaired by TNF-α. Our results suggested that Rev-D4F increases the quantity of endothelial progenitor cells through increasing the SDF-1α levels and decreasing the TNF-α level of peripheral blood in high fat diet-induced C57BL/6J mice, and restores TNF-α induced dysfunctions of EPCs partly through stimulating the PI3K/AKT signal pathway.

Suppression of the auxin response pathway enhances susceptibility to Phytophthora cinnamomi while phosphite-mediated resistance stimulates the auxin signalling pathway

PubMed Central

2014-01-01

Background Phytophthora cinnamomi is a devastating pathogen worldwide and phosphite (Phi), an analogue of phosphate (Pi) is highly effective in the control of this pathogen. Phi also interferes with Pi starvation responses (PSR), of which auxin signalling is an integral component. In the current study, the involvement of Pi and the auxin signalling pathways in host and Phi-mediated resistance to P. cinnamomi was investigated by screening the Arabidopsis thaliana ecotype Col-0 and several mutants defective in PSR and the auxin response pathway for their susceptibility to this pathogen. The response to Phi treatment was also studied by monitoring its effect on Pi- and the auxin response pathways. Results Here we demonstrate that phr1-1 (phosphate starvation response 1), a mutant defective in response to Pi starvation was highly susceptible to P. cinnamomi compared to the parental background Col-0. Furthermore, the analysis of the Arabidopsis tir1-1 (transport inhibitor response 1) mutant, deficient in the auxin-stimulated SCF (Skp1 − Cullin − F-Box) ubiquitination pathway was also highly susceptible to P. cinnamomi and the susceptibility of the mutants rpn10 and pbe1 further supported a role for the 26S proteasome in resistance to P. cinnamomi. The role of auxin was also supported by a significant (P < 0.001) increase in susceptibility of blue lupin (Lupinus angustifolius) to P. cinnamomi following treatment with the inhibitor of auxin transport, TIBA (2,3,5-triiodobenzoic acid). Given the apparent involvement of auxin and PSR signalling in the resistance to P. cinnamomi, the possible involvement of these pathways in Phi mediated resistance was also investigated. Phi (especially at high concentrations) attenuates the response of some Pi starvation inducible genes such as AT4, AtACP5 and AtPT2 in Pi starved plants. However, Phi enhanced the transcript levels of PHR1 and the auxin responsive genes (AUX1, AXR1and AXR2), suppressed the primary root elongation, and increased root hair formation in plants with sufficient Pi. Conclusions The auxin response pathway, particularly auxin sensitivity and transport, plays an important role in resistance to P. cinnamomi in Arabidopsis, and phosphite-mediated resistance may in some part be through its effect on the stimulation of the PSR and auxin response pathways. PMID:24649892

QTL mapping of downy and powdery mildew resistances in PI 197088 cucumber with genotyping-by-sequencing in RIL population.

PubMed

Wang, Yuhui; VandenLangenberg, Kyle; Wen, Changlong; Wehner, Todd C; Weng, Yiqun

2018-03-01

Host resistances in PI 197088 cucumber to downy and powdery mildew pathogens are conferred by 11 (3 with major effect) and 4 (1 major effect) QTL, respectively, and three of which are co-localized. The downy mildew (DM) and powdery mildew (PM) are the two most important foliar diseases of cucurbit crops worldwide. The cucumber accession PI 197088 exhibits high-level resistances to both pathogens. Here, we reported QTL mapping results for DM and PM resistances with 148 recombinant inbred lines from a cross between PI 197088 and the susceptible line 'Coolgreen'. Phenotypic data on responses to natural DM and PM infection were collected in multi-year and multi-location replicated field trials. A high-density genetic map with 2780 single nucleotide polymorphisms (SNPs) from genotyping-by-sequencing and 55 microsatellite markers was developed, which revealed genomic regions with segregation distortion and mis-assemblies in the '9930' cucumber draft genome. QTL analysis identified 11 and 4 QTL for DM and PM resistances accounting for more than 73.5 and 63.0% total phenotypic variance, respectively. Among the 11 DM resistance QTL, dm5.1, dm5.2, and dm5.3 were major-effect contributing QTL, whereas dm1.1, dm2.1, and dm6.2 conferred susceptibility. Of the 4 QTL for PM resistance, pm5.1 was the major-effect QTL explaining 32.4% phenotypic variance and the minor-effect QTL pm6.1 contributed to disease susceptibility. Three PM QTL, pm2.1, pm5.1, and pm6.1, were co-localized with DM QTL dm2.1, dm5.2, and dm6.1, respectively, which was consistent with the observed linkage of PM and DM resistances in PI 197088. The genetic architecture of DM resistance in PI 197088 and another resistant line WI7120 (PI 330628) was compared, and the potential of using PI 197088 in cucumber breeding for downy and powdery mildew resistances is discussed.

2PI effective theory at next-to-leading order using the functional renormalization group

NASA Astrophysics Data System (ADS)

Carrington, M. E.; Friesen, S. A.; Meggison, B. A.; Phillips, C. D.; Pickering, D.; Sohrabi, K.

2018-02-01

We consider a symmetric scalar theory with quartic coupling in four dimensions. We show that the four-loop 2PI calculation can be done using a renormalization group method. The calculation involves one bare coupling constant which is introduced at the level of the Lagrangian and is therefore conceptually simpler than a standard 2PI calculation, which requires multiple counterterms. We explain how our method can be used to do the corresponding calculation at the 4PI level, which cannot be done using any known method by introducing counterterms.

Measurement of prominent eta-decay branching fractions.

PubMed

Lopez, A; Mehrabyan, S; Mendez, H; Ramirez, J; Ge, J Y; Miller, D H; Sanghi, B; Shipsey, I P J; Xin, B; Adams, G S; Anderson, M; Cummings, J P; Danko, I; Hu, D; Moziak, B; Napolitano, J; He, Q; Insler, J; Muramatsu, H; Park, C S; Thorndike, E H; Yang, F; Artuso, M; Blusk, S; Khalil, S; Li, J; Menaa, N; Mountain, R; Nisar, S; Randrianarivony, K; Sia, R; Skwarnicki, T; Stone, S; Wang, J C; Bonvicini, G; Cinabro, D; Dubrovin, M; Lincoln, A; Asner, D M; Edwards, K W; Naik, P; Briere, R A; Ferguson, T; Tatishvili, G; Vogel, H; Watkins, M E; Rosner, J L; Adam, N E; Alexander, J P; Cassel, D G; Duboscq, J E; Ehrlich, R; Fields, L; Galik, R S; Gibbons, L; Gray, R; Gray, S W; Hartill, D L; Heltsley, B K; Hertz, D; Jones, C D; Kandaswamy, J; Kreinick, D L; Kuznetsov, V E; Mahlke-Krüger, H; Mohapatra, D; Onyisi, P U E; Patterson, J R; Peterson, D; Riley, D; Ryd, A; Sadoff, A J; Shi, X; Stroiney, S; Sun, W M; Wilksen, T; Athar, S B; Patel, R; Yelton, J; Rubin, P; Eisenstein, B I; Karliner, I; Lowrey, N; Selen, M; White, E J; Wiss, J; Mitchell, R E; Shepherd, M R; Besson, D; Pedlar, T K; Cronin-Hennessy, D; Gao, K Y; Hietala, J; Kubota, Y; Klein, T; Lang, B W; Poling, R; Scott, A W; Zweber, P; Dobbs, S; Metreveli, Z; Seth, K K; Tomaradze, A; Ernst, J; Ecklund, K M; Severini, H; Love, W; Savinov, V

2007-09-21

The decay psi(2S) --> etaJ/psi is used to measure, for the first time, all prominent eta-meson branching fractions with the same experiment in the same dataset, thereby providing a consistent treatment of systematics across branching fractions. We present results for eta decays to gamma gamma, pi(+)pi(-)pi(0), 3pi(0), pi(+)pi(-)gamma and e(+)e(-)gamma, accounting for 99.9% of all eta decays. The precision of several of the branching fractions and their ratios is improved. Two channels, pi(+)pi(-)gamma and e(+)e(-)gamma, show results that differ at the level of three standard deviations from those previously determined.

[Effect of Buzhong Yiqi decoction on PI3K and AKT in spleen, stomach and lung of nude mice with lung adenocarcinoma transplantation tumor].

PubMed

Liu, Ya-Li; Wang, Ying; Yi, Jia-Li; Jing, Huan; Liu, Chun-Ying

2014-05-01

To explore the effect of Buzhong Yiqi decoction on PI3K/AKT signaling pathway in spleen, stomach and lung of nude mice with lung adenocarcinoma transplantation tumor. Totally 60 nude mice were randomly divided into the blank control group, the tumor-bearing control group, the cisplatin group, the low-dose Buzhong Yiqi decoction group, the middle-dose Buzhong Yiqi decoction group and the high-dose Buzhong Yiqi decoction group. After the corresponding interventions, efforts were made to measure the transplanted tumor volume and calculate the tumor inhibiting rate. The immunohistochemical method and real time PCR were used to detect the expression of PI3K and AKT level in nude mice spleen, stomach and lung. Buzhong Yiqi decoction of different concentrations combined with cisplatin could inhibit the growth of the transplanted tumor, with the strongest inhibitory effect in the middle-dose Buzhong Yiqi decoction group and the high-dose Buzhong Yiqi decoction group. All of the expressions of PI3K and AKT protein and gene in the spleen, stomach and lung increased, with the most significant increase in the tumor-bearing group. Along with the increase of the concentration of cisplatin and Buzhong Yiqi decoction, the expressions of PI3K and AKT gradually reduced. Compared with the tumor-bearing control group, there were statistical differences in spleen and stomach tissues (P < 0.05). Compared with the cisplatin group, the middle-dose Buzhong Yiqi decoction group and the high-dose Buzhong Yiqi decoction group showed statistical differences (P < 0.05), but without statistical difference compared with the blank control group. Among nude mice with lung adenocarcinoma transplantation tumor, the PI3K and AKT protein and gene expressions in spleen, stomach and lung tissues increased, which might indicated the effect of cisplatin and Buzhong Yiqi decoction in reducing PI3K and AKT expressions and the relations between the reduction degree and the concentrations of Buzhong Yiqi decoction. Cisplatin combined with Buzhong Yiqi decoction could decrease the PI3K and AKT protein and gene expression in spleen, stomach and lung, and make the pathway closer to normal, so as to protect the functions of spleen, stomach and lung, there may be target spots of Buzhong Yiqi decoction in PI3K/AKT signal pathway.

A First Look at PCMH Implementation for Minority Veterans: Room for Improvement.

PubMed

Hernandez, Susan E; Taylor, Leslie; Grembowski, David; Reid, Robert J; Wong, Edwin; Nelson, Karin M; Liu, Chuan-Fen; Fihn, Stephan D; Hebert, Paul L

2016-03-01

Implementation of Patient Aligned Care Teams (PACT), a patient-centered medical home model, has been inconsistent among the >900 primary care facilities in the Veterans Health Administration. Estimate if the degree of PACT implementation at a facility varied with the percentage of minority veteran patients at the facility. Cross-sectional, facility-level analysis of PACT implementation measures in 2012. Veterans Health Administration hospital-based and community-based primary care facilities. We used a previously validated PACT Implementation Progress Index (Pi) and its 8 domains: access, continuity of care, care coordination, comprehensiveness, self-management support, and patient-centered care and communication, shared decision-making domains, and team functioning. Facilities were categorized as low (<5.2%, n=208), medium (5.2%-25.8%, n=413), and high (>25.8%, n=206) percent minority based on the percent of their own veteran population. Most minority veterans received care in high minority (69%) and medium minority facilities (29%). In adjusted analyses, medium and high minority facilities scored 0.773 (P=0.009) and 0.930 (P=0.008) points lower on the Pi score relative to low minority facilities. Relative to low minority facilities, both medium and high minority facilities were less likely of having high Pi scores (≥2) and more likely of having low Pi scores (≤-2). Both medium and high minority facilities had the same 3 domain scores lower than low minority facilities (care coordination, comprehensiveness, and self-management). Overall PACT implementation varied with respect to the racial/ethnic composition of a facility, with medium and high minority facilities having a lower implementation scores.

Pharmacological targeting of the PI3K/mTOR pathway alters the release of angioregulatory mediators both from primary human acute myeloid leukemia cells and their neighboring stromal cells.

PubMed

Reikvam, Håkon; Nepstad, Ina; Bruserud, Øystein; Hatfield, Kimberley Joanne

2013-06-01

Acute myeloid leukemia (AML) is a heterogeneous and aggressive malignancy with poor overall survival. Constitutive as well as cytokine-initiated activation of PI3K/Akt/mTOR signaling is a common feature of AML patients, and inhibition of this pathway is considered as a possible therapeutic strategy in AML. Human AML cells and different stromal cell populations were cultured under highly standardized in vitro conditions. We investigated the effects of mTOR inhibitors (rapamycin and temsirolimus) and PI3K inhibitors (GDC-0941 and 3-methyladenin (3-MA)) on cell proliferation and the constitutive release of angioregulatory mediators by AML and stromal cells. Primary human AML cells were heterogeneous, though most patients showed high CXCL8 levels and detectable release of CXCL10, Ang-1, HGF and MMP-9. Hierarchical clustering analysis showed that disruption of PI3K/Akt/mTOR pathways decreased AML cell release of CXCL8-11 for a large subset of patients, whereas the effects on other mediators were divergent. Various stromal cells (endothelial cells, fibroblasts, cells with osteoblastic phenotype) also showed constitutive release of angioregulatory mediators, and inhibitors of both the PI3K and mTOR pathway had anti-proliferative effects on stromal cells and resulted in decreased release of these angioregulatory mediators. PI3K and mTOR inhibitors can decrease constitutive cytokine release both by AML and stromal cells, suggesting potential direct and indirect antileukemic effects.

Pharmacological targeting of the PI3K/mTOR pathway alters the release of angioregulatory mediators both from primary human acute myeloid leukemia cells and their neighboring stromal cells

PubMed Central

Reikvam, Håkon; Nepstad, Ina; Bruserud, Øystein; Hatfield, Kimberley Joanne

2013-01-01

Acute myeloid leukemia (AML) is a heterogeneous and aggressive malignancy with poor overall survival. Constitutive as well as cytokine-initiated activation of PI3K/Akt/mTOR signaling is a common feature of AML patients, and inhibition of this pathway is considered as a possible therapeutic strategy in AML. Human AML cells and different stromal cell populations were cultured under highly standardized in vitro conditions. We investigated the effects of mTOR inhibitors (rapamycin and temsirolimus) and PI3K inhibitors (GDC-0941 and 3-methyladenin (3-MA)) on cell proliferation and the constitutive release of angioregulatory mediators by AML and stromal cells. Primary human AML cells were heterogeneous, though most patients showed high CXCL8 levels and detectable release of CXCL10, Ang-1, HGF and MMP-9. Hierarchical clustering analysis showed that disruption of PI3K/Akt/mTOR pathways decreased AML cell release of CXCL8-11 for a large subset of patients, whereas the effects on other mediators were divergent. Various stromal cells (endothelial cells, fibroblasts, cells with osteoblastic phenotype) also showed constitutive release of angioregulatory mediators, and inhibitors of both the PI3K and mTOR pathway had anti-proliferative effects on stromal cells and resulted in decreased release of these angioregulatory mediators. PI3K and mTOR inhibitors can decrease constitutive cytokine release both by AML and stromal cells, suggesting potential direct and indirect antileukemic effects. PMID:23919981

PRMT8 Controls the Pluripotency and Mesodermal Fate of Human Embryonic Stem Cells By Enhancing the PI3K/AKT/SOX2 Axis.

PubMed

Jeong, Ho-Chang; Park, Soon-Jung; Choi, Jong-Jin; Go, Young-Hyun; Hong, Soon-Ki; Kwon, Ok-Seon; Shin, Joong-Gon; Kim, Rae-Kwon; Lee, Mi-Ok; Lee, Su-Jae; Shin, Hyoung Doo; Moon, Sung-Hwan; Cha, Hyuk-Jin

2017-09-01

Basic fibroblast growth factor (bFGF) supplementation is critical to maintain the pluripotency of human pluripotent stem cells (hPSCs) through activation of PI3K/AKT, rather than MEK/ERK pathway. Thus, elaborate molecular mechanisms that preserve PI3K/AKT signaling upon bFGF stimulation may exist in hPSCs. Protein arginine methyltransferase 8 (PRMT8) was expressed and then its level gradually decreased during spontaneous differentiation of human embryonic stem cells (hESCs). PRMT8 loss- or gain-of-function studies demonstrated that PRMT8 contributed to longer maintenance of hESC pluripotency, even under bFGF-deprived conditions. Direct interaction of membrane-localized PRMT8 with p85, a regulatory subunit of PI3K, was associated with accumulation of phosphoinositol 3-phosphate and consequently high AKT activity. Furthermore, the SOX2 induction, which was controlled by the PRMT8/PI3K/AKT axis, was linked to mesodermal lineage differentiation. Thus, we propose that PRMT8 in hESCs plays an important role not only in maintaining pluripotency but also in controlling mesodermal differentiation through bFGF signaling toward the PI3K/AKT/SOX2 axis. Stem Cells 2017;35:2037-2049. © 2017 AlphaMed Press.

Chronic Nosema ceranae infection inflicts comprehensive and persistent immunosuppression and accelerated lipid loss in host Apis mellifera honey bees.

PubMed

Li, Wenfeng; Chen, Yanping; Cook, Steven C

2018-05-01

Nosema ceranae is an intracellular microsporidian parasite of the Asian honey bee Apis cerana and the European honey bee Apis mellifera. Until relatively recently, A. mellifera honey bees were naïve to N. ceranae infection. Symptoms of nosemosis, or Nosema disease, in the infected hosts include immunosuppression, damage to gut epithelium, nutrient and energetic stress, precocious foraging and reduced longevity of infected bees. Links remain unclear between immunosuppression, the symptoms of nutrient and energetic stress, and precocious foraging behavior of hosts. To clarify physiological connections, we inoculated newly emerged A. mellifera adult workers with N. ceranae spores, and over 21 days post inoculation (21 days pi), gauged infection intensity and quantified expression of genes representing two innate immune pathways, Toll and Imd. Additionally, we measured each host's whole-body protein, lipids, carbohydrates and quantified respirometric and activity levels. Results show sustained suppression of genes of both humorally regulated immune response pathways after 6 days pi. At 7 days pi, elevated protein levels of infected bees may reflect synthesis of antimicrobial peptides from an initial immune response, but the lack of protein gain compared with uninfected bees at 14 days pi may represent low de novo protein synthesis. Carbohydrate data do not indicate that hosts experience severe metabolic stress related to this nutrient. At 14 days pi infected honey bees show high respirometric and activity levels, and corresponding lipid loss, suggesting lipids may be used as fuel for increased metabolic demands resulting from infection. Accelerated lipid loss during nurse honey bee behavioral development can have cascading effects on downstream physiology that may lead to precocious foraging, which is a major factor driving colony collapse. Published by Elsevier Ltd.

Suppression of the PI3K pathway in vivo reduces cystitis-induced bladder hypertrophy and restores bladder capacity examined by magnetic resonance imaging.

PubMed

Qiao, Zhongwei; Xia, Chunmei; Shen, Shanwei; Corwin, Frank D; Liu, Miao; Guan, Ruijuan; Grider, John R; Qiao, Li-Ya

2014-01-01

This study utilized magnetic resonance imaging (MRI) to monitor the real-time status of the urinary bladder in normal and diseased states following cyclophosphamide (CYP)-induced cystitis, and also examined the role of the phosphoinositide 3-kinase (PI3K) pathway in the regulation of urinary bladder hypertrophy in vivo. Our results showed that under MRI visualization the urinary bladder wall was significantly thickened at 8 h and 48 h post CYP injection. The intravesical volume of the urinary bladder was also markedly reduced. Treatment of the cystitis animals with a specific PI3K inhibitor LY294002 reduced cystitis-induced bladder wall thickening and enlarged the intravesical volumes. To confirm the MRI results, we performed H&E stain postmortem and examined the levels of type I collagen by real-time PCR and western blot. Inhibition of the PI3K in vivo reduced the levels of type I collagen mRNA and protein in the urinary bladder ultimately attenuating cystitis-induced bladder hypertrophy. The bladder mass calculated according to MRI data was consistent to the bladder weight measured ex vivo under each drug treatment. MRI results also showed that the urinary bladder from animals with cystitis demonstrated high magnetic signal intensity indicating considerable inflammation of the urinary bladder when compared to normal animals. This was confirmed by examination of the pro-inflammatory factors showing that interleukin (IL)-1α, IL-6 and tumor necrosis factor (TNF)α levels in the urinary bladder were increased with cystitis. Our results suggest that MRI can be a useful technique in tracing bladder anatomy and examining bladder hypertrophy in vivo during disease development and the PI3K pathway has a critical role in regulating bladder hypertrophy during cystitis.

Magnesium prevents phosphate-induced calcification in human aortic vascular smooth muscle cells.

PubMed

Louvet, Loïc; Büchel, Janine; Steppan, Sonja; Passlick-Deetjen, Jutta; Massy, Ziad A

2013-04-01

Vascular calcification (VC) is prevalent in patients suffering from chronic kidney disease. Factors promoting calcification include abnormalities in mineral metabolism, particularly high phosphate levels. Inorganic phosphate (Pi) is a classical inducer of in vitro VC. Recently, an inverse relationship between serum magnesium concentrations and VC has been reported. The present study aimed to investigate the effects of magnesium on Pi-induced VC at the cellular level using primary HAVSMC. Alive and fixed HAVSMC were assessed during 14 days in the presence of Pi with increasing concentrations of magnesium (Mg(2+)) chloride. Mineralization was measured using quantification of calcium, von Kossa and alizarin red stainings. Cell viability and secretion of classical VC markers were also assessed using adequate tests. Involvement of transient receptor potential melastatin (TRPM) 7 was assessed using 2-aminoethoxy-diphenylborate (2-APB) inhibitor. Co-incubation with Mg(2+) significantly decreased Pi-induced VC in live HAVSMC, no effect was found in fixed cells. At potent concentrations in Pi-induced HAVSMC, Mg(2+) significantly improved cell viability and restored to basal level increased secretions of osteocalcin and matrix gla protein, whereas a decrease in osteopontin secretion was partially restored. The block of TRPM7 with 2-APB at 10(-4) M led to the inefficiency of Mg(2+) to prevent VC. Increasing Mg(2+) concentrations significantly reduced VC, improved cell viability and modulated secretion of VC markers during cell-mediated matrix mineralization clearly pointing to a cellular role for Mg(2+) and 2-APB further involved TRPM7 and a potential Mg(2+) entry to exert its effects. Further investigations are needed to shed light on additional cellular mechanism(s) by which Mg(2+) is able to prevent VC.

PI3 K/Akt/mTOR-mediated translational control regulates proliferation and differentiation of lineage-restricted RoSH stem cell lines

PubMed Central

Que, Jianwen; Lian, Qizhou; El Oakley, Reida M; Lim, Bing; Lim, Sai-Kiang

2007-01-01

Background We have previously derived highly similar lineage-restricted stem cell lines, RoSH and E-RoSH cell lines from mouse embryos and CD9hi SSEA-1- differentiated mouse embryonic stem cells, respectively. These cell lines are not pluripotent and differentiate readily into endothelial cells in vitro and in vivo. Results We investigated the signaling pathway that maintains proliferation of these cells in an undifferentiated state, and demonstrate that PI3 K/Akt/mTOR, but not Raf/MEK/Erk, signaling in these cells was active during proliferation and was downregulated during endothelial differentiation. Inhibition of PI3 K/Akt/mTOR signaling, but not Raf/MEK/Erk, reduced proliferation and induced expression of endothelial specific proteins. During differentiation or inhibition of PI3 K/Akt/mTOR signaling, cyclinD2 transcript abundance in ribosome-enriched RNA but not in total RNA was reduced with a corresponding reduction in protein level. In contrast, transcript abundance of endothelial-specific genes e.g. Kdr, Tek and Pdgfrα in ribosome-enriched RNA fraction was not reduced and their protein levels were increased. Together these observations suggested that translational control mediated by PI3K/Akt/mTOR signaling was critical in regulating proliferation and endothelial differentiation of lineage-restricted RoSH-like stem cell lines. Conclusion This study highlights translation regulation as a critical regulatory mechanism during proliferation and differentiation in stem cells. PMID:17892597

Hepatocyte growth factor (HGF) upregulates heparanase expression via the PI3K/Akt/NF-κB signaling pathway for gastric cancer metastasis.

PubMed

Hao, Ning-Bo; Tang, Bo; Wang, Guo-Zheng; Xie, Rui; Hu, Chang-Jiang; Wang, Su-Min; Wu, Yu-Yun; Liu, En; Xie, Xia; Yang, Shi-Ming

2015-05-28

Heparanase (HPA) is an endoglucuronidase that can promote the shedding of associated cytokines in several types of tumors. However, little is known about what controls the expression of HPA or its role in gastric cancer. In this study, we report for the first time that HGF regulates HPA expression to promote gastric cancer metastasis. In this study, HGF and HPA were found to be significantly expressed in 58 gastric cancer patients. High expression of both HGF and HPA was positively associated with TNM stage, invasion depth and poor prognosis. In MKN74 cells, exogenous HGF significantly increased HPA expression at both the mRNA and protein levels. Further study revealed that HGF first activated PI3K/Akt signaling. NF-κB signaling was activated downstream of PI3K/Akt and promoted HPA expression. However, when c-met, PI3K/Akt or NF-κB signal inhibitors were used, HPA expression was significantly decreased. All of these results indicate that HGF regulates HPA expression by PI3K/Akt and downstream NF-κB signaling. Using bioinformatics and the ChIP assay, p65 was observed to bind to the HPA promoter. Furthermore, HGF significantly induced tumor cell migration, whereas treatment with an NF-κB inhibitor decreased migration. Moreover, when HPA was overexpressed in MKN74 cells, migration was significantly enhanced, and the HGF concentration was increased. However, when HPA was down-regulated in MKN45 cells, migration and HGF levels decreased. Together, these results demonstrate that HGF/c-met can activate PI3K/Akt and downstream NF-κB signaling to promote HPA expression and subsequent tumor metastasis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Peer Instruction at Japanese High School Physics

NASA Astrophysics Data System (ADS)

Takahashi, H.; Nitta, H.

2010-07-01

We report on our attempt to introduce the peer instruction (PI) into a Japanese high-school physics course. To evaluate the effectiveness of PI in the course, we define the PI-efficiency (PIE). It is shown that PIE is useful to find out students' reasoning difficulties as well as effective usages of PI.

Experimental Study of the NaK 3(1)Pi State.

PubMed

Laub; Mazsa; Webb; La Civita J; Prodan; Jabbour; Namiotka; Huennekens

1999-02-01

We report the results of an optical-optical double resonance experiment to determine the NaK 3(1)Pi state potential energy curve. In the first step, a narrow band cw dye laser (PUMP) is tuned to line center of a particular 2(A)1Sigma+(v', J') <-- 1(X)1Sigma+(v", J") transition, and its frequency is then fixed. A second narrowband tunable cw Ti:Sapphirelaser (PROBE) is then scanned, while 3(1)Pi --> 1(X)1Sigma+ violet fluorescence is monitored. The Doppler-free signals accurately map the 3(1)Pi(v, J) ro-vibrational energy levels. These energy levels are then fit to a Dunham expansion to provide a set of molecular constants. The Dunham constants, in turn, are used to construct an RKR potential curve. Resolved 3(1)Pi(v, J) --> 1(X)1Sigma+(v", J") fluorescence scans are also recorded with both PUMP and PROBE laser frequencies fixed. Comparison between observed and calculated Franck-Condon factors is used to determine the absolute vibrational numbering of the 3(1)Pi state levels and to determine the variation of the 3(1)Pi --> 1(X)1Sigma+ transitiondipole moment with internuclear separation. The recent theoretical calculation of the NaK 3(1)Pi state potential reported by Magnier and Millié (1996, Phys. Rev. A 54, 204) is in excellent agreement with the present experimental RKR curve. Copyright 1999 Academic Press.

The Effects of School-Based Parental Involvement on Academic Achievement at the Child and Elementary School Level: A Longitudinal Study

ERIC Educational Resources Information Center

Park, Sira; Holloway, Susan D.

2017-01-01

Policymakers view parental involvement (PI) as a crucial component of school reform efforts, but evidence of its effect on student achievement is equivocal. Using the Early Childhood Longitudinal Study-Kindergarten Cohort dataset, we examined the long-term impact on student- and school-level achievement of three types of school-based PI: PI to…

Survivorship analysis when cure is a possibility: a Monte Carlo study.

PubMed

Goldman, A I

1984-01-01

Parametric survivorship analyses of clinical trials commonly involves the assumption of a hazard function constant with time. When the empirical curve obviously levels off, one can modify the hazard function model by use of a Gompertz or Weibull distribution with hazard decreasing over time. Some cancer treatments are thought to cure some patients within a short time of initiation. Then, instead of all patients having the same hazard, decreasing over time, a biologically more appropriate model assumes that an unknown proportion (1 - pi) have constant high risk whereas the remaining proportion (pi) have essentially no risk. This paper discusses the maximum likelihood estimation of pi and the power curves of the likelihood ratio test. Monte Carlo studies provide results for a variety of simulated trials; empirical data illustrate the methods.

The pollen-specific R-SNARE/longin PiVAMP726 mediates fusion of endo- and exocytic compartments in pollen tube tip growth

PubMed Central

Guo, Feng; McCubbin, Andrew G.

2012-01-01

The growing pollen tube apex is dedicated to balancing exo- and endocytic processes to form a rapidly extending tube. As perturbation of either tends to cause a morphological phenotype, this system provides tractable model for studying these processes. Vesicle-associated membrane protein 7s (VAMP7s) are members of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) family that mediate cognate membrane fusion but their role in pollen tube growth has not been investigated. This manuscript identifies PiVAMP726 of Petunia inflata as a pollen-specific VAMP7 that localizes to the inverted cone of transport vesicles at the pollen tube tip. The endocytic marker FM4-64 was found to colocalize with yellow fluorescent protein (YFP)-PiVAMP726, which is consistent with PiVAMP726 containing an amino-acid motif implicated in endosomal localization, At high overexpression levels, YFP- PiVAMP726 inhibited growth and caused the formation of novel membrane compartments within the pollen tube tip. Functional dissection of PiVAMP726 implicated the N-terminal longin domain in negative regulation of the SNARE activity, but not localization of PiVAMP726. Expression of the constitutively active C-terminal SNARE domain alone, in pollen tubes, generated similar phenotypes to the full-length protein, but the truncated domain was more potent than the wild-type protein at both inhibiting growth and forming the novel membrane compartments. Both endo- and exocytic markers localized to these compartments in addition to YFP-PiVAMP726, leading to the speculation that PiVAMP726 might be involved in the recycling of endocytic vesicles in tip growth. PMID:22345643

Evaluation of two prognostic indices for adult T cell leukemia/lymphoma in the subtropical endemic area, Okinawa, Japan.

PubMed

Tamaki, Keita; Morishima, Satoko; Nomura, Shogo; Nishi, Yukiko; Nakachi, Sawako; Kitamura, Sakiko; Uchibori, Sachie; Tomori, Shouhei; Hanashiro, Taeko; Shimabukuro, Natsuki; Tedokon, Iori; Morichika, Kazuho; Taira, Naoya; Tomoyose, Takeaki; Miyagi, Takashi; Karimata, Kaori; Ohama, Masayo; Yamanoha, Atsushi; Tamaki, Kazumitsu; Hayashi, Masaki; Uchihara, Jun-Nosuke; Ohshiro, Kazuiku; Asakura, Yoshitaka; Kuba-Miyara, Megumi; Karube, Kennosuke; Fukushima, Takuya; Masuzaki, Hiroaki

2018-05-17

Aggressive adult T-cell leukemia/lymphoma (ATL) has an extremely poor prognosis and is hyperendemic in Okinawa, Japan. This study evaluated two prognostic indices (PIs) for aggressive ATL, the ATL-PI and Japan Clinical Oncology Group (JCOG)-PI, in a cohort from Okinawa. The PIs were developed using two different Japanese cohorts that included few patients from Okinawa. The endpoint was overall survival (OS). Multivariable Cox regression analyses in the cohort of 433 patients revealed that all seven factors for calculating each PI were statistically significant prognostic predictors. Three-year OS rates for ATL-PI were 35.9% (low-risk, n=66), 10.4% (intermediate-risk, n=256), and 1.6% (high-risk, n=111), and those for JCOG-PI were 22.4% (moderate-risk, n=176) and 5.3% (high-risk, n=257). The JCOG-PI moderate-risk group included both the ATL-PI low- and intermediate-risk groups. ATL-PI more clearly identified the low-risk patient subgroup than JCOG-PI. To evaluate the external validity of the two PIs, we also assessed prognostic discriminability among 159 patients who loosely met the eligibility criteria of a previous clinical trial. Three-year OS rates for ATL-PI were 34.5% (low-risk, n=42), 9.2% (intermediate-risk, n=109), and 12.5% (high-risk, n = 8). Those for JCOG-PI were 22.4% (moderate-risk, n=95) and 7.6% (high-risk, n=64). The low-risk ATL-PI group had a better prognosis than the JCOG-PI moderate-risk group, suggesting that ATL-PI would be more useful than JCOG-PI for establishing and examining novel treatment strategies for ATL patients with a better prognosis. In addition, strongyloidiasis, previously suggested to be associated with ATL-related deaths in Okinawa, was not a prognostic factor in this study. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Probing the stellar initial mass function with high-z supernovae

NASA Astrophysics Data System (ADS)

de Souza, R. S.; Ishida, E. E. O.; Whalen, D. J.; Johnson, J. L.; Ferrara, A.

2014-08-01

The first supernovae (SNe) will soon be visible at the edge of the observable universe, revealing the birthplaces of Population III stars. With upcoming near-infrared missions, a broad analysis of the detectability of high-z SNe is paramount. We combine cosmological and radiation transport simulations, instrument specifications and survey strategies to create synthetic observations of primeval core-collapse (CC), Type IIn and pair-instability (PI) SNe with the James Webb Space Telescope (JWST). We show that a dedicated observational campaign with the JWST can detect up to ˜15 PI explosions, ˜300 CC SNe, but less than one Type IIn explosion per year, depending on the Population III star formation history. Our synthetic survey also shows that ≈1-2 × 102 SNe detections, depending on the accuracy of the classification, are sufficient to discriminate between a Salpeter and flat mass distribution for high-redshift stars with a confidence level greater than 99.5 per cent. We discuss how the purity of the sample affects our results and how supervised learning methods may help to discriminate between CC and PI SNe.

Observation of pi+pi-pi+pi- photoproduction in ultraperipheral heavy-ion collisions at sqrt sNN = 200 GeV at the STAR detector

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

STAR Collaboration; Abelev, Betty

We present a measurement of {pi}{sup +}{pi}{sup -}{pi}{sup +}{pi}{sup -} photonuclear production in ultra-peripheral Au-Au collisions at {radical}s{sub NN} = 200 GeV from the STAR experiment. The {pi}{sup +}{pi}{sup -}{pi}{sup +}{pi}{sup -} final states are observed at low transverse momentum and are accompanied by mutual nuclear excitation of the beam particles. The strong enhancement of the production cross section at low transverse momentum is consistent with coherent photoproduction. The {pi}{sup +}{pi}{sup -}{pi}{sup +}{pi}{sup -} invariant mass spectrum of the coherent events exhibits a broad peak around 1540 {+-} 40 MeV/c{sup 2} with a width of 570 {+-} 60 MeV/c{sup 2},more » in agreement with the photoproduction data for the {rho}{sup 0}(1700). We do not observe a corresponding peak in the {pi}{sup +}{pi}{sup -} final state and measure an upper limit for the ratio of the branching fractions of the {rho}{sup 0}(1700) to {pi}{sup +}{pi}{sup -} and {pi}{sup +}{pi}{sup -}{pi}{sup +}{pi}{sup -} of 2.5% at 90% confidence level. The ratio of {rho}{sup 0}(1700) and {rho}{sup 0}(770) coherent production cross sections is measured to be 13.4 {+-} 0.8{sub stat.} {+-} 4.4{sub syst.}%.« less

Observation of pi+ pi- pi+pi- photoproduction in ultraperipheral heavy-ion collisons at sqrt sNN = 200 GeV at the STAR Detector

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

Abelev, B.I.; Dunlop, J.; et al. STAR Collaboration

We present a measurement of {pi}{sup +}{pi}{sup -}{pi}{sup +}{pi}{sup -} photonuclear production in ultraperipheral Au-Au collisions at {radical}s{sub NN} = 200 GeV from the STAR experiment. The {pi}{sup +}{pi}{sup -}{pi}{sup +}{pi}{sup -} final states are observed at low transverse momentum and are accompanied by mutual nuclear excitation of the beam particles. The strong enhancement of the production cross section at low transverse momentum is consistent with coherent photoproduction. The {pi}{sup +}{pi}{sup -}{pi}{sup +}{pi}{sup -} invariant mass spectrum of the coherent events exhibits a broad peak around 1540 {+-} 40 MeV/c{sup 2} with a width of 570 {+-} 60 MeV/c{sup 2},more » in agreement with the photoproduction data for the {rho}{sup 0}(1700). We do not observe a corresponding peak in the {pi}{sup +}{pi}{sup -} final state and measure an upper limit for the ratio of the branching fractions of the {rho}{sup 0}(1700) to {pi}{sup +}{pi}{sup -} and {pi}{sup +}{pi}{sup -}{pi}{sup +}{pi}{sup -} of 2.5% at 90% confidence level. The ratio of {rho}{sup 0}(1700) and {rho}{sup 0}(770) coherent production cross sections is measured to be 13.4 {+-} 0.8{sub stat.}{+-}4.4{sub syst.}%.« less

Dipole moments and transition probabilities of the i 3Pi sub g-b 3Sigma(+) sub u, c 3Pi sub u-a 3Sigma(+) sub g, and i 3Pi sub g-c 3Pi sub u systems of molecular hydrogen

NASA Technical Reports Server (NTRS)

Guberman, Steven L.; Dalgarno, A.

1992-01-01

Bonn-Oppenheimer-based ab initio calculations of dipole moments from the i 3Pi sub g-b 3Sigma(+) sub u, c 3Pi sub u-a 3Sigma(+) sub g, and i 3Pi sub g-c 3Pi sub u transitions of H2 have been conducted, to yield a tabulation of the dipole transition probabilities and Franck-Condon factors. These factors are given for transitions originating in the lowest vibrational level of the ground X 1Sigma(+) sub g state.

Pancreas Oxygen Persufflation Increases ATP Levels as Shown by Nuclear Magnetic Resonance

PubMed Central

Scott, W.E.; Weegman, B.P.; Ferrer-Fabrega, J.; Stein, S.A.; Anazawa, T.; Kirchner, V.A.; Rizzari, M.D.; Stone, J.; Matsumoto, S.; Hammer, B.E.; Balamurugan, A.N.; Kidder, L.S.; Suszynski, T.M.; Avgoustiniatos, E.S.; Stone, S.G.; Tempelman, L.A.; Sutherland, D.E.R.; Hering, B.J.; Papas, K.K.

2010-01-01

Background Islet transplantation is a promising treatment for type 1 diabetes. Due to a shortage of suitable human pancreata, high cost, and the large dose of islets presently required for long-term diabetes reversal; it is important to maximize viable islet yield. Traditional methods of pancreas preservation have been identified as suboptimal due to insufficient oxygenation. Enhanced oxygen delivery is a key area of improvement. In this paper, we explored improved oxygen delivery by persufflation (PSF), ie, vascular gas perfusion. Methods Human pancreata were obtained from brain-dead donors. Porcine pancreata were procured by en bloc viscerectomy from heparinized donation after cardiac death donors and were either preserved by either two-layer method (TLM) or PSF. Following procurement, organs were transported to a 1.5-T magnetic resonance (MR) system for 31P nuclear magnetic resonance spectroscopy to investigate their bioenergetic status by measuring the ratio of adenosine triphosphate to inorganic phosphate (ATP:Pi) and for assessing PSF homogeneity by MRI. Results Human and porcine pancreata can be effectively preserved by PSF. MRI showed that pancreatic tissue was homogeneously filled with gas. TLM can effectively raise ATP:Pi levels in rat pancreata but not in larger porcine pancreata. ATP:Pi levels were almost undetectable in porcine organs preserved with TLM. When human or porcine organs were preserved by PSF, ATP:Pi was elevated to levels similar to those observed in rat pancreata. Conclusion The methods developed for human and porcine pancreas PSF homogeneously deliver oxygen throughout the organ. This elevates ATP levels during preservation and may improve islet isolation outcomes while enabling the use of marginal donors, thus expanding the usable donor pool. PMID:20692395

The antagonistic effect of selenium on cadmium-induced apoptosis via PPAR-γ/PI3K/Akt pathway in chicken pancreas.

PubMed

Jin, Xi; Jia, Tiantian; Liu, Ruohan; Xu, Shiwen

2018-06-01

The animal experiment was preformed to investigate the roles of PPAR-γ/PI3K/Akt pathway in apoptosis triggered by cadmium (Cd) and in the antagonistic effects of selenium (Se) on Cd in the pancreas of chicken. The current study showed that Cd treatment obviously increased the accumulation of Cd and directly led to lower activities of amylase, trypsin and lipase in chicken pancreas. The expression of PPAR-γ, PI3K, and Akt was declined, whereas the level of Bax, Cyt C and caspase-3 were increased in Cd group. In the result of TUNEL assay and the histological examination, typical apoptosis characteristics in the pancreas of Cd group were confirmed. Cd group also showed high levels of inducible nitric oxide synthase (iNOS) activity and nitric oxide (NO) content in pancreas. However, those Cd-induced changes were obviously alleviated in Cd + Se group. Our study revealed that Cd could impact the pancreas function and induce the activation of Bax and the overproduction of NO via PPAR-γ/PI3K/Akt pathway to promote apoptosis in chicken pancreas. However, Se could reduce Cd accumulation and antagonize Cd-triggered apoptosis in chicken pancreas. Copyright © 2018 Elsevier B.V. All rights reserved.

Alzheimer risk genes modulate the relationship between plasma apoE and cortical PiB binding

DOE PAGES

Lazaris, Andreas; Hwang, Kristy S.; Goukasian, Naira; ...

2015-10-15

Objective: We investigated the association between apoE protein plasma levels and brain amyloidosis and the effect of the top 10 Alzheimer disease (AD) risk genes on this association. Methods: Our dataset consisted of 18 AD, 52 mild cognitive impairment, and 3 cognitively normal Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) participants with available [ 11C]-Pittsburgh compound B (PiB) and peripheral blood protein data. We used cortical pattern matching to study associations between plasma apoE and cortical PiB binding and the effect of carrier status for the top 10 AD risk genes. Results: Low plasma apoE was significantly associated with high PiBmore » SUVR, except in the sensorimotor and entorhinal cortex. For BIN1 rs744373, the association was observed only in minor allele carriers. For CD2AP rs9349407 and CR1 rs3818361, the association was preserved only in minor allele noncarriers. We did not find evidence for modulation by CLU, PICALM, ABCA7, BIN1, and MS4A6A. Conclusions: Our data show that BIN1 rs744373, CD2AP rs9349407, and CR1 rs3818361 genotypes modulate the association between apoE protein plasma levels and brain amyloidosis, implying a potential epigenetic/downstream interaction.« less

Branched-Chain Amino Acid Negatively Regulates KLF15 Expression via PI3K-AKT Pathway

PubMed Central

Liu, Yunxia; Dong, Weibing; Shao, Jing; Wang, Yibin; Zhou, Meiyi; Sun, Haipeng

2017-01-01

Recent studies have linked branched-chain amino acid (BCAA) with numerous metabolic diseases. However, the molecular basis of BCAA's roles in metabolic regulation remains to be established. KLF15 (Krüppel-like factor 15) is a transcription factor and master regulator of glycemic, lipid, and amino acids metabolism. In the present study, we found high concentrations of BCAA suppressed KLF15 expression while BCAA starvation induced KLF15 expression, suggesting KLF15 expression is negatively controlled by BCAA.Interestingly, BCAA starvation induced PI3K-AKT signaling. KLF15 induction by BCAA starvation was blocked by PI3K and AKT inhibitors, indicating the activation of PI3K-AKT signaling pathway mediated the KLF15 induction. BCAA regulated KLF15 expression at transcriptional level but not post-transcriptional level. However, BCAA starvation failed to increase the KLF15-promoter-driven luciferase expression, suggesting KLF15 promoter activity was not directly controlled by BCAA. Finally, fasting reduced BCAA abundance in mice and KLF15 expression was dramatically induced in muscle and white adipose tissue, but not in liver. Together, these data demonstrated BCAA negatively regulated KLF15 expression, suggesting a novel molecular mechanism underlying BCAA's multiple functions in metabolic regulation. PMID:29118722

Branched-Chain Amino Acid Negatively Regulates KLF15 Expression via PI3K-AKT Pathway.

PubMed

Liu, Yunxia; Dong, Weibing; Shao, Jing; Wang, Yibin; Zhou, Meiyi; Sun, Haipeng

2017-01-01

Recent studies have linked branched-chain amino acid (BCAA) with numerous metabolic diseases. However, the molecular basis of BCAA's roles in metabolic regulation remains to be established. KLF15 (Krüppel-like factor 15) is a transcription factor and master regulator of glycemic, lipid, and amino acids metabolism. In the present study, we found high concentrations of BCAA suppressed KLF15 expression while BCAA starvation induced KLF15 expression, suggesting KLF15 expression is negatively controlled by BCAA.Interestingly, BCAA starvation induced PI3K-AKT signaling. KLF15 induction by BCAA starvation was blocked by PI3K and AKT inhibitors, indicating the activation of PI3K-AKT signaling pathway mediated the KLF15 induction. BCAA regulated KLF15 expression at transcriptional level but not post-transcriptional level. However, BCAA starvation failed to increase the KLF15-promoter-driven luciferase expression, suggesting KLF15 promoter activity was not directly controlled by BCAA. Finally, fasting reduced BCAA abundance in mice and KLF15 expression was dramatically induced in muscle and white adipose tissue, but not in liver. Together, these data demonstrated BCAA negatively regulated KLF15 expression, suggesting a novel molecular mechanism underlying BCAA's multiple functions in metabolic regulation.

Activation of the PI3K/Akt pathway by oxidative stress mediates high glucose-induced increase of adipogenic differentiation in primary rat osteoblasts.

PubMed

Zhang, Yu; Yang, Jian-Hong

2013-11-01

Diabetes mellitus is associated with increased risk of osteopenia and bone fracture that may be related to hyperglycemia. However, the mechanisms accounting for diabetic bone disorder are unclear. Here, we showed that high glucose significantly promoted the production of reactive oxygen species (ROS) in rat primary osteoblasts. Most importantly, we reported for the first time that ROS induced by high glucose increased alkaline phosphatase activity, inhibited type I collagen (collagen I) protein level and cell mineralization, as well as gene expression of osteogenic markers including runt-related transcription factor 2 (Runx2), collagen I, and osteocalcin, but promoted lipid droplet formation and gene expression of adipogenic markers including peroxisome proliferator-activated receptor gamma, adipocyte fatty acid binding protein (aP2), and adipsin, which were restored by pretreatment with N-acetyl-L-cysteine (NAC), a ROS scavenger. Moreover, high glucose-induced oxidative stress activated PI3K/Akt pathway to inhibited osteogenic differentiation but stimulated adipogenic differentiation. In contrast, NAC and a PI3K inhibitor, LY-294002, reversed the down-regulation of osteogenic markers and the up-regulation of adipogenic markers as well as the activation of Akt under high glucose. These results indicated that oxidative stress played a key role in high glucose-induced increase of adipogenic differentiation, which contributed to the inhibition of osteogenic differentiation. This process was mediated by PI3K/Akt pathway in rat primary osteoblasts. Hence, suppression of oxidative stress could be a potential therapeutic approach for diabetic osteopenia. © 2013 Wiley Periodicals, Inc.

Can Prostate Imaging Reporting and Data System Version 2 reduce unnecessary prostate biopsies in men with PSA levels of 4-10 ng/ml?

PubMed

Xu, Ning; Wu, Yu-Peng; Chen, Dong-Ning; Ke, Zhi-Bin; Cai, Hai; Wei, Yong; Zheng, Qing-Shui; Huang, Jin-Bei; Li, Xiao-Dong; Xue, Xue-Yi

2018-05-01

To explore the value of Prostate Imaging Reporting and Data System Version 2 (PI-RADS v2) for predicting prostate biopsy results in patients with prostate specific antigen (PSA) levels of 4-10 ng/ml. We retrospectively reviewed multi-parameter magnetic resonance images from 528 patients with PSA levels of 4-10 ng/ml who underwent transrectal ultrasound-guided prostate biopsies between May 2015 and May 2017. Among them, 137 were diagnosed with prostate cancer (PCa), and we further subdivided them according to pathological results into the significant PCa (S-PCa) and insignificant significant PCa (Ins-PCa) groups (121 cases were defined by surgical pathological specimen and 16 by biopsy). Age, PSA, percent free PSA, PSA density (PSAD), prostate volume (PV), and PI-RADS score were collected. Logistic regression analysis was performed to determine predictors of pathological results. Receiver operating characteristic curves were constructed to analyze the diagnostic value of PI-RADS v2 in PCa. Multivariate analysis indicated that age, PV, percent free PSA, and PI-RADS score were independent predictors of biopsy findings, while only PI-RADS score was an independent predictor of S-PCa (P < 0.05). The areas under the receiver operating characteristic curve for diagnosing PCa with respect to age, PV, percent free PSA, and PI-RADS score were 0.570, 0.430, 0.589 and 0.836, respectively. The area under the curve for diagnosing S-PCa with respect to PI-RADS score was 0.732. A PI-RADS score of 3 was the best cutoff for predicting PCa, and 4 was the best cutoff for predicting S-PCa. Thus, 92.8% of patients with PI-RADS scores of 1-2 would have avoided biopsy, but at the cost of missing 2.2% of the potential PCa cases. Similarly, 83.82% of patients with a PI-RADS score ≤ 3 would have avoided biopsy, but at the cost of missing 3.3% of the potential S-PCa cases. PI-RADS v2 could be used to reduce unnecessary prostate biopsies in patients with PSA levels of 4-10 ng/ml.

Effect of variations in dietary Pi intake on intestinal Pi transporters (NaPi-IIb, PiT-1, and PiT-2) and phosphate-regulating factors (PTH, FGF-23, and MEPE).

PubMed

Aniteli, Tatiana Martins; de Siqueira, Flávia Ramos; Dos Reis, Luciene Machado; Dominguez, Wagner Vasques; de Oliveira, Elizabeth Maria Costa; Castelucci, Patrícia; Moysés, Rosa Maria Affonso; Jorgetti, Vanda

2018-04-01

Hyperphosphatemia is a common condition in patients with chronic kidney disease (CKD) and can lead to bone disease, vascular calcification, and increased risks of cardiovascular disease and mortality. Inorganic phosphate (P i ) is absorbed in the intestine, an important step in the maintenance of homeostasis. In CKD, it is not clear to what extent P i absorption is modulated by dietary P i . Thus, we investigated 5/6 nephrectomized (Nx) Wistar rats to test whether acute variations in dietary P i concentration over 2 days would alter hormones involved in P i metabolism, expression of sodium-phosphate cotransporters, apoptosis, and the expression of matrix extracellular phosphoglycoprotein (MEPE) in different segments of the small intestine. The animals were divided into groups receiving different levels of dietary phosphate: low (Nx/LP i ), normal (Nx/NP i ), and high (Nx/HP i ). Serum phosphate, fractional excretion of phosphate, intact serum fibroblast growth factor 23 (FGF-23), and parathyroid hormone (PTH) were significantly higher and ionized calcium was significantly lower in the Nx/HP i group than in the Nx/LP i group. The expression levels of NaPi-IIb and PiT-1/2 were increased in the total jejunum mucosa of the Nx/LP i group compared with the Nx/HP i group. Modification of P i concentration in the diet affected the apoptosis of enterocytes, particularly with P i overload. MEPE expression was higher in the Nx/HP i group than in the Nx/NP i . These data reveal the importance of early control of P i in uremia to prevent an increase in serum PTH and FGF-23. Uremia may be a determining factor that explains the expressional modulation of the cotransporters in the small intestine segments.

A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria

PubMed Central

Mbengue, Alassane; Bhattacharjee, Souvik; Pandharkar, Trupti; Liu, Haining; Estiu, Guillermina; Stahelin, Robert V.; Rizk, Shahir; Njimoh, Dieudonne L.; Ryan, Yana; Chotivanich, Kesinee; Nguon, Chea; Ghorbal, Mehdi; Lopez-Rubio, Jose-Juan; Pfrender, Michael; Emrich, Scott; Mohandas, Narla; Dondorp, Arjen M.; Wiest, Olaf; Haldar, Kasturi

2015-01-01

Artemisinins are the corner stone of anti-malarial drugs1. Emergence and spread of resistance to them2–4 raises risk of wiping out recent gains achieved in reducing world-wide malaria burden and threatens future malaria control and elimination on a global level. Genome wide association studies (GWAS) have revealed parasite genetic loci associated with artemisinin resistance5–10. However, there is no consensus on biochemical targets of artemisinin. Whether and how these targets interact with genes identified by GWAS, remains unknown. Here we provide biochemical and cellular evidence that artemisinins are potent inhibitors of Plasmodium falciparum phosphatidylinositol-3-kinase (PfPI3K), revealing an unexpected mechanism of action. In resistant clinical strains, increased PfPI3K was associated with the C580Y mutation in P. falciparum Kelch13 (PfKelch13), a primary marker of artemisinin resistance. Polyubiquitination of PfPI3K and its binding to PfKelch13 were reduced by PfKelch13 mutation, which limited proteolysis of PfPI3K and thus increased levels of the kinase as well as its lipid product phosphatidylinositol 3-phosphate (PI3P). We find PI3P levels to be predictive of artemisinin resistance in both clinical and engineered laboratory parasites as well as across non-isogenic strains. Elevated PI3P induced artemisinin resistance in absence of PfKelch13 mutations, but remained responsive to regulation by PfKelch13. Evidence is presented for PI3P-dependent signaling, where transgenic expression of an additional kinase confers resistance. Together these data present PI3P as the key mediator of artemisinin resistance and the sole PfPI3K as an important target for malaria elimination. PMID:25874676

A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria.

PubMed

Mbengue, Alassane; Bhattacharjee, Souvik; Pandharkar, Trupti; Liu, Haining; Estiu, Guillermina; Stahelin, Robert V; Rizk, Shahir S; Njimoh, Dieudonne L; Ryan, Yana; Chotivanich, Kesinee; Nguon, Chea; Ghorbal, Mehdi; Lopez-Rubio, Jose-Juan; Pfrender, Michael; Emrich, Scott; Mohandas, Narla; Dondorp, Arjen M; Wiest, Olaf; Haldar, Kasturi

2015-04-30

Artemisinins are the cornerstone of anti-malarial drugs. Emergence and spread of resistance to them raises risk of wiping out recent gains achieved in reducing worldwide malaria burden and threatens future malaria control and elimination on a global level. Genome-wide association studies (GWAS) have revealed parasite genetic loci associated with artemisinin resistance. However, there is no consensus on biochemical targets of artemisinin. Whether and how these targets interact with genes identified by GWAS, remains unknown. Here we provide biochemical and cellular evidence that artemisinins are potent inhibitors of Plasmodium falciparum phosphatidylinositol-3-kinase (PfPI3K), revealing an unexpected mechanism of action. In resistant clinical strains, increased PfPI3K was associated with the C580Y mutation in P. falciparum Kelch13 (PfKelch13), a primary marker of artemisinin resistance. Polyubiquitination of PfPI3K and its binding to PfKelch13 were reduced by the PfKelch13 mutation, which limited proteolysis of PfPI3K and thus increased levels of the kinase, as well as its lipid product phosphatidylinositol-3-phosphate (PI3P). We find PI3P levels to be predictive of artemisinin resistance in both clinical and engineered laboratory parasites as well as across non-isogenic strains. Elevated PI3P induced artemisinin resistance in absence of PfKelch13 mutations, but remained responsive to regulation by PfKelch13. Evidence is presented for PI3P-dependent signalling in which transgenic expression of an additional kinase confers resistance. Together these data present PI3P as the key mediator of artemisinin resistance and the sole PfPI3K as an important target for malaria elimination.

Relationship between perfusion index and patent ductus arteriosus in preterm infants.

PubMed

Gomez-Pomar, Enrique; Makhoul, Majd; Westgate, Philip M; Ibonia, Katrina T; Patwardhan, Abhijit; Giannone, Peter J; Bada, Henrietta S; Abu Jawdeh, Elie G

2017-05-01

Perfusion index (PI) is a noninvasive measure of perfusion. ΔPI (difference between pre- and postductal PI) may identify hemodynamically significant PDA. However, studies are limited to brief and intermittent ΔPI sampling. Our objective is to assess the value of continuous high resolution ΔPI monitoring in the diagnosis of PDA. Continuous ΔPI monitoring in preterm infants was prospectively performed using two high-resolution pulse oximeters. Perfusion Index measures (ΔPI mean and variability, pre- and postductal PI) were analyzed over a 4-h period prior to echocardiography. A cardiologist blinded to the results evaluated for PDA on echocardiography. Linear mixed regression models were utilized for analyses. We obtained 31 echocardiography observations. Mean ΔPI (-0.23 vs. 0.16; P < 0.05), mean pre-PI (0.86 vs. 1.26; P < 0.05), and ΔPI variability (0.39 vs. 0.61; P = 0.05) were lower in infants with PDA compared to infants without PDA at the time of echocardiography. Mean ΔPI, ΔPI variability, and mean pre-PI measured 4 h prior to echocardiography detect PDA in preterm infants. PI is dynamic and should be assessed continuously. Perfusion index is a promising bedside measurement to identify PDA in preterm infants.

Measurement of branching fractions and charge asymmetries in B+/--->rho+/-pi0 and B+/--->rho0pi+/- decays, and search for B0-->rho0pi0.

PubMed

Aubert, B; Barate, R; Boutigny, D; Couderc, F; Gaillard, J-M; Hicheur, A; Karyotakis, Y; Lees, J P; Robbe, P; Tisserand, V; Zghiche, A; Palano, A; Pompili, A; Chen, J C; Qi, N D; Rong, G; Wang, P; Zhu, Y S; Eigen, G; Ofte, I; Stugu, B; Abrams, G S; Borgland, A W; Breon, A B; Brown, D N; Button-Shafer, J; Cahn, R N; Charles, E; Day, C T; Gill, M S; Gritsan, A V; Groysman, Y; Jacobsen, R G; Kadel, R W; Kadyk, J; Kerth, L T; Kolomensky, Yu G; Kukartsev, G; LeClerc, C; Levi, M E; Lynch, G; Mir, L M; Oddone, P J; Orimoto, T J; Pripstein, M; Roe, N A; Romosan, A; Ronan, M T; Shelkov, V G; Telnov, A V; Wenzel, W A; Ford, K; Harrison, T J; Hawkes, C M; Knowles, D J; Morgan, S E; Penny, R C; Watson, A T; Watson, N K; Goetzen, K; Held, T; Koch, H; Lewandowski, B; Pelizaeus, M; Peters, K; Schmuecker, H; Steinke, M; Boyd, J T; Chevalier, N; Cottingham, W N; Kelly, M P; Latham, T E; Mackay, C; Wilson, F F; Abe, K; Cuhadar-Donszelmann, T; Hearty, C; Mattison, T S; McKenna, J A; Thiessen, D; Kyberd, P; McKemey, A K; Teodorescu, L; Blinov, V E; Bukin, A D; Golubev, V B; Ivanchenko, V N; Kravchenko, E A; Onuchin, A P; Serednyakov, S I; Skovpen, Yu I; Solodov, E P; Yushkov, A N; Best, D; Bruinsma, M; Chao, M; Kirkby, D; Lankford, A J; Mandelkern, M; Mommsen, R K; Roethel, W; Stoker, D P; Buchanan, C; Hartfiel, B L; Gary, J W; Layter, J; Shen, B C; Wang, K; del Re, D; Hadavand, H K; Hill, E J; MacFarlane, D B; Paar, H P; Rahatlou, Sh; Sharma, V; Berryhill, J W; Campagnari, C; Dahmes, B; Levy, S L; Long, O; Lu, A; Mazur, M A; Richman, J D; Verkerke, W; Beck, T W; Beringer, J; Eisner, A M; Heusch, C A; Lockman, W S; Schalk, T; Schmitz, R E; Schumm, B A; Seiden, A; Spradlin, P; Turri, M; Walkowiak, W; Williams, D C; Wilson, M G; Albert, J; Chen, E; Dubois-Felsmann, G P; Dvoretskii, A; Erwin, R J; Hitlin, D G; Narsky, I; Piatenko, T; Porter, F C; Ryd, A; Samuel, A; Yang, S; Jayatilleke, S; Mancinelli, G; Meadows, B T; Sokoloff, M D; Abe, T; Blanc, F; Bloom, P; Chen, S; Clark, P J; Ford, W T; Nauenberg, U; Olivas, A; Rankin, P; Roy, J; Smith, J G; van Hoek, W C; Zhang, L; Harton, J L; Hu, T; Soffer, A; Toki, W H; Wilson, R J; Zhang, J; Altenburg, D; Brandt, T; Brose, J; Colberg, T; Dickopp, M; Dubitzky, R S; Hauke, A; Lacker, H M; Maly, E; Müller-Pfefferkorn, R; Nogowski, R; Otto, S; Schubert, J; Schubert, K R; Schwierz, R; Spaan, B; Wilden, L; Bernard, D; Bonneaud, G R; Brochard, F; Cohen-Tanugi, J; Grenier, P; Thiebaux, Ch; Vasileiadis, G; Verderi, M; Khan, A; Lavin, D; Muheim, F; Playfer, S; Swain, J E; Andreotti, M; Azzolini, V; Bettoni, D; Bozzi, C; Calabrese, R; Cibinetto, G; Luppi, E; Negrini, M; Piemontese, L; Sarti, A; Treadwell, E; Baldini-Ferroli, R; Calcaterra, A; de Sangro, R; Falciai, D; Finocchiaro, G; Patteri, P; Piccolo, M; Zallo, A; Buzzo, A; Capra, R; Contri, R; Crosetti, G; Lo Vetere, M; Macri, M; Monge, M R; Passaggio, S; Patrignani, C; Robutti, E; Santroni, A; Tosi, S; Bailey, S; Morii, M; Won, E; Bhimji, W; Bowerman, D A; Dauncey, P D; Egede, U; Eschrich, I; Gaillard, J R; Morton, G W; Nash, J A; Taylor, G P; Grenier, G J; Lee, S-J; Mallik, U; Cochran, J; Crawley, H B; Lamsa, J; Meyer, W T; Prell, S; Rosenberg, E I; Yi, J; Davier, M; Grosdidier, G; Höcker, A; Laplace, S; Le Diberder, F; Lepeltier, V; Lutz, A M; Petersen, T C; Plaszczynski, S; Schune, M H; Tantot, L; Wormser, G; Brigljević, V; Cheng, C H; Lange, D J; Simani, M C; Wright, D M; Bevan, A J; Coleman, J P; Fry, J R; Gabathuler, E; Gamet, R; Kay, M; Parry, R J; Payne, D J; Sloane, R J; Touramanis, C; Back, J J; Harrison, P F; Shorthouse, H W; Vidal, P B; Brown, C L; Cowan, G; Flack, R L; Flaecher, H U; George, S; Green, M G; Kurup, A; Marker, C E; McMahon, T R; Ricciardi, S; Salvatore, F; Vaitsas, G; Winter, M A; Brown, D; Davis, C L; Allison, J; Barlow, N R; Barlow, R J; Hart, P A; Hodgkinson, M C; Jackson, F; Lafferty, G D; Lyon, A J; Weatherall, J H; Williams, J C; Farbin, A; Jawahery, A; Kovalskyi, D; Lae, C K; Lillard, V; Roberts, D A; Blaylock, G; Dallapiccola, C; Flood, K T; Hertzbach, S S; Kofler, R; Koptchev, V B; Moore, T B; Saremi, S; Staengle, H; Willocq, S; Cowan, R; Sciolla, G; Taylor, F; Yamamoto, R K; Mangeol, D J J; Patel, P M; Robertson, S H; Lazzaro, A; Palombo, F; Bauer, J M; Cremaldi, L; Eschenburg, V; Godang, R; Kroeger, R; Reidy, J; Sanders, D A; Summers, D J; Zhao, H W; Brunet, S; Cote-Ahern, D; Taras, P; Nicholson, H; Cartaro, C; Cavallo, N; De Nardo, G; Fabozzi, F; Gatto, C; Lista, L; Paolucci, P; Piccolo, D; Sciacca, C; Baak, M A; Raven, G; LoSecco, J M; Gabriel, T A; Brau, B; Gan, K K; Honscheid, K; Hufnagel, D; Kagan, H; Kass, R; Pulliam, T; Wong, Q K; Brau, J; Frey, R; Igonkina, O; Potter, C T; Sinev, N B; Strom, D; Torrence, E; Colecchia, F; Dorigo, A; Galeazzi, F; Margoni, M; Morandin, M; Posocco, M; Rotondo, M; Simonetto, F; Stroili, R; Tiozzo, G; Voci, C; Benayoun, M; Briand, H; Chauveau, J; David, P; de la Vaissière, Ch; Del Buono, L; Hamon, O; John, M J J; Leruste, Ph; Ocariz, J; Pivk, M; Roos, L; Stark, J; T'Jampens, S; Therin, G; Manfredi, P F; Re, V; Behera, P K; Gladney, L; Guo, Q H; Panetta, J; Anulli, F; Biasini, M; Peruzzi, I M; Pioppi, M; Angelini, C; Batignani, G; Bettarini, S; Bondioli, M; Bucci, F; Calderini, G; Carpinelli, M; Del Gamba, V; Forti, F; Giorgi, M A; Lusiani, A; Marchiori, G; Martinez-Vidal, F; Morganti, M; Neri, N; Paoloni, E; Rama, M; Rizzo, G; Sandrelli, F; Walsh, J; Haire, M; Judd, D; Paick, K; Wagoner, D E; Danielson, N; Elmer, P; Lu, C; Miftakov, V; Olsen, J; Smith, A J S; Tanaka, H A; Varnes, E W; Bellini, F; Cavoto, G; Faccini, R; Ferrarotto, F; Ferroni, F; Gaspero, M; Mazzoni, M A; Morganti, S; Pierini, M; Piredda, G; Safai Tehrani, F; Voena, C; Christ, S; Wagner, G; Waldi, R; Adye, T; De Groot, N; Franek, B; Geddes, N I; Gopal, G P; Olaiya, E O; Xella, S M; Aleksan, R; Emery, S; Gaidot, A; Ganzhur, S F; Giraud, P-F; Hamel de Monchenault, G; Kozanecki, W; Langer, M; Legendre, M; London, G W; Mayer, B; Schott, G; Vasseur, G; Yeche, Ch; Zito, M; Purohit, M V; Weidemann, A W; Yumiceva, F X; Aston, D; Bartoldus, R; Berger, N; Boyarski, A M; Buchmueller, O L; Convery, M R; Cristinziani, M; Dong, D; Dorfan, J; Dujmic, D; Dunwoodie, W; Elsen, E E; Field, R C; Glanzman, T; Gowdy, S J; Grauges-Pous, E; Hadig, T; Halyo, V; Hast, C; Hryn'ova, T; Innes, W R; Jessop, C P; Kelsey, M H; Kim, P; Kocian, M L; Langenegger, U; Leith, D W G S; Libby, J; Luitz, S; Luth, V; Lynch, H L; Marsiske, H; Messner, R; Muller, D R; O'Grady, C P; Ozcan, V E; Perazzo, A; Perl, M; Petrak, S; Ratcliff, B N; Roodman, A; Salnikov, A A; Schindler, R H; Schwiening, J; Simi, G; Snyder, A; Soha, A; Stelzer, J; Su, D; Sullivan, M K; Va'vra, J; Wagner, S R; Weaver, M; Weinstein, A J R; Wisniewski, W J; Wright, D H; Young, C C; Burchat, P R; Edwards, A J; Meyer, T I; Petersen, B A; Roat, C; Ahmed, M; Ahmed, S; Alam, M S; Ernst, J A; Saeed, M A; Saleem, M; Wappler, F R; Bugg, W; Krishnamurthy, M; Spanier, S M; Eckmann, R; Kim, H; Ritchie, J L; Schwitters, R F; Izen, J M; Kitayama, I; Lou, X C; Ye, S; Bianchi, F; Bona, M; Gallo, F; Gamba, D; Borean, C; Bosisio, L; Della Ricca, G; Dittongo, S; Grancagnolo, S; Lanceri, L; Poropat, P; Vitale, L; Vuagnin, G; Panvini, R S; Banerjee, Sw; Brown, C M; Fortin, D; Jackson, P D; Kowalewski, R; Roney, J M; Band, H R; Dasu, S; Datta, M; Eichenbaum, A M; Johnson, J R; Kutter, P E; Li, H; Liu, R; Di Lodovico, F; Mihalyi, A; Mohapatra, A K; Pan, Y; Prepost, R; Sekula, S J; von Wimmersperg-Toeller, J H; Wu, J; Wu, S L; Yu, Z; Neal, H

2004-07-30

We present measurements of branching fractions and charge asymmetries in B-meson decays to rho(+)pi(0), rho(0)pi(+), and rho(0)pi(0). The data sample comprises 89x10(6) Upsilon(4S)-->BBmacr; decays collected with the BABAR detector at the PEP-II asymmetric-energy B Factory at SLAC. We find the charge-averaged branching fractions B(B+-->rho(+)pi(0))=[10.9+/-1.9(stat)+/-1.9(syst)]x10(-6) and B(B+-->rho(0)pi(+))=(9.5+/-1.1+/-0.9)x10(-6), and we set a 90% confidence-level upper limit B(B0-->rho(0)pi(0))<2.9x10(-6). We measure the charge asymmetries ACP(pi(0))(rho(+))=0.24+/-0.16+/-0.06 and ACP(pi(+))(rho(0))=-0.19+/-0.11+/-0.02.

77 FR 55880 - Prudential Short Duration High Yield Fund, Inc. and Prudential Investments LLC; Notice of...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-11

... High Yield Fund, Inc. (``Initial Fund'') and Prudential Investments LLC (``PI'' or the ``Adviser... investment company currently advised or to be advised in the future by PI (including any successor in... 2(a)(9) of the Act) with PI (such entities, together with PI, the ``Advisers'') that decides in the...

VizieR Online Data Catalog: H2 d3{Pi}u excitation by elec

NASA Astrophysics Data System (ADS)

Liu, X.; Shemansky, D. E.; Yoshii, J.; Johnson, P. V.; Malone, C. P.; Ajello, J. M.

2016-05-01

Electron-impact excitation of H2 triplet states plays an imp role in the heating of outer planet upper thermospheres. The d3{Pi}u state is the third ungerade triplet state, and the d3{Pi}u-a3{Sigma}g+ emission is the largest cascade channel for the a3{Sigma}g+ state. Accurate energies of the d3{Pi}u-(v, J) levels are calculated from an ab initio potential energy curve. Radiative lifetimes of the d3{Pi}u(v,J) levels are obtained by an accurate evaluation of the d3{Pi}u-a3{Sigma}g+ transition probabilities. The emission yields are determined from experimental lifetimes and calculated radiative lifetimes and are further verified by comparing experimental and synthetic d3{Pi}u-a3{Sigma}g+ spectra at 20eV impact energy. Spectral analysis revealed that multipolar components beyond the dipolar term are required to model the X1{Sigma}g+-d3{Pi}u excitation, and significant cascade excitation occurs at the d3{Pi}u (v=0,1) levels. Kinetic energy (Ek) distributions of H atoms produced via predissociation of the 3{Pi}u state and the d3{Pi}u-a3{Sigma}g+-b3{Sigma}u+ cascade dissociative emission are obtained. Predissociation of the d3{Pi}u state produces H atoms with an average Ek of 2.3+/-0.4 eV/atom, while the Ekdistribution of the d3{Pi}u-a3{Sigma}g+-b3{Sigma}u+ channel is similar to that of the X1{Sigma}g+-a3{Sigma}g+-b3{Sigma}u+ channel and produces H(1s) atoms with an average Ek of 1.15+/-0.05eV/atom. On average, each H2 excited to the d3{Pi}u state in an H2-dominated atmosphere deposits 3.3+/-0.4eV into the atmosphere, while each H2directly excited to the a3{Sigma}g+ state gives 2.2-2.3eV to the atmosphere. The spectral distribution of the calculated a3{Sigma}g+-b3{Sigma}u+ continuum emission due to the X1{Sigma}g+-d3{Pi}u excitation is significantly different from that of direct a3{Sigma}g+ excitation. (2 data files).

Downregulation of RBO-PI4KIIIα Facilitates Aβ42 Secretion and Ameliorates Neural Deficits in Aβ42-Expressing Drosophila.

PubMed

Zhang, Xiao; Wang, Wen-An; Jiang, Li-Xiang; Liu, Hai-Yan; Zhang, Bao-Zhu; Lim, Nastasia; Li, Qing-Yi; Huang, Fu-De

2017-05-10

Phosphoinositides and their metabolizing enzymes are involved in Aβ 42 metabolism and Alzheimer's disease pathogenesis. In yeast and mammals, Eighty-five requiring 3 (EFR3), whose Drosophila homolog is Rolling Blackout (RBO), forms a plasma membrane-localized protein complex with phosphatidylinositol-4-kinase Type IIIα (PI4KIIIα) and a scaffold protein to tightly control the level of plasmalemmal phosphatidylinositol-4-phosphate (PI 4 P). Here, we report that RBO binds to Drosophila PI4KIIIα, and that in an Aβ 42 -expressing Drosophila model, separate genetic reduction of PI4KIIIα and RBO, or pharmacological inhibition of PI4KIIIα ameliorated synaptic transmission deficit, climbing ability decline, premature death, and reduced neuronal accumulation of Aβ 42 Moreover, we found that RBO-PI4KIIIa downregulation increased neuronal Aβ 42 release and that PI4P facilitated the assembly or oligomerization of Aβ 42 in/on liposomes. These results indicate that RBO-PI4KIIIa downregulation facilitates neuronal Aβ 42 release and consequently reduces neuronal Aβ 42 accumulation likely via decreasing Aβ 42 assembly in/on plasma membrane. This study suggests the RBO-PI4KIIIα complex as a potential therapeutic target and PI4KIIIα inhibitors as drug candidates for Alzheimer's disease treatment. SIGNIFICANCE STATEMENT Phosphoinositides and their metabolizing enzymes are involved in Aβ 42 metabolism and Alzheimer's disease pathogenesis. Here, in an Aβ 42 -expressing Drosophila model, we discovered and studied the beneficial role of downregulating RBO or its interacting protein PI4KIIIα-a protein that tightly controls the plasmalemmal level of PI 4 P-against the defects caused by Aβ 42 expression. Mechanistically, RBO-PI4KIIIα downregulation reduced neuronal Aβ 42 accumulation, and interestingly increased neuronal Aβ 42 release. This study suggests the RBO-PI4KIIIα complex as a novel therapeutic target, and PI4KIIIα inhibitors as new drug candidates. Copyright © 2017 the authors 0270-6474/17/374928-14$15.00/0.

Immune challenge differentially affects transcript abundance of three antimicrobial peptides in hemocytes from the moth Pseudoplusia includens.

PubMed

Lavine, M D; Chen, G; Strand, M R

2005-12-01

Inducible expression of antimicrobial peptides and other humoral immune factors by the insect fat body is well documented. Hemocytes comprise the second essential arm of the insect immune system but it is unclear whether antimicrobial peptide genes are expressed by all or only some types of hemocytes. Here we report the cloning of cecropin A (Pi-cecA), lebocin (Pi-leb) and lysozyme (Pi-lys) homologs from the moth Pseudoplusia includens. Relative-quantitative real-time PCR (rq-rtPCR) indicated that transcript abundance for each antimicrobial gene increased in fat body and hemocytes following immune challenge with the Gram-negative bacterium Escherichia coli. Relative transcript abundance of Pi-cecA was much higher in fat body than hemocytes. In contrast, transcript levels of Pi-leb were three-fold lower in hemocytes than fat body while transcript levels of Pi-lys were three-fold higher. Estimates for the overall contribution of the fat body and hemocytes to antimicrobial peptide expression suggested that hemocytes contribute significantly to Pi-lys transcript levels in larvae but produce much smaller amounts of Pi-cecA and Pi-leb compared to the fat body. Each antimicrobial peptide was also inducibly expressed in hemocytes following challenge with the Gram-positive bacterium Micrococcus luteus or when hemocytes formed capsules around chromatography beads. Analysis of hemocyte types indicated that granulocytes and plasmatocytes expressed all three antimicrobial peptides, whereas spherule cells and oenocytoids expressed only lysozyme. Transcriptional profiles of these antimicrobial genes were similar in granulocytes and plasmatocytes in vivo but were very different in vitro.

Pinus pinaster seedlings and their fungal symbionts show high plasticity in phosphorus acquisition in acidic soils.

PubMed

Ali, M A; Louche, J; Legname, E; Duchemin, M; Plassard, C

2009-12-01

Young seedlings of maritime pine (Pinus pinaster Soland in Aït.) were grown in rhizoboxes using intact spodosol soil samples from the southwest of France, in Landes of Gascogne, presenting a large variation of phosphorus (P) availability. Soils were collected from a 93-year-old unfertilized stand and a 13-year-old P. pinaster stand with regular annual fertilization of either only P or P and nitrogen (N). After 6 months of culture in controlled conditions, different morphotypes of ectomycorrhiza (ECM) were used for the measurements of acid phosphatase activity and molecular identification of fungal species using amplification of the ITS region. Total biomass, N and P contents were measured in roots and shoots of plants. Bicarbonate- and NaOH-available inorganic P (Pi), organic P (Po) and ergosterol concentrations were measured in bulk and rhizosphere soil. The results showed that bulk soil from the 93-year-old forest stand presented the highest Po levels, but relatively higher bicarbonate-extractable Pi levels compared to 13-year-old unfertilized stand. Fertilizers significantly increased the concentrations of inorganic P fractions in bulk soil. Ergosterol contents in rhizosphere soil were increased by fertilizer application. The dominant fungal species was Rhizopogon luteolus forming 66.6% of analysed ECM tips. Acid phosphatase activity was highly variable and varied inversely with bicarbonate-extractable Pi levels in the rhizosphere soil. Total P or total N in plants was linearly correlated with total plant biomass, but the slope was steep only between total P and biomass in fertilized soil samples. In spite of high phosphatase activity in ECM tips, P availability remained a limiting nutrient in soil samples from unfertilized stands. Nevertheless young P. pinaster seedlings showed a high plasticity for biomass production at low P availability in soils.

Low phosphate alters lateral root setpoint angle and gravitropism.

PubMed

Bai, Hanwen; Murali, Bhavna; Barber, Kevin; Wolverton, Chris

2013-01-01

Lateral roots, responsible for water and nutrient uptake, maintain nonvertical angles throughout development. Soil phosphate is one limiting nutrient for plant growth that is known to induce changes to root system architecture, such as increased lateral root formation. This study seeks to determine whether phosphate concentration affects lateral root orientation in addition to its previously described influences on root architecture. Images of intact Arabidopsis root systems were recorded for 24 h, and lateral root tip angles were measured for wild-type and mutant pgm-1 and pin3-1 roots on a full or low phosphate medium. Setpoint angles of unstimulated root systems were determined, as were gravitropic responses of lateral roots over time. The root system setpoint angles of wild-type and mutant pin3-1 roots showed a shift toward a more vertical orientation on low orthophosphate (Pi) medium. The gravitropic responses of both pgm-1 and pin3-1 roots on low Pi medium was elevated relative to control Pi medium. Mutations in two phosphate transporters with high levels of expression in the root showed a gravitropic response similar to wild-type roots grown on low Pi, supporting a role for Pi status in regulating lateral root gravitropism. Lateral root orientation and gravitropism are affected by Pi status and may provide an important additional parameter for describing root responses to low Pi. The data also support the conclusion that gravitropic setpoint angle reacts to nutrient status and is under dynamic regulation.

Kaiser Permanente's performance improvement system, Part 1: From benchmarking to executing on strategic priorities.

PubMed

Schilling, Lisa; Chase, Alide; Kehrli, Sommer; Liu, Amy Y; Stiefel, Matt; Brentari, Ruth

2010-11-01

By 2004, senior leaders at Kaiser Permanente, the largest not-for-profit health plan in the United States, recognizing variations across service areas in quality, safety, service, and efficiency, began developing a performance improvement (PI) system to realizing best-in-class quality performance across all 35 medical centers. MEASURING SYSTEMWIDE PERFORMANCE: In 2005, a Web-based data dashboard, "Big Q," which tracks the performance of each medical center and service area against external benchmarks and internal goals, was created. PLANNING FOR PI AND BENCHMARKING PERFORMANCE: In 2006, Kaiser Permanente national and regional continued planning the PI system, and in 2007, quality, medical group, operations, and information technology leaders benchmarked five high-performing organizations to identify capabilities required to achieve consistent best-in-class organizational performance. THE PI SYSTEM: The PI system addresses the six capabilities: leadership priority setting, a systems approach to improvement, measurement capability, a learning organization, improvement capacity, and a culture of improvement. PI "deep experts" (mentors) consult with national, regional, and local leaders, and more than 500 improvement advisors are trained to manage portfolios of 90-120 day improvement initiatives at medical centers. Between the second quarter of 2008 and the first quarter of 2009, performance across all Kaiser Permanente medical centers improved on the Big Q metrics. The lessons learned in implementing and sustaining PI as it becomes fully integrated into all levels of Kaiser Permanente can be generalized to other health care systems, hospitals, and other health care organizations.

How a high working memory capacity can increase proactive interference.

PubMed

Steinwascher, Merle A; Meiser, Thorsten

2016-08-01

Previous findings suggested that a high working memory capacity (WMC) is potentially associated with a higher susceptibility to proactive interference (PI) if the latter is measured under high cognitive load. To explain such a finding, we propose to consider susceptibility to PI as a net effect of individual executive processes and the intrinsic potential for PI. With the latter, we refer to the amount of information that is activated at a given time and that has the potential to exert PI subsequently. In two studies deploying generalized linear mixed models, susceptibility to PI was modeled as the decline of performance over trials of a complex span task. The results revealed that a higher WMC was associated with a higher susceptibility to PI. Moreover, the number of stimuli recalled in one trial as a proxy variable for the intrinsic potential for PI negatively affected memory performance in the subsequent trial. Copyright © 2016 Elsevier Inc. All rights reserved.

Prevotella intermedia Induces Severe Bacteremic Pneumococcal Pneumonia in Mice with Upregulated Platelet-Activating Factor Receptor Expression

PubMed Central

Nagaoka, Kentaro; Morinaga, Yoshitomo; Nakamura, Shigeki; Harada, Tatsuhiko; Hasegawa, Hiroo; Izumikawa, Koichi; Ishimatsu, Yuji; Kakeya, Hiroshi; Nishimura, Masaharu; Kohno, Shigeru

2014-01-01

Streptococcus pneumoniae is the leading cause of respiratory infection worldwide. Although oral hygiene has been considered a risk factor for developing pneumonia, the relationship between oral bacteria and pneumococcal infection is unknown. In this study, we examined the synergic effects of Prevotella intermedia, a major periodontopathic bacterium, on pneumococcal pneumonia. The synergic effects of the supernatant of P. intermedia (PiSup) on pneumococcal pneumonia were investigated in mice, and the stimulation of pneumococcal adhesion to human alveolar (A549) cells by PiSup was assessed. The effects of PiSup on platelet-activating factor receptor (PAFR) transcript levels in vitro and in vivo were analyzed by quantitative real-time PCR, and the differences between the effects of pneumococcal infection induced by various periodontopathic bacterial species were verified in mice. Mice inoculated with S. pneumoniae plus PiSup exhibited a significantly lower survival rate, higher bacterial loads in the lungs, spleen, and blood, and higher inflammatory cytokine levels in the bronchoalveolar lavage fluid (macrophage inflammatory protein 2 and tumor necrosis factor alpha) than those infected without PiSup. In A549 cells, PiSup increased pneumococcal adhesion and PAFR transcript levels. PiSup also increased lung PAFR transcript levels in mice. Similar effects were not observed in the supernatants of Porphyromonas gingivalis or Fusobacterium nucleatum. Thus, P. intermedia has the potential to induce severe bacteremic pneumococcal pneumonia with enhanced pneumococcal adhesion to lower airway cells. PMID:24478074

Prevotella intermedia induces severe bacteremic pneumococcal pneumonia in mice with upregulated platelet-activating factor receptor expression.

PubMed

Nagaoka, Kentaro; Yanagihara, Katsunori; Morinaga, Yoshitomo; Nakamura, Shigeki; Harada, Tatsuhiko; Hasegawa, Hiroo; Izumikawa, Koichi; Ishimatsu, Yuji; Kakeya, Hiroshi; Nishimura, Masaharu; Kohno, Shigeru

2014-02-01

Streptococcus pneumoniae is the leading cause of respiratory infection worldwide. Although oral hygiene has been considered a risk factor for developing pneumonia, the relationship between oral bacteria and pneumococcal infection is unknown. In this study, we examined the synergic effects of Prevotella intermedia, a major periodontopathic bacterium, on pneumococcal pneumonia. The synergic effects of the supernatant of P. intermedia (PiSup) on pneumococcal pneumonia were investigated in mice, and the stimulation of pneumococcal adhesion to human alveolar (A549) cells by PiSup was assessed. The effects of PiSup on platelet-activating factor receptor (PAFR) transcript levels in vitro and in vivo were analyzed by quantitative real-time PCR, and the differences between the effects of pneumococcal infection induced by various periodontopathic bacterial species were verified in mice. Mice inoculated with S. pneumoniae plus PiSup exhibited a significantly lower survival rate, higher bacterial loads in the lungs, spleen, and blood, and higher inflammatory cytokine levels in the bronchoalveolar lavage fluid (macrophage inflammatory protein 2 and tumor necrosis factor alpha) than those infected without PiSup. In A549 cells, PiSup increased pneumococcal adhesion and PAFR transcript levels. PiSup also increased lung PAFR transcript levels in mice. Similar effects were not observed in the supernatants of Porphyromonas gingivalis or Fusobacterium nucleatum. Thus, P. intermedia has the potential to induce severe bacteremic pneumococcal pneumonia with enhanced pneumococcal adhesion to lower airway cells.

A comparative proteomic analysis of Vibrio cholerae O1 wild-type cells versus a phoB mutant showed that the PhoB/PhoR system is required for full growth and rpoS expression under inorganic phosphate abundance.

PubMed

Lery, Letícia M S; Goulart, Carolina L; Figueiredo, Felipe R; Verdoorn, Karine S; Einicker-Lamas, Marcelo; Gomes, Fabio M; Machado, Ednildo A; Bisch, Paulo M; von Kruger, Wanda M A

2013-06-28

PhoB/PhoR is a two-component system originally described as involved in inorganic phosphate (Pi) transport and metabolism under Pi limitation. In order to disclose other roles of this system, a proteomic analysis of Vibrio cholerae 569BSR and its phoB/phoR mutant under high Pi levels was performed. Most of the proteins downregulated by the mutant have roles in energy production and conversion and in amino acid transport and metabolism. In contrast, the phoB/phoR mutant upregulated genes mainly involved in adaptation to atypical conditions, indicating that the absence of a functional PhoB/PhoR caused increased expression of a number of genes from distinct stress response pathways. This might be a strategy to overcome the lack of RpoS, whose expression in the stationary phase cells of V. cholerae seems to be controlled by PhoB/PhoR. Moreover, compared to the wild-type strain the phoB/phoR mutant presented a reduced cell density at stationary phase of culture in Pi abundance, lower resistance to acid shock, but higher tolerance to thermal and osmotic stresses. Together our findings show, for the first time, the requirement of PhoB/PhoR for full growth under high Pi level and for the accumulation of RpoS, indicating that PhoB/PhoR is a fundamental system for the biology of V. cholerae. Certain V. cholerae strains are pathogenic to humans, causing cholera, an acute dehydrating diarrhoeal disease endemic in Southern Asia, parts of Africa and Latin America, where it has been responsible for significant mortality and economical damage. Its ability to grow within distinct niches is dependent on gene expression regulation. PhoB/PhoR is a two-component system originally described as involved in inorganic phosphate (Pi) transport and metabolism under Pi limitation. However, Pho regulon genes also play roles in virulence, motility and biofilm formation, among others. In this paper we report that the absence of a functional PhoB/PhoR caused increased expression of a number of genes from distinct stress response pathways, in Pi abundance. Moreover, we showed, for the first time, that the interrelationship between PhoB-RpoS-(p)ppGpp-poly(P) in V. cholerae, is somewhat diverse from the model of inter-regulation between those systems, described in Escherichia coli. The V. cholerae dependence on PhoB/PhoR for the RpoS mediated stress response and cellular growth under Pi abundance, suggests that this system's roles are broader than previously thought. Copyright © 2013. Published by Elsevier B.V.

Long-Term Administration of Dehydroepiandrosterone Accelerates Glucose Catabolism via Activation of PI3K/Akt-PFK-2 Signaling Pathway in Rats Fed a High-Fat Diet

PubMed Central

Kang, Jian; Ge, Chongyang; Yu, Lei; Li, Longlong; Ma, Haitian

2016-01-01

Dehydroepiandrosterone (DHEA) has a fat-reducing effect, while little information is available on whether DHEA regulates glucose metabolism, which would in turn affect fat deposition. To investigate the effects of DHEA on glucose metabolism, rats were administered a high-fat diet containing either 0 (HCG), 25 (HLG), 50 (HMG), or 100 (HHG) mg·kg-1 DHEA per day via gavage for 8 weeks. Results showed that long-term administration of DHEA inhibited body weight gain in rats on a high-fat diet. No statistical differences in serum glucose levels were observed, whereas hepatic glycogen content in HMG and HHG groups and muscle glycogen content in HLG and HMG groups were higher than those in HCG group. Glucokinase, malate dehydrogenase and phosphofructokinase-2 activities in HMG and HHG groups, pyruvate kinase and succinate dehydrogenase activities in HMG group, and pyruvate dehydrogenase activity in all DHEA treatment groups were increased compared with those in HCG group. Phosphoenolpyruvate carboxykinase and glycogen phosphorylase mRNA levels were decreased in HMG and HHG groups, whereas glycogen synthase-2 mRNA level was increased in HMG group compared with those in HCG. The abundance of Glut2 mRNA in HMG and HHG groups and Glut4 mRNA in HMG group was higher than that in HCG group. DHEA treatment increased serum leptin content in HMG and HHG groups compared with that in HCG group. Serum insulin content and insulin receptor mRNA level in HMG group and insulin receptor substrate-2 mRNA level in HMG and HHG group were increased compared with those in HCG group. Furthermore, Pi3k mRNA level in HMG and Akt mRNA level in HMG and HHG groups were significantly increased than those in HCG group. These data showed that DHEA treatment could enhance glycogen storage and accelerate glucose catabolism in rats fed a high-fat diet, and this effect may be associated with the activation of PI3K/Akt-PFK-2 signaling pathway. PMID:27410429

Long-Term Administration of Dehydroepiandrosterone Accelerates Glucose Catabolism via Activation of PI3K/Akt-PFK-2 Signaling Pathway in Rats Fed a High-Fat Diet.

PubMed

Kang, Jian; Ge, Chongyang; Yu, Lei; Li, Longlong; Ma, Haitian

2016-01-01

Dehydroepiandrosterone (DHEA) has a fat-reducing effect, while little information is available on whether DHEA regulates glucose metabolism, which would in turn affect fat deposition. To investigate the effects of DHEA on glucose metabolism, rats were administered a high-fat diet containing either 0 (HCG), 25 (HLG), 50 (HMG), or 100 (HHG) mg·kg-1 DHEA per day via gavage for 8 weeks. Results showed that long-term administration of DHEA inhibited body weight gain in rats on a high-fat diet. No statistical differences in serum glucose levels were observed, whereas hepatic glycogen content in HMG and HHG groups and muscle glycogen content in HLG and HMG groups were higher than those in HCG group. Glucokinase, malate dehydrogenase and phosphofructokinase-2 activities in HMG and HHG groups, pyruvate kinase and succinate dehydrogenase activities in HMG group, and pyruvate dehydrogenase activity in all DHEA treatment groups were increased compared with those in HCG group. Phosphoenolpyruvate carboxykinase and glycogen phosphorylase mRNA levels were decreased in HMG and HHG groups, whereas glycogen synthase-2 mRNA level was increased in HMG group compared with those in HCG. The abundance of Glut2 mRNA in HMG and HHG groups and Glut4 mRNA in HMG group was higher than that in HCG group. DHEA treatment increased serum leptin content in HMG and HHG groups compared with that in HCG group. Serum insulin content and insulin receptor mRNA level in HMG group and insulin receptor substrate-2 mRNA level in HMG and HHG group were increased compared with those in HCG group. Furthermore, Pi3k mRNA level in HMG and Akt mRNA level in HMG and HHG groups were significantly increased than those in HCG group. These data showed that DHEA treatment could enhance glycogen storage and accelerate glucose catabolism in rats fed a high-fat diet, and this effect may be associated with the activation of PI3K/Akt-PFK-2 signaling pathway.

Integrated corridor management modeling results report : Dallas, Minneapolis, and San Diego.

DOT National Transportation Integrated Search

2012-02-01

This executive summary documents the analysis methodologies, tools, and performance measures used to analyze Integrated Corridor Management (ICM) strategies; and presents high-level results for the successful implementation of ICM at three Stage 2 Pi...

Observation of pi{sup +}pi{sup -}pi{sup +}pi{sup -} photoproduction in ultraperipheral heavy-ion collisions at sq root(s{sub NN})=200 GeV at the STAR detector

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

Abelev, B. I.; Betts, R. R.; Evdokimov, O.

We present a measurement of pi{sup +}pi{sup -}pi{sup +}pi{sup -} photonuclear production in ultraperipheral Au-Au collisions at sq root(s{sub N{sub N}})=200 GeV from the STAR experiment. The pi{sup +}pi{sup -}pi{sup +}pi{sup -} final states are observed at low transverse momentum and are accompanied by mutual nuclear excitation of the beam particles. The strong enhancement of the production cross section at low transverse momentum is consistent with coherent photoproduction. The pi{sup +}pi{sup -}pi{sup +}pi{sup -} invariant mass spectrum of the coherent events exhibits a broad peak around 1540+-40 MeV/c{sup 2} with a width of 570+-60 MeV/c{sup 2}, in agreement with themore » photoproduction data for the rho{sup 0}(1700). We do not observe a corresponding peak in the pi{sup +}pi{sup -} final state and measure an upper limit for the ratio of the branching fractions of the rho{sup 0}(1700) to pi{sup +}pi{sup -} and pi{sup +}pi{sup -}pi{sup +}pi{sup -} of 2.5% at 90% confidence level. The ratio of rho{sup 0}(1700) and rho{sup 0}(770) coherent production cross sections is measured to be 13.4+-0.8{sub stat.}+-4.4{sub syst.}%.« less

Resonances in the predissociation of the A{sup 2}{Pi}{sub {Omega}} state of MgBr

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

Sadygov, R.G.; Rostas, J.; Taieb, G.

1997-03-01

Electronic structure methods and nonperturbative resonance theory are applied to study the radiative and radiationless decay mechanisms of the MgBr (A{sup 2}{Pi}{sub {Omega}}) vibrational levels. The X{sup 2}{Sigma}{sup +} and 1,2{sup 2}{Pi}{sub {Omega}} adiabatic electronic states are characterized using {ital ab initio} state-averaged multiconfigurational self-consistent field/second order configuration interaction wave functions. Interstate derivative couplings between the {sup 2}{Pi} states have been calculated and used to construct a rigorous diabatic basis. The nonrelativistic potential energy curves are modified in the first order of degenerate perturbation theory to take account of the spin{endash}orbit interactions treated within Breit{endash}Pauli approximation. All vibrational levels inmore » the A{sup 2}{Pi}{sub {Omega}} manifold are resonances predissociated by the repulsive 2{sup 2}{Pi} state. A recently developed computational approach [S. Han and D. R. Yarkony, Mol. Phys. {bold 88}, 53 (1996)] based on a Feshbach formalism is employed to determine energies, linewidths, and radiative and radiationless decay rates in a coupled diabatic states basis within a Hund`s case (a) approximation. Large nonadiabatic interactions cause significant energy shifts in the resonances levels. It is shown that a pronounced {Omega}-dependence in the radiationless decay rates results from the large fine structure splitting in the 2{sup 2}{Pi}{sub {Omega}} diabatic state which corresponds to Mg({sup 1}S)Br({sup 2}P). Comparisons with absorption and fluorescence spectra reveal important insights into A{sup 2}{Pi}{sub {Omega}} state decay. The spectroscopic constants of the A{sup 2}{Pi}{sub {Omega}}, {Omega}=3/2 and 1/2 states and the A{sup 2}{Pi}{sub 3/2} state predissociation are well described in a Hund`s case (a) approximation. However it is found that the A{sup 2}{Pi}{sub 1/2} state predissociation is significantly underestimated in this limit. (Abstract Truncated)« less

Dual functions of Macpiwi1 in transposon silencing and stem cell maintenance in the flatworm Macrostomum lignano

PubMed Central

Zhou, Xin; Battistoni, Giorgia; El Demerdash, Osama; Gurtowski, James; Wunderer, Julia; Falciatori, Ilaria; Ladurner, Peter; Schatz, Michael C.; Hannon, Gregory J.; Wasik, Kaja A.

2015-01-01

PIWI proteins and piRNA pathways are essential for transposon silencing and some aspects of gene regulation during animal germline development. In contrast to most animal species, some flatworms also express PIWIs and piRNAs in somatic stem cells, where they are required for tissue renewal and regeneration. Here, we have identified and characterized piRNAs and PIWI proteins in the emerging model flatworm Macrostomum lignano. We found that M. lignano encodes at least three PIWI proteins. One of these, Macpiwi1, acts as a key component of the canonical piRNA pathway in the germline and in somatic stem cells. Knockdown of Macpiwi1 dramatically reduces piRNA levels, derepresses transposons, and severely impacts stem cell maintenance. Knockdown of the piRNA biogenesis factor Macvasa caused an even greater reduction in piRNA levels with a corresponding increase in transposons. Yet, in Macvasa knockdown animals, we detected no major impact on stem cell self-renewal. These results may suggest stem cell maintenance functions of PIWI proteins in flatworms that are distinguishable from their impact on transposons and that might function independently of what are considered canonical piRNA populations. PMID:26323280

Design of a high-speed optical dark-soliton detector using a phase-shifted waveguide Bragg grating in reflection.

PubMed

Ngo, Nam Quoc

2007-12-01

A theoretical study of a new application of a simple pi-phase-shifted waveguide Bragg grating (PSWBG) in reflection mode as a high-speed optical dark-soliton detector is presented. The PSWBG consists of two concatenated identical uniform waveguide Bragg gratings with a pi phase shift between them. The reflective PSWBG, with grating reflectivities equal to 0.9, a free spectral range of 1.91 THz, and a nonlinear phase response, can convert a 40 Gbit/s noisy dark-soliton signal into a high-quality 40 Gbit/s return-to-zero signal with a peak power level of approximately 17.5 dB greater than that by the existing Mach-Zehnder interferometer with free spectral range of 1.91 THz and a linear phase response.

Relative lumbar lordosis and lordosis distribution index: individualized pelvic incidence-based proportional parameters that quantify lumbar lordosis more precisely than the concept of pelvic incidence minus lumbar lordosis.

PubMed

Yilgor, Caglar; Sogunmez, Nuray; Yavuz, Yasemin; Abul, Kadir; Boissiére, Louis; Haddad, Sleiman; Obeid, Ibrahim; Kleinstück, Frank; Sánchez Pérez-Grueso, Francisco Javier; Acaroğlu, Emre; Mannion, Anne F; Pellise, Ferran; Alanay, Ahmet

2017-12-01

OBJECTIVE The subtraction of lumbar lordosis (LL) from the pelvic incidence (PI) offers an estimate of the LL required for a given PI value. Relative LL (RLL) and the lordosis distribution index (LDI) are PI-based individualized measures. RLL quantifies the magnitude of lordosis relative to the ideal lordosis as defined by the magnitude of PI. LDI defines the magnitude of lower arc lordosis in proportion to total lordosis. The aim of this study was to compare RLL and PI - LL for their ability to predict postoperative complications and their correlations with health-related quality of life (HRQOL) scores. METHODS Inclusion criteria were ≥ 4 levels of fusion and ≥ 2 years of follow-up. Mechanical complications were proximal junctional kyphosis/proximal junctional failure, distal junctional kyphosis/distal junctional failure, rod breakage, and implant-related complications. Correlations between PI - LL, RLL, PI, and HRQOL were analyzed using the Pearson correlation coefficient. Mechanical complication rates in PI - LL, RLL, LDI, RLL, and LDI interpreted together, and RLL subgroups for each PI - LL category were compared using chi-square tests and the exact test. Predictive models for mechanical complications with RLL and PI - LL were analyzed using binomial logistic regressions. RESULTS Two hundred twenty-two patients (168 women, 54 men) were included. The mean age was 52.2 ± 19.3 years (range 18-84 years). The mean follow-up was 28.8 ± 8.2 months (range 24-62 months). There was a significant correlation between PI - LL and PI (r = 0.441, p < 0.001), threatening the use of PI - LL to quantify spinopelvic mismatch for different PI values. RLL was not correlated with PI (r = -0.093, p > 0.05); therefore, it was able to quantify divergence from ideal lordosis for all PI values. Compared with PI - LL, RLL had stronger correlations with HRQOL scores (p < 0.05). Discrimination performance was better for the model with RLL than for PI - LL. The agreement between RLL and PI - LL was high (κ = 0.943, p < 0.001), moderate (κ = 0.455, p < 0.001), and poor (κ = -0.154, p = 0.343), respectively, for large, average, and small PI sizes. When analyzed by RLL, each PI - LL category was further divided into distinct groups of patients who had different mechanical complication rates (p < 0.001). CONCLUSIONS Using the formula of PI - LL may be insufficient to quantify normolordosis for the whole spectrum of PI values when applied as an absolute numeric value in conjunction with previously reported population-based average thresholds of 10° and 20°. Schwab PI - LL groups were found to constitute an inhomogeneous group of patients. RLL offers an individualized quantification of LL for all PI sizes. Compared with PI - LL, RLL showed a greater association with both mechanical complications and HRQOL. The use of RLL and LDI together, instead of PI - LL, for surgical planning may result in lower mechanical complication rates and better long-term HRQOL.

Immunophenotyping in post-giardiasis functional gastrointestinal disease and chronic fatigue syndrome.

PubMed

Hanevik, Kurt; Kristoffersen, Einar K; Sørnes, Steinar; Mørch, Kristine; Næss, Halvor; Rivenes, Ann C; Bødtker, Jørn E; Hausken, Trygve; Langeland, Nina

2012-10-14

A Giardia outbreak was associated with development of post-infectious functional gastrointestinal disorders (PI-FGID) and chronic fatigue syndrome (PI-CFS). Markers of immune dysfunction have given conflicting results in CFS and FGID patient populations. The aim of this study was to evaluate a wide selection of markers of immune dysfunction in these two co-occurring post-infectious syndromes. 48 patients, reporting chronic fatigue in a questionnaire study, were clinically evaluated five years after the outbreak and grouped according to Fukuda criteria for CFS (n=19) and idiopathic chronic fatigue (n=5) and Rome II criteria for FGIDs (n=54). 22 Giardia exposed non-fatigued individuals and 10 healthy unexposed individuals were recruited as controls. Peripheral blood lymphocyte subsets were analyzed by flow cytometry. In peripheral blood we found significantly higher CD8 T-cell levels in PI-FGID, and significantly lower NK-cell levels in PI-CFS patients. Severity of abdominal and fatigue symptoms correlated negatively with NK-cell levels. A tendency towards lower T-cell CD26 expression in FGID was seen. Patients with PI-CFS and/or PI-FGID 5 years after Giardia lamblia infection showed alterations in NK-cell and CD8-cell populations suggesting a possible immunological abnormality in these conditions. We found no significant changes in other markers examined in this well-defined group of PI-CFS and PI-FGID elicited by a gastrointestinal infection. Controlling for co-morbid conditions is important in evaluation of CFS-biomarkers.

Ischemic preconditioning inhibits over-expression of arginyl-tRNA synthetase gene Rars in ischemia-injured neurons.

PubMed

Shen, Yin; Zhao, Hong-Yang; Wang, Hai-Jun; Wang, Wen-Liang; Zhang, Li-Zhi; Fu, Rong

2016-08-01

The expression changes of Rars gene in ischemia-injured neurons were investigated by detecting its translational product arginyl-tRNA synthetase (ArgRS), and the inhibitory effects of ischemic preconditioning (IPC) on Rars gene were explored. Both IPC model and prolonged ischemia (PI) model were established by using the classic oxygen glucose deprivation (OGD) method. The primary cultured neurons were assigned into the following groups: the experimental group (IPC+PI group), undergoing PI after a short period of IPC; the conditional control group (PI control group), subjected to PI without IPC; blank control group, the normally cultured neurons. The Rars transcriptional activities and ArgRS expression levels were measured at different time points after re-oxygenation (3 h/6 h/12 h/24 h). Data were collected and statistically analyzed. Compared to the blank control group, the Rars activities and ArgRS levels were significantly increased in PI control group, peaking at the time point of 6 h after re-oxygenation. Rars activities and ArgRS levels were significantly lower in the experimental group than in the PI control group at different time points after re-oxygenation. PI insult can induce an escalating activity of Rars and lead to ArgRS over-expression in primary cultured neurons. IPC can inhibit the increased Rars activity and down-regulate ArgRS expression of ischemia-insulted neurons. This mechanism may confer ischemic tolerance on neurons.

The PI3K inhibitor GDC-0941 combines with existing clinical regimens for superior activity in multiple myeloma.

PubMed

Munugalavadla, V; Mariathasan, S; Slaga, D; Du, C; Berry, L; Del Rosario, G; Yan, Y; Boe, M; Sun, L; Friedman, L S; Chesi, M; Leif Bergsagel, P; Ebens, A

2014-01-16

The phosphatidylinositol 3'-kinase (PI3K) pathway is dysregulated in multiple myeloma (MM); we therefore tested a highly selective class I PI3K inhibitor, GDC-0941, for anti-myeloma activity. Functional and mechanistic studies were first performed in MM cell lines, then extended to primary MM patient samples cultured in vitro. GDC-0941 was then assessed as a single agent and in various combinations in myeloma tumor xenograft models. We show p110 α and β are the predominant PI3K catalytic subunits in MM and that a highly selective class I PI3K inhibitor, GDC-0941, has robust activity as a single agent to induce cell cycle arrest and apoptosis of both MM cell lines and patient myeloma cells. Mechanistic studies revealed an induction of cell cycle arrest at G0/G1, with decreased phospho-FoxO1/3a levels, decreased cyclin D1 and c-myc expression, and an increase in the cell cycle inhibitor, p27kip. Induction of apoptosis correlated with increased expression of the pro-apoptotic BH3-only protein BIM, cleaved caspase 3 and cleaved poly (ADP-ribose) polymerase (PARP). In vitro, GDC-0941 synergized with dexamethasone (Dex) and lenalidomide (combination index values of 0.3-0.4 and 0.4-0.8, respectively); in vivo GDC-0941 has anti-myeloma activity and significantly increases the activity of the standard of care agents in several murine xenograft tumor models (additional tumor growth inhibition of 37-53% (Dex) and 22-72% (lenalidomide)). These data provide a clear therapeutic hypothesis for the inhibition of PI3K and provide a rationale for clinical development of GDC-0941 in myeloma.

Mortality in Subalpine Forests of the Sierra Nevada, California, USA: Differential Response of Pines (Pinus albicaulis and P. flexilis) to Climate Variability

NASA Astrophysics Data System (ADS)

Millar, C. I.; Westfall, R. D.; Delany, D. L.

2010-12-01

Widespread forest mortality in high-elevation forests has been increasing across western North American mountains in recent years, with climate, insects, and disease the primary causes. Subalpine forests in the eastern Sierra Nevada, by contrast, have experienced far less mortality than other ranges, and mortality events have been patchy and episodic. This situation, and lack of significant effect of non-native white-pine blister rust, enable investigation of fine-scale response of two subalpine Sierran species, whitebark pine (Pinus albicaulis, PiAl) and limber pine (P. flexilis, PiFl), to climate variability. We report similarities and differences between the two major mortality events in these pines in the last 150 years: 1988-1992 for PiFl and 2006-ongoing for PiAl. In both species, the events occurred within monotypic, closed-canopy, relatively young stands (< 200 yrs PiAl, < 300 yrs in PiFl); were localized to central-eastern Sierra Nevada; and occurred at 2740-2840 m along the eastern edge of the escarpment on north/northeast aspects with slopes > 40%. Mortality patches averaged 40-80 ha in both species, with mean stand mortality of trees > 10 cm diameter 91% in PiAl and 60% in PiFl. The ultimate cause of tree death was mountain pine beetle (Dendroctonus ponderosae) in both species, with increasing 20th/21st C minimum temperatures combined with drought the pre-conditioning factors. Overall growth in the past 150 years suggests that PiFl is more drought hardy than PiAl but responds sensitively to the combined effects of drought and increasing warmth. After the 1988-1992 drought, surviving PiFl recovered growth. PiAl trees grew very poorly during that drought, and continued poor growth in the years until 2006 when the mortality event occurred in PiAl. A significant species effect is the apparent difference in levels of within-stand genetic diversity for climate factors. Differential growth between 19th C (cool, wet) and 20th/21st C (warming, drying) of PiFl trees that died versus survivors indicates that considerable within-stand genetic diversity for climate existed in PiFl. For PiFl, the late 20th C mortality event acted as strong natural selection to improve within-stand fitness for warmer and drier conditions. PiFl trees that survived the 1988-1992 drought remained healthy through subsequent droughts, including the drought that is currently causing PiAl mortality. By contrast, the PiAl stands do not appear to have contained adaptive genetic diversity for drought and warmth, and PiAl trees growth behavior over the past 150 years was similar in pattern to the PiFl trees that died. As a result, the mortality event in PiAl is creating forest openings, with unknown future stand conditions, rather than rapid within-species adaptation that occurred in PiFl.

Glutathione-s-transferase-pi expression in early breast cancer: association with outcome and response to chemotherapy.

PubMed

Arun, Banu K; Granville, Laura A; Yin, Guosheng; Middleton, Lavinia P; Dawood, Shaheenah; Kau, Shu-Wan; Kamal, Arif; Hsu, Limin; Hortobagyi, Gabriel N; Sahin, Aysegul A

2010-06-01

Glutathione-S-transferase-pi (GST-pi) is a detoxification enzyme expressed in breast cancer; however its involvement in chemotherapy sensitivity and prognosis is not well understood. We evaluated the expression of GSTpi and its predictive role of chemotherapy response. Breast tumor samples from 166 patients at stage I/II of the disease were immunostained for GST-pi, and the expression was 96 %. There was a trend toward improved disease-free survival with high GST-pi expression (p =.09). There was a statistically non-significant association between high GST-pi expression and improved outcome with adjuvant chemotherapy (p =.055). Further studies should evaluate the role of GST-pi expression in relation to response to different chemotherapies.

Quercetin attenuates high fructose feeding-induced atherosclerosis by suppressing inflammation and apoptosis via ROS-regulated PI3K/AKT signaling pathway.

PubMed

Lu, Xue-Li; Zhao, Cui-Hua; Yao, Xin-Liang; Zhang, Han

2017-01-01

Quercetin is a dietary flavonoid compound extracted from various plants, such as apple and onions. Previous studies have revealed its anti-inflammatory, anti-cancer, antioxidant and anti-apoptotic activities. This study investigated the ability of quercetin to inhibit high fructose feeding- or LPS-induced atherosclerosis through regulating oxidative stress, apoptosis and inflammation response in vivo and in vitro experiments. 50 and 100mg/kg quercetin were used in our study, showing significant inhibitory role in high fructose-induced atherosclerosis via reducing reactive oxygen species (ROS) levels, Caspase-3 activation, inflammatory cytokines releasing, the number of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive cells and collagen contents as well as modulating apoptosis- and inflammation-related proteins expression. We also explored the protective effects of quercetin on atherosclerosis by phosphatidylinositide 3-kinases (PI3K)/Protein kinase B (AKT)-associated Bcl-2/Caspase-3 and nuclear factor kappa B (NF-κB) signal pathways activation, promoting AKT and Bcl-2 expression and reducing Caspase-3 and NF-κB activation. Quercetin reduced the atherosclerotic plaque size in vivo in high fructose feeding-induced mice assessed by oil red O. Also, in vitro experiments, quercetin displayed inhibitory role in LPS-induced ROS production, inflammatory response and apoptosis, which were linked with PI3K/AKT-regulated Caspase-3 and NF-κB activation. In conclusion, our results showed that quercetin inhibited atherosclerotic plaque development in high fructose feeding mice via PI3K/AKT activation regulated by ROS. Copyright © 2016. Published by Elsevier Masson SAS.

MRI pallidal signal in children exposed to manganese in drinking water.

PubMed

Dion, Laurie-Anne; Bouchard, Maryse F; Sauvé, Sébastien; Barbeau, Benoit; Tucholka, Alan; Major, Philipe; Gilbert, Guillaume; Mergler, Donna; Saint-Amour, Dave

2016-03-01

Manganese (Mn) can have neurotoxic effects upon overexposure. We previously reported poorer cognitive and motor development in children exposed to Mn through drinking water, suggesting possible neurotoxic effects from Mn in water. Hyperintensity in the globus pallidus (GP) on T1-weighted magnetic resonance imaging (MRI) indicates excessive brain Mn accumulation. Previous studies have reported GP hyperintensity related to Mn exposure in occupationally exposed individuals. However, no study has used MRI in children exposed to Mn in drinking water and who show no sign of overt intoxication. To examine MRI signal intensity in the GP in children exposed to contrasted levels of Mn in drinking water. We enrolled 13 children exposed to low Mn concentration in water and 10 children (ages 9-15 years) with high concentration (median of 1 and 145μg/L, respectively). We calculated three MRI T1 indexes: (i) standard pallidal index (PI) using frontal white matter as reference; (ii) PI using pericranial muscles as reference; and (iii) T1 relaxation time. Each MRI index was compared between exposure groups, and with respect to the estimated Mn intake from water consumption. The standard PI did not differ between Mn-exposure groups. However, children in the group with high water-Mn concentration had significantly lower pericranial muscles PI than those with lower exposure and, accordingly, higher T1 relaxation time. Mn intake from water consumption was not correlated with the standard PI, but was significantly related to the pericranial muscles PI and T1 relaxation time. Motor performance was significantly lower in the high-exposure group. We observed lower signal intensity in the GP of children with higher exposure to Mn from drinking water. This result stands in contrast to previous MRI reports showing GP hyperintensity with greater Mn exposure. Differences in exposure pathways are discussed as a potential explanation for this discrepancy. Copyright © 2016 Elsevier Inc. All rights reserved.

Analysis, control and design of a non-inverting buck-boost converter: A bump-less two-level T-S fuzzy PI control.

PubMed

Almasi, Omid Naghash; Fereshtehpoor, Vahid; Khooban, Mohammad Hassan; Blaabjerg, Frede

2017-03-01

In this paper, a new modified fuzzy Two-Level Control Scheme (TLCS) is proposed to control a non-inverting buck-boost converter. Each level of fuzzy TLCS consists of a tuned fuzzy PI controller. In addition, a Takagi-Sugeno-Kang (TSK) fuzzy switch proposed to transfer the fuzzy PI controllers to each other in the control system. The major difficulty in designing fuzzy TLCS which degrades its performance is emerging unwanted drastic oscillations in the converter output voltage during replacing the controllers. Thereby, the fuzzy PI controllers in each level of TLCS structure are modified to eliminate these oscillations and improve the system performance. Some simulations and digital signal processor based experiments are conducted on a non-inverting buck-boost converter to support the effectiveness of the proposed TLCS in controlling the converter output voltage. Copyright © 2016 ISA. Published by Elsevier Ltd. All rights reserved.

Fibroblast-induced switching to the mesenchymal-like phenotype and PI3K/mTOR signaling protects melanoma cells from BRAF inhibitors

PubMed Central

Seip, Kotryna; Nygaard, Vigdis; Haugen, Mads H.; Engesæter, Birgit Ø.; Mælandsmo, Gunhild M.; Prasmickaite, Lina

2016-01-01

The knowledge on how tumor-associated stroma influences efficacy of anti-cancer therapy just started to emerge. Here we show that lung fibroblasts reduce melanoma sensitivity to the BRAF inhibitor (BRAFi) vemurafenib only if the two cell types are in close proximity. In the presence of fibroblasts, the adjacent melanoma cells acquire de-differentiated mesenchymal-like phenotype. Upon treatment with BRAFi, such melanoma cells maintain high levels of phospho ribosomal protein S6 (pS6), i.e. active mTOR signaling, which is suppressed in the BRAFi sensitive cells without stromal contacts. Inhibitors of PI3K/mTOR in combination with BRAFi eradicate pS6high cell subpopulations and potentiate anti-cancer effects in melanoma protected by the fibroblasts. mTOR and BRAF co-inhibition also delayed the development of early-stage lung metastases in vivo. In conclusion, we demonstrate that upon influence from fibroblasts, melanoma cells undergo a phenotype switch to the mesenchymal state, which can support PI3K/mTOR signaling. The lost sensitivity to BRAFi in such cells can be overcome by co-targeting PI3K/mTOR. This knowledge could be explored for designing BRAFi combination therapies aiming to eliminate both stroma-protected and non-protected counterparts of metastases. PMID:26918352

VizieR Online Data Catalog: H2, D2, and HD c3Πu;

NASA Astrophysics Data System (ADS)

Liu, X.; Shemansky, D. E.; Yoshii, J.; Liu, M. J.; Johnson, P. V.; Malone, C. P.; Khakoo, M. A.

2017-11-01

The c3{Pi}u state of the hydrogen molecule has the triplet-state excitation cross-section, and plays an important role in the heating of the upper thermospheres of outer planets by electron excitation. Precise energies of the H2, D2, and HD c3{Pi}u-(v,N) levels are calculated from highly accurate ab initio potential energy curves that include relativistic, radiative, and empirical non-adiabatic corrections. The emission yields are determined from predissociation rates and refined radiative transition probabilities. The excitation function and excitation cross-section of the c3{Pi}u state are extracted from previous theoretical calculations and experimental measurements. The emission cross-section is determined from the calculated emission yield and the extracted excitation cross-section. The kinetic energy (Ek) distributions of H atoms produced via the predissociation of the c3{Pi}u state, the c3{Pi}u--b3{Sigma}u+ dissociative emission by the magnetic dipole and electric quadrupole, and the c3{Pi}u-a3{Sigma}g+-b3{Sigma}u+ cascade dissociative emission by the electric dipole are obtained. The predissociation of the c3{Pi}u+ and c3{Pi}u- states both produce H(1s) atoms with an average Ek of ~4.1eV/atom, while the c3{Pi}u--b3{Sigma}u+ dissociative emissions by the magnetic dipole and electric quadrupole give an average Ek of ~1.0 and ~0.8eV/atom, respectively. The c3{Pi}u-a3{Sigma}g+-b3{Sigma}u+ cascade and dissociative emission gives an average Ek of ~1.3 eV/atom. On average, each H2 excited to the c3{Pi}u state in an H2-dominated atmosphere deposits ~7.1eV into the atmosphere while each H2 directly excited to the a3{Sigma}g+ and d3{Pi}u states contribute ~2.3 and ~3.3eV, respectively, to the atmosphere. The spectral distribution of the calculated continuum emission arising from the X1{Sigma}g+-c3{Pi}u excitation is significantly different from that of direct a3{Sigma}g+ or d3{Pi}u excitations. (5 data files).

Genome-wide identification of heat stress-responsive small RNAs in tall fescue (Festuca arundinacea) by high-throughput sequencing.

PubMed

Li, Huiying; Hu, Tao; Amombo, Erick; Fu, Jinmin

2017-06-01

MicroRNAs (miRNAs) play vital roles in the adaptive response of plants to various abiotic and biotic stresses. Tall fescue (Festuca arundinacea Schreb.) is a major cool-season forage and turf grass species which is severely influenced by heat stress. To unravel possible heat stress-responsive miRNAs, high-throughput sequencing was employed for heat-tolerant PI578718 and heat-sensitive PI234881 genotypes growing in presence and absence of heat stress (40°C for 36h). By searching against the miRBase database, among 1421 reference monocotyledon miRNAs, more than 850 were identified in all samples. Among these miRNAs, 1.46% and 2.29% were differentially expressed in PI234881 and PI578718 under heat stress, respectively, and most of them were down-regulated. In addition, a total of 170 novel miRNAs belonging to 145 miRNA families were identified. Furthermore, putative targets of differentially expressed miRNAs were predicted. The regulation of selected miRNAs by heat stress was revalidated through quantitative reverse transcription PCR (qRT-PCR) analysis. Most of these miRNAs shared similar expression patterns; however, some showed distinct expression patterns under heat stress, with their putative targets displaying different transcription levels. This is the first genome-wide miRNA identification in tall fescue. miRNAs specific to PI578718, or those that exhibited differential expression profiles between the two genotypes under high temperature, were probably associated with the variation in thermotolerance of tall fescue. The differentially expressed miRNAs between these two tall fescue genotypes and their putative targeted genes will provide essential information for further study on miRNAs mediating heat response and facilitate to improve turf grass breeding. Copyright © 2017. Published by Elsevier GmbH.

Berberine suppressed epithelial mesenchymal transition through cross-talk regulation of PI3K/AKT and RARα/RARβ in melanoma cells.

PubMed

Kou, Yu; Li, Lei; Li, Hong; Tan, Yuhui; Li, Bin; Wang, Kun; Du, Biaoyan

2016-10-14

Berberine is a natural compound extracted from Coptidis rhizoma, and accumulating proof has shown its potent anti-tumor properties with diverse action on melanoma cells, including inhibiting cancer viability, blocking cell cycle and migration. However, the mechanisms of berberine have not been fully clarified. In this study, we identified that berberine reduced the migration and invasion capacities of B16 cells, and notably altered pluripotency of epithelial to mesenchymal transition associated factors. We found that berberine also downregulation the expression level of p-PI3K, p-AKT and retinoic acid receptor α (RARα) and upregulation the expression level of retinoic acid receptor β and γ (RARβ and RARγ). These effects of PI3 kinase inhibitor LY294002 treatment mimicked Berberine treatment except the expression level of RARγ. Moreover, Western blot analysis showed that the decreased PI3K and AKT phosphorylation, increased the epithelial maker E-cadherin, and upregulation level of RARβ while decreased the mesenchymal markers N-cadherin and downregulation level of RARα by incubation with LY294002 in mouse melanoma B16 cells. In conclusion, Our study reveal that berberine can reverse the epithelial to mesenchymal transition of mouse melanoma B16 cells and may be a useful adjuvant therapeutic agent in the treatment of melanoma through the PI3K/Akt pathway and inactivation PI3K/AKT could regulate RARα/RARβ expression. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Measurement of the branching ratios of D(+) and D(+)(s) hadronic decays to four-body final states containing a K(S).

PubMed

Link, J M; Reyes, M; Yager, P M; Anjos, J C; Bediaga, I; Göbel, C; Magnin, J; Massafferi, A; de Miranda, J M; Pepe, I M; dos Reis, A C; Simão, F R; Carrillo, S; Casimiro, E; Sánchez-Hernández, A; Uribe, C; Vázquez, F; Cinquini, L; Cumalat, J P; O'Reilly, B; Ramirez, J E; Vaandering, E W; Butler, J N; Cheung, H W; Gaines, I; Garbincius, P H; Garren, L A; Gottschalk, E; Kasper, P H; Kreymer, A E; Kutschke, R; Bianco, S; Fabbri, F L; Sarwar, S; Zallo, A; Cawlfield, C; Kim, D Y; Rahimi, A; Wiss, J; Gardner, R; Chung, Y S; Kang, J S; Ko, B R; Kwak, J W; Lee, K B; Park, H; Alimonti, G; Boschini, M; Caccianiga, B; D'Angelo, P; DiCorato, M; Dini, P; Giammarchi, M; Inzani, P; Leveraro, F; Malvezzi, S; Menasce, D; Mezzadri, M; Milazzo, L; Moroni, L; Pedrini, D; Pontoglio, C; Prelz, F; Rovere, M; Sala, A; Sala, S; Davenport, T F; Agostino, L; Arena, V; Boca, G; Bonomi, G; Gianini, G; Liguori, G; Merlo, M; Pantea, D; Ratti, S P; Riccardi, C; Segoni, I; Viola, L; Vitulo, P; Hernandez, H; Lopez, A M; Mendez, H; Mendez, L; Mirles, A; Montiel, E; Olaya, D; Paris, A; Quinones, J; Rivera, C; Xiong, W; Zhang, Y; Wilson, J R; Cho, K; Handler, T; Engh, D; Hosack, M; Johns, W E; Nehring, M; Sheldon, P D; Stenson, K; Webster, M; Sheaff, M

2001-10-15

We have studied hadronic four-body decays of D(+) and D(+)(s) mesons with a K(S) in the final state using data recorded during the 1996-1997 fixed-target run of the Fermilab high energy photoproduction experiment FOCUS. We report a new branching ratio measurement of gamma(D(+)-->K(S)K-pi(+)pi(+))/gamma(D(+)-->K(S)pi(+)pi(+)pi(-)) = 0.0768+/-0.0041+/-0.0032. We make the first observation of three new decay modes with branching ratios gamma(D(+)-->K(S)K+pi(+)pi(-))/gamma(D(+)-->K(S)pi(+)pi(+)pi(-)) = 0.0562+/-0.0039+/-0.0040, gamma(D(+)-->K(S)K+K-pi(+))/gamma(D(+)-->K(S)pi(+)pi(+)pi(-)) = 0.0077+/-0.0015+/-0.0009, and gamma(D(+)(s)-->K(S)K+pi(+)pi(-))/gamma(D(+)(s)-->K(S)K-pi(+)pi(+)) = 0.586+/-0.052+/-0.043, where in each case the first error is statistical and the second error is systematic.

Nucleon resonance structure studies via exclusive KY electroproduction

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

Carman, Daniel S.

Studying the structure of excited nucleon states employing the electroproduction of exclusive reactions is an important avenue for exploring the nature of the non-perturbative strong interaction. The electrocouplings ofmore » $N^*$ states in the mass range below 1.8~GeV have been determined from analyses of CLAS $$\\pi N$$, $$\\eta N$$, and $$\\pi \\pi N$$ data. This work has made it clear that consistent results from independent analyses of several exclusive channels with different couplings and non-resonant backgrounds but the same $N^*$ electro excitation amplitudes, is essential to have confidence in the extracted results. In terms of hadronic coupling, many high-lying $N^*$ states preferentially decay through the $$\\pi \\pi N$$ channel instead of $$\\pi N$$. Data from the $KY$ channels will therefore be critical to provide an independent analysis to compare the extracted electrocouplings for the high-lying $N^*$ states against those determined from the $$\\pi N$$ and $$\\pi \\pi N$$ channels. Lastly, a program to study excited $N^*$ state structure in both non-strange and strange exclusive electroproduction channels using CLAS12 will measure differential cross sections and polarization observables to be used as input to extract the $$\\gamma_vNN^*$$ electrocoupling amplitudes for the most prominent $N^*$ states in the range of invariant energy $W$ up 3~GeV in the virtually unexplored domain of momentum transfers $Q^2$ up to 12~GeV$^2$.« less

Nucleon resonance structure studies via exclusive KY electroproduction

DOE PAGES

Carman, Daniel S.

2016-06-16

Studying the structure of excited nucleon states employing the electroproduction of exclusive reactions is an important avenue for exploring the nature of the non-perturbative strong interaction. The electrocouplings ofmore » $N^*$ states in the mass range below 1.8~GeV have been determined from analyses of CLAS $$\\pi N$$, $$\\eta N$$, and $$\\pi \\pi N$$ data. This work has made it clear that consistent results from independent analyses of several exclusive channels with different couplings and non-resonant backgrounds but the same $N^*$ electro excitation amplitudes, is essential to have confidence in the extracted results. In terms of hadronic coupling, many high-lying $N^*$ states preferentially decay through the $$\\pi \\pi N$$ channel instead of $$\\pi N$$. Data from the $KY$ channels will therefore be critical to provide an independent analysis to compare the extracted electrocouplings for the high-lying $N^*$ states against those determined from the $$\\pi N$$ and $$\\pi \\pi N$$ channels. Lastly, a program to study excited $N^*$ state structure in both non-strange and strange exclusive electroproduction channels using CLAS12 will measure differential cross sections and polarization observables to be used as input to extract the $$\\gamma_vNN^*$$ electrocoupling amplitudes for the most prominent $N^*$ states in the range of invariant energy $W$ up 3~GeV in the virtually unexplored domain of momentum transfers $Q^2$ up to 12~GeV$^2$.« less

Interaction Between Meloidogyne arenaria and Glomus fascicuqlatus in Grape.

PubMed

Atilano, R A; Menge, J A; Gundy, S D

1981-01-01

Root zones of grape (Fitis vinifera cv Thompson Seedless) cuttings were infested with chlamydospores of Glomus fasciculatus or eggs of Meloidogyne arenaria or both. Growth of grapevines was greatest in mycorrhizal (G. fasciculatus) plants. Mycorrhizal development and growth of mycorrhizal and nonmycorrhizal plants were reduced in the presence of M. arenaria. At low initial nematode inoculum (PI) levels (approx. 200 eggs/plant), the presence of mycorrhizae enhanced plant growth during 1 yr, but no significant benefit was achieved by mycorrhizae where PI was high (approx. 2,000 eggs/plant). Final nematode populations were highest in mycorrhizal plants.

[Study on rules of TCM syndrome in patients with dyslipidemia and its objectization].

PubMed

Lei, Yan; Wang, Zhen-Hua; Liu, Jian-Gang

2007-12-01

To explore the rules of TCM syndrome in patients with dyslipidemia and its relation with C-reactive protein (CRP), homocysteine (Hcy), carotid ultrasonic picture, blood lipids and blood viscosity. From 152 recruited patients symptoms and physical signs (including figures of tongue and pulse) were selected and analyzed in grading and quantifying by factor analysis. At the same time, blood lipids, CRP, Hcy, carotid ultrasonic picture and blood viscosity were detected to conduct a canonical correlation analysis for exploring the relationship between different TCM syndromes and their corresponding physical and/or chemical indexes. Five types of TCM syndrome obtained by factor analysis were syndrome of Shen-yin deficiency (I), Pi-qi deficiency (II), turbid-phlegm impediment (III), blood stasis (IV), and phlegm-blood block (V). By canonical correlation analysis, they were characterized with: Type I, high levels of CRP and blood viscosity; Type II, high level of very low-density lipoprotein cholesterol (VLDL-C); Type III, high level of total cholesterol (TC) and low level of high-density lipoprotein cholesterol (HDL-C); and Type V, high level of Hcy. The five syndrome types frequently found in patients with dyslipidemia are syndrome of Shen-yin deficiency, Pi-qi deficiency, turbid-phlegm impediment, blood stasis, and phlegm-blood block. Different syndrome has its own correlation with some corresponding physical and/or chemical laboratory indexes, the issue provides new evidences for the objectification of TCM syndromes in patients with dyslipidemia.

Search for resonances decaying to etac pi pi- in two-photon interactions

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

Lees, J.P.; Poireau, V.; Tisserand, V.

2012-06-18

We report a study of the process {gamma}{gamma} {yields} X {yields} {eta}{sub c}{pi}{sup +}{pi}{sup -}, where X stands for one of the resonances {chi}{sub c2}(1P), {eta}{sub c}(2S), X(3872), X(3915), or {chi}{sub c2}(2P). The analysis is performed with a data sample of 473.9 fb{sup -1} collected with the BABAR detector at the PEP-II asymmetric-energy electron-positron collider. We do not observe a significant signal for any channel, and calculate 90% confidence-level upper limits on the products of branching fractions and two-photon widths {Lambda}{sub X{yields}{gamma}{gamma}} {Beta}(X {yields} {eta}{sub c}{pi}{sup +}{pi}{sup -}): 15.7 eV for {chi}{sub c2}(1P), 133 eV for {eta}{sub c}(2S), 11.1 eVmore » for X(3872) (assuming it to be a spin-2 state), 16 eV for X(3915) (assuming it to be a spin-2 state), and 19 eV for {chi}{sub c2}(2P). We also report upper limits on the ratios of branching fractions {Beta}({eta}{sub c}(2S) {yields} {eta}{sub c}{pi}{sup +}{pi}{sup -})/{Beta}({eta}{sub c}(2S) {yields} K{sub S}{sup 0}K{sup +}{pi}{sup -}) < 10.0 and {Beta}({chi}{sub c2}(1P) {yields} {eta}{sub c}{pi}{sup +}{pi}{sup -})/{Beta}({chi}{sub c2}(1P) {yields} K{sub S}{sup 0}K{sup +}{pi}{sup -}) < 32.9 at the 90% confidence level.« less

Cbp80 is needed for the expression of piRNA components and piRNAs

PubMed Central

Colombo, Martino; Hernandez, Greco; Beuchle, Dirk; Berger, Fabienne; Peischl, Stephan; Bruggmann, Rémy

2017-01-01

Cap binding protein 80 (Cbp80) is the larger subunit of the nuclear cap-binding complex (nCBC), which is known to play important roles in nuclear mRNA processing, export, stability and quality control events. Reducing Cbp80 mRNA levels in the female germline revealed that Cbp80 is also involved in defending the germline against transposable elements. Combining such knockdown experiments with large scale sequencing of small RNAs further showed that Cbp80 is involved in the initial biogenesis of piRNAs as well as in the secondary biogenesis pathway, the ping-pong amplification cycle. We further found that Cbp80 knockdown not only led to the upregulation of transposons, but also to delocalization of Piwi, Aub and Ago3, key factors in the piRNA biosynthesis pathway. Furthermore, compared to controls, levels of Piwi and Aub were also reduced upon knock down of Cbp80. On the other hand, with the same treatment we could not detect significant changes in levels or subcellular distribution (nuage localization) of piRNA precursor transcripts. This shows that Cbp80 plays an important role in the production and localization of the protein components of the piRNA pathway and it seems to be less important for the production and export of the piRNA precursor transcripts. PMID:28746365

Effects of rare earth oxide additive on surface and tribological properties of polyimide composites

NASA Astrophysics Data System (ADS)

Pan, Zihe; Wang, Tianchang; Chen, Li; Idziak, Stefan; Huang, Zhaohui; Zhao, Boxin

2017-09-01

Rare earth oxide La2O3 microparticles-reinforced polyimide (PI) composites (La-PI-Cs) were fabricated, aiming to improve the tribological property of PI. Surface roughness, surface composition, bulk structure, friction force (Ff) and coefficient of friction (COF) at macro/micro preload, and anti-wear performances of La-PI-Cs were studied and compared with neat PI. With La2O3 microparticles, La-PI-Cs showed larger surface roughness, lower surface energy, and higher hydrophobicity than neat PI, and displayed beneficial layered structure different from the compact structure of PI. Owing to these advantages, La-PI-Cs were found to show a 70% reduction in Ff and COF, and a 30% reduction in wear rate, indicating significantly lowered friction and enhanced anti-wear properties after adding La2O3 microparticles. Our research findings demonstrated an easy and low cost method to fabricate polymer composites with low friction and high wear resistance, and help meet the demanding of polymer composites with high tribological performances in broaden applications.

Editor’s Highlight: Lower Fractional Anisotropy in the Globus Pallidus of Asymptomatic Welders, a Marker for Long-Term Welding Exposure

PubMed Central

Lee, Eun-Young; Flynn, Michael R.; Du, Guangwei; Lewis, Mechelle M.; Herring, Amy H.; Van Buren, Eric; Van Buren, Scott; Kong, Lan; Mailman, Richard B.; Huang, Xuemei

2016-01-01

Introduction: Welding fumes contain several metals including manganese (Mn), iron (Fe), and copper (Cu) that at high exposure may co-influence welding-related neurotoxicity. The relationship between brain accumulation of these metals and neuropathology, especially in welders with subclinical exposure levels, is unclear. This study examined the microstructural integrity of basal ganglia (BG) regions in asymptomatic welders using diffusion tensor imaging (DTI). Methods: Subjects with (n = 43) and without (age- and gender-matched controls; n = 31) history of welding were studied. Occupational questionnaires estimated short-term (HrsW; welding hours and E90; cumulative exposure, past 90 days) and long-term (YrsW; total years welding and ELT; cumulative exposure, lifetime) exposure. Whole blood metal levels (Mn, Fe, and Cu) were obtained. Brain MRI pallidal index (PI), R1 (1/T1), and R2* (1/T2*) were measured to estimate Mn and Fe accumulation in BG [caudate, putamen, and globus pallidus (GP)]. DTI was used to assess BG microstructural differences, and related with exposure measurements. Results: When compared with controls, welders had significantly lower fractional anisotropy (FA) in the GP. In welders, GP FA values showed non-linear relationships to YrsW, blood Mn, and PI. GP FA decreased after a critical level of YrsW or Mn was reached, whereas it decreased with increasing PI values until plateauing at the highest PI values. GP FA, however, did not show any relationship with short-term exposure measurements (HrsW, E90), blood Cu and Fe, or R2* values. Conclusion: GP FA captured microstructural changes associated with chronic low-level Mn exposure, and may serve as a biomarker for neurotoxicity in asymptomatic welders. PMID:27466214

Cryptotanshinone exhibits therapeutical effects on cerebral stroke through the PI3K/AKT‑eNOS signaling pathway.

PubMed

Zhu, Weixin; Qiu, Weihong; Lu, Ailan

2017-12-01

Cerebral stroke is a kind of acute cerebrovascular disease with high incidence, morbidity and disability. Treatments against various types of cerebral stroke are limited at preventive measurements due to the lack of effective therapeutic method. The present study aimed to investigate the protective effect of cryptotanshinone (CPT) on cerebral stroke, and investigate the possible mechanism involved in order to develop a novel therapy against stoke. The phosphoinositide 3‑kinase membrane translocation of cerebral stroke rats pretreated with CPT at various concentrations were measured, as well as the phosphorylation of protein kinase B (AKT) and endothelial nitric oxide synthase (eNOS). Additionally, the expression level of B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated X protein (Bax) and vascular endothelial growth factor were also assessed using western blotting and reverse transcription‑quantitative polymerase chain reaction. Furthermore, biochemical tests were used to measure the activity of superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO) in both the cerebral cortex and peripheral blood. As a result, CPT‑pretreated rats presented declined phosphoinositide 3‑kinase (PI3K) and AKT expression levels, indicating that the PI3K/AKT signaling pathway was inhibited. Increased Bcl‑2 and NO levels in both the cerebral cortex and peripheral blood demonstrated the anti‑apoptosis and blood vessel protection effect of CPT. Furthermore, increased SOD activity and declined MDA levels demonstrated suppressed lipid peroxidation. In conclusion, CPT exhibited a protective effect against cerebral stroke through inhibition of the PI3K/AKT‑eNOS signaling pathway. These results suggested the potential of CPT as a promising agent in the treatment of cerebral stroke.

African swine fever virus infection in Classical swine fever subclinically infected wild boars.

PubMed

Cabezón, Oscar; Muñoz-González, Sara; Colom-Cadena, Andreu; Pérez-Simó, Marta; Rosell, Rosa; Lavín, Santiago; Marco, Ignasi; Fraile, Lorenzo; de la Riva, Paloma Martínez; Rodríguez, Fernando; Domínguez, Javier; Ganges, Llilianne

2017-08-01

Recently moderate-virulence classical swine fever virus (CSFV) strains have been proven capable of generating postnatal persistent infection (PI), defined by the maintenance of viremia and the inability to generate CSFV-specific immune responses in animals. These animals also showed a type I interferon blockade in the absence of clinical signs. In this study, we assessed the infection generated in 7-week-old CSFV PI wild boars after infection with the African swine fever virus (ASFV). The wild boars were divided in two groups and were infected with ASFV. Group A comprised boars who were CSFV PI in a subclinical form and Group B comprised pestivirus-free wild boars. Some relevant parameters related to CSFV replication and the immune response of CSFV PI animals were studied. Additionally, serum soluble factors such as IFN-α, TNF-α, IL-6, IL-10, IFN-γ and sCD163 were analysed before and after ASFV infection to assess their role in disease progression. After ASFV infection, only the CSFV PI wild boars showed progressive acute haemorrhagic disease; however, the survival rates following ASFV infection was similar in both experimental groups. Notwithstanding, the CSFV RNA load of CSFV PI animals remained unaltered over the study; likewise, the ASFV DNA load detected after infection was similar between groups. Interestingly, systemic type I FN-α and IL-10 levels in sera were almost undetectable in CSFV PI animals, yet detectable in Group B, while detectable levels of IFN-γ were found in both groups. Finally, the flow cytometry analysis showed an increase in myelomonocytic cells (CD172a + ) and a decrease in CD4 + T cells in the PBMCs from CSFV PI animals after ASFV infection. Our results showed that the immune response plays a role in the progression of disease in CSFV subclinically infected wild boars after ASFV infection, and the immune response comprised the systemic type I interferon blockade. ASFV does not produce any interference with CSFV replication, or vice versa. ASFV infection could be a trigger factor for the disease progression in CSFV PI animals, as their survival after ASFV was similar to that of the pestivirus-free ASFV-infected group. This fact suggests a high resistance in CSFV PI animals even against a virus like ASFV; this may mean that there are relevant implications for CSF control in endemic countries. The diagnosis of ASFV and CSFV co-infection in endemic countries cannot be ruled out and need to be studied in greater depth.

Relationship among Periodontal Disease, Insulin Resistance, Salivary Cortisol, and Stress Levels during Pregnancy.

PubMed

Seraphim, Ana Paula Castilho Garcia; Chiba, Fernando Yamamoto; Pereira, Renato Felipe; Mattera, Maria Sara de Lima Coutinho; Moimaz, Suzely Adas Saliba; Sumida, Doris Hissako

2016-01-01

Pregnancy is a period involving important metabolic changes that enable the maintenance of the mother's health and development of the fetus. This study aimed to assess the relationship among periodontal disease, insulin resistance, salivary cortisol concentration and level of perceived stress in pregnant women. This was a cross-sectional study. The sample comprised 96 pregnant women between the fifth and seventh month of pregnancy registered at the Basic Health Units of the Unified Health System (SUS). The periodontal condition was assessed after obtainment free and informed consent from the participants. Participants were divided into three groups: control subjects with a healthy periodontal condition (CN; n=46), patients with gingivitis (GI; n=26), and patients with periodontitis (PI; n=24). Saliva and blood samples were collected for evaluation of salivary cortisol concentration, glycemia, insulinemia and Homeostasis Model Assessment-Insulin Resistance index. A validated survey for the assessment of perceived stress levels was also performed. PI group showed significantly higher (p<0.05) blood glucose levels (CN: 4.43±0.05; GI: 4.46±0.04; PI: 4.68±0.08), insulinemia (CN: 6.93±0.45; GI: 8.87±0.79; PI: 12.77±1.30), insulin resistance (CN: 1.40±0.10; GI: 1.81±0.18; PI: 2.66±0.29) compared with the CN and GI groups. The levels of perceived stress were higher (p<0.05) in PI and GI groups when compared to CN group (CN: 20.5±1.26; GI: 25.8±1.95; PI: 26.6±1.36). There was no significant difference in the concentration of salivary cortisol between the groups (CN: 11.13±0.58; GI: 11.96±0.74; PI: 11.47±0.74). It was concluded that there is a relationship between higher levels of perceived stress, insulin resistance and the occurrence of periodontal disease during pregnancy. This study emphasizes the importance of preventing periodontitis in order to avoid insulin resistance and stress during pregnancy since these can cause systemic complications for the mother and the fetus.

Multiple ground-based and satellite observations of global Pi 2 magnetic pulsations

NASA Technical Reports Server (NTRS)

Yumoto, K.; Takahashi, K.; Sakurai, T.; Sutcliffe, P. R.; Kokubun, S.

1990-01-01

Four Pi 2 events are examined using data obtained concurrently at the Syowa-Iceland conjugate stations, the EISCAT-Magnetometer Cross, low-latitude stations HER on the nightside and KAK on the dayside, and at AMPTE/CCE in the outer magnetosphere during the period from 2300 UT on May 22 to 0300 UT on May 23, 1985. Several characteristics of Pi 2 are established on the basis of high time resolution magnetic field data. First of all, horizontal components, H and D, of the Pi 2 oscillate nearly antiphase and in-phase, respectively, between the high- and low-altitude stations in the midnight southern hemisphere. Both H and D components of the Pi 2 have nearly in-phase relationships between the nightside and the dayside stations at low altitude. The Pi 2 amplitude is larger at the high-latitude station and decreases toward low latitudes. The dominant periods of the Pi 2 are nearly identical at all stations.

Genome-wide profiling of the PIWI-interacting RNA-mRNA regulatory networks in epithelial ovarian cancers.

PubMed

Singh, Garima; Roy, Jyoti; Rout, Pratiti; Mallick, Bibekanand

2018-01-01

PIWI-interacting (piRNAs), ~23-36 nucleotide-long small non-coding RNAs (sncRNAs), earlier believed to be germline-specific, have now been identified in somatic cells, including cancer cells. These sncRNAs impact critical biological processes by fine-tuning gene expression at post-transcriptional and epigenetic levels. The expression of piRNAs in ovarian cancer, the most lethal gynecologic cancer is largely uncharted. In this study, we investigated the expression of PIWILs by qRT-PCR and western blotting and then identified piRNA transcriptomes in tissues of normal ovary and two most prevalent epithelial ovarian cancer subtypes, serous and endometrioid by small RNA sequencing. We detected 219, 256 and 234 piRNAs in normal ovary, endometrioid and serous ovarian cancer samples respectively. We observed piRNAs are encoded from various genomic regions, among which introns harbor the majority of them. Surprisingly, piRNAs originated from different genomic contexts showed the varied level of conservations across vertebrates. The functional analysis of predicted targets of differentially expressed piRNAs revealed these could modulate key processes and pathways involved in ovarian oncogenesis. Our study provides the first comprehensive piRNA landscape in these samples and a useful resource for further functional studies to decipher new mechanistic views of piRNA-mediated gene regulatory networks affecting ovarian oncogenesis. The RNA-seq data is submitted to GEO database (GSE83794).

Restoration of Lumbar Lordosis in Flat Back Deformity: Optimal Degree of Correction

PubMed Central

Kim, Ki-Tack; Lee, Sang-Hun; Kim, Hyo-Jong; Kim, Jung-Youn; Lee, Jung-Hee

2015-01-01

Study Design A retrospective comparative study. Purpose To provide an ideal correction angle of lumbar lordosis (LL) in degenerative flat back deformity. Overview of Literature The degree of correction in degenerative flat back in relation to pelvic incidence (PI) remains controversial. Methods Forty-nine patients with flat back deformity who underwent corrective surgery were enrolled. Posterior-anterior-posterior sequential operation was performed. Mean age and mean follow-up period was 65.6 years and 24.2 months, respectively. We divided the patients into two groups based on immediate postoperative radiographs-optimal correction (OC) group (PI-9°≤LL

High permittivity induced by interaction between PI matrix and graphite oxide filler

NASA Astrophysics Data System (ADS)

Lai, Maobai; Kou, Siwang; Yu, Shuhui; Sun, Rong; Wong, Ching-Ping

2014-09-01

Functionalized graphite oxide was introduced to polyimide and a colossal permittivity was obtained in the derived GO/PI composites. At 1 kHz, the permittivity of the composite with 3 wt% GO loading was up to 7179. In comparison, the permittivities of rGO/PI with 3 wt% rGO loading and GO/ER with 3 wt% GO loading were only 14.41 and 26.64, respectively. By analyzing the molecular structure and chemical bonding of GO/PI composites, we proposed that interaction occurred between the GO fillers carrying functional groups and the PI matrix with a conjugate system, which accounts for the high permittivity of GO/PI composites.

Doping dependence of ordered phases and emergent quasiparticles in the doped Hubbard-Holstein model

DOE PAGES

Mendl, C. B.; Nowadnick, E. A.; Huang, E. W.; ...

2017-11-15

Here, we present determinant quantum Monte Carlo simulations of the hole-doped single-band Hubbard-Holstein model on a square lattice, to investigate how quasiparticles emerge when doping a Mott insulator (MI) or a Peierls insulator (PI). The MI regime at large Hubbard interaction U and small relative e-ph coupling strength λ is quickly suppressed upon doping, by drawing spectral weight from the upper Hubbard band and shifting the lower Hubbard band towards the Fermi level, leading to a metallic state with emergent quasiparticles at the Fermi level. On the other hand, the PI regime at large λ and small U persists outmore » to relatively high doping levels. We study the evolution of the d-wave superconducting susceptibility with doping, and find that it increases with lowering temperature in a regime of intermediate values of U and λ.« less

Doping dependence of ordered phases and emergent quasiparticles in the doped Hubbard-Holstein model

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

Mendl, C. B.; Nowadnick, E. A.; Huang, E. W.

Here, we present determinant quantum Monte Carlo simulations of the hole-doped single-band Hubbard-Holstein model on a square lattice, to investigate how quasiparticles emerge when doping a Mott insulator (MI) or a Peierls insulator (PI). The MI regime at large Hubbard interaction U and small relative e-ph coupling strength λ is quickly suppressed upon doping, by drawing spectral weight from the upper Hubbard band and shifting the lower Hubbard band towards the Fermi level, leading to a metallic state with emergent quasiparticles at the Fermi level. On the other hand, the PI regime at large λ and small U persists outmore » to relatively high doping levels. We study the evolution of the d-wave superconducting susceptibility with doping, and find that it increases with lowering temperature in a regime of intermediate values of U and λ.« less

Glutathione S-transferase Pi expression predicts response to adjuvant chemotherapy for stage C colon cancer: a matched historical control study

PubMed Central

2012-01-01

Background This study examined the association between overall survival and Glutathione S-transferase Pi (GST Pi) expression and genetic polymorphism in stage C colon cancer patients after resection alone versus resection plus 5-fluourouracil-based adjuvant chemotherapy. Methods Patients were drawn from a hospital registry of colorectal cancer resections. Those receiving chemotherapy after it was introduced in 1992 were compared with an age and sex matched control group from the preceding period. GST Pi expression was assessed by immunohistochemistry. Overall survival was analysed by the Kaplan-Meier method and Cox regression. Results From an initial 104 patients treated with chemotherapy and 104 matched controls, 26 were excluded because of non-informative immunohistochemistry, leaving 95 in the treated group and 87 controls. Survival did not differ significantly among patients with low GST Pi who did or did not receive chemotherapy and those with high GST Pi who received chemotherapy (lowest pair-wise p = 0.11) whereas patients with high GST Pi who did not receive chemotherapy experienced markedly poorer survival than any of the other three groups (all pair-wise p <0.01). This result was unaffected by GST Pi genotype. Conclusion Stage C colon cancer patients with low GST Pi did not benefit from 5-fluourouracil-based adjuvant chemotherapy whereas those with high GST Pi did. PMID:22639861

Glutathione S-transferase Pi expression predicts response to adjuvant chemotherapy for stage C colon cancer: a matched historical control study.

PubMed

Jankova, Lucy; Robertson, Graham; Chan, Charles; Tan, King L; Kohonen-Corish, Maija; Fung, Caroline L-S; Clarke, Candice; Lin, Betty P C; Molloy, Mark; Chapuis, Pierre H; Bokey, Les; Dent, Owen F; Clarke, Stephen J

2012-05-28

This study examined the association between overall survival and Glutathione S-transferase Pi (GST Pi) expression and genetic polymorphism in stage C colon cancer patients after resection alone versus resection plus 5-fluourouracil-based adjuvant chemotherapy. Patients were drawn from a hospital registry of colorectal cancer resections. Those receiving chemotherapy after it was introduced in 1992 were compared with an age and sex matched control group from the preceding period. GST Pi expression was assessed by immunohistochemistry. Overall survival was analysed by the Kaplan-Meier method and Cox regression. From an initial 104 patients treated with chemotherapy and 104 matched controls, 26 were excluded because of non-informative immunohistochemistry, leaving 95 in the treated group and 87 controls. Survival did not differ significantly among patients with low GST Pi who did or did not receive chemotherapy and those with high GST Pi who received chemotherapy (lowest pair-wise p = 0.11) whereas patients with high GST Pi who did not receive chemotherapy experienced markedly poorer survival than any of the other three groups (all pair-wise p <0.01). This result was unaffected by GST Pi genotype. Stage C colon cancer patients with low GST Pi did not benefit from 5-fluourouracil-based adjuvant chemotherapy whereas those with high GST Pi did.

Osmoregulatory inositol transporter SMIT1 modulates electrical activity by adjusting PI(4,5)P2 levels

PubMed Central

Dai, Gucan; Yu, Haijie; Traynor-Kaplan, Alexis

2016-01-01

Myo-inositol is an important cellular osmolyte in autoregulation of cell volume and fluid balance, particularly for mammalian brain and kidney cells. We find it also regulates excitability. Myo-inositol is the precursor of phosphoinositides, key signaling lipids including phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. However, whether myo-inositol accumulation during osmoregulation affects signaling and excitability has not been fully explored. We found that overexpression of the Na+/myo-inositol cotransporter (SMIT1) and myo-inositol supplementation enlarged intracellular PI(4,5)P2 pools, modulated several PI(4,5)P2-dependent ion channels including KCNQ2/3 channels, and attenuated the action potential firing of superior cervical ganglion neurons. Further experiments using the rapamycin-recruitable phosphatase Sac1 to hydrolyze PI(4)P and the P4M probe to visualize PI(4)P suggested that PI(4)P levels increased after myo-inositol supplementation with SMIT1 expression. Elevated relative levels of PIP and PIP2 were directly confirmed using mass spectrometry. Inositol trisphosphate production and release of calcium from intracellular stores also were augmented after myo-inositol supplementation. Finally, we found that treatment with a hypertonic solution mimicked the effect we observed with SMIT1 overexpression, whereas silencing tonicity-responsive enhancer binding protein prevented these effects. These results show that ion channel function and cellular excitability are under regulation by several “physiological” manipulations that alter the PI(4,5)P2 setpoint. We demonstrate a previously unrecognized linkage between extracellular osmotic changes and the electrical properties of excitable cells. PMID:27217553

Transgenerationally inherited piRNAs trigger piRNA biogenesis by changing the chromatin of piRNA clusters and inducing precursor processing

PubMed Central

Le Thomas, Adrien; Stuwe, Evelyn; Li, Sisi; Marinov, Georgi; Rozhkov, Nikolay; Chen, Yung-Chia Ariel; Luo, Yicheng; Sachidanandam, Ravi; Toth, Katalin Fejes; Patel, Dinshaw; Aravin, Alexei A.

2014-01-01

Small noncoding RNAs that associate with Piwi proteins, called piRNAs, serve as guides for repression of diverse transposable elements in germ cells of metazoa. In Drosophila, the genomic regions that give rise to piRNAs, the so-called piRNA clusters, are transcribed to generate long precursor molecules that are processed into mature piRNAs. How genomic regions that give rise to piRNA precursor transcripts are differentiated from the rest of the genome and how these transcripts are specifically channeled into the piRNA biogenesis pathway are not known. We found that transgenerationally inherited piRNAs provide the critical trigger for piRNA production from homologous genomic regions in the next generation by two different mechanisms. First, inherited piRNAs enhance processing of homologous transcripts into mature piRNAs by initiating the ping-pong cycle in the cytoplasm. Second, inherited piRNAs induce installment of the histone 3 Lys9 trimethylation (H3K9me3) mark on genomic piRNA cluster sequences. The heterochromatin protein 1 (HP1) homolog Rhino binds to the H3K9me3 mark through its chromodomain and is enriched over piRNA clusters. Rhino recruits the piRNA biogenesis factor Cutoff to piRNA clusters and is required for efficient transcription of piRNA precursors. We propose that transgenerationally inherited piRNAs act as an epigenetic memory for identification of substrates for piRNA biogenesis on two levels: by inducing a permissive chromatin environment for piRNA precursor synthesis and by enhancing processing of these precursors. PMID:25085419

Dual functions of Macpiwi1 in transposon silencing and stem cell maintenance in the flatworm Macrostomum lignano.

PubMed

Zhou, Xin; Battistoni, Giorgia; El Demerdash, Osama; Gurtowski, James; Wunderer, Julia; Falciatori, Ilaria; Ladurner, Peter; Schatz, Michael C; Hannon, Gregory J; Wasik, Kaja A

2015-11-01

PIWI proteins and piRNA pathways are essential for transposon silencing and some aspects of gene regulation during animal germline development. In contrast to most animal species, some flatworms also express PIWIs and piRNAs in somatic stem cells, where they are required for tissue renewal and regeneration. Here, we have identified and characterized piRNAs and PIWI proteins in the emerging model flatworm Macrostomum lignano. We found that M. lignano encodes at least three PIWI proteins. One of these, Macpiwi1, acts as a key component of the canonical piRNA pathway in the germline and in somatic stem cells. Knockdown of Macpiwi1 dramatically reduces piRNA levels, derepresses transposons, and severely impacts stem cell maintenance. Knockdown of the piRNA biogenesis factor Macvasa caused an even greater reduction in piRNA levels with a corresponding increase in transposons. Yet, in Macvasa knockdown animals, we detected no major impact on stem cell self-renewal. These results may suggest stem cell maintenance functions of PIWI proteins in flatworms that are distinguishable from their impact on transposons and that might function independently of what are considered canonical piRNA populations. © 2015 Zhou et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

The Moderating Effects of Perceived Intentionality: Exploring the Relationships Between Ideas of Reference, Paranoia, and Social Anxiety in Schizotypy

PubMed Central

Morrison, Sean C.; Cohen, Alex S.

2014-01-01

Introduction Ideas of reference (IOR), paranoia, and social anxiety are features of schizophrenia-spectrum disorders, which appear to be conceptually related; however, the precise nature of these relationships is unclear. These relationships may be partially explained by perceived intentionality (PI), a social-cognitive bias for perceiving other people’s actions during unpleasant situations as being directed at oneself in an intentionally malicious manner. Our primary aim was to examine the moderating role of PI on the relationships between IOR and paranoia, and between IOR and social anxiety amongst individuals with psychometrically-defined schizotypy. Methods We assessed IOR, paranoia, and social anxiety amongst individuals with psychometrically-defined schizotypy (n = 44) and controls (n = 36), and examined the moderating effects of PI within each group. Results As hypothesized, PI moderated the relationship between IOR and paranoia such that higher PI predicted higher levels of paranoia as IOR increased. Additionally, we found that PI moderated the relationship between IOR and social anxiety such that higher PI predicted lower levels of social anxiety as IOR increased. Discussion Theoretical and practical implications are discussed including the potential for assessing PI as a proxy for paranoia when clinicians suspect a client is underreporting paranoia due to positive impression management. PMID:24987988

Modulation of small intestinal phosphate transporter by dietary supplements of mineral phosphorus and phytase in broilers.

PubMed

Huber, Korinna; Zeller, Ellen; Rodehutscord, Markus

2015-05-01

Dietary phosphorus (P) is known as a main modulator of phosphate (Pi) transporter expression. The effect of supplemented mineral P with or without phytase on protein expression of two sodium-dependent Pi (NaPi) transporters and a calcium channel was studied in the small intestine of broilers. Thirty-six broilers were randomly assigned to six different diets at 15 days of age. Two levels of total P (tP, adjusted by monocalcium phosphate (MCP) supplementation), 0.39% (BD-) and 0.47% (BD+) were fed until day 25; and at each tP level, three levels of phytase were used with 0, 500, and 12,500 FTU/kg of an E. coli phytase. Mucosa samples from jejunum and ileum were taken and apical membranes were isolated by MgCl2 precipitation. Protein expression of NaPi IIb, NaPi type III (PiT1) and the calcium channel TRPV6 were semiquantitatively measured by Western blotting and jejunal mucosal phytase activity by measurement of Pi release. The jejunal NaPi IIb transporter was expressed with two distinct bands, which were modulated differently by diet. NaPi IIb Band1 increased (P < 0.05) and Band2 decreased (P < 0.05) with phytase supplementation but was not affected by MCP supplementation. This inverse modulation of Band1 and Band2 was significantly related to the amount of net absorbed P with higher expression of Band1 at higher amounts of net absorbed P. In addition, a second Pi transporter, PiT1, was detected in which ileal expression decreased (P < 0.05) in response to higher phytase supplementation. The expression of the calcium channel TRPV6 was increased in BD+ groups. A trend for an interaction between MCP and phytase supplementation on mucosal phytase activity was observed (P = 0.079) with a decrease in activity when BD+ with 12,500 FTU/kg phytase was fed. Chicken intestinal epithelial cells responded to dietary supplemented phytase and MCP by changing the Pi transporter expression in apical membranes. In conclusion, availability of Pi is most likely the key modulator of transporter protein expression. However, a contribution of lower inositol phosphates generated by phytases and other phosphatases may also be relevant. © 2015 Poultry Science Association Inc.

PI3K and Bcl-2 inhibition primes glioblastoma cells to apoptosis through downregulation of Mcl-1 and Phospho-BAD.

PubMed

Pareja, Fresia; Macleod, David; Shu, Chang; Crary, John F; Canoll, Peter D; Ross, Alonzo H; Siegelin, Markus D

2014-07-01

Glioblastoma multiforme (GBM) is a highly malignant human brain neoplasm with limited therapeutic options. GBMs display a deregulated apoptotic pathway with high levels of the antiapoptotic Bcl-2 family of proteins and overt activity of the phosphatidylinositol 3-kinase (PI3K) signaling pathway. Therefore, combined interference of the PI3K pathway and the Bcl-2 family of proteins is a reasonable therapeutic strategy. ABT-263 (Navitoclax), an orally available small-molecule Bcl-2 inhibitor, and GDC-0941, a PI3K inhibitor, were used to treat established glioblastoma and glioblastoma neurosphere cells, alone or in combination. Although GDC-0941 alone had a modest effect on cell viability, treatment with ABT-263 displayed a marked reduction of cell viability and induction of apoptotic cell death. Moreover, combinatorial therapy using ABT-263 and GDC-0941 showed an enhanced effect, with a further decrease in cellular viability. Furthermore, combination treatment abrogated the ability of stem cell-like glioma cells to form neurospheres. ABT-263 and GDC-0941, in combination, resulted in a consistent and significant increase of Annexin V positive cells and loss of mitochondrial membrane potential compared with either monotherapy. The combination treatment led to enhanced cleavage of both initiator and effector caspases. Mechanistically, GDC-0941 depleted pAKT (Serine 473) levels and suppressed Mcl-1 protein levels, lowering the threshold for the cytotoxic actions of ABT-263. GDC-0941 decreased Mcl-1 in a posttranslational manner and significantly decreased the half-life of Mcl-1 protein. Ectopic expression of human Mcl-1 mitigated apoptotic cell death induced by the drug combination. Furthermore, GDC-0941 modulated the phosphorylation status of BAD, thereby further enhancing ABT-263-mediated cell death. Combination therapy with ABT-263 and GDC-0941 has novel therapeutic potential by specifically targeting aberrantly active, deregulated pathways in GBM, overcoming endogenous resistance to apoptosis. ©2014 American Association for Cancer Research.

Reprint Series: Nature and History of Pi. RS-6.

ERIC Educational Resources Information Center

Schaaf, William L., Ed.

This is one in a series of SMSG supplementary and enrichment pamphlets for high school students. This series makes available expository articles which appeared in a variety of mathematical periodicals. Topics covered include: (1) the history of the number pi; (2) what's new about pi; (3) the number pi; (4) pi and probability; and (5) from the…

EVALUATION, ASSESSMENT, AND DETERMINATION OF RISK TO HIGH TROPHIC LEVEL PISCIVORES IN THE MID-ATLANTIC: A SPATIAL, BIOLOGICAL, AND COMPARATIVE CASE STUDY OF MERCURY IN VIRGINIA AND NEW ENGLAND BALD EAGLE (HALIAEETUS LEUCOCEPHALUS) POPULATIONS

EPA Science Inventory

I predict that some portion of the Virginia bald eagle population will exhibit levels at or above those considered detrimental to productivity and reproductive success. The analysis of independent variables and their relationship to elevated blood mercury levels will help t...

Amplitude Analysis of B0 to K^ pi^-pi^0 and Evidence of Direct CP Violation in B to K^* pi decays

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

Lees, J.P.

We analyze the decay B{sup 0} {yields} K{sup +} {pi}{sup -} {pi}{sup 0} with a sample of 454 million B{bar B} events collected by the BABAR detector at the PEP-II asymmetric-energy B factory at SLAC, and extract the complex amplitudes of seven interfering resonances over the Dalitz plot. These results are combined with amplitudes measured in B{sup 0} {yields} K{sup 0}{sub s}{pi}{sup +}{pi}{sup -} decays to construct isospin amplitudes from B{sup 0} {yields} K{sup *}{pi} and B{sup 0} {yields} {rho}K decays. We measure the phase of the isospin amplitude {Phi}{sub 3/2}, useful in constraining the CKM unitarity triangle angle {gamma}more » and evaluate a CP rate asymmetry sum rule sensitive to the presence of new physics operators. We measure direct CP violation in B{sup 0} {yields} K{sup *+}{pi}{sup -} decays at the level of 3 {sigma} when measurements from both B{sup 0} {yields} K{sup +}{pi}{sup -}{pi}{sup 0} and B{sup 0} {yields} K{sup 0}{sub s}{pi}{sup +}{pi}{sup -} decays are combined.« less

{{\\rm{H}}}_{2}\\,X{}^{1}{{\\rm{\\Sigma }}}_{g}^{+}-c{}^{3}{{\\rm{\\Pi }}}_{u} Excitation by Electron Impact: Energies, Spectra, Emission Yields, Cross-sections, and H(1s) Kinetic Energy Distributions

NASA Astrophysics Data System (ADS)

Liu, Xianming; Shemansky, Donald E.; Yoshii, Jean; Liu, Melinda J.; Johnson, Paul V.; Malone, Charles P.; Khakoo, Murtadha A.

2017-10-01

The c{}3{{{\\Pi }}}u state of the hydrogen molecule has the second largest triplet-state excitation cross-section, and plays an important role in the heating of the upper thermospheres of outer planets by electron excitation. Precise energies of the H2, D2, and HD c{}3{{{\\Pi }}}u-(v,N) levels are calculated from highly accurate ab initio potential energy curves that include relativistic, radiative, and empirical non-adiabatic corrections. The emission yields are determined from predissociation rates and refined radiative transition probabilities. The excitation function and excitation cross-section of the c{}3{{{\\Pi }}}u state are extracted from previous theoretical calculations and experimental measurements. The emission cross-section is determined from the calculated emission yield and the extracted excitation cross-section. The kinetic energy (E k ) distributions of H atoms produced via the predissociation of the c{}3{{{\\Pi }}}u state, the c{}3{{{\\Pi }}}u- - b{}3{{{Σ }}}u+ dissociative emission by the magnetic dipole and electric quadrupole, and the c{}3{{{\\Pi }}}u - a{}3{{{Σ }}}g+ - b{}3{{{Σ }}}u+ cascade dissociative emission by the electric dipole are obtained. The predissociation of the c{}3{{{\\Pi }}}u+ and c{}3{{{\\Pi }}}u- states both produce H(1s) atoms with an average E k of ˜4.1 eV/atom, while the c{}3{{{\\Pi }}}u- - b{}3{{{Σ }}}u+ dissociative emissions by the magnetic dipole and electric quadrupole give an average E k of ˜1.0 and ˜0.8 eV/atom, respectively. The c{}3{{{\\Pi }}}u - a{}3{{{Σ }}}g+ - b{}3{{{Σ }}}u+ cascade and dissociative emission gives an average E k of ˜1.3 eV/atom. On average, each H2 excited to the c{}3{{{\\Pi }}}u state in an H2-dominated atmosphere deposits ˜7.1 eV into the atmosphere while each H2 directly excited to the a{}3{{{Σ }}}g+ and d{}3{{{\\Pi }}}u states contribute ˜2.3 and ˜3.3 eV, respectively, to the atmosphere. The spectral distribution of the calculated continuum emission arising from the X{}1{{{Σ }}}g+ - c{}3{{{\\Pi }}}u excitation is significantly different from that of direct a{}3{{{Σ }}}g+ or d{}3{{{\\Pi }}}u excitations.

Molecular Mechanisms of Phosphorus Metabolism and Transport during Leaf Senescence

PubMed Central

Stigter, Kyla A.; Plaxton, William C.

2015-01-01

Leaf senescence, being the final developmental stage of the leaf, signifies the transition from a mature, photosynthetically active organ to the attenuation of said function and eventual death of the leaf. During senescence, essential nutrients sequestered in the leaf, such as phosphorus (P), are mobilized and transported to sink tissues, particularly expanding leaves and developing seeds. Phosphorus recycling is crucial, as it helps to ensure that previously acquired P is not lost to the environment, particularly under the naturally occurring condition where most unfertilized soils contain low levels of soluble orthophosphate (Pi), the only form of P that roots can directly assimilate from the soil. Piecing together the molecular mechanisms that underpin the highly variable efficiencies of P remobilization from senescing leaves by different plant species may be critical for devising effective strategies for improving overall crop P-use efficiency. Maximizing Pi remobilization from senescing leaves using selective breeding and/or biotechnological strategies will help to generate P-efficient crops that would minimize the use of unsustainable and polluting Pi-containing fertilizers in agriculture. This review focuses on the molecular mechanisms whereby P is remobilized from senescing leaves and transported to sink tissues, which encompasses the action of hormones, transcription factors, Pi-scavenging enzymes, and Pi transporters. PMID:27135351

Social Network Characteristics, Social Support, and Cigarette Smoking among Asian/Pacific Islander Young Adults

PubMed Central

Pokhrel, Pallav; Fagan, Pebbles; Cassel, Kevin; Trinidad, Dennis R.; Kaholokula, Joseph Keawe‘aimoku; Herzog, Thaddeus A.

2016-01-01

Cigarette smoking may be one of the factors contributing to the high levels of cancer-related mortality experienced by certain Asian/Pacific Islander (A/PI) subgroups (e.g., Native Hawaiian). Given the collectivist cultural orientation attributed to A/PI groups, social strategies are recommended for substance abuse or smoking cessation treatment among A/PI. However, research examining how social network characteristics and social support relate to smoking across A/PI subgroups has been lacking. This study investigated the associations between social network characteristics (e.g., size, composition), perceived social support, and recent cigarette use across Native Hawaiian, Filipino, and East Asian (e.g., Japanese, Chinese) young adults (18–35 year old). Cross-sectional, self-report data were collected from N = 435 participants (M age = 25.6, SD = 8.3; 61% women). Ethnic differences were found in a number of pathways linking social network characteristics, perceived social support, and cigarette smoking. Larger network size was strongly associated with higher perceived social support and lower recent cigarette smoking among Native Hawaiians but not Filipinos or East Asians. Higher perceived social support was associated with lower recent smoking among East Asians and Filipinos but not Native Hawaiians. Implications are discussed with regard to smoking prevention and cessation among A/PI. PMID:27297612

Pht2;1 encodes a low-affinity phosphate transporter from Arabidopsis.

PubMed Central

Daram, P; Brunner, S; Rausch, C; Steiner, C; Amrhein, N; Bucher, M

1999-01-01

An Arabidopsis genomic sequence was recently shown to share similarity with bacterial and eukaryotic phosphate (Pi) transporters. We have cloned the corresponding cDNA, which we named Pht2;1, and subsequently performed gene expression studies and functional analysis of the protein product. The cDNA encodes a 61-kD protein with a putative topology of 12 transmembrane (TM) domains interrupted by a large hydrophilic loop between TM8 and TM9. Two boxes of eight and nine amino acids, located in the N- and C-terminal domains, respectively, are highly conserved among species across all kingdoms (eubacteria, archea, fungi, plants, and animals). The Pht2;1 gene is predominantly expressed in green tissue, the amount of transcript staying constant in leaves irrespective of the Pi status of the shoot; in roots, however, there is a marginal increase in mRNA amounts in response to Pi deprivation. Although the protein is highly similar to eukaryotic sodium-dependent Pi transporters, functional analysis of the Pht2;1 protein in mutant yeast cells indicates that it is a proton/Pi symporter dependent on the electrochemical gradient across the plasma membrane. Its fairly high apparent K(m) for Pi (0.4 mM) and high mRNA content in the shoot, especially in leaves, suggest a role for shoot organs in Pi loading. Pht2;1 thus differs from members of the recently described plant Pi transporter family in primary structure, affinity for Pi, and presumed function. PMID:10559441

[Effects of phosphorus sources on phosphorus fractions in rhizosphere soil of wild barley genotypes with high phosphorus utilization efficiency].

PubMed

Cai, Qiu-Yan; Zhang, Xi-Zhou; Li, Ting-Xuan; Chen, Guang-Deng

2014-11-01

High P-efficiency (IS-22-30, IS-22-25) and low P-efficiency (IS-07-07) wild barley cultivars were chosen to evaluate characteristics of phosphorus uptake and utilization, and properties of phosphorus fractions in rhizosphere and non-rhizosphere in a pot experiment with 0 (CK) and 30 mg P · kg(-1) supplied as only Pi (KH2PO4), only Po (phytate) or Pi + Po (KH2PO4+ phytate). The results showed that dry matter and phosphorus accumulation of wild barley in the different treatments was ranked as Pi > Pi + Po > Po > CK. In addition, dry matter yield and phosphorus uptake of wild barley with high P-efficiency exhibited significantly greater than that with low P-efficiency. The concentration of soil available phosphorus was significantly different after application of different phosphorus sources, which was presented as Pi > Pi + Po > Po. The concentration of soil available phosphorus in high P-efficiency wild barley was significantly higher than that of low P-efficiency in the rhizosphere soil. There was a deficit in rhizosphere available phosphorus of high P-efficiency wild barley, especially in Pi and Pi+Po treatments. The inorganic phosphorus fractions increased with the increasing Pi treatment, and the concentrations of inorganic phosphorus fractions in soil were sorted as follows: Ca10-P > O-P > Fe-P > Al-P > Ca2-P > Ca8-P. The contents of Ca2-P and Ca8-P for high P-efficiency wild barley showed deficits in rhizosphere soil under each phosphorus source treatment. In addition, enrichment of Al-P and Fe-P was observed in Pi treatment in rhizosphere soil. The concentrations of organic phosphorus fractions in soil were sorted as follows: moderate labile organic phosphorus > moderate resistant, resistant organic phosphorus > labile organic phosphorus. The labile and moderate labile organic phosphorus enriched in rhizosphere soil and the greatest enrichment appeared in Pi treatment. Furthermore, the concentrations of moderate resistant organic phosphorus and resistant organic phosphorus decreased in rhizosphere soil. The concentrations of labile and moderate labile organic phosphorus in rhizosphere soil of high P-efficiency wild barley were significantly higher than that of low P-efficiency wild barley in each phosphorus source treatment. However, moderate resistant organic phosphorus and resistant organic phosphorus concentrations had no significant difference between the two genotypes. Wild barley with high P-efficiency demonstrated a greater ability of mobilization and uptake Ca2-P, Ca8-P, Al-P and labile organic phosphorus than that with low P-efficiency under Pi deficiency.

Quantitative disease progression model of α‐1 proteinase inhibitor therapy on computed tomography lung density in patients with α‐1 antitrypsin deficiency

PubMed Central

Rogers, James A.; Vit, Oliver; Bexon, Martin; Sandhaus, Robert A.; Burdon, Jonathan; Chorostowska‐Wynimko, Joanna; Thompson, Philip; Stocks, James; McElvaney, Noel G.; Chapman, Kenneth R.; Edelman, Jonathan M.

2017-01-01

Aims Early‐onset emphysema attributed to α‐1 antitrypsin deficiency (AATD) is frequently overlooked and undertreated. RAPID‐RCT/RAPID‐OLE, the largest clinical trials of purified human α‐1 proteinase inhibitor (A1‐PI; 60 mg kg–1 week–1) therapy completed to date, demonstrated for the first time that A1‐PI is clinically effective in slowing lung tissue loss in AATD. A posthoc pharmacometric analysis was undertaken to further explore dose, exposure and response. Methods A disease progression model was constructed, utilizing observed A1‐PI exposure and lung density decline rates (measured by computed tomography) from RAPID‐RCT/RAPID‐OLE, to predict effects of population variability and higher doses on A1‐PI exposure and clinical response. Dose–exposure and exposure–response relationships were characterized using nonlinear and linear mixed effects models, respectively. The dose–exposure model predicts summary exposures and not individual concentration kinetics; covariates included baseline serum A1‐PI, forced expiratory volume in 1 s and body weight. The exposure–response model relates A1‐PI exposure to lung density decline rate at varying exposure levels. Results A dose of 60 mg kg–1 week–1 achieved trough serum levels >11 μmol l–1 (putative ‘protective threshold’) in ≥98% patients. Dose–exposure–response simulations revealed increasing separation between A1‐PI and placebo in the proportions of patients achieving higher reductions in lung density decline rate; improvements in decline rates ≥0.5 g l–1 year–1 occurred more often in patients receiving A1‐PI: 63 vs. 12%. Conclusion Weight‐based A1‐PI dosing reliably raises serum levels above the 11 μmol l–1 threshold. However, our exposure–response simulations question whether this is the maximal, clinically effective threshold for A1‐PI therapy in AATD. The model suggested higher doses of A1‐PI would yield greater clinical effects. PMID:28662542

Reduced interstitial cells of Cajal and increased intraepithelial lymphocytes are associated with development of small intestinal bacterial overgrowth in post-infectious IBS mouse model.

PubMed

Chen, Binrui; Zhu, Shuwen; Du, Lijun; He, Huiqin; Kim, John J; Dai, Ning

2017-10-01

Intestinal dysmotility and immune activation are likely involved in the pathogenesis of small intestinal bacteria overgrowth (SIBO) in irritable bowel syndrome (IBS). We aimed at investigating the role of interstitial cells of Cajal (ICC) and intestinal inflammation in the development of SIBO using a post-infectious IBS (PI-IBS) mouse model. NIH mice were randomly infected with Trichinella spiralis. Visceral sensitivity and stool pattern were assessed at 8-weeks post-infection (PI). Intestinal bacteria counts from jejunum and ileum were measured by quantitative real-time PCR to evaluate the presence of SIBO. ICC density, intraepithelial lymphocytes (IELs) counts, and intestinal cytokine levels (IL1-β, IL-6, toll-like receptor-4 (TLR-4), IL-10) in the ileum were examined. PI-IBS mice demonstrated increased visceral sensitivity compared with the control group. One-third of the PI-IBS mice developed SIBO (SIBO+/PI-IBS) and was more likely to have abnormal stool form compared with SIBO negative PI-IBS (SIBO-/PI-IBS) mice but without difference in visceral sensitivity. SIBO+/PI-IBS mice had decreased ICC density and increased IELs counts in the ileum compared with SIBO-/PI-IBS mice. No difference in inflammatory cytokine expression levels were detected among the groups except for increased TLR-4 in PI-IBS mice compared with the control group. Development of SIBO in PI-IBS mice was associated with reduced ICC density and increased IELs counts in the ileum. Our findings support the role of intestinal dysmotility and inflammation in the pathogenesis of SIBO in IBS and may provide potential therapeutic targets.

A Comparative study between MPC and PI controller to control vacuum distillation unit for producing LVGO, MVGO, and HVGO

NASA Astrophysics Data System (ADS)

Wahid, A.; Prasetyo, A. P.

2018-03-01

This study describes the selection of controllers in the vacuum distillation unit (VDU) between a model predictive control (MPC) and a proportional-integral (PI) controller by comparing the integral square error (ISE) values. Design of VDU in this simulation is based on modified Metso Automation Inc. scheme. Controlled variables in this study are feed flow rate, feed temperature, top stage pressure, condenser level, bottom stage temperature, LVGO (light vacuum gas oil), MVGO (medium vacuum gas oil), and HVGO (heavy vacuum gas oil) flow rate. As a result, control performance improvements occurred as using MPC compared to PI controllers, when testing a set-point change, of feed flow rate control, feed temperature, top-stage pressure, bottom-stage temperature and flow rate of LVGO, MVGO, and HVGO, respectively, 36%, 6%, 92%, 53%, 90%, 96% and 88%. Only on condenser level control PI performs much better than the MPC. So PI controller is used for level condenser control. While for the test of disturbance rejection, by changing feed flow rate by 10%, there is improvement of control performance using MPC compared to PI controller on feed temperature control, top-stage pressure, bottom-stage temperature and flow rate LVGO, MVGO and HVGO 0.3%, 0.7%, 14%, 2.7%, 10.6% and 4.3%, respectively.

High phosphorus diet-induced changes in NaPi-IIb phosphate transporter expression in the rat kidney: DNA microarray analysis.

PubMed

Suyama, Tatsuya; Okada, Shinji; Ishijima, Tomoko; Iida, Kota; Abe, Keiko; Nakai, Yuji

2012-01-01

The mechanism by which phosphorus levels are maintained in the body was investigated by analyzing changes in gene expression in the rat kidney following administration of a high phosphorus (HP) diet. Male Wistar rats were divided into two groups and fed a diet containing 0.3% (control) or 1.2% (HP) phosphorous for 24 days. Phosphorous retention was not significantly increased in HP rats, but fractional excretion of phosphorus was significantly increased in the HP group compared to controls, with an excessive amount of the ingested phosphorus being passed through the body. DNA microarray analysis of kidney tissue from both groups revealed changes in gene expression profile induced by a HP diet. Among the genes that were upregulated, Gene Ontology (GO) terms related to ossification, collagen fibril organization, and inflammation and immune response were significantly enriched. In particular, there was significant upregulation of type IIb sodium-dependent phosphate transporter (NaPi-IIb) in the HP rat kidney compared to control rats. This upregulation was confirmed by in situ hybridization. Distinct signals for NaPi-IIb in both the cortex and medulla of the kidney were apparent in the HP group, while the corresponding signals were much weaker in the control group. Immunohistochemical analysis showed that NaPi-IIb localized to the basolateral side of kidney epithelial cells surrounding the urinary duct in HP rats but not in control animals. These data suggest that NaPi-IIb is upregulated in the kidney in response to the active excretion of phosphate in HP diet-fed rats.

Distribution, evolution, and diversity of retrotransposons at the flamenco locus reflect the regulatory properties of piRNA clusters

PubMed Central

Zanni, Vanessa; Eymery, Angéline; Coiffet, Michael; Zytnicki, Matthias; Luyten, Isabelle; Quesneville, Hadi; Vaury, Chantal; Jensen, Silke

2013-01-01

Most of our understanding of Drosophila heterochromatin structure and evolution has come from the annotation of heterochromatin from the isogenic y; cn bw sp strain. However, almost nothing is known about the heterochromatin’s structural dynamics and evolution. Here, we focus on a 180-kb heterochromatic locus producing Piwi-interacting RNAs (piRNA cluster), the flamenco (flam) locus, known to be responsible for the control of at least three transposable elements (TEs). We report its detailed structure in three different Drosophila lines chosen according to their capacity to repress or not to repress the expression of two retrotransposons named ZAM and Idefix, and we show that they display high structural diversity. Numerous rearrangements due to homologous and nonhomologous recombination, deletions and segmental duplications, and loss and gain of TEs are diverse sources of active genomic variation at this locus. Notably, we evidence a correlation between the presence of ZAM and Idefix in this piRNA cluster and their silencing. They are absent from flam in the strain where they are derepressed. We show that, unexpectedly, more than half of the flam locus results from recent TE insertions and that most of the elements concerned are prone to horizontal transfer between species of the melanogaster subgroup. We build a model showing how such high and constant dynamics of a piRNA master locus open the way to continual emergence of new patterns of piRNA biogenesis leading to changes in the level of transposition control. PMID:24248389

Longitudinal variation in pressure injury incidence among long-term aged care facilities.

PubMed

Jorgensen, Mikaela; Siette, Joyce; Georgiou, Andrew; Westbrook, Johanna I

2018-05-04

To examine variation in pressure injury (PI) incidence among long-term aged care facilities and identify resident- and facility-level factors that explain this variation. Longitudinal incidence study using routinely-collected electronic care management data. A large aged care service provider in New South Wales and the Australian Capital Territory, Australia. About 6556 people aged 65 years and older who were permanent residents in 60 long-term care facilities between December 2014 and November 2016. Risk-adjusted PI incidence rates over eight study quarters. Incidence density over the study period was 1.33 pressure injuries per 1000 resident days (95% confidence interval (CI) = 1.29-1.37). Funnel plots were used to identify variation among facilities. On average, 14% of facilities had risk-adjusted PI rates that were higher than expected in each quarter (above 95% funnel plot control limits). Ten percent of facilities had persistently high rates in any three or more consecutive quarters (n = 6). The variation between facilities was only partly explained by resident characteristics in multilevel regression models. Residents were more likely to have higher-pressure injury rates in facilities in regional areas compared with major city areas (adjusted incidence rate ratio = 1.25, 95% CI = 1.04-1.51), and facilities with persistently high rates were more likely to be located in areas with low socioeconomic status (P = 0.038). There is considerable variation among facilities in PI incidence. This study demonstrates the potential of routinely-collected care management data to monitor PI incidence and to identify facilities that may benefit from targeted intervention.

Participation in sport in persons with spinal cord injury in Switzerland.

PubMed

Rauch, A; Fekete, C; Oberhauser, C; Marti, A; Cieza, A

2014-09-01

Secondary data analysis of a questionnaire-based, cross-sectional survey in persons with spinal cord injury (SCI) in Switzerland. To describe the frequency of participation in sport (PiS) and to identify correlates for PiS in persons with SCI in Switzerland. Community sampleMethods:Frequency of PiS was assessed retrospectively for the time before the onset of SCI and the time of the survey using a single-item question. A comprehensive set of independent variables was selected from the original questionnaire. Descriptive statistics, bivariate analyses and ordinal regressions were carried out. Data from 505 participants were analyzed. Twenty independent variables were selected for analyses. PiS decreased significantly from the time before the onset of SCI to the time of the survey (P<0.001). Sport levels were significantly lower in women than men for the time of the survey (P<0.001), whereas no difference was observed before onset of SCI (P=0.446). Persons with tetraplegia participated significantly less often in sport than persons with paraplegia (P<0.001). Lesion level, active membership in a club, frequency of PiS before the onset of SCI and the subjective evaluation of the importance of sport correlate with PiS. When controlling for gender differences, only the subjective importance of sport for persons with SCI determines PiS, particularly among women. Persons with tetraplegia and women need special attention when planning interventions to improve PiS. Furthermore, the subjective importance of sport is important for PiS, particularly among women, whereas most other factors were only weakly associated with PiS.

Expression of thymidylate synthase and glutathione-s-transferase pi in patients with esophageal squamous cell carcinoma.

PubMed

Huang, Jun-Xing; Li, Feng-Yue; Xiao, Wei; Song, Zheng-Xiang; Qian, Rong-Yu; Chen, Ping; Salminen, Eeva

2009-09-14

To investigate the expression of thymidylate synthase (TS) and glutathione-s-transferase pi (GST-pi) in esophageal squamous cell carcinoma and their association with the clinicopathologic characteristics. Immunohistochemical methods were used to detect the expression of TS and GST-pi in surgically resected formalin-fixed, paraffin-embedded esophageal squamous cell carcinoma (ESCC) tissue sections from 102 patients (median age, 58 years) and in 28 normal esophageal mucosa (NEM) samples. The relationship between TS and GST-pi expression and clinicopathologic factors was examined. The expression of TS and GST-pi was not statistically significantly associated with age of the patients, tumor size, lymph node metastasis, depth of invasion or tumor stage. TS staining was positive in 17.86% of normal esophageal mucosa and in 42.16% of ESCC samples (P < 0.05). The expression level of TS was not only significantly lower in well-differentiated (21.88%) than in poorly-differentiated carcinomas (51.43%, P < 0.05), but was also significantly higher in samples from male patients (46.51%) than from female patients (18.75%, P < 0.05). GST-pi was positively stained in 78.57% of normal esophageal mucosa and in 53.92% of ESCC samples (P < 0.05). The expression level of GST-pi was also significantly higher in well-differentiated carcinomas (65.63%) than in poorly-differentiated carcinomas (35.00%, P < 0.05). The expression of TS and of GST-pi may be used as molecular markers for the characterization of ESCC. Poorly-differentiated cells showed increased expression of TS and reduced expression of GST-pi.

Upregulation of Phosphatidylinositol 3-Kinase (PI3K) Enhances Ethylene Biosynthesis and Accelerates Flower Senescence in Transgenic Nicotiana tabacum L.

PubMed

Dek, Mohd Sabri Pak; Padmanabhan, Priya; Sherif, Sherif; Subramanian, Jayasankar; Paliyath, And Gopinadhan

2017-07-15

Phosphatidylinositol 3-kinase (PI3K) is a key enzyme that phosphorylates phosphatidylinositol at 3'-hydroxyl position of the inositol head group initiating the generation of several phosphorylated phosphatidylinositols, collectively referred to as phosphoinositides. The function of PI3K in plant senescence and ethylene signal transduction process was studied by expression of Solanum lycopersicum PI3K in transgenic Nicotiana tabacum , and delineating its effect on flower senescence. Detached flowers of transgenic tobacco plants with overexpressed Sl - PI3K (OX) displayed accelerated senescence and reduced longevity, when compared to the flowers of wild type plants. Flowers from PI3K-overexpressing plants showed enhanced ethylene production and upregulated expression of 1-aminocyclopropane-1-carboxylic acid oxidase 1 ( ACO1 ). Real time polymerase chain reaction (PCR) analysis showed that PI3K was expressed at a higher level in OX flowers than in the control. Seedlings of OX-lines also demonstrated a triple response phenotype with characteristic exaggerated apical hook, shorter hypocotyls and increased sensitivity to 1-aminocyclopropane-1-carboxylate than the control wild type seedlings. In floral tissue from OX-lines, Solanum lycopersicum phosphatidylinositol 3-kinase green fluorescent protein (PI3K-GFP) chimera protein was localized primarily in stomata, potentially in cytoplasm and membrane adjacent to stomatal pores in the guard cells. Immunoblot analysis of PI3K expression in OX lines demonstrated increased protein level compared to the control. Results of the present study suggest that PI3K plays a crucial role in senescence by enhancing ethylene biosynthesis and signaling.

Phosphate-Dependent Root System Architecture Responses to Salt Stress1[OPEN

PubMed Central

Sommerfeld, Hector Montero; ter Horst, Anneliek; Haring, Michel A.

2016-01-01

Nutrient availability and salinity of the soil affect the growth and development of plant roots. Here, we describe how inorganic phosphate (Pi) availability affects the root system architecture (RSA) of Arabidopsis (Arabidopsis thaliana) and how Pi levels modulate responses of the root to salt stress. Pi starvation reduced main root length and increased the number of lateral roots of Arabidopsis Columbia-0 seedlings. In combination with salt, low Pi dampened the inhibiting effect of mild salt stress (75 mm) on all measured RSA components. At higher salt concentrations, the Pi deprivation response prevailed over the salt stress only for lateral root elongation. The Pi deprivation response of lateral roots appeared to be oppositely affected by abscisic acid signaling compared with the salt stress response. Natural variation in the response to the combination treatment of salt and Pi starvation within 330 Arabidopsis accessions could be grouped into four response patterns. When exposed to double stress, in general, lateral roots prioritized responses to salt, while the effect on main root traits was additive. Interestingly, these patterns were not identical for all accessions studied, and multiple strategies to integrate the signals from Pi deprivation and salinity were identified. By genome-wide association mapping, 12 genomic loci were identified as putative factors integrating responses to salt stress and Pi starvation. From our experiments, we conclude that Pi starvation interferes with salt responses mainly at the level of lateral roots and that large natural variation exists in the available genetic repertoire of accessions to handle the combination of stresses. PMID:27208277

Peak Locations and Relative Phase of Different Decay Modes of the a 1 Axial Vector Resonance in Diffractive Production

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

Basdevant, Jean-Louis; Berger, Edmond L.

2015-05-01

We show that a single I = 1 spin-parity J(PC) = 1(++) a(1) resonance can manifest itself as two separated mass peaks, one decaying into an S-wave rho pi system and the second decaying into a P-wave f(0)(980)pi system, with a rapid increase of the phase difference between their amplitudes arising mainly from the structure of the diffractive production process. This study clarifies questions related to the mass, width, and decay rates of the a(1) resonance raised by the recent high statistics data of the COMPASS Collaboration on a 1 production in pi N -> pi pi pi N atmore » high energies.« less

Investigation of 124Xe nuclear structure with the 8Pi spectrometer at TRIUMF-ISAC

NASA Astrophysics Data System (ADS)

Radich, Allison; Garrett, P.; Jigmeddorj, B.; Michetti-Wilson, J.; Diaz Varela, A.; Hadinia, B.; Bianco, L.; Wong, J.; Chagnon-Lessard, S.; Dunlop, R.; Finlay, P.; Laffoley, A.; Leach, K. G.; Rand, E.; Sumithrarachchi, C.; Svennson, C. E.; Wood, J. L.; Yates, S. W.; Andreoiu, C.; Starosta, K.; Cross, D.; Garnsworthy, A. B.; Hackman, G.; Ball, G.; Triambak, S.

2013-10-01

The 124Xe nucleus has been thought to obey O(6) symmetry but a recent Coulomb excitation study has found that while O(5) may be preserved, O(6) appears to be badly broken. To further characterize the structure of this nucleus, a beta-decay experiment was performed at the TRIUMF-ISAC facility. A beam of radioactive 124Cs at a rate of 9.8 × 107 ions/s was implanted at the center of the 8Pi spectrometer where it underwent β + /EC decay into stable 124Xe. High-statistics gamma-gamma coincidence measurements have been analyzed to add to the level scheme of 124Xe, which has been extended considerably. The high statistics data set has revealed a new decay branch from a 124Cs high-spin isomer as well as several very-weak transitions between low-spin states in 124Xe. Branching ratios and B(E2) transition strengths have been calculated for the updated level scheme. The results will be important in determining collective properties and nuclear structure of the 124Xe.

Recreating History with Archimedes and Pi

ERIC Educational Resources Information Center

Santucci, Lora C.

2011-01-01

Using modern technology to examine classical mathematics problems at the high school level can reduce difficult computations and encourage generalizations. When teachers combine historical context with access to technology, they challenge advanced students to think deeply, spark interest in students whose primary interest is not mathematics, and…

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

Gao, Zhan

Cleft palate is caused by the failure of palatal midline epithelial cells to disintegrate, which is necessary for palatal mesenchymal confluence. Although 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposure is linked to cleft palate at a high rate, the mechanism remains to be elucidated. The present study was designed to determine the effects of TCDD on the fate of epithelial cell isolated from human fetal palatal shelves (hFPECs). We demonstrate that TCDD increased cell proliferation and promoted the progression of cells from G1 to S phase as well as increased the number of cells entering the G2/M phase. We found that TCDD has nomore » measurable effect on apoptosis of hFPECs. The protein level assays revealed that TCDD increased cyclin-dependent kinases 4 (cdk4), cyclin D1, cyclin E and p21 (Waf1/Cip1) but not cdk2, bcl-2, cyclin B1 and cyclin A. Furthermore, TCDD activated PI3K/AKT signaling, and the PI3K inhibitor, LY294002, partially abrogated TCDD-induced cell proliferation and gene modulations. TCDD treatment increased CYP1A1 mRNA and protein levels, which indicated the activation of AhR signaling. Knockdown of the AhR with siRNA suppressed TCDD-induced cell proliferation and PI3K/AKT signaling activation. Taken together, these data demonstrated that TCDD is able to promote growth of hFPECs through AhR-dependent activation of the PI3K/AKT pathway, which may account for the underlying mechanism by which TCDD causes a failure of palatal fusion. - Highlights: • TCDD promoted the cell growth with a character of significant accumulation of cells in G2/M. • TCDD treatment induced a various profile of cell cycle regulatory proteins. • PI3K/AKT pathway was involved in TCDD-induced cell proliferation and gene modifications. • AhR knockdown blocked TCDD-induced cell proliferation and PI3K/Akt signaling activation.« less

Accelerated Spirometric Decline in New York City Firefighters With α1-Antitrypsin Deficiency

PubMed Central

Brantly, Mark; Izbicki, Gabriel; Hall, Charles; Shanske, Alan; Chavko, Robert; Santhyadka, Ganesha; Christodoulou, Vasilios; Weiden, Michael D.; Prezant, David J.

2010-01-01

Background: On September 11, 2001, the World Trade Center (WTC) collapse caused massive air pollution, producing variable amounts of lung function reduction in the New York City Fire Department (FDNY) rescue workforce. α1-Antitrypsin (AAT) deficiency is a risk factor for obstructive airway disease. Methods: This prospective, longitudinal cohort study of the first 4 years post-September 11, 2001, investigated the influence of AAT deficiency on adjusted longitudinal spirometric change (FEV1) in 90 FDNY rescue workers with WTC exposure. Workers with protease inhibitor (Pi) Z heterozygosity were considered moderately AAT deficient. PiS homozygosity or PiS heterozygosity without concomitant PiZ heterozygosity was considered mild deficiency, and PiM homozygosity was considered normal. Alternately, workers had low AAT levels if serum AAT was ≤ 20 μmol/L. Results: In addition to normal aging-related decline (37 mL/y), significant FEV1 decline accelerations developed with increasing AAT deficiency severity (110 mL/y for moderate and 32 mL/y for mild) or with low AAT serum levels (49 mL/y). Spirometric rates pre-September 11, 2001, did not show accelerations with AAT deficiency. Among workers with low AAT levels, cough persisted in a significant number of participants at 4 years post-September 11, 2001. Conclusions: FDNY rescue workers with AAT deficiency had significant spirometric decline accelerations and persistent airway symptoms during the first 4 years after WTC exposure, representing a novel gene-by-environment interaction. Clinically meaningful decline acceleration occurred even with the mild serum AAT level reductions associated with PiS heterozygosity (without concomitant PiZ heterozygosity). PMID:20634282

Behavioral and Emotional Symptoms of Post-Institutionalized Children in Middle Childhood

PubMed Central

Wiik, Kristen L.; Loman, Michelle M.; Van Ryzin, Mark J.; Armstrong, Jeffrey M.; Essex, Marilyn J.; Pollak, Seth D.; Gunnar, Megan R.

2010-01-01

Background Experience in institutional/orphanage care has been linked to increased mental health problems. Research suggests children adopted from institutions experience specific difficulties related to inattention/overactivity. Evidence of internalizing and conduct problems relative to non-adopted peers has been found in early childhood and early adolescence, but problems may not differ from other adopted children. This study clarifies the understanding of behavioral and emotional symptoms of post-institutionalized (PI) children during middle childhood. Methods Eight to eleven-year-old PI children (n=68) and two comparison groups, children internationally adopted from foster care (n=74) and non-adopted children (n=76), and their parents completed the MacArthur Health and Behavior Questionnaire related to ADHD, externalizing, and internalizing symptoms. Group means for symptom level and number of children with symptoms above clinical cutoffs were compared. Results PI children displayed an increased level of ADHD symptoms per parent report. PI child and parent report indicated a higher number of PI children above clinical ADHD cutoff. Both groups of internationally adopted (IA) children had higher levels of externalizing symptoms relative to non-adopted children, with parent report indicating higher numbers of IA children above the externalizing clinical threshold. Informants differed in their report of internalizing symptoms. Parents indicated both IA groups displayed increased internalizing symptom levels and greater numbers above clinical threshold; however, children reported this to be true only for the PI group. Conclusions PI children differ from non-adopted peers across symptom domains in middle childhood. Whether these concerns were more broadly associated with international adoption rather than institutional care depended on symptom domain and informant. An understanding of this variability may be beneficial for treatment and intervention. PMID:20649913

Variation in piñon pine growth responses to climate across gradients of environmental stress using an individual-based approach

NASA Astrophysics Data System (ADS)

Redmond, M. D.; Kelsey, K.; Urza, A.; Barger, N. N.

2015-12-01

Forest and woodland ecosystems play a crucial role in the global carbon cycle and may be strongly affected by changing climate. Here we use an individual-based approach to model piñon pine (Pinus edulis) radial growth responses to climate across gradients of environmental stress. We sampled piñon pine trees at 24 sites across southwestern Colorado that varied in soil available water capacity, elevation, and latitude, obtaining a total of 552 pinon pine tree ring series. We used linear mixed effect models to assess piñon pine growth responses to climate and site-level environmental stress (mean annual climatic water deficit and soil available water capacity). Using a similar modeling approach, we also determined long-term growth trends across our gradients of environmental stress. Piñon pine growth was strongly positively associated with winter precipitation and strongly negatively associated with summer vapor pressure deficit. However, the strength of the relationship between winter precipitation and piñon pine growth was affected by site-level environmental stress. Trees at sites with greater climatic water deficit (i.e. hotter, drier sites) were more sensitive to winter precipitation. Interestingly, trees at sites with greater soil available water capacity were also more sensitive to winter precipitation, as these trees had much higher growth rates during years of high precipitation. We found weak evidence of long-term declines in piñon growth rates over the past century within our study area. Growth trends overtime did vary across our soil available water capacity gradient: trees growing at sites with higher soil available water capacity responded more positively to the cool, wet climate conditions of the 1910s and 1980s, whereas tree growth rates at sites with lower soil available water capacity declined more linearly over the last century. Our findings suggest that the sensitivity of woodland ecosystems to changing climate will vary across the landscape due to differences in edaphic and physiographic factors. These results support recent dendroecology studies that emphasize the need to use a more individual-based approach to enhance our understanding of tree growth responses to climate.

Long-term effects of interference on short-term memory performance in the rat

PubMed Central

Missaire, Mégane; Fraize, Nicolas; Joseph, Mickaël Antoine; Hamieh, Al Mahdy; Parmentier, Régis; Marighetto, Aline; Salin, Paul Antoine; Malleret, Gaël

2017-01-01

A distinction has always been made between long-term and short-term memory (also now called working memory, WM). The obvious difference between these two kinds of memory concerns the duration of information storage: information is supposedly transiently stored in WM while it is considered durably consolidated into long-term memory. It is well acknowledged that the content of WM is erased and reset after a short time, to prevent irrelevant information from proactively interfering with newly stored information. In the present study, we used typical WM radial maze tasks to question the brief lifespan of spatial WM content in rodents. Groups of rats were submitted to one of two different WM tasks in a radial maze: a WM task involving the repetitive presentation of a same pair of arms expected to induce a high level of proactive interference (PI) (HIWM task), or a task using a different pair in each trial expected to induce a low level of PI (LIWM task). Performance was effectively lower in the HIWM group than in LIWM in the final trial of each training session, indicative of a “within-session/short-term” PI effect. However, we also observed a different “between-session/long-term” PI effect between the two groups: while performance of LIWM trained rats remained stable over days, the performance of HIWM rats dropped after 10 days of training, and this impairment was visible from the very first trial of the day, hence not attributable to within-session PI. We also showed that a 24 hour-gap across training sessions known to allow consolidation processes to unfold, was a necessary and sufficient condition for the long-term PI effect to occur. These findings suggest that in the HIWM task, WM content was not entirely reset between training sessions and that, in specific conditions, WM content can outlast its purpose by being stored more permanently, generating a long-term deleterious effect of PI. The alternative explanation is that WM content could be transferred and stored more permanently in an intermediary form or memory between WM and long-term memory. PMID:28288205

Long-term effects of interference on short-term memory performance in the rat.

PubMed

Missaire, Mégane; Fraize, Nicolas; Joseph, Mickaël Antoine; Hamieh, Al Mahdy; Parmentier, Régis; Marighetto, Aline; Salin, Paul Antoine; Malleret, Gaël

2017-01-01

A distinction has always been made between long-term and short-term memory (also now called working memory, WM). The obvious difference between these two kinds of memory concerns the duration of information storage: information is supposedly transiently stored in WM while it is considered durably consolidated into long-term memory. It is well acknowledged that the content of WM is erased and reset after a short time, to prevent irrelevant information from proactively interfering with newly stored information. In the present study, we used typical WM radial maze tasks to question the brief lifespan of spatial WM content in rodents. Groups of rats were submitted to one of two different WM tasks in a radial maze: a WM task involving the repetitive presentation of a same pair of arms expected to induce a high level of proactive interference (PI) (HIWM task), or a task using a different pair in each trial expected to induce a low level of PI (LIWM task). Performance was effectively lower in the HIWM group than in LIWM in the final trial of each training session, indicative of a "within-session/short-term" PI effect. However, we also observed a different "between-session/long-term" PI effect between the two groups: while performance of LIWM trained rats remained stable over days, the performance of HIWM rats dropped after 10 days of training, and this impairment was visible from the very first trial of the day, hence not attributable to within-session PI. We also showed that a 24 hour-gap across training sessions known to allow consolidation processes to unfold, was a necessary and sufficient condition for the long-term PI effect to occur. These findings suggest that in the HIWM task, WM content was not entirely reset between training sessions and that, in specific conditions, WM content can outlast its purpose by being stored more permanently, generating a long-term deleterious effect of PI. The alternative explanation is that WM content could be transferred and stored more permanently in an intermediary form or memory between WM and long-term memory.

Pi in the Sky

NASA Astrophysics Data System (ADS)

O'Brien, W. P.

2008-12-01

Pi In The Sky (PITS) consists of a loose collection of virtual globe (VG) activities with a slight mathematical twist, wherein students search for interesting circular structures on the surface of Earth (Moon or other planets) and measure the circumference C and diameter D of each structure, using the built-in VG measure tool, in order to determine experimental values of pi from the C/D ratios. Examples of man-made circular structures visible using VG browsers include Fermilab and l"Arc de Triomphe roundabout; quasi-circular natural structures include certain volcano calderas and impact craters. Since a circle is but a special case of an ellipse, a natural extension of the activity involves making similar measurements of perimeter P, semi-major axis a, and semi-minor axis b of a visible elliptical structure (such as one of the thousands of elliptical Carolina bays, enigmatic depressions on the Atlantic Coast of North America) and solving for pi using Ramanujan's first approximation for the dependence of the perimeter of an ellipse on a and b. PITS exercises can be adapted to a wide range of student ages and teaching goals. For instance, K-6 students could measure C and D of the huge irrigation circles near Circle, Texas, to discover pi in the same way they might infer pi from measurements of coffee-can lids in math class. Middle school and high school students could move beyond man-made circles to consider the near-circularity of certain volcano calderas and impact craters in earth science units, make measurements for Olympus Mons on Mars or Crater Kepler on the moon in astronomy units, or search for circularity among Arctic thermokarst lakes as an introduction to climate change in tundra environments in environmental science units; such studies might ignite student curiosity about planetary processes. High school students of analytic geometry could examine several elliptical Carolina bays and calculate not only values of pi (as noted above) but also determine the range of eccentricities exhibited by these structures; through these exercises, ellipses acquire significance beyond conic sections and planetary orbits. At whatever level, PITS exercises function as easy bait, enticing students to learn to operate VG software and make observations and quantitative measurements of interesting Earth features. On a deeper level, these exercises provide a context and tool enabling VG explorers to fly above Earth's surface, to see this surface megascopically as it heretofore has never been seen, and to play in the metaphorical geometric intertidal zone that resides between shallow, eyes-on-the-ground, normal perception and the deep-blue depths of the cosmos.

Differential Acclimation of Enzymatic Antioxidant Metabolism and Photosystem II Photochemistry in Tall Fescue under Drought and Heat and the Combined Stresses

PubMed Central

Bi, Aoyue; Fan, Jibiao; Hu, Zhengrong; Wang, Guangyang; Amombo, Erick; Fu, Jinmin; Hu, Tao

2016-01-01

Quality inferiority in cool-season turfgrass due to drought, heat, and a combination of both stresses is predicted to be more prevalent in the future. Understanding the various response to heat and drought stress will assist in the selection and breeding of tolerant grass varieties. The objective of this study was to investigate the behavior of antioxidant metabolism and photosystem II (PSII) photochemistry in two tall fescue genotypes (PI 234881 and PI 578718) with various thermotolerance capacities. Wide variations were found between heat-tolerant PI 578718 and heat-sensitive PI 234881 for leaf relative water content, malondialdehyde and electrolyte leakage under drought, high-temperature or a combination of both stresses. The sensitivity of PI 234881 exposed to combined stresses was associated with lower superoxide dismutase activity and higher H2O2 accumulation than that in PI 578718. Various antioxidant enzymes displayed positive correlation with chlorophyll content, but negative with membrane injury index at most of the stages in both tall fescue genotypes. The JIP-test analysis in PI 578718 indicated a significant improvement in ABS/RC, TR0/RC, RE0/RC, RE0/ABS values as compared to the control regime, which indicated that PI 578718 had a high potential to protect the PSII system under drought and high temperature stress. And the PS II photochemistry in PI 234881 was damaged significantly compared with PI578718. Moreover, quantitative RT-PCR revealed that heat and drought stresses deduced the gene expression of psbB and psbC, but induced the expression of psbA. These findings to some extent confirmed that the various adaptations of physiological traits may contribute to breeding in cold-season turfgrass in response to drought, high-temperature, and a combination of both stresses. PMID:27148288

Antibody to fibroblast growth factor 23-peptide reduces excreta phosphorus of laying hens.

PubMed

Ren, Zhouzheng; Ebrahimi, Marziyeh; Bütz, Daniel E; Sand, Jordan M; Zhang, Keying; Cook, Mark E

2017-01-01

Novel strategies to minimize the excretion of phosphorus in swine and poultry are critical in minimizing environmental degradation. We have developed a synthetic peptide vaccine to produce autoantibodies to fibroblast growth factor 23 (FGF-23), a bone-derived hormone that blocks kidney phosphate resorption and indirectly reduces intestinal phosphate absorption. Single Comb White Leghorn laying hens, fed a standard diet (inorganic phosphorus, Pi = 0.4%), were immunized over the course of 4 weeks with either a FGF-23 peptide vaccine or adjuvant control (without FGF-23 peptide). At peak antibody titer to the peptide (week 5), 24-h excreta were collected and hens were blood sampled (represents 0.4% Pi treatment). Hens were then fed a 0.8% Pi diet and blood was sampled at 24 and 72 h and 24-h excreta were collected at 12 to 36 and 60 to 84 h (represents 0.8% Pi treatment). Increasing Pi from 0.4 to 0.8% increased (P < 0.05) percent excreta phosphorus, total 24-h phosphorus excretion, and plasma levels of FGF-23 and phosphate in either control or FGF-23 peptide vaccinated hens as early as the first sampling period. FGF-23 peptide vaccinated hens fed 0.4% Pi had reduced (P < 0.05) percent excreta phosphorus, total 24 h phosphorus excretion, and plasma levels of FGF-23 and iPTH, and increased (P < 0.05) plasma levels of phosphate and 1,25(OH) 2 D 3 when compared to control vaccinated hens fed 0.4% Pi. In the first collection period post 0.8% Pi feeding, FGF-23 peptide vaccinated hens had reduced (P < 0.05) plasma levels of FGF-23 and iPTH, and increased (P < 0.05) plasma levels of phosphate and 1,25(OH) 2 D 3 , and tended to have reduced percent excreta phosphorus (P = 0.085) and total 24 h phosphorus excretion (P = 0.078) when compared to control vaccinated hens. Results during the second collection period post 0.8% Pi feeding were similar to that at the first collection period. These results are the first to show that the inhibition of FGF-23 action by a peptide vaccine (via neutralizing antibody) reduced phosphorus excretion. The approach presented provides new information on phosphorus metabolism in the laying hen. © 2016 Poultry Science Association Inc.

Impact of the integration of proton magnetic resonance imaging spectroscopy to PI-RADS 2 for prediction of high grade and high stage prostate cancer.

PubMed

Leapman, Michael S; Wang, Zhen J; Behr, Spencer C; Kurhanewicz, John; Zagoria, Ronald J; Carroll, Peter R; Westphalen, Antonio C

2017-01-01

To compare the predictions of dominant Gleason pattern ≥ 4 or non-organ confined disease with Prostate Imaging Reporting and Data System (PI-RADS v2) with or without proton magnetic resonance spectroscopic imaging ( 1 H-MRSI). Thirty-nine men underwent 3-tesla endorectal multiparametric MRI including 1 H-MRSI and prostatectomy. Two radiologists assigned PI-RADS v2 and 1 H-MRSI scores to index lesions. Statistical analyses used logistic regressions, receiver operating characteristic (ROC) curves, and 2x2 tables for diagnostic accuracies. The sensitivity and specificity of 1 H-MRSI and PI-RADS v2 for high-grade prostate cancer (PCa) were 85.7% (57.1%) and 92.9% (100%), and 56% (68.0%) and 24.0% (24.0%). The sensitivity and specificity of 1 H-MRSI and PI-RADS v2 for extra-prostatic extension (EPE) were 64.0% (40%) and 20.0% (48%), and 50.0% (57.1%) and 71.4% (64.3%). The area under the ROC curves (AUC) for prediction of high-grade prostate cancer were 0.65 and 0.61 for PI-RADS v2 and 0.72 and 0.70 when combined with 1 H-MRSI (readers 1 and 2, p = 0.04 and 0.21). For prediction of EPE the AUC were 0.54 and 0.60 for PI-RADS v2 and 0.55 and 0.61 when combined with 1 H-MRSI ( p > 0.05). 1 H-MRSI might improve the discrimination of high-grade prostate cancer when combined to PI-RADS v2, particularly for PI-RADS v2 score 4 lesions, but it does not affect the prediction of EPE.

Dibutyl phthalate exposure aggravates type 2 diabetes by disrupting the insulin-mediated PI3K/AKT signaling pathway.

PubMed

Deng, Ting; Zhang, Yu; Wu, Yang; Ma, Ping; Duan, Jiufei; Qin, Wei; Yang, Xu; Chen, Mingqing

2018-06-15

Epidemiological studies suggest a positive relationship between phthalate exposure and diabetes. However, little is known about the impact of dibutyl phthalate (DBP) exposure on the development of diabetes. To determine the role of DBP exposure on the development of type 2 diabetes, mice were orally exposed to DBP dosages of 0.5, 5, 50 mg/kg/day for 7 weeks, combined with a high fat diet and injections of a low dose of streptozotocin (STZ). The results showed that exposure to 50 mg/kg/day DBP alone induced a marked decrease in insulin secretion and glucose intolerance, but had no influence on insulin resistance. However, combined with a high fat diet and STZ treatment, DBP exposure markedly aggravated glucose intolerance, insulin tolerance and insulin resistance and induced lesions in the pancreas and kidney. Investigation of the role of DBP on the insulin signaling pathway, we found that DBP exposure could disrupt the PI3K expression and AKT phosphorylation, and decrease the level of GLUT-2 in the pancreas. Administering demethylasterriquinone B1, significantly increased the level of PI3K, AKT phosphorylation and GLUT-2 expression, effectively inhibiting the aggravation of diabetes. Our results suggested that DBP aggravated type 2 diabetes by disrupting the insulin signaling pathway and impairing insulin secretion. Copyright © 2018 Elsevier B.V. All rights reserved.

Measurement of the eta-meson mass using psi(2S) --> etaJ/psi.

PubMed

Miller, D H; Sanghi, B; Shipsey, I P J; Xin, B; Adams, G S; Anderson, M; Cummings, J P; Danko, I; Ge, J Y; Hu, D; Moziak, B; Napolitano, J; He, Q; Insler, J; Muramatsu, H; Park, C S; Thorndike, E H; Yang, F; Artuso, M; Blusk, S; Khalil, S; Li, J; Menaa, N; Mountain, R; Nisar, S; Randrianarivony, K; Sia, R; Skwarnicki, T; Stone, S; Wang, J C; Bonvicini, G; Cinabro, D; Dubrovin, M; Lincoln, A; Asner, D M; Edwards, K W; Naik, P; Briere, R A; Ferguson, T; Tatishvili, G; Vogel, H; Watkins, M E; Rosner, J L; Adam, N E; Alexander, J P; Cassel, D G; Duboscq, J E; Ehrlich, R; Fields, L; Gibbons, L; Gray, R; Gray, S W; Hartill, D L; Heltsley, B K; Hertz, D; Jones, C D; Kandaswamy, J; Kreinick, D L; Kuznetsov, V E; Mahlke-Krüger, H; Mohapatra, D; Onyisi, P U E; Patterson, J R; Peterson, D; Riley, D; Ryd, A; Sadoff, A J; Shi, X; Stroiney, S; Sun, W M; Wilksen, T; Athar, S B; Patel, R; Yelton, J; Rubin, P; Eisenstein, B I; Karliner, I; Lowrey, N; Selen, M; White, E J; Wiss, J; Mitchell, R E; Shepherd, M R; Besson, D; Pedlar, T K; Cronin-Hennessy, D; Gao, K Y; Hietala, J; Kubota, Y; Klein, T; Lang, B W; Poling, R; Scott, A W; Zweber, P; Dobbs, S; Metreveli, Z; Seth, K K; Tomaradze, A; Ernst, J; Ecklund, K M; Severini, H; Love, W; Savinov, V; Lopez, A; Mehrabyan, S; Mendez, H; Ramirez, J

2007-09-21

We measure the mass of the eta meson using psi(2S) --> etaJ/psi events acquired with the CLEO-c detector operating at the CESR e(+)e(-) collider. Using the four decay modes eta --> gamma gamma, 3pi(0), pi(+)pi(-)pi(0), and pi(+)pi(-)gamma, we find M(eta) = 547.785 +/- 0.017 +/- 0.057 MeV, in which the first uncertainty is statistical and the second systematic. This result has an uncertainty comparable to the two most precise previous measurements and is consistent with that of NA48, but is inconsistent at the level of 6.5 sigma with the much smaller mass obtained by GEM.

Local noise reduction for emphysema scoring in low-dose CT images

NASA Astrophysics Data System (ADS)

Schilham, Arnold; Prokop, Mathias; Gietema, Hester; van Ginneken, Bram

2005-04-01

Computed Tomography (CT) has become the new reference standard for quantification of emphysema. The most popular measure for emphysema derived from CT is the Pixel Index (PI), which expresses the fraction of the lung volume with abnormally low intensity values. As PI is calculated from a single, fixed threshold on intensity, this measure is strongly influenced by noise. This effect shows up clearly when comparing the PI score for a high-dose scan to the PI score for a low-dose (i.e. noisy) scan of the same subject. This paper presents a class of noise filters that make use of a local noise estimate to specify the filtering strength: Local Noise Variance Weighted Averaging (LNVWA). The performance of the filter is assessed by comparing high-dose and low-dose PI scores for 11 subjects. LNVWA improves the reproducibility of high-dose PI scores: For an emphysema threshold of -910 HU, the root-mean-square difference in PI score drops from 10% of the lung volume to 3.3% of the lung volume if LNVWA is used.

Reduced Warburg Effect in Cancer Cells Undergoing Autophagy: Steady- State 1H-MRS and Real-Time Hyperpolarized 13C-MRS Studies

PubMed Central

Wong Te Fong, Anne-Christine; Hill, Deborah K.; Orton, Matthew R.; Parkes, Harry G.; Koh, Dow-Mu; Robinson, Simon P.; Leach, Martin O.; Eykyn, Thomas R.; Chung, Yuen-Li

2014-01-01

Autophagy is a highly regulated, energy dependent cellular process where proteins, organelles and cytoplasm are sequestered in autophagosomes and digested to sustain cellular homeostasis. We hypothesized that during autophagy induced in cancer cells by i) starvation through serum and amino acid deprivation or ii) treatment with PI-103, a class I PI3K/mTOR inhibitor, glycolytic metabolism would be affected, reducing flux to lactate, and that this effect may be reversible. We probed metabolism during autophagy in colorectal HT29 and HCT116 Bax knock-out cells using hyperpolarized 13C-magnetic resonance spectroscopy (MRS) and steady-state 1H-MRS. 24 hr PI103-treatment or starvation caused significant reduction in the apparent forward rate constant (kPL) for pyruvate to lactate exchange compared with controls in HT29 (100 μM PI-103: 82%, p = 0.05) and HCT116 Bax-ko cells (10 μM PI-103: 53%, p = 0.05; 20 μM PI-103: 42%, p<0.0001; starvation: 52%, p<0.001), associated with reduced lactate excretion and intracellular lactate in all cases, and unchanged lactate dehydrogenase (LDH) activity and increased NAD+/NADH ratio following PI103 treatment or decreased LDH activity and unchanged NAD+/NADH ratio following starvation. After 48 hr recovery from PI103 treatment, kPL remained below control levels in HT29 cells (74%, p = 0.02), and increased above treated values, but remained below 24 hr vehicle-treated control levels in HCT116 Bax-ko cells (65%, p = 0.004) both were accompanied by sustained reduction in lactate excretion, recovery of NAD+/NADH ratio and intracellular lactate. Following recovery from starvation, kPL was significantly higher than 24 hr vehicle-treated controls (140%, p = 0.05), associated with increased LDH activity and total cellular NAD(H). Changes in kPL and cellular and excreted lactate provided measureable indicators of the major metabolic processes accompanying starvation- and drug-induced autophagy. The changes are reversible, returning towards and exceeding control values on cellular recovery, which potentially identifies resistance. kPL (hyperpolarized 13C-MRS) and lactate (1H-MRS) provide useful biomarkers for the autophagic process, enabling non-invasive monitoring of the Warburg effect. PMID:24667972

Prevalence of alpha-1 antitrypsin deficiency and allele frequency in patients with COPD in Brazil.

PubMed

Russo, Rodrigo; Zillmer, Laura Russo; Nascimento, Oliver Augusto; Manzano, Beatriz; Ivanaga, Ivan Teruaki; Fritscher, Leandro; Lundgren, Fernando; Miravitlles, Marc; Gondim, Heicilainy Del Carlos; Santos, Gildo; Alves, Marcela Amorim; Oliveira, Maria Vera; Souza, Altay Alves Lino de; Sales, Maria Penha Uchoa; Jardim, José Roberto

2016-01-01

To determine the prevalence of alpha 1-antitrypsin (AAT) deficiency (AATD), as well as allele frequency, in COPD patients in Brazil. This was a cross-sectional study involving 926 COPD patients 40 years of age or older, from five Brazilian states. All patients underwent determination of AAT levels in dried blood spot (DBS) samples by nephelometry. Those with DBS AAT levels ≤ 2.64 mg/dL underwent determination of serum AAT levels. Those with serum AAT levels of < 113 mg/dL underwent genotyping. In case of conflicting results, SERPINA1 gene sequencing was performed. Of the 926 COPD patients studied, 85 had DBS AAT levels ≤ 2.64 mg/dL, and 24 (2.6% of the study sample) had serum AAT levels of < 113 mg/dL. Genotype distribution in this subset of 24 patients was as follows: PI*MS, in 3 (12.5%); PI*MZ, in 13 (54.2%); PI*SZ, in 1 (4.2%); PI*SS, in 1 (4.2%); and PI*ZZ, in 6 (25.0%). In the sample as a whole, the overall prevalence of AATD was 2.8% and the prevalence of the PI*ZZ genotype (severe AATD) was 0.8. The prevalence of AATD in COPD patients in Brazil is similar to that found in most countries and reinforces the recommendation that AAT levels be measured in all COPD patients. Determinar a prevalência da deficiência de alfa 1-antitripsina (AAT), bem como a frequência alélica, em pacientes com DPOC no Brasil. Estudo transversal com 926 pacientes com DPOC, com 40 anos ou mais, oriundos de cinco estados brasileiros. Todos os pacientes foram submetidos a dosagem de AAT em amostras de sangue seco por meio de nefelometria. Aqueles em que a concentração de AAT no sangue seco foi ≤ 2,64 mg/dl foram submetidos a dosagem sérica de AAT. Aqueles em que a concentração sérica de AAT foi < 113 mg/dl foram submetidos a genotipagem. Quando os resultados foram discrepantes, foi realizado o sequenciamento do gene SERPINA1. Dos 926 pacientes com DPOC estudados, 85 apresentaram concentração de AAT em sangue seco ≤ 2,64 mg/dl, e 24 (2,6% da amostra) apresentaram concentração sérica de AAT < 113 mg/dl. A distribuição genotípica nesse subgrupo de 24 pacientes foi a seguinte: PI*MS, em 3 (12,5%); PI*MZ, em 13 (54,2%); PI*SZ, em 1 (4,2%); PI*SS, em 1 (4,2%); e PI*ZZ, em 6 (25,0%). Na amostra estudada, a prevalência global da deficiência de AAT foi de 2,8% e a prevalência do genótipo PI*ZZ (deficiência grave de AAT) foi de 0,8%. A prevalência da deficiência de AAT em pacientes com DPOC no Brasil é semelhante àquela encontrada na maioria dos países e reforça a recomendação de que se deve medir a concentração de AAT em todos pacientes com DPOC.

Search for CP violation in the decays D+--> K(S)pi+ and D+-->K(S)K+.

PubMed

Link, J M; Reyes, M; Yager, P M; Anjos, J C; Bediaga, I; Göbel, C; Magnin, J; Massafferri, A; de Miranda, J M; Pepe, I M; dos Reis, A C; Carrillo, S; Casimiro, E; Sánchez-Hernández, A; Uribe, C; Vázquez, F; Cinquini, L; Cumalat, J P; O'Reilly, B; Ramirez, J E; Vaandering, E W; Butler, J N; Cheung, H W K; Gaines, I; Garbincius, P H; Garren, L A; Gottschalk, E; Kasper, P H; Kreymer, A E; Kutschke, R; Bianco, S; Fabbri, F L; Zallo, A; Cawlfield, C; Kim, D Y; Rahimi, A; Wiss, J; Gardner, R; Kryemadhi, A; Chung, Y S; Kang, J S; Ko, B R; Kwak, J W; Lee, K B; Park, H; Alimonti, G; Boschini, M; D'Angelo, P; DiCorato, M; Dini, P; Giammarchi, M; Inzani, P; Leveraro, F; Malvezzi, S; Menasce, D; Mezzadri, M; Milazzo, L; Moroni, L; Pedrini, D; Pontoglio, C; Prelz, F; Rovere, M; Sala, S; Davenport, T F; Agostino, L; Arena, V; Boca, G; Bonomi, G; Gianini, G; Liguori, G; Merlo, M M; Pantea, D; Ratti, S P; Riccardi, C; Segoni, I; Vitulo, P; Hernandez, H; Lopez, A M; Mendez, H; Mendez, L; Mirles, A; Montiel, E; Olaya, D; Paris, A; Quinones, J; Rivera, C; Xiong, W; Zhang, Y; Wilson, J R; Cho, K; Handler, T; Mitchell, R; Engh, D; Hosack, M; Johns, W E; Nehring, M; Sheldon, P D; Stenson, K; Webster, M; Sheaff, M

2002-01-28

A high-statistics sample of photoproduced charm from the FOCUS experiment has been used to search for direct CP violation in the decay rates for D+-->K(S)pi+ and D+-->K(S)K+. We have measured the following asymmetry parameters relative to D+-->K-pi+pi+: A(CP)(K(S)pi+) = (-1.6+/-1.5+/-0.9)%, A(CP)(K(S)K+) = (+6.9+/-6.0+/-1.5)%, and A(CP)(K(S)K+) = (+7.1+/-6.1+/-1.2)% relative to D+-->K(S)pi+. We have also measured the relative branching ratios and found Gamma(D+-->K(0)pi+)/Gamma(D+-->K-pi+pi+) = (30.60+/-0.46+/-0.32)%, Gamma(D+-->K(0)K+)/Gamma(D+-->K-pi+pi+) = (6.04+/-0.35+/-0.30)%, and Gamma(D+-->K(0)K+)/Gamma(D+-->K(0)pi+) = (19.96+/-1.19+/-0.96)%.

Prolonged Correction of Serum Phosphorus in Adults With X-Linked Hypophosphatemia Using Monthly Doses of KRN23.

PubMed

Imel, Erik A; Zhang, Xiaoping; Ruppe, Mary D; Weber, Thomas J; Klausner, Mark A; Ito, Takahiro; Vergeire, Maria; Humphrey, Jeffrey S; Glorieux, Francis H; Portale, Anthony A; Insogna, Karl; Peacock, Munro; Carpenter, Thomas O

2015-07-01

In X-linked hypophosphatemia (XLH), elevated fibroblast growth factor 23 (FGF23) decreases the renal tubular maximum reabsorption rate of phosphate/glomerular filtration rate (TmP/GFR) and serum inorganic phosphorus (Pi), resulting in rickets and/or osteomalacia. The objective was to test the hypothesis that monthly KRN23 (anti-FGF23 antibody) would safely improve serum Pi in adults with XLH. Two sequential open-label phase 1/2 studies were done. Six academic medical centers were used. Twenty-eight adults with XLH participated in a 4-month dose-escalation study (0.05-0.6 mg/kg); 22 entered a 12-month extension study (0.1-1 mg/kg). KRN23 was injected sc every 28 days. The main outcome measure was the proportion of subjects attaining normal serum Pi and safety. At baseline, mean TmP/GFR, serum Pi, and 1,25-dihydroxyvitamin D [1,25(OH)2D] were 1.6 ± 0.4 mg/dL, 1.9 ± 0.3 mg/dL, and 36.6 ± 14.3 pg/mL, respectively. During dose escalation, TmP/GFR, Pi, and 1,25(OH)2D increased, peaking at 7 days for TmP/GFR and Pi and at 3-7 days for 1,25(OH)2D, remaining above (TmP/GFR, Pi) or near [1,25(OH)2D] pre-dose levels at trough. After each of the four escalating doses, peak Pi was between 2.5 and 4.5 mg/dL in 14.8, 37.0, 74.1, and 88.5% of subjects, respectively. During the 12-month extension, peak Pi was in the normal range for 57.9-85.0% of subjects, and ≥25% maintained trough Pi levels within the normal range. Serum Pi did not exceed 4.5 mg/dL in any subject. Although 1,25(OH)2D levels increased transiently, mean serum and urinary calcium remained normal. KRN23 treatment increased biomarkers of skeletal turnover and had a favorable safety profile. Monthly KRN23 significantly increased serum Pi, TmP/GFR, and 1,25(OH)2D in all subjects. KRN23 has potential for effectively treating XLH.

Prolonged Correction of Serum Phosphorus in Adults With X-Linked Hypophosphatemia Using Monthly Doses of KRN23

PubMed Central

Zhang, Xiaoping; Ruppe, Mary D.; Weber, Thomas J.; Klausner, Mark A.; Ito, Takahiro; Vergeire, Maria; Humphrey, Jeffrey S.; Glorieux, Francis H.; Portale, Anthony A.; Insogna, Karl; Peacock, Munro; Carpenter, Thomas O.

2015-01-01

Context: In X-linked hypophosphatemia (XLH), elevated fibroblast growth factor 23 (FGF23) decreases the renal tubular maximum reabsorption rate of phosphate/glomerular filtration rate (TmP/GFR) and serum inorganic phosphorus (Pi), resulting in rickets and/or osteomalacia. Objective: The objective was to test the hypothesis that monthly KRN23 (anti-FGF23 antibody) would safely improve serum Pi in adults with XLH. Design: Two sequential open-label phase 1/2 studies were done. Setting: Six academic medical centers were used. Participants: Twenty-eight adults with XLH participated in a 4-month dose-escalation study (0.05–0.6 mg/kg); 22 entered a 12-month extension study (0.1–1 mg/kg). Intervention: KRN23 was injected sc every 28 days. Main Outcome Measure: The main outcome measure was the proportion of subjects attaining normal serum Pi and safety. Results: At baseline, mean TmP/GFR, serum Pi, and 1,25-dihydroxyvitamin D [1,25(OH)2D] were 1.6 ± 0.4 mg/dL, 1.9 ± 0.3 mg/dL, and 36.6 ± 14.3 pg/mL, respectively. During dose escalation, TmP/GFR, Pi, and 1,25(OH)2D increased, peaking at 7 days for TmP/GFR and Pi and at 3–7 days for 1,25(OH)2D, remaining above (TmP/GFR, Pi) or near [1,25(OH)2D] pre-dose levels at trough. After each of the four escalating doses, peak Pi was between 2.5 and 4.5 mg/dL in 14.8, 37.0, 74.1, and 88.5% of subjects, respectively. During the 12-month extension, peak Pi was in the normal range for 57.9–85.0% of subjects, and ≥25% maintained trough Pi levels within the normal range. Serum Pi did not exceed 4.5 mg/dL in any subject. Although 1,25(OH)2D levels increased transiently, mean serum and urinary calcium remained normal. KRN23 treatment increased biomarkers of skeletal turnover and had a favorable safety profile. Conclusions: Monthly KRN23 significantly increased serum Pi, TmP/GFR, and 1,25(OH)2D in all subjects. KRN23 has potential for effectively treating XLH. PMID:25919461

Mechanism of Poliovirus Resistance to Host Phosphatidylinositol-4 Kinase III β Inhibitor.

PubMed

Arita, Minetaro

2016-02-12

Phosphatidylinositol-4 kinase III β (PI4KB) and oxysterol-binding protein (OSBP) family I have been identified as the major targets of anti-enterovirus drug candidates. Resistance mutations in poliovirus (PV) to these inhibitors have been identified in viral 3A protein, represented by a G5318A (3A-Ala70Thr) mutation, but the mechanism of viral resistance to host PI4KB/OSBP inhibitors remained unknown. In this study, we found that a G5318A mutation enhances the basal levels of phosphatidylinositol 4-phosphate (PI4P) and of the 3A protein and decreases the levels of the 3AB protein during PV replication. The 3A protein acted as a major effector responsible for the resistance to PI4KB inhibitor, but did not enhance the PI4KB activity in vitro in contrast to the 2C, 2BC, 3AB, and 3D proteins. The 3AB protein acted as the primary target of a G5318A mutation and also as an effector. We identified novel resistance mutations to a PI4KB inhibitor [C5151U (3A-T14M) and C5366U (3A-H86Y) mutations] and found that there is a positive correlation between the extent of the resistance phenotype and the levels of the 3A proteins. These results suggested that the 3A protein overproduced by enhanced processing of the 3AB protein with the resistance mutations overcomes the inhibitory effect of PI4KB inhibitor on PV replication independently of the hyperactivation of the PI4KB/OSBP pathway.

Reaction. pi. /sup -/p. --> pi. /sup -/. pi. /sup +/. pi. /sup -/p at 8 GeV/c

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

Kitagaki, T.; Tanaka, S.; Yuta, H.

1982-10-01

Results from a high-statistics experiment involving an exposure of the SLAC 82-in. hydrogen bubble chamber to a beam of 8-GeV/c ..pi../sup -/ yielding a final state of ..pi../sup -/..pi../sup +/..pi../sup -/p are presented. Copious production of rho, ..delta../sup + +/, and f is found. Considerable quasi-two-body production in which one particle decays to one of the above resonances is also observed. Some double-resonance production involving baryon and meson resonances is also seen. The production properties of rho, ..delta../sup + +/, and f mesons are well described by a double-Regge model.

The C(2)1pi(u) state of Na2 molecule studied by polarization labelling spectroscopy method.

PubMed

Jastrzebski, W; Kowalczyk, P; Camacho, J J; Pardo, A; Poyato, J M

2001-08-01

The C1pi(u) <-- X1sigma(g)+ system of Na2 is studied by the polarization labelling spectroscopy technique. Accurate molecular constants are derived for the observed levels nu = 0-12, J = 12-100 in the C1pi(u) state.

The Network Structure of Human Personality According to the NEO-PI-R: Matching Network Community Structure to Factor Structure

PubMed Central

Goekoop, Rutger; Goekoop, Jaap G.; Scholte, H. Steven

2012-01-01

Introduction Human personality is described preferentially in terms of factors (dimensions) found using factor analysis. An alternative and highly related method is network analysis, which may have several advantages over factor analytic methods. Aim To directly compare the ability of network community detection (NCD) and principal component factor analysis (PCA) to examine modularity in multidimensional datasets such as the neuroticism-extraversion-openness personality inventory revised (NEO-PI-R). Methods 434 healthy subjects were tested on the NEO-PI-R. PCA was performed to extract factor structures (FS) of the current dataset using both item scores and facet scores. Correlational network graphs were constructed from univariate correlation matrices of interactions between both items and facets. These networks were pruned in a link-by-link fashion while calculating the network community structure (NCS) of each resulting network using the Wakita Tsurumi clustering algorithm. NCSs were matched against FS and networks of best matches were kept for further analysis. Results At facet level, NCS showed a best match (96.2%) with a ‘confirmatory’ 5-FS. At item level, NCS showed a best match (80%) with the standard 5-FS and involved a total of 6 network clusters. Lesser matches were found with ‘confirmatory’ 5-FS and ‘exploratory’ 6-FS of the current dataset. Network analysis did not identify facets as a separate level of organization in between items and clusters. A small-world network structure was found in both item- and facet level networks. Conclusion We present the first optimized network graph of personality traits according to the NEO-PI-R: a ‘Personality Web’. Such a web may represent the possible routes that subjects can take during personality development. NCD outperforms PCA by producing plausible modularity at item level in non-standard datasets, and can identify the key roles of individual items and clusters in the network. PMID:23284713

The network structure of human personality according to the NEO-PI-R: matching network community structure to factor structure.

PubMed

Goekoop, Rutger; Goekoop, Jaap G; Scholte, H Steven

2012-01-01

Human personality is described preferentially in terms of factors (dimensions) found using factor analysis. An alternative and highly related method is network analysis, which may have several advantages over factor analytic methods. To directly compare the ability of network community detection (NCD) and principal component factor analysis (PCA) to examine modularity in multidimensional datasets such as the neuroticism-extraversion-openness personality inventory revised (NEO-PI-R). 434 healthy subjects were tested on the NEO-PI-R. PCA was performed to extract factor structures (FS) of the current dataset using both item scores and facet scores. Correlational network graphs were constructed from univariate correlation matrices of interactions between both items and facets. These networks were pruned in a link-by-link fashion while calculating the network community structure (NCS) of each resulting network using the Wakita Tsurumi clustering algorithm. NCSs were matched against FS and networks of best matches were kept for further analysis. At facet level, NCS showed a best match (96.2%) with a 'confirmatory' 5-FS. At item level, NCS showed a best match (80%) with the standard 5-FS and involved a total of 6 network clusters. Lesser matches were found with 'confirmatory' 5-FS and 'exploratory' 6-FS of the current dataset. Network analysis did not identify facets as a separate level of organization in between items and clusters. A small-world network structure was found in both item- and facet level networks. We present the first optimized network graph of personality traits according to the NEO-PI-R: a 'Personality Web'. Such a web may represent the possible routes that subjects can take during personality development. NCD outperforms PCA by producing plausible modularity at item level in non-standard datasets, and can identify the key roles of individual items and clusters in the network.

Reduced Brain GABA in Primary Insomnia: Preliminary Data from 4T Proton Magnetic Resonance Spectroscopy (1H-MRS)

PubMed Central

Winkelman, John W.; Buxton, Orfeu M.; Jensen, J. Eric; Benson, Kathleen L.; O'Connor, Shawn P.; Wang, Wei; Renshaw, Perry F.

2008-01-01

Study Objectives: Both basic and clinical data suggest a potential significant role for GABA in the etiology and maintenance of primary insomnia (PI). Proton magnetic resonance spectroscopy (1H-MRS) can non-invasively determine GABA levels in human brain. Our objective was to assess GABA levels in unmedicated individuals with PI, using 1H-MRS. Design and Setting: Matched-groups, cross-sectional study conducted at two university-based hospitals. Participants: Sixteen non-medicated individuals (8 women) with PI (mean age = 37.3 +/− 8.1) and 16 (7 women) well-screened normal sleepers (mean age = 37.6 +/− 4.5). Methods and Measurements: PI was established with an unstructured clinical interview, a Structured Clinical Interview for DSM-IV (SCID), sleep diary, actigraphy and polysomnography (PSG). 1H-MRS data were collected on a Varian 4 Tesla magnetic resonance imaging/spectroscopy scanner. Global brain GABA levels were averaged from samples in the basal ganglia, thalamus, and temporal, parietal, and occipital white-matter and cortex. Results: Average brain GABA levels were nearly 30% lower in patients with PI (.18 +/− .06) compared to controls (.25 +/− .11). GABA levels were negatively correlated with wake after sleep onset (WASO) on two independent PSGs (r = −0.71, p = 0.0024 and −0.70, p = 0.0048). Conclusions: Our preliminary finding of a global reduction in GABA in non-medicated individuals with PI is the first demonstration of a neurochemical difference in the brains of those with PI compared to normal sleeping controls. 1H-MRS is a valuable tool to assess GABA in vivo, and may provide a means to shed further light on the neurobiology of insomnia. Citation: Winkelman JW; Buxton OM; Jensen JE; Benson KL; O'Connor SP; Wang W; Renshaw PF. Reduced brain GABA in primary insomnia: preliminary data from 4T proton magnetic resonance spectroscopy (1H-MRS). SLEEP 2008;31(11):1499–1506. PMID:19014069

A contribution to examination of propidium iodide and annexin V plasma cells indices in multiple myeloma.

PubMed

Scudla, V; Ordeltova, M; Bacovsky, J; Vytrasova, M; Sumna, E; Martinek, A; Horak, P

2003-01-01

The aim of this study was a contemporaneous measurement and a mutual comparison of plasma cells proliferative activity and grade of apoptosis in patients with monoclonal gammopathy of undetermined significance (MGUS) and various phases of MM i.e. smoldering (SMM), stable/plateau and active (progression/relapse) forms of this disease. The analyzed group of 197 patients consisted of 30 MGUS, 21 SMM, 82 patients examined at the time of MM diagnosis and 64 patients analyzed during various phases of the disease after previous chemotherapy. Plasma cell proliferative activity was measured by means of a propidium iodide index (PC-PI) examined by flow cytometry using a DNA/CD138 double staining technique. For detection of plasma cells entering apoptosis (PC-AI) flow cytometry method with annexin V FITC and MoAb CD138 was used. The individuals with MGUS, SMM and stable/plateau form of MM had overall low levels of PC-PI (M-1.8, 1.7% and 2.1%) and relatively high levels of PC-AI (M-9.1, 10.8 and 9.0%). The correlation between PC-PI and PC-AI was in all the groups mutually highly statistically significant (p=0.000). Analysis of plasma cells proliferative activity (PC-PI) was statistically significant in comparison of MGUS or SMM and versus: patients examined at the time of MM diagnosis (p=0.018 or 0.016); patients evaluated during various phases of MM after previous chemotherapy (p=0.021 or 0.019); stable/plateau MM phase in the cohort of all patients (p=0.017 or 0.040); in the plateau phase after chemotherapy (p=0.008 or 0.024) but insignificant in comparison of MGUS and SMM and with the stable group examined at the time of MM diagnosis. Analysis of the apoptotic process revealed significant differences when comparing PC-AI of SMM but not MGUS group versus all cohort of stable/plateau MM patients (p=0.045); there were also insignificant differences in comparison of MGUS and SMM groupsand versus the stable form of MM measured at the time of MM diagnosis or plateau phase after chemotherapy. There was observed a statistically significant difference in the PC-AI in comparison of SMM group versus group of all patients examined at the time of MM diagnosis (p=0.001) or in various phases of this disease (p=0.015) and the group of MGUS patients compared with patients evaluated at the time of MM diagnosis (p=0.03). Very significant statistical differences of plasma cell proliferative (PC-PI) and apoptotic (PC-AI) activity were found when comparing the levels of both the indices of MGUS, SMM and stable/plateau MM group versus the active (progression/relapse) form of MM marked by a higher level of PC-PI (3.2%, p=0.000) and PC-AI (4.8%, p=0.000) in the whole cohort of MM patients, but also in comparison with both the active forms at the time of MM diagnosis or active forms evaluated during various phases of the disease after chemotherapy. Highly significant inverse relationship between PC-PI versus PC-AI was also revealed in the group of patients in the active (progression/relapse) phase of MM (p=0.000). These results revealed importance of measurement not only of proliferative but also of apoptotic plasma cells indices for a complex evaluation of the cells kinetics of plasma cells compartments in patients with MGUS or MM. This study confirmed the initial hypothesis of a common 'inverse relationship between the proliferative (PC-PI) and the apoptosis activity (PC-AI) in plasma cells compartments in patients with MGUS, smoldering, stable/plateau and active (progression/ relapse) forms of MM'.

Tuning the Electrical Memory Behavior from Nonvolatile to Volatile in Functional Copolyimides Bearing Varied Fluorene and Pyrene Moieties

NASA Astrophysics Data System (ADS)

Jia, Nanfang; Qi, Shengli; Tian, Guofeng; Wang, Xiaodong; Wu, Dezhen

2017-04-01

For producing polymer based electronics with good memory behavior, a series of functional copolyimides were designed and synthesized in this work by copolymerizing 3,3',4,4'-diphenylsulfonetetracarboxylic dianhydride (DSDA) with (9,9'-bis(4-aminophenyl)fluorene) (BAPF) and N, N-bis(4-aminophenyl) aminopyrene (DAPAP) diamines. The synthesized copolyimides DSDA/(DAPAP/BAPF) were denoted as coPI-DAPAP x ( x = 100, 50, 20, 10, 5, 1, 0), where x% represents the molar fraction of the DAPAP unit in the diamines. Characterization results indicate that the coPI-DAPAP x exhibits tunable electrical switching behaviors from write once read many times (WORM, nonvolatile, coPI-DAPAP100, coPI-DAPAP50, coPI-DAPAP20, coPI-DAPAP10) to the static random access memory (SRAM, volatile, coPI-DAPAP5, coPI-DAPAP1) with the variation of the DAPAP content. Optical and electrochemical characterization show gradually decreasing highest occupied molecular orbital levels and enlarged energy gap with the decrease of the DAPAP moiety, suggesting decreasing charge-transfer effect in the copolyimides, which can account for the observed WORM-SRAM memory conversion. Meanwhile, the charge transfer process was elucidated by quantum chemical calculation at B3LYP/6-31G(d) theory level. This work shows the effect of electron donor content on the memory behavior of polymer electronic materials.

The effect of phosphate loading on erythrocyte 2,3-bisphosphoglycerate levels.

PubMed

Bremner, Kyla; Bubb, William A; Kemp, Graham J; Trenell, Michael I; Thompson, Campbell H

2002-09-01

Phosphate supplementation has been used in an effort to enhance athletic performance by increasing erythrocyte 2,3-bisphosphoglycerate levels ([2,3-BPG]) and hence improve oxygen offloading from haemoglobin. Claimed effects of phosphate loading upon both exercise performance and erythrocyte [2,3-BPG] are inconsistent, and the basis of any change in [2,3-BPG] is unknown. We analysed plasma inorganic phosphate concentration ([P(i)]) and erythrocyte [P(i)] and [2,3-BPG] in venous blood samples from 12 healthy subjects. We re-examined a subset of five of these subjects after 7 days of phosphate loading. There were significant positive correlations between plasma [P(i)] and erythrocyte [P(i)] (r(2)=0.51, p=0.009) and between erythrocyte [P(i)] and [2,3-BPG] (r(2)=0.68, p<0.001). Following phosphate loading, there was a 30% increase in plasma [P(i)] (1.02+/-0.22 to 1.29+/-0.15 mmol/l (mean+/-S.D.), p=0.03) and a 25% increase in erythrocyte [2,3-BPG] (6.77+/-1.12 to 9.11+/-1.87 mmol/l cells, p=0.03). There is no relation between [2,3-BPG] and plasma [P(i)]. Phosphate loading increases both plasma and erythrocyte phosphate pools and the rise in [2,3-BPG] is probably a consequence of the rise in cell [P(i)].

De novo post-illumination monoterpene burst in Quercus ilex (holm oak).

PubMed

Srikanta Dani, K G; Marino, Giovanni; Taiti, Cosimo; Mancuso, Stefano; Atwell, Brian J; Loreto, Francesco; Centritto, Mauro

2017-02-01

Explicit proof for de novo origin of a rare post-illumination monoterpene burst and its consistency under low O 2 , shows interaction of photorespiration, photosynthesis, and isoprenoid biosynthesis during light-dark transitions. Quercus ilex L (holm oak) constitutively emits foliar monoterpenes in an isoprene-like fashion via the methyl erythritol phosphate (MEP) pathway located in chloroplasts. Isoprene-emitting plants are known to exhibit post-illumination isoprene burst, a transient emission of isoprene in darkness. An analogous post-illumination monoterpene burst (PiMB) had remained elusive and is reported here for the first time in Q. ilex. Using 13 CO 2 labelling, we show that PiMB is made from freshly fixed carbon. PiMB is rare at ambient (20%) O 2 , absent at high (50%) O 2 , and becomes consistent in leaves exposed to low (2%) O 2 . PiMB is stronger and occurs earlier at higher temperatures. We also show that primary and secondary post-illumination CO 2 bursts (PiCO 2 B) are sensitive to O 2 in Q. ilex. The primary photorespiratory PiCO 2 B is absent under both ambient and low O 2 , but is induced under high (>50%) O 2 , while the secondary PiCO 2 B (of unknown origin) is absent under ambient, but present at low and high O 2 . We propose that post-illumination recycling of photorespired CO 2 competes with the MEP pathway for photosynthetic carbon and energy, making PiMB rare under ambient O 2 and absent at high O 2 . PiMB becomes consistent when photorespiration is suppressed in Q. ilex.

Unique Color Converter Architecture Enabling Phosphor-in-Glass (PiG) Films Suitable for High-Power and High-Luminance Laser-Driven White Lighting.

PubMed

Zheng, Peng; Li, Shuxing; Wang, Le; Zhou, Tian-Liang; You, Shihai; Takeda, Takashi; Hirosaki, Naoto; Xie, Rong-Jun

2018-05-02

As a next-generation high-power lighting technology, laser lighting has attracted great attention in high-luminance applications. However, thermally robust and highly efficient color converters suitable for high-quality laser lighting are scarce. Despite its versatility, the phosphor-in-glass (PiG) has been seldom applied in laser lighting because of its low thermal conductivity. In this work, we develop a unique architecture in which a phosphor-in-glass (PiG) film was directly sintered on a high thermally conductive sapphire substrate coated by one-dimensional photonic crystals. The designed color converter with the composite architecture exhibits a high internal quantum efficiency close to that of the original phosphor powders and an excellent packaging efficiency up to 90%. Furthermore, the PiG film can even be survived under the 11.2 W mm -2 blue laser excitation. Combining blue laser diodes with the YAG-PiG-on-sapphire plate, a uniform white light with a high luminance of 845 Mcd m -2 (luminous flux: 1839 lm), luminous efficacy of 210 lm W -1 , and correlated color temperature of 6504 K was obtained. A high color rendering index of 74 was attained by adding a robust orange or red phosphor layer to the architecture. These outstanding properties meet the standards of vehicle regulations, enabling the PiG films with the composite architecture to be applied in automotive lighting or other high-power and high-luminance laser lighting.

Electronic tuning of the lability of Pt(II) complexes through pi-acceptor effects. Correlations between thermodynamic, kinetic, and theoretical parameters.

PubMed

Hofmann, Andreas; Jaganyi, Deogratius; Munro, Orde Q; Liehr, Günter; van Eldik, Rudi

2003-03-10

pi-Acceptor effects are often used to account for the unusual high lability of [Pt(terpy)L]((2)(-)(n)+) (terpy = 2,2':6',2' '-terpyridine) complexes. To gain further insight into this phenomenon, the pi-acceptor effect was varied systematically by studying the lability of [Pt(diethylenetriamine)OH(2)](2+) (aaa), [Pt(2,6-bis-aminomethylpyridine)OH(2)](2+) (apa), [Pt(N-(pyridyl-2-methyl)-1,2-diamino-ethane)OH(2)](2+) (aap), [Pt(bis(2-pyridylmethyl)amine)OH(2)](2+) (pap), [Pt(2,2'-bipyridine)(NH(3))(OH(2))](2+) (app), and [Pt(terpy)OH(2)](2+) (ppp). The crystal structure of the apa precursor [Pt(2,6-bis-aminomethylpyridine)Cl]Cl.H(2)O was determined. The substitution of water by a series of nucleophiles, viz. thiourea, N,N-dimethylthiourea, N,N,N',N'-tetramethylthiourea, I(-), and SCN(-), was studied under pseudo-first-order conditions as a function of concentration, pH, temperature, and pressure, using stopped-flow techniques. The data enable an overall comparison of the substitution behavior of these complexes, emphasizing the role played by the kinetic cis and trans pi-acceptor effects. The results indicate that the cis pi-acceptor effect is larger than the trans pi-acceptor effect, and that the pi-acceptor effects are multiplicative. DFT calculations at the B3LYP/LACVP level of theory show that, by the addition of pi-acceptor ligands to the metal, the positive charge on the metal center increases, and the energy separation of the frontier molecular orbitals (E(LUMO) - E(HOMO)) of the ground state Pt(II) complexes decreases. The calculations collectively support the experimentally observed additional increase in reactivity when two pi-accepting rings are adjacent to each other (app and ppp), which is ascribed to "electronic communication" between the pyridine rings. The results furthermore indicate that the pK(a) value of the platinum bound water molecule is controlled by the pi-accepting nature of the chelate system and reflects the electron density around the metal center. This in turn controls the rate of the associative substitution reaction and was analyzed using the Hammett equation.

Predissociation of oxygen in the B3Sigma(u)(-) state

NASA Technical Reports Server (NTRS)

Chiu, S. S.-L.; Cheung, A. S.-C.; Finch, M.; Jamieson, M. J.; Yoshino, K.; Dalgarno, A.; Parkinson, W. H.

1992-01-01

The predissociation linewidths and level shifts of vibrational levels of three oxygen isotopic molecules (O2)-16, (O-16)(O-18), and (O2)-18 arising from the interactions of the B3Sigma(u)(-) state with the four repulsive states 5Pi(u), 3Sigma(u)(+), 3Pi(u), and 1Pi(u) have been calculated. A set of parameters characterizing these interactions has been determined. Good agreement between calculated and experimental predissociation widths and shifts has been obtained for all the three isotopic molecules.

Relationship between aflatoxin contamination and physiological responses of corn plants under drought and heat stress.

PubMed

Kebede, Hirut; Abbas, Hamed K; Fisher, Daniel K; Bellaloui, Nacer

2012-11-20

Increased aflatoxin contamination in corn by the fungus Aspergillus flavus is associated with frequent periods of drought and heat stress during the reproductive stages of the plants. The objective of this study was to evaluate the relationship between aflatoxin contamination and physiological responses of corn plants under drought and heat stress. The study was conducted in Stoneville, MS, USA under irrigated and non-irrigated conditions. Five commercial hybrids, P31G70, P33F87, P32B34, P31B13 and DKC63-42 and two inbred germplasm lines, PI 639055 and PI 489361, were evaluated. The plants were inoculated with Aspergillus flavus (K-54) at mid-silk stage, and aflatoxin contamination was determined on the kernels at harvest. Several physiological measurements which are indicators of stress response were determined. The results suggested that PI 639055, PI 489361 and hybrid DKC63-42 were more sensitive to drought and high temperature stress in the non-irrigated plots and P31G70 was the most tolerant among all the genotypes. Aflatoxin contamination was the highest in DKC63-42 and PI 489361 but significantly lower in P31G70. However, PI 639055, which is an aflatoxin resistant germplasm, had the lowest aflatoxin contamination, even though it was one of the most stressed genotypes. Possible reasons for these differences are discussed. These results suggested that the physiological responses were associated with the level of aflatoxin contamination in all the genotypes, except PI 639055. These and other physiological responses related to stress may help examine differences among corn genotypes in aflatoxin contamination.

Silencing c-Myc translation as a therapeutic strategy through targeting PI3Kδ and CK1ε in hematological malignancies.

PubMed

Deng, Changchun; Lipstein, Mark R; Scotto, Luigi; Jirau Serrano, Xavier O; Mangone, Michael A; Li, Shirong; Vendome, Jeremie; Hao, Yun; Xu, Xiaoming; Deng, Shi-Xian; Realubit, Ronald B; Tatonetti, Nicholas P; Karan, Charles; Lentzsch, Suzanne; Fruman, David A; Honig, Barry; Landry, Donald W; O'Connor, Owen A

2017-01-05

Phosphoinositide 3-kinase (PI3K) and the proteasome pathway are both involved in activating the mechanistic target of rapamycin (mTOR). Because mTOR signaling is required for initiation of messenger RNA translation, we hypothesized that cotargeting the PI3K and proteasome pathways might synergistically inhibit translation of c-Myc. We found that a novel PI3K δ isoform inhibitor TGR-1202, but not the approved PI3Kδ inhibitor idelalisib, was highly synergistic with the proteasome inhibitor carfilzomib in lymphoma, leukemia, and myeloma cell lines and primary lymphoma and leukemia cells. TGR-1202 and carfilzomib (TC) synergistically inhibited phosphorylation of the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1), leading to suppression of c-Myc translation and silencing of c-Myc-dependent transcription. The synergistic cytotoxicity of TC was rescued by overexpression of eIF4E or c-Myc. TGR-1202, but not other PI3Kδ inhibitors, inhibited casein kinase-1 ε (CK1ε). Targeting CK1ε using a selective chemical inhibitor or short hairpin RNA complements the effects of idelalisib, as a single agent or in combination with carfilzomib, in repressing phosphorylation of 4E-BP1 and the protein level of c-Myc. These results suggest that TGR-1202 is a dual PI3Kδ/CK1ε inhibitor, which may in part explain the clinical activity of TGR-1202 in aggressive lymphoma not found with idelalisib. Targeting CK1ε should become an integral part of therapeutic strategies targeting translation of oncogenes such as c-Myc. © 2017 by The American Society of Hematology.

[The pharmaceutical industry and specialised medical training: Residents' perceptions in Madrid, Spain].

PubMed

González-Rubio, Raquel; Escortell-Mayor, Esperanza; Del Cura González, Isabel

2017-10-06

To assess the frequency of exposure and attitudes to the pharmaceutical industry (PI) of residents in the Region of Madrid (RM), Spain, and to analyse the association with specialty, professional environment and training. Cross-sectional electronic survey in May and June 2015 of all medical residents in RM. We collected sociodemographic variables and those of interaction with the PI in four blocks: frequency of interactions, attitudes and perceptions, environment and regulatory framework, and skills; with the first two blocks we created a Synthetic PI Interaction Index (SPIII). Bivariate and multivariate analysis of logistic regression. 350 resident's responses (28% family and community medicine [FCM], 57% hospital, 15% others). Ninety-eight percent reported interacting with the PI. Twenty percent believed their prescribing was influenced by the PI and 48% believed it was influenced by other doctors. Sixty-five precent considered more training necessary. Ninety-six percent had received no information from their college of physicians, 80% did not know the regulations in their medical society and 50% were unaware of those of their institution. Hospital specialty residents showed more likelihood of SPIII ≥ percentile 75 than those of FCM (odds ratio [OR]: 3.96; 95% confidence interval [95%CI]: 1.88-8.35). Training in informal settings was associated with SPIII ≤ percentile 25 (OR: 2.83; 95%CI: 1.32-6.07). The medical residents in RM had a high level of interaction with the PI and believed its influence low. Hospital specialty residents showed more interaction with the PI. Regulations were not well known by residents and they consideredmore training necessary. Copyright © 2017 SESPAS. Publicado por Elsevier España, S.L.U. All rights reserved.

Reverse engineering a gene network using an asynchronous parallel evolution strategy

PubMed Central

2010-01-01

Background The use of reverse engineering methods to infer gene regulatory networks by fitting mathematical models to gene expression data is becoming increasingly popular and successful. However, increasing model complexity means that more powerful global optimisation techniques are required for model fitting. The parallel Lam Simulated Annealing (pLSA) algorithm has been used in such approaches, but recent research has shown that island Evolutionary Strategies can produce faster, more reliable results. However, no parallel island Evolutionary Strategy (piES) has yet been demonstrated to be effective for this task. Results Here, we present synchronous and asynchronous versions of the piES algorithm, and apply them to a real reverse engineering problem: inferring parameters in the gap gene network. We find that the asynchronous piES exhibits very little communication overhead, and shows significant speed-up for up to 50 nodes: the piES running on 50 nodes is nearly 10 times faster than the best serial algorithm. We compare the asynchronous piES to pLSA on the same test problem, measuring the time required to reach particular levels of residual error, and show that it shows much faster convergence than pLSA across all optimisation conditions tested. Conclusions Our results demonstrate that the piES is consistently faster and more reliable than the pLSA algorithm on this problem, and scales better with increasing numbers of nodes. In addition, the piES is especially well suited to further improvements and adaptations: Firstly, the algorithm's fast initial descent speed and high reliability make it a good candidate for being used as part of a global/local search hybrid algorithm. Secondly, it has the potential to be used as part of a hierarchical evolutionary algorithm, which takes advantage of modern multi-core computing architectures. PMID:20196855

Entanglement Length in Miscible Blends of cis-Polyisoprene and Poly(ptert-butylstyrene)

NASA Astrophysics Data System (ADS)

Watanabe, Hiroshi; Matsumiya, Yumi

In miscible polymer blends, the entanglement length is common for the components, but its changes with the composition w remain unclear. For this problem, this study analyzed viscoelastic data for miscible blends of cis-polyisoprene (PI) and poly(ptert-butylstyrene) (PtBS), considering the basic feature that the local relaxation is determined only by wPI. On the basis of this feature, a series of unentangled low- M PI/PtBS blends having various M and a given wPI were utilized as references for well-entangled high- M PI/PtBS blends having the same wPI, and the modulus data of the references were subtracted from the high- M blend data. For an optimally chosen reference, the storage modulus Ge'of the high- M blends obtained after the subtraction exhibited a clear entanglement plateau GN and the corresponding Ge' ' decreased in proportion to 1/ ω at high frequencies ω. Thus, the onset of entanglement relaxation was detected. The GN values were well described by a linear mixing rule of the entanglement length with the number fraction of Kuhn segments of the components being utilized as the averaging weight. This result, not explained by a mean-field picture of entanglement, is discussed in relation to local packing of bulky PtBS chains and skinny PI chains.

Accounting for the differences in the structures and relative energies of the highly homoatomic np pi-np pi (n > or = 3)-bonded S2I4 2+, the Se-I pi-bonded Se2I4 2+, and their higher-energy isomers by AIM, MO, NBO, and VB methodologies.

PubMed

Brownridge, Scott; Crawford, Margaret-Jane; Du, Hongbin; Harcourt, Richard D; Knapp, Carsten; Laitinen, Risto S; Passmore, Jack; Rautiainen, J Mikko; Suontamo, Reijo J; Valkonen, Jussi

2007-02-05

The bonding in the highly homoatomic np pi-np pi (n > or = 3)-bonded S2I42+ (three sigma + two pi bonds), the Se-I pi-bonded Se2I42+ (four sigma + one pi bonds), and their higher-energy isomers have been studied using modern DFT and ab initio calculations and theoretical analysis methods: atoms in molecules (AIM), molecular orbital (MO), natural bond orbital (NBO), and valence bond (VB) analyses, giving their relative energies, theoretical bond orders, and atomic charges. The aim of this work was to seek theory-based answers to four main questions: (1) Are the previously proposed simple pi*-pi* bonding models valid for S2I42+ and Se2I42+? (2) What accounts for the difference in the structures of S2I42+ and Se2I42+? (3) Why are the classically bonded isolobal P2I4 and As2I4 structures not adopted? (4) Is the high experimentally observed S-S bond order supported by theoretical bond orders, and how does it relate to high bond orders between other heavier main group elements? The AIM analysis confirmed the high bond orders and established that the weak bonds observed in S2I42+ and Se2I42+ are real and the bonding in these cations is covalent in nature. The full MO analysis confirmed that S2I42+ contains three sigma and two pi bonds, that the positive charge is essentially equally distributed over all atoms, that the bonding between S2 and two I2+ units in S2I42+ is best described by two mutually perpendicular 4c2e pi*-pi* bonds, and that in Se2I42+, two SeI2+ moieties are joined by a 6c2e pi*-pi* bond, both in agreement with previously suggested models. The VB treatment provided a complementary approach to MO analysis and provided insight how the formation of the weak bonds affects the other bonds. The NBO analysis and the calculated AIM charges showed that the minimization of the electrostatic repulsion between EI2+ units (E = S, Se) and the delocalization of the positive charge are the main factors that explain why the nonclassical structures are favored for S2I42+ and Se2I42+. The difference in the structures of S2I42+ and Se2I42+ is related to the high strength of the S-S pi bond compared to the weak S-I sigma bond and the additional stabilization from increased delocalization of positive charge in the structure of S2I42+ compared to the structure of Se2I42+. The investigation of the E2X42+ series (E = S, Se, Te; X = Cl, Br, I) revealed that only S2I42+ adopts the highly np pi-np pi (n > or = 3)-bonded structure, while all other dications favor the pi-bonded Se2I42+ structure. Theoretical bond order calculations for S2I42+ confirm the previously presented experimentally based bond orders for S-S (2.1-2.3) and I-I (1.3-1.5) bonds. The S-S bond is determined to have the highest reported S-S bond order in an isolated compound and has a bond order that is either similar to or slightly less than the Si-Si bond order in the proposed triply bonded [(Me3Si)2CH]2(iPr)SiSi triple bond SiSi(iPr)[CH(SiMe3)2]2 depending on the definition of bond orders used.

Axial resonances a$$_{1}$$(1260), b$$_{1}$$(1235) and their decays from the lattice

DOE PAGES

Lang, C. B.; Leskovec, Luka; Mohler, Daniel; ...

2014-04-28

The light axial-vector resonancesmore » $$a_1(1260)$$ and $$b_1(1235)$$ are explored in Nf=2 lattice QCD by simulating the corresponding scattering channels $$\\rho\\pi$$ and $$\\omega\\pi$$. Interpolating fields $$\\bar{q} q$$ and $$\\rho\\pi$$ or $$\\omega\\pi$$ are used to extract the s-wave phase shifts for the first time. The $$\\rho$$ and $$\\omega$$ are treated as stable and we argue that this is justified in the considered energy range and for our parameters $$m_\\pi\\simeq 266~$$MeV and $$L\\simeq 2~$$fm. We neglect other channels that would be open when using physical masses in continuum. Assuming a resonance interpretation a Breit-Wigner fit to the phase shift gives the $$a_1(1260)$$ resonance mass $$m_{a1}^{res}=1.435(53)(^{+0}_{-109})$$ GeV compared to $$m_{a1}^{exp}=1.230(40)$$ GeV. The $$a_1$$ width $$\\Gamma_{a1}(s)=g^2 p/s$$ is parametrized in terms of the coupling and we obtain $$g_{a_1\\rho\\pi}=1.71(39)$$ GeV compared to $$g_{a_1\\rho\\pi}^{exp}=1.35(30)$$ GeV derived from $$\\Gamma_{a1}^{exp}=425(175)$$ MeV. In the $$b_1$$ channel, we find energy levels related to $$\\pi(0)\\omega(0)$$ and $$b_1(1235)$$, and the lowest level is found at $$E_1 \\gtrsim m_\\omega+m_\\pi$$ but is within uncertainty also compatible with an attractive interaction. Lastly, assuming the coupling $$g_{b_1\\omega\\pi}$$ extracted from the experimental width we estimate $$m_{b_1}^{res}=1.414(36)(^{+0}_{-83})$$.« less

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

Lazaris, Andreas; Hwang, Kristy S.; Goukasian, Naira

Objective: We investigated the association between apoE protein plasma levels and brain amyloidosis and the effect of the top 10 Alzheimer disease (AD) risk genes on this association. Methods: Our dataset consisted of 18 AD, 52 mild cognitive impairment, and 3 cognitively normal Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) participants with available [ 11C]-Pittsburgh compound B (PiB) and peripheral blood protein data. We used cortical pattern matching to study associations between plasma apoE and cortical PiB binding and the effect of carrier status for the top 10 AD risk genes. Results: Low plasma apoE was significantly associated with high PiBmore » SUVR, except in the sensorimotor and entorhinal cortex. For BIN1 rs744373, the association was observed only in minor allele carriers. For CD2AP rs9349407 and CR1 rs3818361, the association was preserved only in minor allele noncarriers. We did not find evidence for modulation by CLU, PICALM, ABCA7, BIN1, and MS4A6A. Conclusions: Our data show that BIN1 rs744373, CD2AP rs9349407, and CR1 rs3818361 genotypes modulate the association between apoE protein plasma levels and brain amyloidosis, implying a potential epigenetic/downstream interaction.« less

The Search for Exotic Mesons in gamma p -> pi+pi+pi-n with CLAS at Jefferson Lab

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

Craig Bookwalter

2011-12-01

The {pi}{sub 1}(1600), a J{sup PC} = 1{sup {-+}} exotic meson has been observed by experiments using pion beams. Theorists predict that photon beams could produce gluonic hybrid mesons, of which the {pi}{sub 1}(1600) is a candidate, at enhanced levels relative to pion beams. The g12 rungroup at Jefferson Lab's CEBAF Large Acceptance Spectrometer (CLAS) has recently acquired a large photoproduction dataset, using a liquid hydrogen target and tagged photons from a 5.71 GeV electron beam. A partial-wave analysis of 502K {gamma}p {yields} {pi}{sup +}{pi}{sup +}{pi}{sup -}n events selected from the g12 dataset has been performed, and preliminary fit resultsmore » show strong evidence for well-known states such as the a{sub 1}(1260), a{sub 2}(1320), and {pi}{sub 2}(1670). However, we observe no evidence for the production of the {pi}{sub 1}(1600) in either the partial-wave intensities or the relative complex phase between the 1{sup {-+}} and the 2{sup {-+}} (corresponding to the {pi}{sub 2}) partial waves.« less

Protein synthesis controls phosphate homeostasis.

PubMed

Pontes, Mauricio H; Groisman, Eduardo A

2018-01-01

Phosphorus is an essential element assimilated largely as orthophosphate (Pi). Cells respond to Pi starvation by importing Pi from their surroundings. We now report that impaired protein synthesis alone triggers a Pi starvation response even when Pi is plentiful in the extracellular milieu. In the bacterium Salmonella enterica serovar Typhimurium , this response entails phosphorylation of the regulatory protein PhoB and transcription of PhoB-dependent Pi transporter genes and is eliminated upon stimulation of adenosine triphosphate (ATP) hydrolysis. When protein synthesis is impaired due to low cytoplasmic magnesium (Mg 2+ ), Salmonella triggers the Pi starvation response because ribosomes are destabilized, which reduces ATP consumption and thus free cytoplasmic Pi. This response is transient because low cytoplasmic Mg 2+ promotes an uptake in Mg 2+ and a decrease in ATP levels, which stabilizes ribosomes, resulting in ATP consumption and Pi increase, thus ending the response. Notably, pharmacological inhibition of protein synthesis also elicited a Pi starvation response in the bacterium Escherichia coli and the yeast Saccharomyces cerevisiae Our findings identify a regulatory connection between protein synthesis and Pi homeostasis that is widespread in nature. © 2018 Pontes and Groisman; Published by Cold Spring Harbor Laboratory Press.

Nitrogen-Doping Enables Covalent-Like pi-pi Bonding between Graphenes

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

Tian, Yong-Hui; Huang, Jingsong; Sumpter, Bobby G

The neighboring layers in bi-layer (and few-layer) graphenes of both AA and AB stacking motifs are known to be separated at a distance corresponding to van der Waals (vdW) interactions. In this Letter, we present for the first time a new aspect of graphene chemistry in terms of a special chemical bonding between the giant graphene molecules . Through rigorous theoretical calculations, we demonstrate that the N-doped graphenes (NGPs) with various doping levels can form an unusual two-dimensional (2D) pi pi bonding in bi-layer NGPs bringing the neighboring NGPs to significantly reduced interlayer separations. The interlayer binding energies can bemore » enhanced by up to 50% compared to the pristine graphene bi-layers that are characterized by only vdW interactions. Such an unusual chemical bonding arises from the pi pi overlap across the vdW gap while the individual layers maintain their in-plane pi-conjugation and are accordingly planar. The existence of the resulting interlayer covalent-like bonding is corroborated by electronic structure calculations and crystal orbital overlap population (COOP) analyses. In NGP-based graphite with the optimal doping level, the NGP layers are uniformly stacked and the 3D bulk exhibits metallic characteristics both in the in-plane and along the stacking directions.« less

Effects of Be, Sr, Fe and Mg interactions on the microstructure and mechanical properties of aluminum based aeronautical alloys

NASA Astrophysics Data System (ADS)

Ibrahim, Mohamed Fawzy

The present work was carried out on a series of heat-treatable aluminum-based aeronautical alloys containing various amounts of magnesium (Mg), iron (Fe), strontium (Sr) and beryllium (Be). Tensile test bars (dendrite arm spacing ~ 24mum) were solutionized for either 5 or 12 hours at 540°C, followed by quenching in warm water (60°C). Subsequently, these quenched samples were aged at 160°C for times up to 12 hours. Microstructural assessment was performed. All heat-treated samples were pulled to fracture at room temperature using a servo-hydraulic tensile testing machine. The results show that Be causes partial modification of the eutectic silicon (Si) particles similar to that reported for Mg addition. Addition of 0.8 wt.% Mg reduced the eutectic temperature by ~10°C. During solidification of alloys containing high levels of Fe and Mg, without Sr, a peak corresponding to the formation of a Be-Fe phase (Al8Fe2BeSi) was detected at 611°C. The Be-Fe phase precipitates in a script-like morphology. A new quinary eutectic-like reaction was observed to take place near the end of solidification of high Mg, high Fe, Be-containing alloys. This new reaction is composed mainly of fine particles of Si, Mg2Si, pi-Al 8Mg3FeSi6 and (Be-Fe) phases. The volume fraction of this reaction decreased with the addition of Sr. The addition of Be has a noticeable effect on decreasing the beta-phase length, or volume fraction, this effect may be limited by adding Sr. Beryllium addition also results in the precipitation of the beta-phase in a nodular form, which reduces the harmful effects of these intermetallics on the alloy mechanical properties. Increasing both Mg and Fe levels led to an increase in the amount of the pi-phase; increasing the iron content led to an increase in the volume fraction of the partially soluble beta- and pi-phases, while Mg2Si particles were completely dissolved. The beta-phase platelets were observed to undergo changes in their morphology due to the dissolution, thinning, necking and fragmentation of these platelets upon increasing the solutionizing time. The pi-phase was observed to dissolve and/or transform into a cluster of very fine beta-phase platelets. In the as-cast conditions, increasing the Mg content leads to increased transformation of beta-phase platelets into Chinese-script pi-phase, regardless of the Fe content. This, in turn, decreases the harmful effect of the beta-phase. Increasing the solutionizing time leads to a decomposition of the pi-phase to the beta-phase, fragmentation of the beta-phase and spheroidization of both the eutectic Si and the pi-phase particles, thus improving alloy tensile properties. Two mechanisms of Mg2Si precipitate coarsening were observed to occur: (1) Ostwald ripening in the solution heat-treated samples and (2) clustering. Coarsening increases with increased solution heat treatment time, increased aging time, as well as with greater Mg contents. Increased Fe levels decrease the alloy quality index (Q) values, whereas adding Mg increases them. Introducing Be, in spite of it being a toxic material, Sr, or both, simultaneously improves the alloy quality index values, regardless of solutionizing time or Fe and Mg levels. Quality index values increase with solution heat treatment time from 5 to 12 hours. Higher Mg contents lead to an increase in alloy ductility, ultimate tensile strength (UTS) and yield strength (YS), while higher Fe levels can drastically decrease these properties. For the same levels of Fe and/or Mg, Be and Sr have significant effects in improving alloy mechanical properties; these effects can be readily observed in low levels of Fe and high Mg contents. Beryllium addition is beneficial in the case of high Fe contents as it lowers the harmful effects of Fe-phases in Al-Si alloys. In the case of high Fe contents, it seems that the addition of 500 ppm of Be is not sufficient for all interactions with other alloying elements. During the melting process the formation of Be-Sr phase (probably SrBe3O4 compound) decreases the free Be content and hence the alloy mechanical properties. The role of Be in preventing the oxidation of Mg and in changing the chemistry and morphology of the Fe-intermetallics is observed through improved mechanical properties of Be-containing alloys. The partial modification effect of both Mg and Be appears to improve the alloy tensile properties. Solutionizing and aging times are important parameters affecting the alloy tensile properties. The Mg2Si precipitates were confirmed to be the main hardening components of the 356 and 357 alloys investigated. The yield strength increases with greater Mg levels, reduced Fe levels, addition of Be, Sr-modification, solution heat treatment time and aging time. The present work was extended to include an investigation of the experimental 7073 aluminum alloy. (Abstract shortened by UMI.).

Decreased 16:0/20:4-phosphatidylinositol level in the post-mortem prefrontal cortex of elderly patients with schizophrenia

PubMed Central

Matsumoto, Junya; Nakanishi, Hiroki; Kunii, Yasuto; Sugiura, Yuki; Yuki, Dai; Wada, Akira; Hino, Mizuki; Niwa, Shin-Ichi; Kondo, Takeshi; Waki, Michihiko; Hayasaka, Takahiro; Masaki, Noritaka; Akatsu, Hiroyasu; Hashizume, Yoshio; Yamamoto, Sakon; Sato, Shinji; Sasaki, Takehiko; Setou, Mitsutoshi; Yabe, Hirooki

2017-01-01

The etiology of schizophrenia includes phospholipid abnormalities. Phospholipids are bioactive substances essential for brain function. To analyze differences in the quantity and types of phospholipids present in the brain tissue of patients with schizophrenia, we performed a global analysis of phospholipids in multiple brain samples using liquid chromatography electrospray ionization mass/mass spectrometry (LC-ESI/MS/MS) and imaging mass spectrometry (IMS). We found significantly decreased 16:0/20:4-phosphatidylinositol (PI) levels in the prefrontal cortex (PFC) in the brains from patients with schizophrenia in the LC-ESI/MS/MS, and that the 16:0/20:4-PI in grey matter was most prominently diminished according to the IMS experiments. Previous reports investigating PI pathology of schizophrenia did not identify differences in the sn-1 and sn-2 fatty acyl chains. This study is the first to clear the fatty acid composition of PI in brains from patients with schizophrenia. Alteration in the characteristic fatty acid composition of PI may also affect neuronal function, and could play a role in the etiology of schizophrenia. Although further studies are necessary to understand the role of reduced 16:0/20:4-PI levels within the prefrontal cortex in the etiology of schizophrenia, our results provide insight into the development of a novel therapy for the clinical treatment of schizophrenia. PMID:28332626

High signal intensity on magnetic resonance imaging is a better predictor of neurobehavioral performances than blood manganese in asymptomatic welders.

PubMed

Chang, Yongmin; Kim, Yangho; Woo, Seung-Tae; Song, Hui-Jin; Kim, Suk Hwan; Lee, Hun; Kwon, Young Joo; Ahn, Joon-Ho; Park, Sin-Jae; Chung, In-Sung; Jeong, Kyoung Sook

2009-07-01

The aim of the study was to evaluate subclinical neurological effects in welders, using an extensive list of neurobehavioral batteries and determine if there is a link between pallidal index (PI) and subclinical neurobehavioral effects in the spectrum of manganese (Mn) symptomatology. A total of 43 asymptomatic male welders and 29 age- and sex-matched healthy control individuals completed questionnaires, and underwent blood examinations, brain magnetic resonance imaging (MRI) scans, and a wide range of neurobehavioral examinations. Digit symbol, auditory verbal learning test (delayed recall), complex figure test (copy and immediate recall), digit span, verbal fluency test, Stroop test, grooved pegboard, finger tapping, frequency dispersion and harmonic index of tremor, and maximum frequency of hand coordination showed differences between welders and control individuals. No differences were noted for simple reaction time, postural sway, smell test, and profile of mood states (POMS). Blood Mn levels were shown to be significantly associated with grooved pegboard (dominant hand) and complex figure test (copy) results. PI was significantly associated with digit symbol, digit span backward, Stroop Word and Stroop error index, and grooved pegboard (dominant hand) results. The present findings that there were significant correlations between several neurobehavioral deficits and PI as well as blood Mn suggest that they may be attributed to Mn exposure in welding fumes. The present study also shows that PI is a better predictor of neurobehavioral performance than blood Mn levels in asymptomatic welders.

Metabolic, Genomic, and Biochemical Analyses of Glandular Trichomes from the Wild Tomato Species Lycopersicon hirsutum Identify a Key Enzyme in the Biosynthesis of MethylketonesW⃞

PubMed Central

Fridman, Eyal; Wang, Jihong; Iijima, Yoko; Froehlich, John E.; Gang, David R.; Ohlrogge, John; Pichersky, Eran

2005-01-01

Medium-length methylketones (C7-C15) are highly effective in protecting plants from numerous pests. We used a biochemical genomics approach to elucidate the pathway leading to synthesis of methylketones in the glandular trichomes of the wild tomato Lycopersicon hirsutum f glabratum (accession PI126449). A comparison of gland EST databases from accession PI126449 and a second L. hirsutum accession, LA1777, whose glands do not contain methylketones, showed that the expression of genes for fatty acid biosynthesis is elevated in PI126449 glands, suggesting de novo biosynthesis of methylketones. A cDNA abundant in the PI126449 gland EST database but rare in the LA1777 database was similar in sequence to plant esterases. This cDNA, designated Methylketone Synthase 1 (MKS1), was expressed in Escherichia coli and the purified protein used to catalyze in vitro reactions in which C12, C14, and C16 β-ketoacyl–acyl-carrier-proteins (intermediates in fatty acid biosynthesis) were hydrolyzed and decarboxylated to give C11, C13, and C15 methylketones, respectively. Although MKS1 does not contain a classical transit peptide, in vitro import assays showed that it was targeted to the stroma of plastids, where fatty acid biosynthesis occurs. Levels of MKS1 transcript, protein, and enzymatic activity were correlated with levels of methylketones and gland density in a variety of tomato accessions and in different plant organs. PMID:15772286

Cell Autonomous Phosphoinositide 3-Kinase Activation in Oocytes Disrupts Normal Ovarian Function Through Promoting Survival and Overgrowth of Ovarian Follicles

PubMed Central

Ebbert, Katherine; Cordeiro, Marilia H.; Romero, Megan; Zhu, Jie; Serna, Vanida Ann; Whelan, Kelly A.; Woodruff, Teresa K.

2015-01-01

In this study, we explored the effects of oocytic phosphoinositide 3-kinase (PI3K) activation on folliculogensis by generating transgenic mice, in which the oocyte-specific Cre-recombinase induces the expression of constitutively active mutant PI3K during the formation of primordial follicles. The ovaries of neonatal transgenic (Cre+) mice showed significantly reduced apoptosis in follicles, which resulted in an excess number of follicles per ovary. Thus, the elevation of phosphatidylinositol (3,4,5)-trisphosphate levels within oocytes promotes the survival of follicles during neonatal development. Despite the increase in AKT phosphorylation, primordial follicles in neonatal Cre+ mice remained dormant demonstrating a nuclear accumulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). These primordial follicles containing a high level of nuclear PTEN persisted in postpubertal females, suggesting that PTEN is the dominant factor in the maintenance of female reproductive lifespan through the regulation of primordial follicle recruitment. Although the oocytic PI3K activity and PTEN levels were elevated, the activation of primordial follicles and the subsequent accumulation of antral follicles with developmentally competent oocytes progressed normally in prepubertal Cre+ mice. However, mature Cre+ female mice were anovulatory. Because postnatal day 50 Cre+ mice released cumulus-oocyte complexes with developmentally competent oocytes in response to super-ovulation treatment, the anovulatory phenotype was not due to follicular defects but rather endocrine abnormalities, which were likely caused by the excess number of overgrown follicles. Our current study has elucidated the critical role of oocytic PI3K activity in follicular function, as well as the presence of a PTEN-mediated mechanism in the prevention of immature follicle activation. PMID:25594701

Altered Expression of Porcine Piwi Genes and piRNA during Development

PubMed Central

Kowalczykiewicz, Dorota; Pawlak, Piotr; Lechniak, Dorota; Wrzesinski, Jan

2012-01-01

Three Sus scrofa Piwi genes (Piwil1, Piwil2 and Piwil4) encoding proteins of 861, 985 and 853 aminoacids, respectively, were cloned and sequenced. Alignment of the Piwi proteins showed the high identity between Sus scrofa and Homo sapiens. Relative transcript abundance of porcine Piwil1, Piwil2 and Piwil4 genes in testes, ovaries and oocytes derived from sexually immature and mature animals was examined using Real-Time PCR. Expression of the three Piwi mRNAs was proved to be tissue specific and restricted exclusively to the gonads. In testes of adult pigs the highest relative transcript abundance was observed for the Sus scrofa Piwil1 gene. On the other hand, in testes of neonatal pigs the Piwil1 transcript level was over 2–fold reduced while the level of Piwil2 transcript was higher. As regards the expression of the Piwil4 transcript, its level was 34-fold elevated in testes of neonatal piglet when compared to adult male. In ovaries of prepubertal and pubertal female pigs transcript abundance of the three Piwi genes was significantly reduced in comparison with testes. However, similarly to testes, in ovaries of neonatal pigs the Piwil2 gene was characterized by the highest relative transcript abundance among the three Piwi genes analysed. In prepubertal and pubertal oocytes Piwil1 transcript was the most abundant whereas the expression of Piwil4 was undetectable. We also demonstrated that expression of piRNA occurs preferentially in the gonads of adult male and female pigs. Moreover, a piRNA subset isolated from ovaries was 2–3 nucleotides longer than the piRNA from testes. PMID:22952772

Identification of a new defective SERPINA1 allele (PI*Zla palma) encoding an alpha-1-antitrypsin with altered glycosylation pattern.

PubMed

Hernández-Pérez, José M; Ramos-Díaz, Ruth; Pérez, José A

2017-10-01

Alpha-1-antitrypsin (AAT) deficiency is a genetic condition that arises from mutations in the SERPINA1 gene and predisposes to develop pulmonary emphysema and, less frequently, liver disease. Occasionally, new defective SERPINA1 alleles are detected as an outcome of targeted-screening programs or case-findings. This study began with a female patient showing bronchial hyperreactivity. Serum level and phenotype for AAT was analysed by immunonephelometry and isoelectric focusing electrophoresis. The SERPINA1 gene of the proband was genotyped by PCR amplification and DNA sequencing. Analysis of AAT deficiency was extended to the proband's family. An abnormal AAT variant that migrated to a more cathodal position than PiZ AAT was detected in the proband's serum. Genetic analysis demonstrated that proband is heterozygous for a new defective SERPINA1 allele (PI*Z la palma ) characterized by the c.321C > A (p.Asn83Lys) mutation in the M1Val213 background. This mutation abolishes the N-glycosylation site in position 83 of the mature AAT. Eight relatives of the proband are carriers of the PI*Z la palma allele and four of them have shown symptoms of bronchial asthma or bronchial hyperreactivity. The mean α1AT level in the serum of PI*MZ la palma individuals was 87.1 mg/dl. The reduction in circulating AAT levels associated to the PI*Z la palma allele was similar to that of PI*Z allele, representing a risk of impairment in lung function. Copyright © 2017 Elsevier Ltd. All rights reserved.

Serum interleukin-6 levels in murine models of Candida albicans infection.

PubMed

Kovács, Renátó; Czudar, Anita; Horváth, László; Szakács, Levente; Majoros, László; Kónya, József

2014-03-01

Two Balb/C mouse models of Candida infection were used to detect serum interleukin-6 (IL-6) responses. The first model used systemic infection by Candida albicans ATCC 10231 strain infected through the lateral tail vein of mice without any specific pretreatment. The median Candida burdens of the kidneys were 1.5 × 106 CFU/ml 24 h postinoculation (p.i.) and 1.2 × 107 CFU/ml 72 h p.i., while median serum IL-6 levels were 479.3 pg/ml and 934.5 pg/ml, respectively. The Candida burden showed significant correlation with serum IL-6 24 h p.i. (R2 = 0.6358; P = 0.0082) but not 72 h p.i.The second model was a mouse vaginitis model applying intravaginal inoculation of mice pretreated with subcutaneous estradiol-valerate (10 mg/ml) 3 days before infection. Candida cell count in vaginal lavage fluid was 2.8 × 106 CFU/ml 24 h p.i. and 1.4 × 108 CFU/ml 72 h p.i. Serum IL-6 response was detected in 4 of 15 mice 24 h p.i. and 9 of 15 mice 72 h p.i. Even the responders had low IL-6 serum levels (mean values 29.9 pg/ml and 60.1 pg/ml, respectively) not correlating with Candida cell count in vaginal lavage fluid.In conclusion, serum IL-6 had strong relationship with systemic C. albicans infection while the local C. albicans infection of the vagina led to partial, prolonged and limited serum IL-6 response.

Inhibition profiles of phosphatidylinositol 3-kinase inhibitors against PI3K superfamily and human cancer cell line panel JFCR39.

PubMed

Kong, Dexin; Dan, Shingo; Yamazaki, Kanami; Yamori, Takao

2010-04-01

As accumulating evidences suggest close involvement of phosphatidylinositol 3-kinase (PI3K) in various diseases particularly cancer, considerable competition occurs in development of PI3K inhibitors. Consequently, novel PI3K inhibitors such as ZSTK474, GDC-0941 and NVP-BEZ235 have been developed. Even though all these inhibitors were reported to inhibit class I PI3K but not dozens of protein kinases, whether they have different molecular targets remained unknown. To investigate such molecular target specificity, we have determined the inhibitory effects of these novel inhibitors together with classical PI3K inhibitor LY294002 on PI3K superfamily (including classes I, II, and III PI3Ks, PI4K and PI3K-related kinases) by using several novel non-radioactive biochemical assays. As a result, ZSTK474 and GDC-0941 indicated highly similar inhibition profiles for PI3K superfamily, with class I PI3K specificity much higher than NVP-BEZ235 and LY294002. We further investigated their growth inhibition effects on JFCR39, a human cancer cell line panel which we established for molecular target identification, and analysed their cell growth inhibition profiles (fingerprints) by using COMPARE analysis programme. Interestingly, we found ZSTK474 exhibited a highly similar fingerprint with GDC-0941 (r=0.863), more similar than with that of either NVP-BEZ235 or LY294002, suggesting that ZSTK474 shares more in molecular targets with GDC-0941 than with either of the other two PI3K inhibitors, consistent with the biochemical assay result. The biological implication of the difference in molecular target specificity of these PI3K inhibitors is under investigation. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Assessing the sensitivity of bovine tuberculosis surveillance in Canada's cattle population, 2009-2013.

PubMed

El Allaki, Farouk; Harrington, Noel; Howden, Krista

2016-11-01

The objectives of this study were (1) to estimate the annual sensitivity of Canada's bTB surveillance system and its three system components (slaughter surveillance, export testing and disease investigation) using a scenario tree modelling approach, and (2) to identify key model parameters that influence the estimates of the surveillance system sensitivity (SSSe). To achieve these objectives, we designed stochastic scenario tree models for three surveillance system components included in the analysis. Demographic data, slaughter data, export testing data, and disease investigation data from 2009 to 2013 were extracted for input into the scenario trees. Sensitivity analysis was conducted to identify key influential parameters on SSSe estimates. The median annual SSSe estimates generated from the study were very high, ranging from 0.95 (95% probability interval [PI]: 0.88-0.98) to 0.97 (95% PI: 0.93-0.99). Median annual sensitivity estimates for the slaughter surveillance component ranged from 0.95 (95% PI: 0.88-0.98) to 0.97 (95% PI: 0.93-0.99). This shows that slaughter surveillance to be the major contributor to overall surveillance system sensitivity with a high probability to detect M. bovis infection if present at a prevalence of 0.00028% or greater during the study period. The export testing and disease investigation components had extremely low component sensitivity estimates-the maximum median sensitivity estimates were 0.02 (95% PI: 0.014-0.023) and 0.0061 (95% PI: 0.0056-0.0066) respectively. The three most influential input parameters on the model's output (SSSe) were the probability of a granuloma being detected at slaughter inspection, the probability of a granuloma being present in older animals (≥12 months of age), and the probability of a granuloma sample being submitted to the laboratory. Additional studies are required to reduce the levels of uncertainty and variability associated with these three parameters influencing the surveillance system sensitivity. Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.

Prognostic index for chronic- and smoldering-type adult T-cell leukemia-lymphoma.

PubMed

Katsuya, Hiroo; Shimokawa, Mototsugu; Ishitsuka, Kenji; Kawai, Kazuhiro; Amano, Masahiro; Utsunomiya, Atae; Hino, Ryosuke; Hanada, Shuichi; Jo, Tatsuro; Tsukasaki, Kunihiro; Moriuchi, Yukiyoshi; Sueoka, Eisaburo; Yoshida, Shinichiro; Suzushima, Hitoshi; Miyahara, Masaharu; Yamashita, Kiyoshi; Eto, Tetsuya; Suzumiya, Junji; Tamura, Kazuo

2017-07-06

Adult T-cell leukemia-lymphoma (ATL) has been divided into 4 clinical subtypes: acute, lymphoma, chronic, and smoldering. The aim of this study is to develop a novel prognostic index (PI) for chronic and smoldering ATL. We conducted a nationwide retrospective survey on ATL patients, and 248 fully eligible individuals were used in this analysis. In the univariate analysis, sex, performance status, log 10 (soluble interleukin-2 receptor [sIL-2R]), neutrophils count, and lymphadenopathy showed values of P < .05 in training samples. A multivariate analysis was performed on these factors, and only log 10 (sIL-2R) was identified as an independent prognostic factor in training samples. Using a regression coefficient of this variable, a prognostic model was formulated to identify different levels of risk: indolent ATL-PI (iATL-PI) = 1.51 × log 10 (sIL-2R [U/mL]). The values calculated by iATL-PI were divided into 3 groups using a quartile point. In the validation sample, median survival times (MSTs) were 1.6 years, 5.5 years, and not reached for patients in the high-, intermediate-, and low-risk groups, respectively ( P < .0001). To make the scoring system clinically practicable, we simplified iATL-PI according to trichotomizing sIL-2R at 1000 and 6000 U/mL, using a quartile point. Patients with more than 6000 U/mL sIL-2R were categorized into the high-risk group, less than and equal to 1000 U/mL into the low-risk group, and the others into the intermediate-risk group, and MSTs were 1.6 years, not reached, and 5.5 years, respectively ( P < .0001). iATL-PI has potential as a novel tool for a risk-adapted therapeutic approach. © 2017 by The American Society of Hematology.

PfIRR Interacts with HrIGF-I and Activates the MAP-kinase and PI3-kinase Signaling Pathways to Regulate Glycogen Metabolism in Pinctada fucata

PubMed Central

Shi, Yu; He, Mao-xian

2016-01-01

The insulin-induced mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways are major intracellular signaling modules and conserved among eukaryotes that are known to regulate diverse cellular processes. However, they have not been investigated in the mollusk species Pinctada fucata. Here, we demonstrate that insulin-related peptide receptor of P. fucata (pfIRR) interacts with human recombinant insulin-like growth factor I (hrIGF-I), and stimulates the MAPK and PI3K signaling pathways in P. fucata oocytes. We also show that inhibition of pfIRR by the inhibitor PQ401 significantly attenuates the basal and hrIGF-I-induced phosphorylation of MAPK and PI3K/Akt at amino acid residues threonine 308 and serine 473. Furthermore, our experiments show that there is cross-talk between the MAPK and PI3K/Akt pathways, in which MAPK kinase positively regulates the PI3K pathway, and PI3K positively regulates the MAPK cascade. Intramuscular injection of hrIGF-I stimulates the PI3K and MAPK pathways to increase the expression of pfirr, protein phosphatase 1, glucokinase, and the phosphorylation of glycogen synthase, decreases the mRNA expression of glycogen synthase kinase-3 beta, decreases glucose levels in hemocytes, and increases glycogen levels in digestive glands. These results suggest that the MAPK and PI3K pathways in P. fucata transmit the hrIGF-I signal to regulate glycogen metabolism. PMID:26911653

An activity index for geomagnetic paleosecular variation, excursions, and reversals

NASA Astrophysics Data System (ADS)

Panovska, S.; Constable, C. G.

2017-04-01

Magnetic indices provide quantitative measures of space weather phenomena that are widely used by researchers in geomagnetism. We introduce an index focused on the internally generated field that can be used to evaluate long term variations or climatology of modern and paleomagnetic secular variation, including geomagnetic excursions, polarity reversals, and changes in reversal rate. The paleosecular variation index, Pi, represents instantaneous or average deviation from a geocentric axial dipole field using normalized ratios of virtual geomagnetic pole colatitude and virtual dipole moment. The activity level of the index, σPi, provides a measure of field stability through the temporal standard deviation of Pi. Pi can be calculated on a global grid from geomagnetic field models to reveal large scale geographic variations in field structure. It can be determined for individual time series, or averaged at local, regional, and global scales to detect long term changes in geomagnetic activity, identify excursions, and transitional field behavior. For recent field models, Pi ranges from less than 0.05 to 0.30. Conventional definitions for geomagnetic excursions are characterized by Pi exceeding 0.5. Strong field intensities are associated with low Pi unless they are accompanied by large deviations from axial dipole field directions. σPi provides a measure of geomagnetic stability that is modulated by the level of PSV or frequency of excursional activity and reversal rate. We demonstrate uses of Pi for paleomagnetic observations and field models and show how it could be used to assess whether numerical simulations of the geodynamo exhibit Earth-like properties.

Piwi-interacting RNAs as novel prognostic markers in clear cell renal cell carcinomas.

PubMed

Busch, Jonas; Ralla, Bernhard; Jung, Monika; Wotschofsky, Zofia; Trujillo-Arribas, Elena; Schwabe, Philipp; Kilic, Ergin; Fendler, Annika; Jung, Klaus

2015-06-14

Piwi-interacting RNAs (piRNAs) are small RNAs of 27-30 nucleotides mapping to transposons or clustering in repeat genomic regions. Preliminary studies suggest an important role in cancerogenesis. This study is the first one investigating their prognostic impact in clear cell renal cell cancer (ccRCC) patients. Three piRNAs (piR-30924, piR-57125, and piR-38756) selected on the basis of initial piRNA microarray analyses were determined using RT-qPCR in non-metastatic (n = 76) and metastatic (n = 30) ccRCC tissue at the time of nephrectomy in comparison to normal renal tissue (n = 77) and tissue from distant ccRCC metastases (n = 13). Primary clinical end points were recurrence-free and overall survival. piR-57125 showed lower expression in metastatic than in non-metastatic tumors, whereas the expression of piR-30924 and piR-38756 increased in metastatic tumors. The higher expression of piR-30924 and piR-38756 as well as the lower expression of piR-57125 in metastatic primary tumors were significantly associated with tumor recurrence and overall survival. Multivariate Cox regression analyses revealed both piR-30924 and piR-57125 as independent prognostic predictors. This impact was even more pronounced in non-metastatic patients. This study demonstrates that the expression levels of these piRNAs in primary non-metastatic and metastatic ccRCC tissue can serve as potential prognostic biomarkers in combination with clinicopathological factors.

Flexible and transparent polyimide films containing two-dimensional alumina nanosheets templated by graphene oxide for improved barrier property.

PubMed

Tseng, I-Hsiang; Tsai, Mei-Hui; Chung, Chi-Wei

2014-08-13

Unique two-dimensional alumina nanosheets (Alns) using graphene oxide (GO) as templates are fabricated and successfully incorporated with organo-soluble polyimide (PI) to obtain highly transparent PI nanocomposite films with improved moisture barrier property. The effects of filler types and contents on water vapor transmission rate (WVTR) and transparency of PI are systematically studied. The hydroxyl groups on GO react with aluminum isopropoxide via sol-gel process to obtain alumina coverd-GO (Al-GO), and then thermal decomposition is applied to obtain Alns. Alns are the most efficient fillers among others to restrict the diffusion of water vapor within PI matrix and simultaneously maintain the transparency of PI. XRD pattern, TEM, and AFM images confirm the sheet-like morphology of Alns with ultrahigh aspect ratio. With only 0.01 wt % of Alns, the PI nanocomposite film exhibits the most significant reduction of 95% in WVTR as compared to that of pure PI film. Most importantly, the resultant PI/Alns-0.01 film exhibits excellent optical transparency and high mechanical strength and great thermal stability.

Retrospective seasonal prediction of summer monsoon rainfall over West Central and Peninsular India in the past 142 years

NASA Astrophysics Data System (ADS)

Li, Juan; Wang, Bin; Yang, Young-Min

2017-04-01

Prediction of Indian summer (June-September) rainfall on regional scales remains an open issue. The operational predictions of West Central Indian summer rainfall (WCI-R) and Peninsular Indian summer rainfall (PI-R) made by the Indian Meteorological Department (IMD) had no skills during 2004-2012. This motivates the present study aiming at better understanding the predictability sources and physical processes governing summer rainfall variability over these two regions. Analysis of 133 year data reveal that although the lower boundary forcing that associated with enhanced WCI-R and PI-R featured a similar developing La-Nina and "east high west low" sea-level pressure (SLP) dipole pattern across the Indo-Pacific, the anomalous high sea surface temperature (SST) over the northern Indian Ocean and weak low pressure over northern Asia tended to enhance PI-R but reduce WCI-R. Based on our understanding of physical linkages with the predictands, we selected four and two causative predictors for predictions of the WCI-R and PI-R, respectively. The intensified summer WCI-R is preceded by (a) Indian Ocean zonal dipole-like SST tendency (west-warming and east-cooling), (b) tropical Pacific zonal dipole SST tendency (west-warming and east-cooling), (c) central Pacific meridional dipole SST tendency (north-cooling and south-warming), and (d) decreasing SLP tendency over northern Asia in the previous season. The enhanced PI-R was lead by the central-eastern Pacific cooling and 2-m temperature cooling tendency east of Lake Balkhash in the previous seasons. These causative processes linking the predictors and WCI-R and PI-R are supported by ensemble numerical experiments using a coupled climate model. For the period of 1871-2012, the physics-based empirical (P-E) prediction models built on these predictors result in cross-validated forecast temporal correlation coefficient skills of 0.55 and 0.47 for WCI-R and PI-R, respectively. The independent forecast skill is significantly higher than the skill of operational seasonal forecast made by the IMD for the period of 2004-2012. These prediction models offer a tool for seasonal prediction and their retrospective forecast skills provide an estimation of the lower bound of the predictability for WCI-R and PI-R.

The Impact of Pre-Industrial Land Use Change on Atmospheric Composition and Aerosol Radiative Forcing.

NASA Astrophysics Data System (ADS)

Hamilton, D. S.; Carslaw, K. S.; Spracklen, D. V.; Folberth, G.; Kaplan, J. O.; Pringle, K.; Scott, C.

2015-12-01

Anthropogenic land use change (LUC) has had a major impact on the climate by altering the amount of carbon stored in vegetation, changing surface albedo and modifying the levels of both biogenic and pyrogenic emissions. While previous studies of LUC have largely focused on the first two components, there has recently been a recognition that changes to aerosol and related pre-cursor gas emissions from LUC are equally important. Furthermore, it has also recently been recognised that the pre-industrial (PI) to present day (PD) radiative forcing (RF) of climate from aerosol cloud interactions (ACI) due to anthropogenic emissions is highly sensitive to the amount of natural aerosol that was present in the PI. This suggests that anthropogenic RF from ACI may be highly sensitive to land-use in the PI. There are currently two commonly used baseline reference years for the PI; 1750 and 1860. Rapid LUC occurred between 1750 and 1860, with large reductions in natural vegetation cover in Eastern Northern America, Europe, Central Russia, India and Eastern China as well as lower reductions in parts of Brazil and Africa. This LUC will have led to significant changes in biogenic and fire emissions with implications for natural aerosol concentrations and PI-to-PD RF. The focus of this study is therefore to quantify the impact of LUC between 1750 and 1860 on aerosol concentrations and PI-to-PD RF calculations from ACI. We use the UK Met Office HadGEM3-UKCA coupled-chemistry-climate model to calculate the impacts of anthropogenic emissions and anthropogenic LUC on aerosol size distributions in both 1750 and 1860. We prescribe LUC using the KK10 historical dataset of land cover change. Monoterpene emissions are coupled directly to the prescribed LUC through the JULES land surface scheme in HadGEM3. Fire emissions from LUC were calculated offline using the fire module LPJ-LMfire in the Lund-Potsdam-Jena dynamic global vegetation model. To separate out the impacts of LUC from anthropogenic emissions a further simulation where only LUC and natural emissions are considered is undertaken. We then explore the sensitivity of PI-to-PD aerosol number concentrations, cloud drop number concentrations and the RF on assumed land-cover in the PI. This work will help determine the need for accurate descriptions of historical LUC in calculations of ACI.

Social Network Characteristics, Social Support, and Cigarette Smoking among Asian/Pacific Islander Young Adults.

PubMed

Pokhrel, Pallav; Fagan, Pebbles; Cassel, Kevin; Trinidad, Dennis R; Kaholokula, Joseph Keawe'aimoku; Herzog, Thaddeus A

2016-06-01

Cigarette smoking may be one of the factors contributing to the high levels of cancer-related mortality experienced by certain Asian/Pacific Islander (A/PI) subgroups (e.g., Native Hawaiian). Given the collectivist cultural orientation attributed to A/PI groups, social strategies are recommended for substance abuse or smoking cessation treatment among A/PI. However, research examining how social network characteristics and social support relate to smoking across A/PI subgroups has been lacking. This study investigated the associations between social network characteristics (e.g., size, composition), perceived social support, and recent cigarette use across Native Hawaiian, Filipino, and East Asian (e.g., Japanese, Chinese) young adults (18-35 year old). Cross-sectional, self-report data were collected from N = 435 participants (M age = 25.6, SD = 8.3; 61% women). Ethnic differences were found in a number of pathways linking social network characteristics, perceived social support, and cigarette smoking. Larger network size was strongly associated with higher perceived social support and lower recent cigarette smoking among Native Hawaiians but not Filipinos or East Asians. Higher perceived social support was associated with lower recent smoking among East Asians and Filipinos but not Native Hawaiians. Implications are discussed with regard to smoking prevention and cessation among A/PI. © Society for Community Research and Action 2016.

The Quest for Pi

NASA Technical Reports Server (NTRS)

Bailey, David H.; Borwein, Jonathan M.; Borwein, Peter B.; Plouffe, Simon

1996-01-01

This article gives a brief history of the analysis and computation of the mathematical constant Pi=3.14159 ..., including a number of the formulas that have been used to compute Pi through the ages. Recent developments in this area are then discussed in some detail, including the recent computation of Pi to over six billion decimal digits using high-order convergent algorithms, and a newly discovered scheme that permits arbitrary individual hexadecimal digits of Pi to be computed.

Constitutive Macropinocytosis in Oncogene-transformed Fibroblasts Depends on Sequential Permanent Activation of Phosphoinositide 3-Kinase and Phospholipase C

PubMed Central

Amyere, Mustapha; Payrastre, Bernard; Krause, Ulrike; Smissen, Patrick Van Der; Veithen, Alex; Courtoy, Pierre J.

2000-01-01

Macropinocytosis results from the closure of lamellipodia generated by membrane ruffling, thereby reflecting cortical actin dynamics. Both transformation of Rat-1 fibroblasts by v-Src or K-Ras and stable transfection for expression of dominant-positive, wild-type phosphoinositide 3-kinase (PI3K) regulatory subunit p85α constitutively led to stress fiber disruption, cortical actin recruitment, extensive ruffling, and macropinosome formation, as measured by a selective acceleration of fluid-phase endocytosis. These alterations closely correlated with activation of PI3K and phosphatidylinositol-specific phospholipase C (PI-PLC), as assayed by 3-phosphoinositide synthesis in situ and in vitro and inositol 1,4,5 trisphosphate steady-state levels, respectively; they were abolished by stable transfection of v-Src–transformed cells for dominant-negative truncated p85α expression and by pharmacological inhibitors of PI3K and PI-PLC, indicating a requirement for both enzymes. Whereas PI3K activation resisted PI-PLC inhibition, PI-PLC activation was abolished by a PI3K inhibitor and dominant-negative transfection, thus placing PI-PLC downstream of PI3K. Together, these data suggest that permanent sequential activation of both PI3K and PI-PLC is necessary for the dramatic reorganization of the actin cytoskeleton in oncogene-transformed fibroblasts, resulting in constitutive ruffling and macropinocytosis. PMID:11029048

[A correlation study between diarrhea-predominant irritable bowel syndrome complicated functional dyspepsia patients of Gan-stagnation Pi-deficiency syndrome and gastrointestinal hormones].

PubMed

Zhao, Liang; Song, Wen; Zhu, Ping; Zhang, Yu; Bu, Ping

2014-10-01

To investigate the correlation between the pathogeneses of diarrhea-pre- dominant irritable bowel syndrome (D-IBS) complicated functional dyspepsia (FD) patients of Gan-stagnation Pi-deficiency Syndrome (GSPDS) and symptoms, psychological states, and gastrointestinal hormones. A total of 111 patients with confirmed D-IBS complicated FD of GSPDS were recruited as the treated group by using Rome III standard and Chinese medical syndrome standard. And 30 healthy volunteers were recruited as the control group. The general condition, scoring for digestive symptoms, and the distribution of GSPDS subtype of all subjects were recorded by a questionnaire, and assessed by Symptom Checklist (SCL-90; a software for psychological test developed by Beijing Huicheng Adult Cor- poration). Meanwhile, plasma levels of 5-hydroxytryptamine (5-HT), somatostatin (SS), vasoactive intestinal peptide (VIP), endothelin (ET), interleukin 10 (IL-10), and interleukin 12 (IL-12) were measured in all subjects. (1) The subtype of D-IBS complicated FD of GSPDS was dominant in Pi-qi deficiency type (51/111,45.9%),Pi yang deficiency type (34/111,30.6%), and GSPDS. There was no statistical difference in the scoring of digestive symptoms among the 3 subtypes (P >0.05). (2) Compared with the control group, the anxiety factor score and the total score significantly increased in all three subtypes of D-IBS complicated FD of GSPDS, and the depression score of Pi yang deficiency type and Gan-depression type also significantly increased (P <0.05, P <0.01); the depression score of Gan-depression type was significantly higher than that of the Pi-qi deficiency type (P <0.01). Plasma 5-HT levels were obviously lower in D-IBS complicated FD patients of GSPDS accompanied with anxiety or depression than in those with no obvious psychological abnormalities, and VIP and IL-10 levels were significantly lower than those in the control group (P <0.05). Plasma VIP levels were also obviously lower in D-IBS complicated FD patients of GSPDS accompanied with anxiety or depression than in those with no obvious psychological abnormalities (P <0.01), and SS levels were significantly lower than those in the control group (P <0.05). There was no statistical difference in plasma ET or IL-12 levels in each patient group, when compared with the control group (P >0.05). (3) Compared with the.control group, plasma 5-HT levels significantly increased, plasma VIP and IL-10 levels significantly decreased in ach subtype of D-IBS complicated FD patients of GSPDS (P <0.05, P <0.01), and no significant change of SS, ET, or IL-12 occurred (P >0.05). Besides, plasma 5-HT levels were significantly higher in Gan-depression type than in Pi yang deficiency type, VIP levels were lower in Gan-depression type than in Pi-qi deficiency type (all P <0.05). Gan stagnation and Pi deficiency were dominant in D-IBS complicated FD patients of GSPDS. Psychological abnormalities, increased plasma 5-HT levels, and decreased plasma VIP levels were closely correlated with Gan stagnation subtype, which provided some reference for looking for objective indicators of Chinese medical syndromes in treating D-IBS complicated FD patients of GSPDS.

Differences in glutathione S-transferase pi expression in transgenic mice with symptoms of neurodegeneration.

PubMed

Kaźmierczak, Beata; Kuźma-Kozakiewicz, Magdalena; Usarek, Ewa; Barańczyk-Kuźma, Anna

2011-01-01

Glutathione S-transferase pi (GST pi) is an enzyme involved in cell protection against toxic electrophiles and products of oxidative stress. GST pi expression was studied in transgenic mice hybrids (B6-C3H) with symptoms of neurodegeneration harboring SOD1G93A (SOD1/+), Dync1h1 (Cra1/+) and double (Cra1/SOD1) mutations, at presymptomatic and symptomatic stages (age 70, 140, 365 days) using RT-PCR and Western blotting. The main changes in GST pi expression were observed in mice with the SODG93A mutation. In SOD1/+ and Cra1/SOD1 transgenics, with the exception of cerebellum, the changes in GST pi-mRNA accompanied those in GST pi protein. In brain cortex of both groups the expression was unchanged at the presymptomatic (age 70 days) but was lower at the symptomatic stage (age 140 days) and at both stages in hippocampus and spinal cord of SOD1/+ but not of Cra1/SOD1 mice compared to age-matched wild-type controls. In cerebellum of the presymptomatic and the symptomatic SOD1/+ mice and presymptomatic Cra1/SOD1 mice, the GST pi-mRNA was drastically elevated but the protein level remained unchanged. In Cra1/+ transgenics there were no changes in GST pi expression in any CNS region both on the mRNA and on the protein level. It can be concluded that the SOD1G93A but not the Dync1h1 mutation significantly decreases detoxification efficiency of GST pi in CNS, however the Dync1h1 mutation reduces the effects caused by the SOD1G93A mutation. Despite similarities in neurological symptoms, the differences in GST pi expression between SOD1/+ and Cra1/+ transgenics indicate a distinct pathogenic entity of these two conditions.

Proinsulin slows retinal degeneration and vision loss in the P23H rat model of retinitis pigmentosa.

PubMed

Fernández-Sánchez, Laura; Lax, Pedro; Isiegas, Carolina; Ayuso, Eduard; Ruiz, José M; de la Villa, Pedro; Bosch, Fatima; de la Rosa, Enrique J; Cuenca, Nicolás

2012-12-01

Proinsulin has been characterized as a neuroprotective molecule. In this work we assess the therapeutic potential of proinsulin on photoreceptor degeneration, synaptic connectivity, and functional activity of the retina in the transgenic P23H rat, an animal model of autosomal dominant retinitis pigmentosa (RP). P23H homozygous rats received an intramuscular injection of an adeno-associated viral vector serotype 1 (AAV1) expressing human proinsulin (hPi+) or AAV1-null vector (hPi-) at P20. Levels of hPi in serum were determined by enzyme-linked immunosorbent assay (ELISA), and visual function was evaluated by electroretinographic (ERG) recording at P30, P60, P90, and P120. Preservation of retinal structure was assessed by immunohistochemistry at P120. Human proinsulin was detected in serum from rats injected with hPi+ at all times tested, with average hPi levels ranging from 1.1 nM (P30) to 1.4 nM (P120). ERG recordings showed an amelioration of vision loss in hPi+ animals. The scotopic b-waves were significantly higher in hPi+ animals than in control rats at P90 and P120. This attenuation of visual deterioration correlated with a delay in photoreceptor degeneration and the preservation of retinal cytoarchitecture. hPi+ animals had 48.7% more photoreceptors than control animals. Presynaptic and postsynaptic elements, as well as the synaptic contacts between photoreceptors and bipolar or horizontal cells, were preserved in hPi+ P23H rats. Furthermore, in hPi+ rat retinas the number of rod bipolar cell bodies was greater than in control rats. Our data demonstrate that hPi expression preserves cone and rod structure and function, together with their contacts with postsynaptic neurons, in the P23H rat. These data strongly support the further development of proinsulin-based therapy to counteract retinitis pigmentosa.

Vascular-mediated signalling involved in early phosphate stress response in plants.

PubMed

Zhang, Zhaoliang; Zheng, Yi; Ham, Byung-Kook; Chen, Jieyu; Yoshida, Akiko; Kochian, Leon V; Fei, Zhangjun; Lucas, William J

2016-04-04

Depletion of finite global rock phosphate (Pi) reserves will impose major limitations on future agricultural productivity and food security. Hence, modern breeding programmes seek to develop Pi-efficient crops with sustainable yields under reduced Pi fertilizer inputs. In this regard, although the long-term responses of plants to Pi stress are well documented, the early signalling events have yet to be elucidated. Here, we show plant tissue-specific responses to early Pi stress at the transcription level and a predominant role of the plant vascular system in this process. Specifically, imposition of Pi stress induces rapid and major changes in the mRNA population in the phloem translocation stream, and grafting studies have revealed that many hundreds of phloem-mobile mRNAs are delivered to specific sink tissues. We propose that the shoot vascular system acts as the site of root-derived Pi stress perception, and the phloem serves to deliver a cascade of signals to various sinks, presumably to coordinate whole-plant Pi homeostasis.

All over the map: An interobserver agreement study of tumor location based on the PI-RADSv2 sector map.

PubMed

Greer, Matthew D; Shih, Joanna H; Barrett, Tristan; Bednarova, Sandra; Kabakus, Ismail; Law, Yan Mee; Shebel, Haytham; Merino, Maria J; Wood, Bradford J; Pinto, Peter A; Choyke, Peter L; Turkbey, Baris

2018-01-17

Prostate imaging reporting and data system version 2 (PI-RADSv2) recommends a sector map for reporting findings of prostate cancer mulitparametric MRI (mpMRI). Anecdotally, radiologists may demonstrate inconsistent reproducibility with this map. To evaluate interobserver agreement in defining prostate tumor location on mpMRI using the PI-RADSv2 sector map. Retrospective. Thirty consecutive patients who underwent mpMRI between October, 2013 and March, 2015 and who subsequently underwent prostatectomy with whole-mount processing. 3T mpMRI with T 2 W, diffusion-weighted imaging (DWI) (apparent diffusion coefficient [ADC] and b-2000), dynamic contrast-enhanced (DCE). Six radiologists (two high, two intermediate, and two low experience) from six institutions participated. Readers were blinded to lesion location and detected up to four lesions as per PI-RADSv2 guidelines. Readers marked the long-axis of lesions, saved screen-shots of each lesion, and then marked the lesion location on the PI-RADSv2 sector map. Whole-mount prostatectomy specimens registered to the MRI served as ground truth. Index lesions were defined as the highest grade lesion or largest lesion if grades were equivalent. Agreement was calculated for the exact, overlap, and proportion of agreement. Readers detected an average of 1.9 lesions per patient (range 1.6-2.3). 96.3% (335/348) of all lesions for all readers were scored PI-RADS ≥3. Readers defined a median of 2 (range 1-18) sectors per lesion. Agreement for detecting index lesions by screen shots was 83.7% (76.1%-89.9%) vs. 71.0% (63.1-78.3%) overlap agreement on the PI-RADS sector map (P < 0.001). Exact agreement for defining sectors of detected index lesions was only 21.2% (95% confidence interval [CI]: 14.4-27.7%) and rose to 49.0% (42.4-55.3%) when overlap was considered. Agreement on defining the same level of disease (ie, apex, mid, base) was 61.4% (95% CI 50.2-71.8%). Readers are highly likely to detect the same index lesion on mpMRI, but exhibit poor reproducibility when attempting to define tumor location on the PI-RADSv2 sector map. The poor agreement of the PI-RADSv2 sector map raises concerns its utility in clinical practice. 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. © 2018 International Society for Magnetic Resonance in Medicine.

Vacuolar SPX-MFS transporters are essential for phosphate adaptation in plants.

PubMed

Liu, Jinlong; Fu, Shaomin; Yang, Lei; Luan, Mingda; Zhao, Fugeng; Luan, Sheng; Lan, Wenzhi

2016-08-02

To survive in most soils in which inorganic phosphate (Pi) levels are limited and constantly changing, plants universally use the vacuoles as cellular Pi "sink" and "source" to maintain Pi homeostasis. However, the transporters that mediate Pi sequestration into the vacuoles remain unknown. Recently, we and other 2 groups independently identified the members of SPS-MSF family as the candidates for tonoplast Pi transporters in Arabidopsis thaliana and Oryza sativa. We and Liu et al. demonstrated that one of SPS-MSF member, VPT1 (Vacuolar Phosphate Transporter 1), also named as PHT5;1 (Phosphate Transporter 5;1), plays a predominant role in Pi sequestration of vacuoles in Arabidopsis. Here we show that vpt1 mutants and VPT1-GFP overexpressing lines displayed sensitive to Pi stress under the hydroponic system containing the medium with low iron, supporting that VPT1 is essential for Arabidopsis to adapt phosphate stress.

HIV-infected patients receiving lopinavir/ritonavir-based antiretroviral therapy achieve high rates of virologic suppression despite adherence rates less than 95%.

PubMed

Shuter, Jonathan; Sarlo, Julie A; Kanmaz, Tina J; Rode, Richard A; Zingman, Barry S

2007-05-01

The observation that extremely high levels of medication adherence are required to achieve complete virologic suppression is based largely on studies of treatment-experienced patients receiving HIV protease inhibitor (PI)-based therapy without ritonavir boosting. This study aims to define the level of adherence needed to achieve virologic suppression in patients receiving boosted PI-based highly active antiretroviral therapy (HAART) with lopinavir/ritonavir. HIV-infected adults receiving a regimen containing lopinavir/ritonavir were recruited into a prospective, observational study of the relation between adherence to lopinavir/ritonavir and virologic outcomes. Adherence was measured using the Medication Event Monitoring System (MEMS; Aardex, Union City, CA). HIV-1 viral load (VL) was measured at week 24. The final study population contained 64 subjects. Eighty percent had AIDS, 97% received lopinavir/ritonavir before enrollment, and most had more than 7 years of HAART experience. Mean adherence overall was 73%. Eighty percent and 59% achieved a VL <400 copies/mL and a VL <75 copies/mL, respectively. Mean adherence was 75% in those achieving a VL <75 copies/mL. High rates of virologic suppression were observed in all adherence quartiles, including the lowest quartile (range of adherence: 23.5%-53.3%). Moderate levels of adherence can lead to virologic suppression in most patients taking lopinavir/ritonavir-based HAART.

Early intervention influences positively quality of life as reported by prematurely born children at age nine and their parents; a randomized clinical trial.

PubMed

Landsem, Inger Pauline; Handegård, Bjørn Helge; Ulvund, Stein Erik; Kaaresen, Per Ivar; Rønning, John A

2015-02-22

The Tromsø Intervention Study on Preterms evaluates an early, sensitizing intervention given to parents of prematurely born children (birth-weight < 2000 g). The current study investigated the potential influence of the intervention on children's self-reported and parental proxy-reported quality of life (QoL) at children's age of nine. Participants were randomized to either intervention (PI, n = 72) or preterm control (PC, n = 74) in the neonatal care unit, while healthy term-born infants were recruited to a term reference group (TR, n = 75). The intervention was a modified version of the Mother-Infant Transaction Program, and comprised eight one-hour sessions during the last week before discharge and four home visits at 1, 2, 4 and 12 weeks post-discharge. The two control groups received care in accordance with written guidelines drawn up at the hospital. Participants and parents reported QoL independently on the Kinder Lebensqualität Fragebogen (KINDL) questionnaire. Differences between groups were analyzed by SPSS; Linear Mixed Models and parent-child agreement were analyzed and compared by intra-class correlations within each group. On average, children in all groups reported high levels of well-being. The PI children reported better physical well-being than the PC children (p = 0.002). In all other aspects of QoL both the PI and the PC children reported at similar levels as the term reference group. PI parents reported better emotional wellbeing (p = 0.05) and a higher level of contentment in school (p = 0.003) compared with PC parents. Parent-child agreement was significantly weaker in the PI group than in the PC group on dimensions such as emotional well-being and relationships with friends (p < 0.05). PI parents reported QoL similar to parents of terms on all aspects except the subscale self-esteem, while PC parents generally reported moderately lower QoL than TR parents. This early intervention appears to have generated long-lasting positive effects, improving perceived physical well-being among prematurely born children and parent's perception of these children's QoL in middle childhood. Clinical Trials Gov NCT00222456 .

[Variation of long-chain 3-hydroxyacyl-CoA dehydrogenase DNA methylation in placenta of different preeclampsia-like mouse models].

PubMed

Han, Yiwei; Yang, Zi; Ding, Xiaoyan; Yu, Huan; Yi, Yanhong

2015-10-01

By detecting the variation of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) DNA methylation in preeclampsia-like mouse models generated by different ways, to explore the roles of multifactor and multiple pathways in preeclampsia pathogenesis on molecular basis. Established preeclampsia-like mouse models in different ways and divided into groups as follows: (1) Nw-nitro-L-arginine-methyl ester (L-NAME) group: wild-type pregnant mouse received subcutaneous injection of L-NAME; (2) lipopolysaccharide (LPS) group: wild-type pregnant mouse received intraperitoneal injection of LPS; (3) apolipoprotein C-III (ApoC3) group: ApoC3 transgenic pregnant mouse with dysregulated lipid metabolism received subcutaneous injection of L-NAME; (4) β2 glycoprotein I (β-2GPI) group: wild-type pregnant mouse received subcutaneous injection of β-2GPI. According to the first injection time (on day 3, 11, 16 respectively), the L-NAME, LPS and ApoC3 groups were further subdivided into: pre-implantation (PI) experimental stage, early gestation (EG) experimental stage, and late gestation (LG) experimental stage. β-2GPI group was only injected before implantation. LCHAD gene methylation levels in placental were detected in different experimental stage. Normal saline control groups were set within wild-type and ApoC3 transgenic pregnant mice simultaneously. (1) CG sites in LCHAD DNA: 45 CG sites were detected in the range of 728 bp before LCHAD gene transcription start site, the 5, 12, 13, 14, 15, 16, 19, 24, 25, 27, 28, 29, 30, 31, 32, 34, 35, 43 CG sites were complex sites which contained two or more CG sequences, others were single site which contained one CG sequence. The 3, 5, 6, 11, 13, 14, 18, 28 sites in L-NAME, LPS, ApoC3 and β-2GPI groups showed different high levels of methylation; the 16, 25, 31, 42, 44 sites showed different low levels of methylation; other 32 sites were unmethylated. (2) Comparison of LCHAD gene methylation between different groups: the methylation levels of LCAHD gene at 3, 11, 13, 14, 18 sites in L-NAME, LPS, ApoC3 and β-2GPI groups were significantly higher than those in the normal saline control group (P < 0.05); and the methylation levels of 42, 44 sites in these groups were significantly lower than those in the normal saline control group (P < 0.05). (3) Methylation of LCHAD gene at the same site between different experimental stages: ① The 3, 11, 18 sites of EG experimental stage was significantly lower than PI and LG experimental stage in L-NAME group (P < 0.05); the 3, 11, 18 sites of PI experimental stage was significantly lower than EG and LG experimental stage in LPS group (P < 0.05); these sites of PI experimental stage was significantly higher than EG and LG experimental stages in ApoC3 group (P < 0.05). ② The methylation of site 5 in L-NAME and LPS groups were significantly higher than that of the normal saline control group (P < 0.05), and the LG experimental stages were significantly higher than other stages, but in ApoC3 group, only PI and EG stages were significantly higher than the normal saline control group (P < 0.05). ③ At site 6 in L-NAME group which showed high methylation level was significantly higher than the same site in other groups which showed low methylation level (P < 0.05). ④ At 13, 14 sites, earlier preeclampsia onset caused a lower methylation level in L-NAME group, but PI experimental stage was significantly higher than EG and LG experimental stages in LPS group (P < 0.05), EG experimental stage was significantly higher than PI and LG experimental stages in ApoC3 group (P < 0.05). ⑤ At site 28, earlier preeclampsia onset caused a higher methylation level in L-NAME group, but PI experimental stage was significantly lower than EG and LG experimental stages in LPS group (P < 0.05), EG experimental stage was significantly higher than PI and LG experimental stages in ApoC3 group (P < 0.05). ⑥ The 16, 25, 31 sites in ApoC3 group were significantly higher than other groups (P < 0.05). ⑦ At site 42 in β-2GPI group was unmethylated, but it in other groups showed low methylation level, the methylation level of site 42 in β-2GPI group was significantly lower than that in other groups (P < 0.05). The methylation of 6 and 42 CG sites may be related to LCHAD gene expression in placenta of L-NAME and β-2GPI induced preeclampsia-like models respectively; LCHAD gene expression and DNA methylation may not have obvious correlation in LPS and ApoC3 induced preeclampsia-like models. Differences exist in LCHAD DNA methylation in preeclampsia-like models generated by different ways, revealed a molecular basis to expand our understanding of the multi-factorial pathogenesis of preeclampsia.

Temperature sensitivity of phospho-Ser{sup 473}-PKB/AKT

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

Oehler-Jaenne, Christoph; Bueren, Andre O. von; Vuong, Van

2008-10-24

The phospho-PKB/Akt status is often used as surrogate marker to measure activation of the PI3K/Akt/mTOR signal transduction pathway. Though, inconsistencies of the p-Ser{sup 473}-PKB/Akt status have raised doubts in the validity of p-Ser{sup 473}-PKB/Akt phosphorylation as endpoint. Here, we determined that p-Ser{sup 473}-PKB/Akt but not p-Thr{sup 308}-PKB/Akt phosphorylation is highly temperature sensitive. p-Ser{sup 473}-PKB/Akt phosphorylation was rapidly reduced to levels below 50% on exposure to 20-25 deg. C in murine and human cell lines including cells expressing constitutively active PI3K or lacking PTEN. Down-regulation of p-Ser{sup 473}-PKB/Akt was reversible and re-exposure to physiological temperature resulted in increased p-Ser{sup 473}-PKB/Akt phosphorylationmore » levels. Phosphatase activity at low temperature was sustained at 75% baseline level and phosphatase inhibition prevented p-Ser{sup 473}-PKB/Akt dephosphorylation induced by the low temperature shift. Interestingly temperature-dependent deregulation of the p-Ser{sup 473}-PKB/Akt status was also observed in response to irradiation. Thus our data demonstrate that minimal additional stress factors deregulate the PI3K/Akt-survival pathway and the p-Ser{sup 473}-PKB/Akt status as experimental endpoint.« less

Reprint Series: Computation of Pi. RS-7.

ERIC Educational Resources Information Center

Schaaf, William L., Ed.

This is one in a series of SMSG supplementary and enrichment pamphlets for high school students. This series makes available expository articles which appeared in a variety of mathematical periodicals. Topics covered include: (1) the latest about pi; (2) a series useful in the computation of pi; (3) an ENIAC determination of pi and e to more than…

Entanglement Dynamics in Miscible Polyisoprene / Poly(p-tert-butyl styrene) Blends

NASA Astrophysics Data System (ADS)

Watanabe, Hiroshi

2011-03-01

Viscoelastic and dielectric behavior was examined for well entangled, miscible blends of high- M cis-polyisoprene (PI) and poly(p-tert-butyl styrene) (PtBS). The dielectric data of the blends, reflecting the global motion of the PI chains having the type-A dipoles, indicated that PI and PtBS were the fast and slow components therein. At high temperatures T , the blends exhibited two-step entanglement plateau. The high frequency (ω) plateau height was well described by a simple mixing rule of the entanglement length based on the number fraction of the Kuhn segments. At low T , the blend exhibited the Rouse-like power-law behavior of storage and loss moduli, G ' = G ~ω0.5 , in the range of ω where the high- ω plateau was supposed to emerge. This lack of the high- ω plateau was attributed to retardation of the Rouse equilibration of the PI chain over the entanglement length due to the hindrance from the slow PtBS chains: The PI and PtBS chains were equilibrated cooperatively, and the retardation due to PtBS shortened the plateau for PI to a width not resolved experimentally. A simple model for this cooperative equilibration formulated on the basis of the dielectric data described the viscoelastic data surprisingly well.

Dynamics of Disordered PI-PtBS Diblock Copolymer

NASA Astrophysics Data System (ADS)

Watanabe, Hiroshi

2009-03-01

Viscoelastic (G^*) and dielectric (ɛ'') data were examined for a LCST-type diblock copolymer composed of polyisoprene (PI; M = 53K) and poly(p-tert- butyl styrene) (PtBS; M = 42K) blocks disordered at T <=120 C^o. Only PI had the type-A dipole parallel along the chain backbone. Thus, the ɛ'' data reflected the global motion of the PI block, while the G^* data detected the motion of the copolymer chain as a whole. Comparison of these data indicated that the PI block relaxed much faster than the PtBS block at low T and the dynamic heterogeneity due to PtBS was effectively quenched to give a frictional nonuniformity for the PI block relaxation. The ɛ'' data were thermo-rheologically complex at low T, partly due to this nonuniformity. However, the block connectivity could have also led to the complexity. For testing this effect, the ɛ'' data were reduced at the iso- frictional state defined with respect to bulk PI. In this state, the ɛ'' data of the copolymer at low and high T, respectively, were close to the data for the star-branched and linear bulk PI. Thus, the PI block appeared to be effectively tethered in space at low T thereby behaving similarly to the star arm while the PI block tended to move cooperatively with the PtBS block at high T to behave similarly to the linear PI, which led to the complexity of the ɛ'' data. The PtBS block also exhibited the complexity (noted from the G^* data), which was well correlated with the complexity of the PI block.

Self-clearance from BVDV infections--a frequent finding in dairy herds in an endemically infected region in Peru.

PubMed

Ståhl, K; Lindberg, A; Rivera, H; Ortiz, C; Moreno-López, J

2008-03-17

In this cross-sectional study, a stratified two-stage random sampling procedure was employed to select 221 dairy herds for bulk tank milk (BTM) sampling, and a subset of 55 dairy herds for individual blood sampling of a number of young animals (spot test), to predict presence or absence of current BVDV infection, and for data collection. The prediction was based on the high probability of seropositivity in groups of animals where PI animals are present because of the efficient spread of virus from PI animals to the surrounding group. BTM samples were collected in August 2003 (n=192) and February 2004 (n=195), and the 55 herds selected for spot testing and data collection were visited in December 2003. All samples were tested for presence of BVDV specific antibodies using a commercial indirect ELISA (SVANOVA Biotech AB, Uppsala, Sweden). The results demonstrated a very high level of exposure to BVDV in the region, and the proportion of herds with high antibody levels in the BTM was above 95% on both occasions. Despite this, almost two thirds of the herds had spot test results indicating absence of current infection, suggesting a high probability of self-clearance. A logistic regression model with the results from the spot tests as dependent variable was used to investigate possible herd and management factors associated with self-clearance, and suggested that this may occur regardless of herd size. Even though it is well established that the process of identification and elimination of PI animals is required within a systematic BVDV eradication programme, the present study strongly suggests that many herds may be cleared without intervention even in regions with high cattle density and high BVDV prevalence. Consequently, in any BVDV infected population (regardless of the herd-level BVDV seroprevalence), and at any given point of time, a large proportion of the herds will be free from infection due to self-clearance. Self-clearance is therefore a process that works in favour of any effort to control BVDV, which should be taken into account when planning and assessing the cost-effectiveness of a systematic control programme.

Coactivation of the PI3K/Akt and ERK signaling pathways in PCB153-induced NF-κB activation and caspase inhibition

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

Liu, Changjiang; Key Lab of Birth Defects and Reproductive Health of National Health and Family Planning Commission, Chongqing Population and Family Planning Science and Technology Research Institute, Chongqing 400020; Yang, Jixin

2014-06-15

Polychlorinated biphenyls (PCBs) are a group of persistent and widely distributed environmental pollutants that have various deleterious effects, e.g., neurotoxicity, endocrine disruption and reproductive abnormalities. In order to verify the hypothesis that the PI3K/Akt and MAPK pathways play important roles in hepatotoxicity induced by PCBs, Sprague–Dawley (SD) rats were dosed with PCB153 intraperitoneally at 0, 4, 16 and 32 mg/kg for five consecutive days; BRL cells (rat liver cell line) were treated with PCB153 (0, 1, 5, and 10 μM) for 24 h. Results indicated that the PI3K/Akt and ERK pathways were activated in vivo and in vitro after exposuremore » to PCB153, and protein levels of phospho-Akt and phospho-ERK were significantly increased. Nuclear factor-κB (NF-κB) activation and caspase-3, -8 and -9 inhibition caused by PCB153 were also observed. Inhibiting the ERK pathway significantly attenuated PCB153-induced NF-κB activation, whereas inhibiting the PI3K/Akt pathway hardly influenced phospho-NF-κB level. However, inhibiting the PI3K/Akt pathway significantly elevated caspase-3, -8 and -9 activities, while the ERK pathway only synergistically regulated caspase-9. Proliferating cell nuclear antigen (PCNA), a reliable indicator of cell proliferation, was also induced. Moreover, PCB153 led to hepatocellular hypertrophy and elevated liver weight. Taken together, PCB153 leads to aberrant proliferation and apoptosis of hepatocytes through NF-κB activation and caspase inhibition, and coactivated PI3K/Akt and ERK pathways play critical roles in PCB153-induced hepatotoxicity. - Highlights: • PCB153 led to hepatotoxicity through NF-κB activation and caspase inhibition. • The PI3K/Akt and ERK pathways were coactivated in vivo and in vitro by PCB153. • The ERK pathway regulated levels of phospho-NF-κB and caspase-9. • The PI3K/Akt pathway regulated levels of caspase-3, -8 and -9.« less

Effect of saw palmetto extract on PI3K cell signaling transduction in human glioma.

PubMed

Yang, Yang; Hui, Lv; Yuqin, Che; Jie, Li; Shuai, Hou; Tiezhu, Zhou; Wei, Wang

2014-08-01

Saw palmetto extract can induce the apoptosis of prostate cancer cells. The aim of the present study was to investigate the effect of saw palmetto extract on the phosphatidylinositol 3-kinase (PI3K)/Akt signaling transduction pathway in human glioma U87 and U251 cell lines. Suspensions of U87 and U251 cells in a logarithmic growth phase were seeded into six-well plates at a density of 10 4 cells/well. In the experimental group, 1 μl/ml saw palmetto extract was added, while the control group was cultured without a drug for 24 h. The expression levels of PI3K, B-cell lymphoma-extra large (Bcl-xL) and p53 were evaluated through western blot analysis. In the experimental group, the U87 and U251 cells exhibited a lower expression level of PI3K protein as compared with the control group (t=6.849; P<0.001). In addition, the two cell lines had a higher expression level of p53 protein in the experimental group as compared with the control group (t=40.810; P<0.001). Protein expression levels of Bcl-xL decreased significantly in the experimental group as compared with the control group (t=19.640; P=0.000). Therefore, saw palmetto extract induces glioma cell growth arrest and apoptosis via decreasing PI3K/Akt signal transduction.

Protective role for ovarian glutathione S-transferase isoform pi during 7,12-dimethylbenz[a]anthracene-induced ovotoxicity

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

Bhattacharya, Poulomi, E-mail: poulomib@iastate.edu; Keating, Aileen F., E-mail: akeating@iastate.edu

2012-04-15

7,12-Dimethylbenz[a]anthracene (DMBA) destroys ovarian follicles at all developmental stages. This study investigated a role for the glutathione S-transferase (Gst) isoforms alpha (a), mu (m) and pi (p) and the transcription factors, Ahr and Nrf2, during DMBA-induced ovotoxicity, and their regulation by phosphatidylinositol-3 kinase (PI3K) signaling. Negative regulation of JNK by GSTP during DMBA exposure was also studied. Post-natal day (PND) 4 Fischer 344 rat ovaries were exposed to vehicle control (1% DMSO) ± DMBA (1 μM) or vehicle control (1% DMSO) ± LY294002 (PI3K inhibitor; 20 μM) for 1, 2, 4, or 6 days. Total RNA or protein was isolated,more » followed by RT-PCR or Western blotting to determine mRNA or protein level, respectively. Immunoprecipitation using an anti-GSTP antibody was performed to determine interaction between GSTP and JNK, followed by Western blotting to determine JNK and p-c-Jun protein level. DMBA had no impact on Gsta, Gstm or Nrf2 mRNA level, but increased Gstp mRNA and protein after 2 days. Ahr mRNA and protein increased after 2 and 4 days of DMBA exposure, respectively and DMBA increased NRF2 protein level after 4 days. JNK bound to GSTP was increased during DMBA exposure, with a concomitant decrease in unbound JNK and p-c-Jun. Ahr and Gstp mRNA were decreased (2 days) and increased (4 days) by PI3K inhibition, while Gstm mRNA increased (P < 0.05) after both time points, and there was no effect on Nrf2 mRNA. PI3K inhibition increased AHR, NRF2 and GSTP protein level. These findings support involvement of ovarian GSTP during DMBA exposure, and indicate a regulatory role for the PI3K signaling pathway on ovarian xenobiotic metabolism gene expression. -- Highlights: ► Ovarian GSTP is activated in response to DMBA exposure. ► AhR and Nrf2 transcription factors are up-regulated by DMBA. ► PI3K signaling regulates Ahr, Nrf2 and Gstp expression. ► GSTP negatively regulates ovarian JNK in response to DMBA exposure.« less

Editor's Highlight: Lower Fractional Anisotropy in the Globus Pallidus of Asymptomatic Welders, a Marker for Long-Term Welding Exposure.

PubMed

Lee, Eun-Young; Flynn, Michael R; Du, Guangwei; Lewis, Mechelle M; Herring, Amy H; Van Buren, Eric; Van Buren, Scott; Kong, Lan; Mailman, Richard B; Huang, Xuemei

2016-09-01

Welding fumes contain several metals including manganese (Mn), iron (Fe), and copper (Cu) that at high exposure may co-influence welding-related neurotoxicity. The relationship between brain accumulation of these metals and neuropathology, especially in welders with subclinical exposure levels, is unclear. This study examined the microstructural integrity of basal ganglia (BG) regions in asymptomatic welders using diffusion tensor imaging (DTI). Subjects with (n = 43) and without (age- and gender-matched controls; n = 31) history of welding were studied. Occupational questionnaires estimated short-term (HrsW; welding hours and E90; cumulative exposure, past 90 days) and long-term (YrsW; total years welding and ELT; cumulative exposure, lifetime) exposure. Whole blood metal levels (Mn, Fe, and Cu) were obtained. Brain MRI pallidal index (PI), R1 (1/T1), and R2* (1/T2*) were measured to estimate Mn and Fe accumulation in BG [caudate, putamen, and globus pallidus (GP)]. DTI was used to assess BG microstructural differences, and related with exposure measurements. When compared with controls, welders had significantly lower fractional anisotropy (FA) in the GP. In welders, GP FA values showed non-linear relationships to YrsW, blood Mn, and PI. GP FA decreased after a critical level of YrsW or Mn was reached, whereas it decreased with increasing PI values until plateauing at the highest PI values. GP FA, however, did not show any relationship with short-term exposure measurements (HrsW, E90), blood Cu and Fe, or R(2)* values. GP FA captured microstructural changes associated with chronic low-level Mn exposure, and may serve as a biomarker for neurotoxicity in asymptomatic welders. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

PI16 is a shear stress and inflammation-regulated inhibitor of MMP2

PubMed Central

Hazell, Georgina G. J.; Peachey, Alasdair M. G.; Teasdale, Jack E.; Sala-Newby, Graciela B.; Angelini, Gianni D.; Newby, Andrew C.; White, Stephen J.

2016-01-01

Raised endothelial shear stress is protective against atherosclerosis but such protection may be lost at sites of inflammation. We found that four splice variants of the peptidase inhibitor 16 (PI16) mRNA are among the most highly shear stress regulated transcripts in human coronary artery endothelial cells (HCAECs), in vitro but that expression is reduced by inflammatory mediators TNFα and IL-1β. Immunohistochemistry demonstrated that PI16 is expressed in human coronary endothelium and in a subset of neointimal cells and medial smooth muscle cells. Adenovirus-mediated PI16 overexpression inhibits HCAEC migration and secreted matrix metalloproteinase (MMP) activity. Moreover, PI16 inhibits MMP2 in part by binding an exposed peptide loop above the active site. Our results imply that, at high endothelial shear stress, PI16 contributes to inhibition of protease activity; protection that can be reversed during inflammation. PMID:27996045

Phosphaturic action of fibroblast growth factor 23 in Npt2 null mice.

PubMed

Tomoe, Yuka; Segawa, Hiroko; Shiozawa, Kazuyo; Kaneko, Ichiro; Tominaga, Rieko; Hanabusa, Etsuyo; Aranami, Fumito; Furutani, Junya; Kuwahara, Shoji; Tatsumi, Sawako; Matsumoto, Mitsutu; Ito, Mikiko; Miyamoto, Ken-ichi

2010-06-01

In the present study, we evaluated the roles of type II and type III sodium-dependent P(i) cotransporters in fibroblast growth factor 23 (FGF23) activity by administering a vector encoding FGF23 with the R179Q mutation (FGF23M) to wild-type (WT) mice, Npt2a knockout (KO) mice, Npt2c KO mice, and Npt2a(-/-)Npt2c(-/-) mice (DKO mice). In Npt2a KO mice, FGF23M induced severe hypophosphatemia and markedly decreased the levels of Npt2c, type III Na-dependent P(i) transporter (PiT2) protein, and renal Na/P(i) transport activity. In contrast, in Npt2c KO mice, FGF23M decreased plasma phosphate levels comparable to those in FGF23M-injected WT mice. In DKO mice with severe hypophosphatemia, FGF23M administration did not induce an additional increase in urinary phosphate excretion. FGF23 administration significantly decreased intestinal Npt2b protein levels in WT mice but had no effect in Npt2a, Npt2c, and DKO mice, despite marked suppression of plasma 1,25(OH)(2)D(3) levels in all the mutant mice. The main findings were as follow: 1) FGF23-dependent phosphaturic activity in Npt2a KO mice is dependent on renal Npt2c and PiT-2 protein; 2) in DKO mice, renal P(i) reabsorption is not further decreased by FGF23M, but renal vitamin D synthesis is suppressed; and 3) downregulation of intestinal Npt2b may be mediated by a factor(s) other than 1,25(OH)(2)D(3). These findings suggest that Npt2a, Npt2c, and PiT-2 are necessary for the phosphaturic activity of FGF23. Thus complementary regulation of Npt2 family proteins may be involved in systemic P(i) homeostasis.

Control of actin polymerization via the coincidence of phosphoinositides and high membrane curvature

PubMed Central

Daste, Frederic; Walrant, Astrid; Mason, Julia; Lee, Ji-Eun; Brook, Daniel; Mettlen, Marcel; Larsson, Elin; Lee, Steven F.; Lundmark, Richard

2017-01-01

The conditional use of actin during clathrin-mediated endocytosis in mammalian cells suggests that the cell controls whether and how actin is used. Using a combination of biochemical reconstitution and mammalian cell culture, we elucidate a mechanism by which the coincidence of PI(4,5)P2 and PI(3)P in a curved vesicle triggers actin polymerization. At clathrin-coated pits, PI(3)P is produced by the INPP4A hydrolysis of PI(3,4)P2, and this is necessary for actin-driven endocytosis. Both Cdc42⋅guanosine triphosphate and SNX9 activate N-WASP–WIP- and Arp2/3-mediated actin nucleation. Membrane curvature, PI(4,5)P2, and PI(3)P signals are needed for SNX9 assembly via its PX–BAR domain, whereas signaling through Cdc42 is activated by PI(4,5)P2 alone. INPP4A activity is stimulated by high membrane curvature and synergizes with SNX9 BAR domain binding in a process we call curvature cascade amplification. We show that the SNX9-driven actin comets that arise on human disease–associated oculocerebrorenal syndrome of Lowe (OCRL) deficiencies are reduced by inhibiting PI(3)P production, suggesting PI(3)P kinase inhibitors as a therapeutic strategy in Lowe syndrome. PMID:28923975

Stress inducible proteinase inhibitor diversity in Capsicum annuum

PubMed Central

2012-01-01

Background Wound-inducible Pin-II Proteinase inhibitors (PIs) are one of the important plant serine PIs which have been studied extensively for their structural and functional diversity and relevance in plant defense against insect pests. To explore the functional specialization of an array of Capsicum annuum (L.) proteinase inhibitor (CanPIs) genes, we studied their expression, processing and tissue-specific distribution under steady-state and induced conditions. Inductions were performed by subjecting C. annuum leaves to various treatments, namely aphid infestation or mechanical wounding followed by treatment with either oral secretion (OS) of Helicoverpa armigera or water. Results The elicitation treatments regulated the accumulation of CanPIs corresponding to 4-, 3-, and 2-inhibitory repeat domains (IRDs). Fourty seven different CanPI genes composed of 28 unique IRDs were identified in total along with those reported earlier. The CanPI gene pool either from uninduced or induced leaves was dominated by 3-IRD PIs and trypsin inhibitory domains. Also a major contribution by 4-IRD CanPI genes possessing trypsin and chymotrypsin inhibitor domains was specifically revealed in wounded leaves treated with OS. Wounding displayed the highest number of unique CanPIs while wounding with OS treatment resulted in the high accumulation of specifically CanPI-4, -7 and −10. Characterization of the PI protein activity through two dimensional gel electrophoresis revealed tissue and induction specific patterns. Consistent with transcript abundance, wound plus OS or water treated C. annuum leaves exhibited significantly higher PI activity and isoform diversity contributed by 3- and 4-IRD CanPIs. CanPI accumulation and activity was weakly elicited by aphid infestation yet resulted in the higher expression of CanPI-26, -41 and −43. Conclusions Plants can differentially perceive various kinds of insect attacks and respond appropriately through activating plant defenses including regulation of PIs at transcriptional and post-translational levels. Based on the differentially elicited CanPI accumulation patterns, it is intriguing to speculate that generating sequence diversity in the form of multi-IRD PIs is a part of elaborative plant defense strategy to obtain a diverse pool of functional units to confine insect attack. PMID:23153298

Food Prices Are Associated with Dietary Quality, Fast Food Consumption, and Body Mass Index among U.S. Children and Adolescents123

PubMed Central

Beydoun, May A.; Powell, Lisa M.; Chen, Xiaoli; Wang, Youfa

2011-01-01

Food prices are expected to affect dietary intakes, however, previous findings are mixed and few are based on nationally representative data. We examined the associations of price indices of fast foods (FF-PI) and fruits and vegetables (FV-PI) with dietary intakes and BMI among U.S. children and adolescents using data from the Continuing Survey of Food Intakes by Individuals (CSFII; 1994–1998) for 6759 children (2–9 y) and 1679 adolescents (10–18 y). FF-PI and FV-PI were linked to individuals’ CSFII dietary data through city-level geocodes. Main outcomes included intakes of selected nutrients and food groups, a fast food consumption index (FF-CI), diet quality using the 2005 Healthy Eating Index (HEI), and BMI. Among children (2–9 y), a higher FF-PI (by $1) was associated with intakes of lower FF-CI (β ± SE: −0.9 ± 0.3 count/d), higher HEI (6.6 ± 2.5), higher intakes of fiber (2.7 ± 0.7 g/d), calcium (225.7 ± 52.3 mg/d), dairy (172.5 ± 36.2 g/d), and fruits and vegetables (113.3 ± 23.4 cup equivalents/d). FV-PI was inversely related to fiber intake (β ± SE: −3.3 ± 1.5 g/d) and positively associated with BMI (4.3 ± 1.2 kg/m2). Less consistent findings were ascribed to FV-PI and among adolescents (10–18 y). Significant associations were almost equally balanced between low and high family income groups, with some significant interactions between food prices and family income observed, particularly among children (2–9 y). Our findings suggest that among U.S. children aged 2–9 y, higher FF-PI is associated with better dietary quality, whereas higher FV-PI is linked to higher BMI and lower fiber intake. Associations varied by family income in children for many dietary intake variables. PMID:21178080

Down-regulation of Gab1 inhibits cell proliferation and migration in hilar cholangiocarcinoma.

PubMed

Sang, Haiquan; Li, Tingting; Li, Hangyu; Liu, Jingang

2013-01-01

Hilar cholangiocarcinoma is a highly aggressive malignancy originating from the hilar biliary duct epithelium. Due to few effective comprehensive treatments, the prognosis of hilar cholangiocarcinoma is poor. In this study, immunohistochemistry was first used to detect and analyze the expression of Gab1, VEGFR-2, and MMP-9 in hilar cholangiocarcinoma solid tumors and the relationships to the clinical pathological features. Furthermore, Gab1 and VEGFR-2 siRNA were used to interfere the hilar cholangiocarcinoma cell line ICBD-1 and then detect the PI3K/Akt signaling pathway, MMP-9 levels and malignant biological behaviors of tumor cells. The data showed that 1. Gab1, VEGFR-2, and MMP-9 were highly expressed and positively correlated with each other in hilar cholangiocarcinoma tissues, which were related to lymph node metastasis and differentiation. 2. After Gab1 or VEGFR-2 siRNA interference, PI3K/Akt pathway activity and MMP-9 levels were decreased in ICBD-1 cells. At the same time, cell proliferation decreased, cell cycle arrested in G1 phase, apoptosis increased and invasion decreased. These results suggest that the expression of Gab1, VEGFR-2, and MMP-9 are significantly related to the malignant biological behavior of hilar cholangiocarcinoma. Gab1 regulates growth, apoptosis and invasion through the VEGFR-2/Gab1/PI3K/Akt signaling pathway in hilar cholangiocarcinoma cells and influences the invasion of tumor cells via MMP-9.

Bioavailability of organic and inorganic phosphates adsorbed on short-range ordered aluminum precipitate.

PubMed

Shang, C; Caldwell, D E; Stewart, J W; Tiessen, H; Huang, P M

1996-01-01

A nonreductive community-level study of P availability was conducted using various forms of adsorbed P. Orthophosphate (Pi), inositol hexaphosphate (IHP), and glucose 6-phosphate (G6P) were adsorbed to a short-range ordered Al precipitate. These bound phosphates provided a P source sufficient to support the growth of microbial communities from acidic Brazilian soils (oxisols). Adsorbed IHP, the most abundant form of organic phosphate in most soils, had the lowest bioavailability among the three phosphates studied. Adsorbed G6P and Pi were almost equally available. The amount of adsorbed Pi (1 cmol P kg(-1)) required to support microbial growth was at least 30 times less than that of IHP (30 cmol P kg(-1)). With increased surface coverage, adsorbed IHP became more bioavailable. This availability was attributed to a change in the structure of surface complexes and presumably resulted from the decreased number of high-affinity surface sites remaining at high levels of coverage. It thus appears that the bioavailability of various forms of adsorbed phosphate was determined primarily by the stability of the phosphate-surface complexes that they formed, rather than by the total amount of phosphate adsorbed. IHP, having the potential to form stable multiple-ring complexes, had the highest surface affinity and the lowest bioavailability. Bioaggregates consisting of bacteria and Al precipitate were observed and may be necessary for effective release of adsorbed P. Bacteria in the genera Enterobacter and Pseudomonas were the predominate organisms selected during these P-limited enrichments.

Down-Regulation of Gab1 Inhibits Cell Proliferation and Migration in Hilar Cholangiocarcinoma

PubMed Central

Sang, Haiquan; Li, Tingting; Li, Hangyu; Liu, Jingang

2013-01-01

Hilar cholangiocarcinoma is a highly aggressive malignancy originating from the hilar biliary duct epithelium. Due to few effective comprehensive treatments, the prognosis of hilar cholangiocarcinoma is poor. In this study, immunohistochemistry was first used to detect and analyze the expression of Gab1, VEGFR-2, and MMP-9 in hilar cholangiocarcinoma solid tumors and the relationships to the clinical pathological features. Furthermore, Gab1 and VEGFR-2 siRNA were used to interfere the hilar cholangiocarcinoma cell line ICBD-1 and then detect the PI3K/Akt signaling pathway, MMP-9 levels and malignant biological behaviors of tumor cells. The data showed that 1. Gab1, VEGFR-2, and MMP-9 were highly expressed and positively correlated with each other in hilar cholangiocarcinoma tissues, which were related to lymph node metastasis and differentiation. 2. After Gab1 or VEGFR-2 siRNA interference, PI3K/Akt pathway activity and MMP-9 levels were decreased in ICBD-1 cells. At the same time, cell proliferation decreased, cell cycle arrested in G1 phase, apoptosis increased and invasion decreased. These results suggest that the expression of Gab1, VEGFR-2, and MMP-9 are significantly related to the malignant biological behavior of hilar cholangiocarcinoma. Gab1 regulates growth, apoptosis and invasion through the VEGFR-2/Gab1/PI3K/Akt signaling pathway in hilar cholangiocarcinoma cells and influences the invasion of tumor cells via MMP-9. PMID:24312291

Mapping of the minimal inorganic phosphate transporting unit of human PiT2 suggests a structure universal to PiT-related proteins from all kingdoms of life

PubMed Central

2011-01-01

Background The inorganic (Pi) phosphate transporter (PiT) family comprises known and putative Na+- or H+-dependent Pi-transporting proteins with representatives from all kingdoms. The mammalian members are placed in the outer cell membranes and suggested to supply cells with Pi to maintain house-keeping functions. Alignment of protein sequences representing PiT family members from all kingdoms reveals the presence of conserved amino acids and that bacterial phosphate permeases and putative phosphate permeases from archaea lack substantial parts of the protein sequence when compared to the mammalian PiT family members. Besides being Na+-dependent Pi (NaPi) transporters, the mammalian PiT paralogs, PiT1 and PiT2, also are receptors for gamma-retroviruses. We have here exploited the dual-function of PiT1 and PiT2 to study the structure-function relationship of PiT proteins. Results We show that the human PiT2 histidine, H502, and the human PiT1 glutamate, E70, - both conserved in eukaryotic PiT family members - are critical for Pi transport function. Noticeably, human PiT2 H502 is located in the C-terminal PiT family signature sequence, and human PiT1 E70 is located in ProDom domains characteristic for all PiT family members. A human PiT2 truncation mutant, which consists of the predicted 10 transmembrane (TM) domain backbone without a large intracellular domain (human PiT2ΔR254-V483), was found to be a fully functional Pi transporter. Further truncation of the human PiT2 protein by additional removal of two predicted TM domains together with the large intracellular domain created a mutant that resembles a bacterial phosphate permease and an archaeal putative phosphate permease. This human PiT2 truncation mutant (human PiT2ΔL183-V483) did also support Pi transport albeit at very low levels. Conclusions The results suggest that the overall structure of the Pi-transporting unit of the PiT family proteins has remained unchanged during evolution. Moreover, in combination, our studies of the gene structure of the human PiT1 and PiT2 genes (SLC20A1 and SLC20A2, respectively) and alignment of protein sequences of PiT family members from all kingdoms, along with the studies of the dual functions of the human PiT paralogs show that these proteins are excellent as models for studying the evolution of a protein's structure-function relationship. PMID:21586110

Involvement of PI3K/Akt and p38 MAPK in the induction of COX-2 expression by bacterial lipopolysaccharide in murine adrenocortical cells.

PubMed

Mercau, M E; Astort, F; Giordanino, E F; Martinez Calejman, C; Sanchez, R; Caldareri, L; Repetto, E M; Coso, O A; Cymeryng, C B

2014-03-25

Previous studies from our laboratory demonstrated the involvement of COX-2 in the stimulation of steroid production by LPS in murine adrenocortical Y1 cells, as well as in the adrenal cortex of male Wistar rats. In this paper we analyzed signaling pathways involved in the induction of this key regulatory enzyme in adrenocortical cells and demonstrated that LPS triggers an increase in COX-2 mRNA levels by mechanisms involving the stimulation of reactive oxygen species (ROS) generation and the activation of p38 MAPK and Akt, in addition to the previously demonstrated increase in NFκB activity. In this sense we showed that: (1) inhibition of p38 MAPK or PI3K/Akt (pharmacological or molecular) prevented the increase in COX-2 protein levels by LPS, (2) LPS induced p38 MAPK and Akt phosphorylation, (3) antioxidant treatment blocked the effect of LPS on p38 MAPK phosphorylation and in COX-2 protein levels, (4) PI3K inhibition with LY294002 prevented p38 MAPK phosphorylation and, (5) the activity of an NFκB reporter was decreased by p38 MAPK or PI3K inhibition. These results suggest that activation of both p38 MAPK and PI3K/Akt pathways promote the stimulation of NFκB activity and that PI3K/Akt activity might regulate both p38 MAPK and NFκB signaling pathways. In summary, in this study we showed that in adrenal cells, LPS induces COX-2 expression by activating p38 MAPK and PI3K/Akt signaling pathways and that both pathways converge in the modulation of NFκB transcriptional activity. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Neuronal suppressor of cytokine signaling-3 deficiency enhances hypothalamic leptin-dependent phosphatidylinositol 3-kinase signaling.

PubMed

Metlakunta, Anantha S; Sahu, Maitrayee; Yasukawa, Hideo; Dhillon, Sandeep S; Belsham, Denise D; Yoshimura, Akihiko; Sahu, Abhiram

2011-05-01

Suppressor of cytokine signaling-3 (SOCS3) is thought to be involved in the development of central leptin resistance and obesity by inhibiting STAT3 pathway. Because phosphatidylinositol 3-kinase (PI3K) pathway plays an important role in transducing leptin action in the hypothalamus, we examined whether SOCS3 exerted an inhibition on this pathway. We first determined whether leptin sensitivity in the hypothalamic PI3K pathway was increased in brain-specific Socs3-deficient (NesKO) mice. In NesKO mice, hypothalamic insulin receptor substrate-1 (IRS1)-associated PI3K activity was significantly increased at 30 min and remained elevated up to 2 h after leptin intraperitoneal injection, but in wild-type (WT) littermates, the significant increase was only at 30 min. Hypothalamic p-STAT3 levels were increased up to 5 h in NesKO as opposed to 2 h in WT mice. In food-restricted WT mice with reduced body weight, leptin increased hypothalamic PI3K activity only at 30 min, and p-STAT3 levels at 30-120 min postinjection. These results suggest increased leptin sensitivity in both PI3K and STAT3 pathways in the hypothalamus of NesKO mice, which was not due to a lean phenotype. In the next experiment with a clonal hypothalamic neuronal cell line expressing proopiomelanocortin, we observed that whereas leptin significantly increased IRS1-associated PI3K activity and p-JAK2 levels in cells transfected with control vector, it failed to do so in SOCS3-overexpressed cells. Altogether, these results imply a SOCS3 inhibition of the PI3K pathway of leptin signaling in the hypothalamus, which may be one of the mechanisms behind the development of central leptin resistance and obesity.

Neuronal suppressor of cytokine signaling-3 deficiency enhances hypothalamic leptin-dependent phosphatidylinositol 3-kinase signaling

PubMed Central

Metlakunta, Anantha S.; Sahu, Maitrayee; Yasukawa, Hideo; Dhillon, Sandeep S.; Belsham, Denise D.; Yoshimura, Akihiko

2011-01-01

Suppressor of cytokine signaling-3 (SOCS3) is thought to be involved in the development of central leptin resistance and obesity by inhibiting STAT3 pathway. Because phosphatidylinositol 3-kinase (PI3K) pathway plays an important role in transducing leptin action in the hypothalamus, we examined whether SOCS3 exerted an inhibition on this pathway. We first determined whether leptin sensitivity in the hypothalamic PI3K pathway was increased in brain-specific Socs3-deficient (NesKO) mice. In NesKO mice, hypothalamic insulin receptor substrate-1 (IRS1)-associated PI3K activity was significantly increased at 30 min and remained elevated up to 2 h after leptin intraperitoneal injection, but in wild-type (WT) littermates, the significant increase was only at 30 min. Hypothalamic p-STAT3 levels were increased up to 5 h in NesKO as opposed to 2 h in WT mice. In food-restricted WT mice with reduced body weight, leptin increased hypothalamic PI3K activity only at 30 min, and p-STAT3 levels at 30–120 min postinjection. These results suggest increased leptin sensitivity in both PI3K and STAT3 pathways in the hypothalamus of NesKO mice, which was not due to a lean phenotype. In the next experiment with a clonal hypothalamic neuronal cell line expressing proopiomelanocortin, we observed that whereas leptin significantly increased IRS1-associated PI3K activity and p-JAK2 levels in cells transfected with control vector, it failed to do so in SOCS3-overexpressed cells. Altogether, these results imply a SOCS3 inhibition of the PI3K pathway of leptin signaling in the hypothalamus, which may be one of the mechanisms behind the development of central leptin resistance and obesity. PMID:21325649

A phosphatidylinositol species acutely generated by activated macrophages regulates innate immune responses.

PubMed

Gil-de-Gómez, Luis; Astudillo, Alma M; Meana, Clara; Rubio, Julio M; Guijas, Carlos; Balboa, María A; Balsinde, Jesús

2013-05-15

Activation of macrophages with stimuli of the innate immune response results in the intense remodeling of arachidonate-containing phospholipids, leading to the mobilization of large quantities of this fatty acid for conversion into biologically active eicosanoids. As a consequence of this process, the arachidonate levels in membrane phospholipids markedly decrease. We have applied mass spectrometry-based lipid profiling to study the levels of arachidonate-containing phospholipids under inflammatory activation of macrophages. We identify an unusual inositol phospholipid molecule, PI(20:4/20:4), the levels of which do not decrease but actually increase by 300% after activation of the macrophages. PI(20:4/20:4) is formed and degraded rapidly, suggesting a role for this molecule in regulating cell signaling events. Using a metabolipidomic approach consisting in exposing the cells to deuterium-labeled arachidonate at the time they are exposed to stimuli, we show that PI(20:4/20:4) biosynthesis occurs via the sequential incorporation of arachidonate, first into the sn-2 position of a preformed phosphatidylinositol (PI) molecule, followed by the rapid introduction of a second arachidonate moiety into the sn-1 position. Generation requires the participation of cytosolic phospholipase A2α and CoA-dependent acyltransferases. PI(20:4/20:4) formation is also detected in vivo in murine peritonitis exudates. Elevating the intracellular concentration of PI(20:4/20:4) by introducing the lipid into the cells results in enhancement of the microbicidal capacity of macrophages, as measured by reactive oxygen metabolite production and lysozyme release. These findings suggest that PI(20:4/20:4) is a novel bioactive inositol phospholipid molecule that regulates innate immune responses in macrophages.

Performance indicators for public mental healthcare: a systematic international inventory

PubMed Central

2012-01-01

Background The development and use of performance indicators (PI) in the field of public mental health care (PMHC) has increased rapidly in the last decade. To gain insight in the current state of PI for PMHC in nations and regions around the world, we conducted a structured review of publications in scientific peer-reviewed journals supplemented by a systematic inventory of PI published in policy documents by (non-) governmental organizations. Methods Publications on PI for PMHC were identified through database- and internet searches. Final selection was based on review of the full content of the publications. Publications were ordered by nation or region and chronologically. Individual PI were classified by development method, assessment level, care domain, performance dimension, diagnostic focus, and data source. Finally, the evidence on feasibility, data reliability, and content-, criterion-, and construct validity of the PI was evaluated. Results A total of 106 publications were included in the sample. The majority of the publications (n = 65) were peer-reviewed journal articles and 66 publications specifically dealt with performance of PMHC in the United States. The objectives of performance measurement vary widely from internal quality improvement to increasing transparency and accountability. The characteristics of 1480 unique PI were assessed. The majority of PI is based on stakeholder opinion, assesses care processes, is not specific to any diagnostic group, and utilizes administrative data sources. The targeted quality dimensions varied widely across and within nations depending on local professional or political definitions and interests. For all PI some evidence for the content validity and feasibility has been established. Data reliability, criterion- and construct validity have rarely been assessed. Only 18 publications on criterion validity were included. These show significant associations in the expected direction on the majority of PI, but mixed results on a noteworthy number of others. Conclusions PI have been developed for a broad range of care levels, domains, and quality dimensions of PMHC. To ensure their usefulness for the measurement of PMHC performance and advancement of transparency, accountability and quality improvement in PMHC, future research should focus on assessment of the psychometric properties of PI. PMID:22433251

Arabidopsis pdr2 reveals a phosphate-sensitive checkpoint in root development.

PubMed

Ticconi, Carla A; Delatorre, Carla A; Lahner, Brett; Salt, David E; Abel, Steffen

2004-03-01

Plants have evolved complex strategies to maintain phosphate (Pi) homeostasis and to maximize Pi acquisition when the macronutrient is limiting. Adjustment of root system architecture via changes in meristem initiation and activity is integral to the acclimation process. However, the mechanisms that monitor external Pi status and interpret the nutritional signal remain to be elucidated. Here, we present evidence that the Pi deficiency response, pdr2, mutation disrupts local Pi sensing. The sensitivity and amplitude of metabolic Pi-starvation responses, such as Pi-responsive gene expression or accumulation of anthocyanins and starch, are enhanced in pdr2 seedlings. However, the most conspicuous alteration of pdr2 is a conditional short-root phenotype that is specific for Pi deficiency and caused by selective inhibition of root cell division followed by cell death below a threshold concentration of about 0.1 mm external Pi. Measurements of general Pi uptake and of total phosphorus (P) in root tips exclude a defect in high-affinity Pi acquisition. Rescue of root meristem activity in Pi-starved pdr2 by phosphite (Phi), a non-metabolizable Pi analog, and divided-root experiments suggest that pdr2 disrupts sensing of low external Pi availability. Thus, PDR2 is proposed to function at a Pi-sensitive checkpoint in root development, which monitors environmental Pi status, maintains and fine-tunes meristematic activity, and finally adjusts root system architecture to maximize Pi acquisition.

Photoproduction of the f 1 ( 1285 ) meson

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

Dickson, Ryan; Schumacher, Reinhard A.; Adhikari, K. P.

Themore » $$f_1(1285)$$ meson with mass $$1281.0 \\pm 0.8$$ MeV/$c^2$ and width $$18.4 \\pm 1.4$$ MeV (FWHM) was measured for the first time in photoproduction from a proton target using CLAS at Jefferson Lab. Differential cross sections were obtained via the $$\\eta\\pi^{+}\\pi^{-}$$, $$K^+\\bar{K}^0\\pi^-$$, and $$K^-K^0\\pi^+$$ decay channels from threshold up to a center-of-mass energy of 2.8 GeV. mass, width, and an amplitude analysis of the $$\\eta\\pi^{+}\\pi^{-}$$ final-state Dalitz distribution are consistent with the axial-vector $J^P=1^+$ $$f_1(1285)$$ identity, rather than the pseudoscalar $0^-$ $$\\eta(1295)$$. production mechanism is more consistent with $s$-channel decay of a high-mass $N^*$ state, and not with $t$-channel meson exchange. Decays to $$\\eta\\pi\\pi$$ go dominantly via the intermediate $$a_0^\\pm(980)\\pi^\\mp$$ states, with the branching ratio $$\\Gamma(a_0\\pi \\text{ (no} \\bar{K} K\\text{)}) / \\Gamma(\\eta\\pi\\pi \\text{(all)}) = 0.74\\pm0.09$$. branching ratios $$\\Gamma(K \\bar{K} \\pi)/\\Gamma(\\eta\\pi\\pi) = 0.216\\pm0.033$$ and $$\\Gamma(\\gamma\\rho^0)/\\Gamma(\\eta\\pi\\pi) = 0.047\\pm0.018$$ were also obtained. first is in agreement with previous data for the $$f_1(1285)$$, while the latter is lower than the world average.« less

Photoproduction of the f 1 ( 1285 ) meson

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

Dickson, R.; Schumacher, R. A.; Adhikari, K. P.

The f(1)(1285) meson withmass 1281.0 +/- 0.8MeV/c(2) and width 18.4 +/- 1.4MeV (full width at half maximum) was measured for the first time in photoproduction from a proton target using CLAS at Jefferson Lab. Differential cross sections were obtained via the eta pi(+)pi(-), K+(K) over bar (0) pi(-), and (K-K0)pi(+) decay channels from threshold up to a center-of-mass energy of 2.8 GeV. The mass, width, and an amplitude analysis of the eta pi(+)pi(-) final-state Dalitz distribution are consistent with the axial-vector J(P) = 1(+) f(1)(1285) identity, rather than the pseudoscalar 0(-) eta(1295). The production mechanism is more consistent with s-channelmore » decay of a high-mass N* state and not with t-channel meson exchange. Decays to eta pi pi go dominantly via the intermediate a(0)(+/-) (980)pi(-/+) states, with the branching ratio Gamma [a(0)pi (no (K) over barK)]/Gamma[eta pi pi (all)] = 0.74 +/- 0.09. The branching ratios Gamma (K (K) over bar pi)/Gamma(eta pi pi) = 0.216 +/- 0.033 and Gamma (gamma rho(0))/Gamma(eta pi pi) = 0.047 +/- 0.018 were also obtained. The first is in agreement with previous data for the f(1)(1285), while the latter is lower than the world average.« less

Effect of side-chain structure of rigid polyimide dispersant on mechanical properties of single-walled carbon nanotube/cyanate ester composite.

PubMed

Yuan, Wei; Li, Weifeng; Mu, Yuguang; Chan-Park, Mary B

2011-05-01

Three kinds of polymer, polyimide without side-chain (PI), polyimide-graft-glyceryl 4-nonylphenyl ether (PI-GNE), and polyimide-graft-bisphenol A diglyceryl acrylate (PI-BDA), have been synthesized and used to disperse single-walled carbon nanotubes (SWNTs) and to improve the interfacial bonding between SWNTs and cyanate ester (CE) matrix. Visual observation, UV-vis-near-IR (UV-vis-NIR) spectra, and atomic force microscopy (AFM) images show that both PI-GNE and PI-BDA are highly effective at dispersing and debundling SWNTs in DMF, whereas PI is less effective. Interaction between SWNTs and PI, PI-GNE or PI-BDA was confirmed by computer simulation and Raman spectra. A series of CE-based composite films reinforced with different loadings of SWNTs, SWNTs/PI, SWNTs/PI-GNE and SWNTs/PI-BDA were prepared by solution casting. It was found that, because of the unique side-chain structure of PI-BDA, SWNTs/PI-BDA disperse better in CE matrix than do SWNTs/PI-GNE, SWNTs/PI, and SWNTs. As a result, SWNTs/PI-BDA/CE composites have the greatest improvement in mechanical properties of the materials tested. These results imply that the choice of side-chain on a dispersant is very important to the dispersion of SWNTs in matrix and the filler/matrix interfacial adhesion, which are two key requirements for achieving effective reinforcement.

Isolation of two biologically active cell surface proteins from Brucella abortus by chromatofocusing

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

Tabatabai, L.B.; Deyoe, B.L.

1983-01-01

Brucella abortus contains a group of immunogenic cell surface proteins which have potential value as a vaccine or as a diagnostic reagent for the prevention and diagnosis of bovine brucellosis. Under nondenaturing conditions, these proteins range in molecular weight from 10,000-124,000, as determined by high performance liquid chromatography (HPLC) on TSK 3000sw. By analytical isoelectrofocusing, 6 major protein bands could be distinguished with pI's ranging from 4.0 to 6.0 and 3 additional major proteins with pI's of 7.5, 9.5, and 10. By chromatofocusing on Polybuffer Exchanger 94 with a pH gradient from 6-4, two of the six proteins from pImore » 4-6 were separated, a pI 4.9 and a pI 4.7 protein; a third fraction contained the high pI proteins. The former two proteins were homogeneous by analytical isoelectrofocusing, and a molecular weight of 54,000 daltons was found for both protein species by HPLC on TSK 3000sw. The pI 4-6 and not the pI 9.5 and 10 proteins, could be radiolabeled when intact cells were radioiodinated with diazotized (/sup 125/I)-iodosulfanilic acid. Biological activity of the proteins as assessed in lemmings indicated that immunization with the pI 4.7 and 4.9 proteins afforded better protection against experimental brucellosis than immunization with the high pI proteins. These results support our view that a single surface protein may be sufficient for the prevention of experimental brucellosis.« less

[EARLY DETECTION OF PREECLAMPSIA].

PubMed

Todorov, N

2016-01-01

The preeclampsia is one of the most serious complications in the second half of the pregnancy with a high risk of perinatal maternal and neonatal mortality. The study is aiming to determine which pregnant women have a higher risk of developing preeclampsia with a view to the subsequent antenatal care, on the base of the individual factors. From prospectively followed pacients is collected information by a questionnaire and sonographic examination at 11-13 weeks of gestation/w.g./ + 6 days, at the point of biochemical screening implementation. Selected is a group of women with one fetus pregnancy, non-smokers, without chromosomal and structural anomalies of the fetus, excluding those taking prophylactic low-dose of aspirin. The Doppler examination was transabdominaly performed on the ascending branch of the A. Uterina at the level of OICC.Pusatility and resistance index /Pi and Ri/ are bilaterally evaluated and converted to MoM for the relevant age of gestation. The information about the taken values of Pi, Ri, the presence of diastolic incisures and the development of preeclampsia /PE/ or pregnancy indused hypertension /PIH/ is analyzed at 205 pregnant women. Out of them high values of Pi have 9 pregnant women, who subsequently developed PE or PlH. The measurement of Pi at 12-13 weeks of gestation and presence of diastolic incisures have prognostic importance for the development of PE in the later period of pregnancy. The values of Ri, taken at 12-13 weeks of gestation have not essential importance in the forecast of preeclamsia development.

Inhibition of PI3K suppresses propagation of drug-tolerant cancer cell subpopulations enriched by 5-fluorouracil.

PubMed

Ishida, Kaoru; Ito, Chie; Ohmori, Yukimi; Kume, Kohei; Sato, Kei A; Koizumi, Yuka; Konta, Akari; Iwaya, Takeshi; Nukatsuka, Mamoru; Kobunai, Takashi; Takechi, Teiji; Nishizuka, Satoshi S

2017-05-23

Drug-tolerant cancer cell subpopulations are responsible for relapse after chemotherapy. By continuously exposing the gastric cancer cell line MKN45 to 5-FU for >100 passages, we established a 5-fluorouracil (5-FU)-tolerant line, MKN45/5FU. Orthotopic xenografts of MKN45/5FU cells in the stomach of nude mice revealed that these cells had a high potential to metastasize to sites such as the liver. Levels of phosphorylated phosphatidylinositide 3-kinase (PI3K) increased both in 5-FU-tolerant subpopulations according to the 5-FU dose, and in gastric submucosal orthotopic xenografts of MKN45/5FU cells. Sequential administration of 5-FU and a PI3K inhibitor, GDC-0941, targeted the downstream ribosomal S6 kinase phosphorylation to significantly suppress 5-FU-tolerant subpopulations and tumor propagation of orthotopic MKN45/5FU xenografts. These results suggest that administration of 5-FU followed by GDC-0941 may suppress disease relapse after 5-FU-based gastric cancer chemotherapy.

Biomineralization of Uranium by PhoY Phosphatase Activity Aids Cell Survival in Caulobacter crescentus

PubMed Central

Yung, Mimi C.

2014-01-01

Caulobacter crescentus is known to tolerate high levels of uranium [U(VI)], but its detoxification mechanism is poorly understood. Here we show that C. crescentus is able to facilitate U(VI) biomineralization through the formation of U-Pi precipitates via its native alkaline phosphatase activity. The U-Pi precipitates, deposited on the cell surface in the form of meta-autunite structures, have a lower U/Pi ratio than do chemically produced precipitates. The enzyme that is responsible for the phosphatase activity and thus the biomineralization process is identified as PhoY, a periplasmic alkaline phosphatase with broad substrate specificity. Furthermore, PhoY is shown to confer a survival advantage on C. crescentus toward U(VI) under both growth and nongrowth conditions. Results obtained in this study thus highlight U(VI) biomineralization as a resistance mechanism in microbes, which not only improves our understanding of bacterium-mineral interactions but also aids in defining potential ecological niches for metal-resistant bacteria. PMID:24878600

Chemically modified graphene/polyimide composite films based on utilization of covalent bonding and oriented distribution.

PubMed

Huang, Ting; Lu, Renguo; Su, Chao; Wang, Hongna; Guo, Zheng; Liu, Pei; Huang, Zhongyuan; Chen, Haiming; Li, Tongsheng

2012-05-01

Herein, we have developed a rather simple composite fabrication approach to achieving molecular-level dispersion and planar orientation of chemically modified graphene (CMG) in the thermosetting polyimide (PI) matrix as well as realizing strong adhesion at the interfacial regions between reinforcing filler and matrix. The covalent adhesion of CMG to PI matrix and oriented distribution of CMG were carefully confirmed and analyzed by detailed investigations. Combination of covalent bonding and oriented distribution could enlarge the effectiveness of CMG in the matrix. Efficient stress transfer was found at the CMG/PI interfaces. Significant improvements in the mechanical performances, thermal stability, electrical conductivity, and hydrophobic behavior were achieved by addition of only a small amount of CMG. Furthermore, it is noteworthy that the hydrophilic-to-hydrophobic transition and the electrical percolation were observed at only 0.2 wt % CMG in this composite system. This facile methodology is believed to afford broad application potential in graphene-based polymer nanocomposites, especially other types of high-performance thermosetting systems.

Fosamprenavir calcium plus ritonavir for HIV infection.

PubMed

Torres, Harrys A; Arduino, Roberto C

2007-06-01

Fosamprenavir is a protease inhibitor (PI) approved for the treatment of HIV-1 infection. Fosamprenavir is a prodrug of amprenavir developed to reduce the pill burden yet maintain the unique resistance pattern and efficacy associated with amprenavir. In a head-to-head, noninferiority trial in antiretroviral treatment-naive HIV-infected patients, the antiviral efficacy and tolerability of ritonavir-boosted fosamprenavir was not inferior to ritonavir-boosted lopinavir, when the PIs were combined with two other nucleoside reverse transcriptase inhibitors. There are fewer studies published about fosamprenavir use in antiretroviral treatment-experienced HIV-infected patients. The high genetic barrier to the development of resistance to fosamprenavir and the low level of cross-resistance between ritonavir-boosted fosamprenavir and other PI regimens are notable. As with amprenavir, gastrointestinal disturbance and rash are the most frequent short-term treatment-limiting events with fosamprenavir. Treatment with ritonavir-boosted fosamprenavir can produce a durable response. To date, fosamprenavir is one of the recommended preferred PI components for the treatment of antiretroviral-naive HIV-infected patients.

Periprosthetic Artifact Reduction Using Virtual Monochromatic Imaging Derived From Gemstone Dual-Energy Computed Tomography and Dedicated Software.

PubMed

Reynoso, Exequiel; Capunay, Carlos; Rasumoff, Alejandro; Vallejos, Javier; Carpio, Jimena; Lago, Karen; Carrascosa, Patricia

2016-01-01

The aim of this study was to explore the usefulness of combined virtual monochromatic imaging and metal artifact reduction software (MARS) for the evaluation of musculoskeletal periprosthetic tissue. Measurements were performed in periprosthetic and remote regions in 80 patients using a high-definition scanner. Polychromatic images with and without MARS and virtual monochromatic images were obtained. Periprosthetic polychromatic imaging (PI) showed significant differences compared with remote areas among the 3 tissues explored (P < 0.0001). No significant differences were observed between periprosthetic and remote tissues using monochromatic imaging with MARS (P = 0.053 bone, P = 0.32 soft tissue, and P = 0.13 fat). However, such differences were significant using PI with MARS among bone (P = 0.005) and fat (P = 0.02) tissues. All periprosthetic areas were noninterpretable using PI, compared with 11 (9%) using monochromatic imaging. The combined use of virtual monochromatic imaging and MARS reduced periprosthetic artifacts, achieving attenuation levels comparable to implant-free tissue.

Identifying the function of LvPI3K during the pathogenic infection of Litopenaeus vannamei by Vibrio alginolyticus.

PubMed

Kong, Jing-Rong; Wei, Wei; Liang, Qing-Jian; Qiao, Xue-Li; Kang, Huan; Liu, Yuan; Wang, Wei-Na

2018-05-01

It is well known that PI3K regulates various processes in mammalian cells by generating a secondary messenger that later activates AKT. However, its innate immune function in crustaceans remains unclear. We report the characterization of Litopenaeus vannamei PI3K (LvPI3K) for investigating how PI3K participates in the innate immunity of crustaceans. Full-length LvPI3K cDNA was 3357 bp long, with a 3222 bp open reading frame (ORF) that encodes a putative protein of 1292 amino acids. The PI3K catalytic domain (PI3Kc) of LvPI3K was found to be rather conserved when the PI3Ks from other species were analyzed. The LvPI3K protein was shown to be localized to the cytoplasm of Drosophila S2 cells, while LvPI3K mRNA was ubiquitously expressed in healthy L. vannamei, with the highest expression found in hemolymph. A dual luciferase reporter gene assay demonstrated that LvPI3K overexpression activated the promoter of antibacterial peptide LvPEN4 in a dose-dependent manner. However, the addition of PDTC, a specific inhibitor of NF-κB, suppressed the LvPI3K-induced LvPEN4 promoter activation. Moreover, Vibrio alginolyticus challenge induced a rapid up-regulation of LvPI3K expression. Further experiments showed that LvPI3K silencing in shrimp challenged with V. alginolyticus significantly increased Vibrio number, ROS production and DNA damage in the hemolymph, as well as significantly decreased total hemocyte count. The mRNA levels of certain molecules related to LvPI3K signaling, such as LvAKT and LvPEN4, also decreased following LvPI3K silencing. Taken together, these results suggest that LvPI3K regulates the downstream signal component LvPEN4 and functions in V. alginolyticus resistance. Copyright © 2018 Elsevier Ltd. All rights reserved.

Metformin and pioglitazone combination therapy ameliorate polycystic ovary syndrome through AMPK/PI3K/JNK pathway

PubMed Central

Wu, Yuanyuan; Li, Pengfen; Zhang, Dan; Sun, Yingpu

2018-01-01

Polycystic ovary syndrome (PCOS) is a common gynecological endocrine disorder, which results in health problems such as menstrual disorders, hyperandrogenism and persistent anovulation. Hyperandrogenism and insulin resistance are the basic characteristics of PCOS. To investigate the combined effect of metformin and pioglitazone on POCS and the potential mechanisms, a rat model of PCOS was established by intramuscular injection of estradiol valerate (EV). The effect of metformin and pioglitazone monotherapy or combination therapy in control rats and PCOS rats was evaluated, involving the testosterone level, follicular development and insulin resistance. The potential mechanism for the therapeutic effect of metformin and pioglitazone on POCS was explored through using three inhibitors of the 5′adenosine monophosphate-activated protein kinase (AMPK)/phosphoinositide-3 kinase (PI3K)/c-Jun N-terminal kinase (JNK) pathway (Compound C, Wortmannin and SP600125). The results showed that EV-induced PCOS rats demonstrated hyperandrogenemia, hyperinsulinemia and follicular dysplasia. Metformin or pioglitazone monotherapy significantly suppressed the high level of testosterone, reduced the raised percentage of cystic follicles and primary follicles, promoted the number of early antral follicles, and markedly decreased the high concentration of fasting insulin and homeostatic model assessment for insulin resistance index in PCOS rats. In addition, metformin and pioglitazone combination therapy demonstrated greater efficacy than its individual components. Furthermore, individual or joint treatment with metformin and pioglitazone affected the phosphorylation level of JNK in PCOS rats. Compound C and Wortmannin eliminated the effect of metformin and pioglitazone combination therapy on improving the follicular growth in PCOS rats, whereas SP600125 treatment enhanced this combination therapy effect. These data suggested that metformin and pioglitazone combination therapy demonstrated great efficacy in ameliorating PCOS through regulating the AMPK/PI3K/JNK pathway. PMID:29434814

Correlations of OGO-V plasmapause crossing with observations of type Pi micropulsations on the ground.

NASA Technical Reports Server (NTRS)

Heacock, R. R.; Mullen, A. J.; Hessler, V. P.; Sucksdorff, C.; Kivinen, M.; Kataja, E.

1971-01-01

Comparison of plasmapause positions with Pi micropulsation events observed at College (L 5.4) or at Sodankyla (L 5.1), showing that in almost all cases the plasmapause was inside the field line of the observing site when the Pi event was recorded. Strong Pi events were seen at Nurmijaarvi (L 3.4) only when Kp was very high, when the plasmapause would be expected to be inside L 3.4. When Pi events and structure Pc 1 events were observed nearly simultaneously, the Pi activity was always more prominent at the poleward site. A demarcation line seems to exist, separating the Pi and structured Pc 1 source regions. This line may be the plasmapause, with structured Pc 1 inside and Pi outside.

Unusual pi-donating effects of pi-accepting substituents on the stabilities of benzylic cations: a theoretical study.

PubMed

Kim, Chang Kon; Han, In Suk; Ryu, Wang Sun; Lee, Hai Whang; Lee, Bon-Su; Kim, Chan Kyung

2006-02-23

The pi-donating effects of pi-accepting X-substituents in substituted benzylic cations, X-C(6)H(5)-CHR(+) where R = CF(3), H and OCH(3), and X = p-NH(2), p-OCH(3), p-CH(3), H, p-F, p-Cl, p-CHO, m-CN, p-CN, m-NO(2) or p-NO(2), have been studied theoretically by using isodesmic hydride transfer reactions at various levels of theory. It might be difficult to determine the pi-donating effects of pi-acceptors using the simple Hammett-type linear equation, because it is not sensitive enough to include small pi-donating effects. Therefore, this effect was estimated using the NBO deletion energy (DeltaE(D)) of the second-order charge-transfer interaction (DeltaE(ct)) between the pi-orbitals (or lone pair orbitals) of the X-substituent and the pi-orbitals of phenyl ring. The extents of pi-donating effects increased in the order X = p-NO(2) < p-CHO < p-CN < p-Cl for both neutral and cationic species, and these effects were found to be more important for para- than for meta-substituents. Moreover, this could represent a general trend for pi-donation by pi-acceptors. On the other hand, the effects of R-substituents on this pi-donating effect were found to be in the order R = OCH(3) < H congruent with CF(3), as predicted by natural resonance theory (NRT) analyses.

The role of the PI3K/mTOR signaling pathway in Staphylococcus epidermidis small colony variants intracellular survival.

PubMed

Magryś, Agnieszka; Bogut, Agnieszka; Kiełbus, Michał; Olender, Alina

2018-04-01

The objective of this study was to analyze how Staphylococcus epidermidis SCV and WT strains manipulate the PI3K/Akt/mTOR signaling pathway. Six S. epidermidis strains with normal phenotype (WT) and six S. epidermidis strains with SCV phenotype were isolated in parallel from six patients with the prosthetic hip joint infections. THP-1 activated cells were incubated with or without PI3K inhibitor-wortmannin or with mTOR inhibitor-rapamycin. Next, macrophages were exposed to S. epidermidis WT and SCV strains. After 4 h incubation, bacterial survival inside macrophages as well as PI3K-mTOR activation was analyzed. SCV strains of S. epidermidis increased the level of Akt phosphorylation, compared to uninfected macrophages and to their parental WT forms. Wild type variants of S. epidermidis phosphorylated Akt at similar or lower levels as control uninfected cells. Next, the induction of mTOR target, phosphorylated ribosomal protein S6, was measured in bacteria-infected macrophages. The level of phosphorylation was significantly reduced when the cells were exposed to WT strains of S. epidermidis. In contrast, the SCV strains activated S6 protein mostly at a level comparable to the control cells. Rapamycin inhibited mTOR activation as the number of p-S6 positive cells decreased in the tested cases. To conclude, the SCV strains activate the PI3K-Akt signaling pathway in opposite to WT strains. This fact however did not influence the increase in the number of live SCV bacteria as compared to the WT strains. Knowing that the PI3K-Akt pathway is involved in proinflammatory cytokines suppression, SCVs seem to use this pathway to reduce the inflammatory response during the infection.

The facilitators and barriers associated with implementation of a patient-centered medical home in VHA.

PubMed

Helfrich, Christian D; Sylling, Philip W; Gale, Randall C; Mohr, David C; Stockdale, Susan E; Joos, Sandra; Brown, Elizabeth J; Grembowski, David; Asch, Steven M; Fihn, Stephan D; Nelson, Karin M; Meredith, Lisa S

2016-02-24

The patient-centered medical home (PCMH) is a team-based, comprehensive model of primary care. When effectively implemented, PCMH is associated with higher patient satisfaction, lower staff burnout, and lower hospitalization for ambulatory care-sensitive conditions. However, less is known about what factors contribute to (or hinder) PCMH implementation. We explored the associations of specific facilitators and barriers reported by primary care employees with a previously validated, clinic-level measure of PCMH implementation, the Patient Aligned Care Team Implementation Progress Index (Pi(2)). We used a 2012 survey of primary care employees in the Veterans Health Administration to perform cross-sectional, respondent-level multinomial regressions. The dependent variable was the Pi(2) categorized as high implementation (top decile, 54 clinics, 235 respondents), medium implementation (middle eight deciles, 547 clinics, 4537 respondents), and low implementation (lowest decile, 42 clinics, 297 respondents) among primary care clinics. The independent variables were ordinal survey items rating 19 barriers to patient-centered care and 10 facilitators of PCMH implementation. For facilitators, we explored clinic Pi(2) score decile both as a function of respondent-reported availability of facilitators and of rating of facilitator helpfulness. The availability of five facilitators was associated with higher odds of a respondent's clinic's Pi(2) scores being in the highest versus lowest decile: teamlet huddles (OR = 3.91), measurement tools (OR = 3.47), regular team meetings (OR = 2.88), information systems (OR = 2.42), and disease registries (OR = 2.01). The helpfulness of four facilitators was associated with higher odds of a respondent's clinic's Pi(2) scores being in the highest versus lowest decile. Six barriers were associated with significantly higher odds of a respondent's clinic's Pi(2) scores being in the lowest versus highest decile, with the strongest associations for the difficulty recruiting and retaining providers (OR = 2.37) and non-provider clinicians (OR = 2.17). Results for medium versus low Pi(2) score clinics were similar, with fewer, smaller significant associations, all in the expected direction. A number of specific barriers and facilitators were associated with PCMH implementation, notably recruitment and retention of clinicians, team huddles, and local education. These findings can guide future research, and may help healthcare policy makers and leaders decide where to focus attention and limited resources.

Vitamin D status in relation to postural stability in the elderly.

PubMed

Boersma, D; Demontiero, O; Mohtasham Amiri, Z; Hassan, S; Suarez, H; Geisinger, D; Suriyaarachchi, P; Sharma, A; Duque, G

2012-03-01

Postural instability (PI) is an important risk factor for falls, especially in the frail older population. In this study, we investigated the impact of vitamin D deficiency on PI in a sample of community dwelling older subjects. Our objective was to determine the potential association between vitamin D deficiency and PI in older fallers. Cross-sectional study. Falls and Fractures Clinic, Department of Geriatric Medicine, Nepean Hospital, Penrith, Australia. One hundred and forty-five adults aged 65 years and older who have had at least one episode of a fall within the six months prior to assessment at the Falls and Fractures Clinic. Serum 25(OH) vitamin D3 [25(OH)D3] and parathyroid hormone concentrations were determined at baseline. Subjects were separated into 3 groups based on serum 25(OH)D3 levels with the following cut-off values: < 30 nmol/L (deficient), 30-50 nmol/L (insufficient) and > 50 nmol/L (normal). Other baseline measurements included body mass index, mini-nutritional assessment, grip strength, serum calcium concentration and creatinine clearance, which were used as covariables. PI was assessed using a computerized virtual reality system (Medicaa, Uruguay). Measured parameters included limits of stability (LOS) and centre of pressure (COP) under eyes closed on foam (ECF) and visio-vestibular stimulation. The estimated swaying area, computed from the ellipse of confidence under eyes closed standing on foam (ECF), was also used as a PI parameter. Gait velocity (GV) was measured using a GaitRITE walkway system. Posture was impaired in vitamin D deficiency (<30 nmol/L) as indicated by lower LOS (90 +/- 18), higher ECF (25 +/- 10) and slower GV (55 +/- 7) as compared with the insufficient and normal groups. After adjustment for demographic, biochemical and anthropometric variables, vitamin D deficiency significantly correlated with low LOS and high COP under ECF. Low levels of vitamin D were associated with PI. This association could also have an effect on slow GV and increased risk of falls. In conclusion, using an objective method to measure balance in older fallers we have identified a novel role of vitamin D in balance control. Prospective studies are required to confirm the effect of vitamin D on PI and elucidate the mechanisms of this association.

Late Cretaceous climate simulations with different CO2 levels and subarctic gateway configurations: A model-data comparison

NASA Astrophysics Data System (ADS)

Niezgodzki, Igor; Knorr, Gregor; Lohmann, Gerrit; Tyszka, Jarosław; Markwick, Paul J.

2017-09-01

We investigate the impact of different CO2 levels and different subarctic gateway configurations on the surface temperatures during the latest Cretaceous using the Earth System Model COSMOS. The simulated temperatures are compared with the surface temperature reconstructions based on a recent compilation of the latest Cretaceous proxies. In our numerical experiments, the CO2 level ranges from 1 to 6 times the preindustrial (PI) CO2 level of 280 ppm. On a global scale, the most reasonable match between modeling and proxy data is obtained for the experiments with 3 to 5 × PI CO2 concentrations. However, the simulated low- (high-) latitude temperatures are too high (low) as compared to the proxy data. The moderate CO2 levels scenarios might be more realistic, if we take into account proxy data and the dead zone effect criterion. Furthermore, we test if the model-data discrepancies can be caused by too simplistic proxy-data interpretations. This is distinctly seen at high latitudes, where most proxies are biased toward summer temperatures. Additional sensitivity experiments with different ocean gateway configurations and constant CO2 level indicate only minor surface temperatures changes (< 1°C) on a global scale, with higher values (up to 8°C) on a regional scale. These findings imply that modeled and reconstructed temperature gradients are to a large degree only qualitatively comparable, providing challenges for the interpretation of proxy data and/or model sensitivity. With respect to the latter, our results suggest that an assessment of greenhouse worlds is best constrained by temperatures in the midlatitudes.

Mapping of the minimal inorganic phosphate transporting unit of human PiT2 suggests a structure universal to PiT-related proteins from all kingdoms of life.

PubMed

Bøttger, Pernille; Pedersen, Lene

2011-05-17

The inorganic (Pi) phosphate transporter (PiT) family comprises known and putative Na(+)- or H(+)-dependent Pi-transporting proteins with representatives from all kingdoms. The mammalian members are placed in the outer cell membranes and suggested to supply cells with Pi to maintain house-keeping functions. Alignment of protein sequences representing PiT family members from all kingdoms reveals the presence of conserved amino acids and that bacterial phosphate permeases and putative phosphate permeases from archaea lack substantial parts of the protein sequence when compared to the mammalian PiT family members. Besides being Na(+)-dependent P(i) (NaP(i)) transporters, the mammalian PiT paralogs, PiT1 and PiT2, also are receptors for gamma-retroviruses. We have here exploited the dual-function of PiT1 and PiT2 to study the structure-function relationship of PiT proteins. We show that the human PiT2 histidine, H(502), and the human PiT1 glutamate, E(70),--both conserved in eukaryotic PiT family members--are critical for P(i) transport function. Noticeably, human PiT2 H(502) is located in the C-terminal PiT family signature sequence, and human PiT1 E(70) is located in ProDom domains characteristic for all PiT family members.A human PiT2 truncation mutant, which consists of the predicted 10 transmembrane (TM) domain backbone without a large intracellular domain (human PiT2ΔR(254)-V(483)), was found to be a fully functional P(i) transporter. Further truncation of the human PiT2 protein by additional removal of two predicted TM domains together with the large intracellular domain created a mutant that resembles a bacterial phosphate permease and an archaeal putative phosphate permease. This human PiT2 truncation mutant (human PiT2ΔL(183)-V(483)) did also support P(i) transport albeit at very low levels. The results suggest that the overall structure of the P(i)-transporting unit of the PiT family proteins has remained unchanged during evolution. Moreover, in combination, our studies of the gene structure of the human PiT1 and PiT2 genes (SLC20A1 and SLC20A2, respectively) and alignment of protein sequences of PiT family members from all kingdoms, along with the studies of the dual functions of the human PiT paralogs show that these proteins are excellent as models for studying the evolution of a protein's structure-function relationship. © 2011 Bøttger and Pedersen; licensee BioMed Central Ltd.

High-resolution confocal imaging of wall ingrowth deposition in plant transfer cells: Semi-quantitative analysis of phloem parenchyma transfer cell development in leaf minor veins of Arabidopsis.

PubMed

Nguyen, Suong T T; McCurdy, David W

2015-04-23

Transfer cells (TCs) are trans-differentiated versions of existing cell types designed to facilitate enhanced membrane transport of nutrients at symplasmic/apoplasmic interfaces. This transport capacity is conferred by intricate wall ingrowths deposited secondarily on the inner face of the primary cell wall, hence promoting the potential trans-membrane flux of solutes and consequently assigning TCs as having key roles in plant growth and productivity. However, TCs are typically positioned deep within tissues and have been studied mostly by electron microscopy. Recent advances in fluorophore labelling of plant cell walls using a modified pseudo-Schiff-propidium iodide (mPS-PI) staining procedure in combination with high-resolution confocal microscopy have allowed visualization of cellular details of individual tissue layers in whole mounts, hence enabling study of tissue and cellular architecture without the need for tissue sectioning. Here we apply a simplified version of the mPS-PI procedure for confocal imaging of cellulose-enriched wall ingrowths in vascular TCs at the whole tissue level. The simplified mPS-PI staining procedure produced high-resolution three-dimensional images of individual cell types in vascular bundles and, importantly, wall ingrowths in phloem parenchyma (PP) TCs in minor veins of Arabidopsis leaves and companion cell TCs in pea. More efficient staining of tissues was obtained by replacing complex clearing procedures with a simple post-fixation bleaching step. We used this modified procedure to survey the presence of PP TCs in other tissues of Arabidopsis including cotyledons, cauline leaves and sepals. This high-resolution imaging enabled us to classify different stages of wall ingrowth development in Arabidopsis leaves, hence enabling semi-quantitative assessment of the extent of wall ingrowth deposition in PP TCs at the whole leaf level. Finally, we conducted a defoliation experiment as an example of using this approach to statistically analyze responses of PP TC development to leaf ablation. Use of a modified mPS-PI staining technique resulted in high-resolution confocal imaging of polarized wall ingrowth deposition in TCs. This technique can be used in place of conventional electron microscopy and opens new possibilities to study mechanisms determining polarized deposition of wall ingrowths and use reverse genetics to identify regulatory genes controlling TC trans-differentiation.

Search for Proton Decay via p{yields}e{sup +}{pi}{sup 0} and p{yields}{mu}{sup +}{pi}{sup 0} in a Large Water Cherenkov Detector

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

Nishino, H.; Hazama, S.; Higuchi, I.

2009-04-10

We have searched for proton decays via p{yields}e{sup +}{pi}{sup 0} and p{yields}{mu}{sup +}{pi}{sup 0} using data from a 91.7 kt{center_dot}yr exposure of Super-Kamiokande-I and a 49.2 kt{center_dot}yr exposure of Super-Kamiokande-II. No candidate events were observed with expected backgrounds induced by atmospheric neutrinos of 0.3 events for each decay mode. From these results, we set lower limits on the partial lifetime of 8.2x10{sup 33} and 6.6x10{sup 33} years at 90% confidence level for p{yields}e{sup +}{pi}{sup 0} and p{yields}{mu}{sup +}{pi}{sup 0} modes, respectively.

The biogenesis pathway of tRNA-derived piRNAs in Bombyx germ cells

PubMed Central

Honda, Shozo; Kawamura, Takuya; Loher, Phillipe; Morichika, Keisuke; Rigoutsos, Isidore

2017-01-01

Abstract Transfer RNAs (tRNAs) function in translational machinery and further serves as a source of short non-coding RNAs (ncRNAs). tRNA-derived ncRNAs show differential expression profiles and play roles in many biological processes beyond translation. Molecular mechanisms that shape and regulate their expression profiles are largely unknown. Here, we report the mechanism of biogenesis for tRNA-derived Piwi-interacting RNAs (td-piRNAs) expressed in Bombyx BmN4 cells. In the cells, two cytoplasmic tRNA species, tRNAAspGUC and tRNAHisGUG, served as major sources for td-piRNAs, which were derived from the 5′-part of the respective tRNAs. cP-RNA-seq identified the two tRNAs as major substrates for the 5′-tRNA halves as well, suggesting a previously uncharacterized link between 5′-tRNA halves and td-piRNAs. An increase in levels of the 5′-tRNA halves, induced by BmNSun2 knockdown, enhanced the td-piRNA expression levels without quantitative change in mature tRNAs, indicating that 5′-tRNA halves, not mature tRNAs, are the direct precursors for td-piRNAs. For the generation of tRNAHisGUG-derived piRNAs, BmThg1l-mediated nucleotide addition to −1 position of tRNAHisGUG was required, revealing an important function of BmThg1l in piRNA biogenesis. Our study advances the understanding of biogenesis mechanisms and the genesis of specific expression profiles for tRNA-derived ncRNAs. PMID:28645172

A slice of pi : an exploratory neuroimaging study of digit encoding and retrieval in a superior memorist.

PubMed

Raz, Amir; Packard, Mark G; Alexander, Gerianne M; Buhle, Jason T; Zhu, Hongtu; Yu, Shan; Peterson, Bradley S

2009-10-01

Subject PI demonstrated superior memory using a variant of a Method of Loci (MOL) technique to recite the first digits of the mathematical constant pi to more than 2(16) decimal places. We report preliminary behavioral, functional magnetic resonance imaging (fMRI), and brain volumetric data from PI. fMRI data collected while PI recited the first 540 digits of pi (i.e., during retrieval) revealed increased activity in medial frontal gyrus and dorsolateral prefrontal cortex. Encoding of a novel string of 100 random digits activated motor association areas, midline frontal regions, and visual association areas. Volumetric analyses indicated an increased volume of the right subgenual cingulate, a brain region implicated in emotion, mentalizing, and autonomic arousal. Wechsler Abbreviated Scale of Intelligence (WASI) testing indicated that PI is of average intelligence, and performance on mirror tracing, rotor pursuit, and the Silverman and Eals Location Memory Task revealed normal procedural and implicit memory. PI's performance on the Wechsler Memory Scale (WMS-III) revealed average general memory abilities (50th percentile), but superior working memory abilities (99th percentile). Surprisingly, PI's visual memory (WMS-III) for neutral faces and common events was remarkably poor (3rd percentile). PI's self-report indicates that imagining affective situations and high emotional content is critical for successful recall. We speculate that PI's reduced memory for neutral/non-emotional faces and common events, and the observed increase in volume of the right subgenual cingulate, may be related to extensive practice with memorizing highly emotional material.

[An analysis for the clinical difference between post infectious irritable bowel syndrome and non post infectious irritable bowel syndrome].

PubMed

Shi, Hui; Wan, Jun; Liu, Wenhui; Su, Binbin

2015-04-01

To study the clinical discrepancy between patients with post infectious irritable bowel syndrome (PI-IBS) and non post infectious irritable bowel syndrome (NPI-IBS) , and assess the value of serum intestinal fatty acid binding protein (I-FABP) for differential diagnosis. A total of 117 patients with PI-IBS, 201 patients with NPI-IBS and 31 healthy controls were prospectively recruited in General Liberation Army Hospital from 2010 to 2013. Plasma samples and clinical data were collected. Serum I-FABP level was measured by an enzyme-linked immunosorbent assay. The median age of patients with PI-IBS was 36 years. The median time to diagnosis in PI-IBS group was significantly longer than that in NPI-IBS group [(19.7 ± 10.3)months vs (11.4 ± 5.3) months, P < 0.05]. Similarly, the proportion of anxiety [58.1%(68/117) vs 28.9%(58/201), P < 0.05] and the value of I-FABP [(42.6 ± 14.8) µg/L vs (17.3 ± 11.5) µg/L, P < 0.05] in PI-IBS group were significant higher than NPI-IBS patients. The level of I-FABP of healthy controls [(10.6 ± 8.2) µg/L] was also significantly lower than that of PI-IBS patients (P < 0.05), yet no difference from that of NPI-IBS group. The I-FABP value of subgroup PI-IBS patients with diarrhoea (IBS-D) was significant higher than that of NPI-IBS group [(54.8 ± 9.3)µg/L vs (12.3 ± 6.2) µg/L, P < 0.05]. However, other parameters including gender, age, GSRS score, and I-FABP value of subgroup constipation (IBS-C) and mix (IBS-M), were not different between PI-IBS group and NPI-IBS group (all P > 0.05). PI-IBS is an occult intestinal inflammation disease with mucosa injury. I-FABP might be a potential testing marker for the diagnosis of PI-IBS.

Comparative magnitude and kinetics of human cytomegalovirus-specific CD4⁺ and CD8⁺ T-cell responses in pregnant women with primary versus remote infection and in transmitting versus non-transmitting mothers: Its utility for dating primary infection in pregnancy.

PubMed

Fornara, Chiara; Furione, Milena; Arossa, Alessia; Gerna, Giuseppe; Lilleri, Daniele

2016-07-01

To discriminate between primary (PI) and remote (RI) human cytomegalovirus (HCMV) infection, several immunological parameters were monitored for a 2-year period in 53 pregnant women with PI, and 33 pregnant women experiencing HCMV PI at least 5 years prior. Cytokine (IFN-γ and IL-2) production by and phenotype (effector/memory CD45RA(+)) of HCMV-specific CD4(+) and CD8(+) T-cells as well as the lymphoproliferative responses (LPR) were evaluated, with special reference to the comparison between a group of women transmitting (T) and a group of non-transmitting (NT) the infection to fetus. While HCMV-specific CD4(+) T-cells reached at 90 days post-infection (p.i.) values comparable to RI, CD8(+) T-cells reached at 60 days p.i. levels significantly higher and persisting throughout the entire follow-up. Instead, IL-2 production and lymphoproliferative responses were lower in PI than RI for the entire follow-up period. Effector memory CD45RA(+) CD4(+) and CD8(+) HCMV-specific T-cells increased until 90 days p.i., reaching and maintaining levels higher than RI. The comparison between T and NT women showed that, at 30 days p.i., in NT women there was a significantly higher IL-2 production by HCMV-specific CD4(+) T-cells, and at 60 days p.i. a significantly higher frequency of both specific CD4(+) and CD8(+) CD45RA(+) T-cells. HCMV T-cell response appears to correlate with virus transmission to fetus and some parameters (CD4(+) lymphoproliferation, and frequency of HCMV-specific CD8(+) IL2(+) T-cells) may help in dating PI during pregnancy. © 2015 Wiley Periodicals, Inc.

The Golgi localization of phosphatidylinositol transfer protein beta requires the protein kinase C-dependent phosphorylation of serine 262 and is essential for maintaining plasma membrane sphingomyelin levels.

PubMed

van Tiel, Claudia M; Westerman, Jan; Paasman, Marten A; Hoebens, Martha M; Wirtz, Karel W A; Snoek, Gerry T

2002-06-21

Recombinant mouse phosphatidylinositol transfer protein (PI-TP)beta is a substrate for protein kinase C (PKC)-dependent phosphorylation in vitro. Based on site-directed mutagenesis and two-dimensional tryptic peptide mapping, Ser(262) was identified as the major site of phosphorylation and Ser(165) as a minor phosphorylation site. The phospholipid transfer activities of wild-type PI-TP beta and PI-TP beta(S262A) were identical, whereas PI-TP beta(S165A) was completely inactive. PKC-dependent phosphorylation of Ser(262) also had no effect on the transfer activity of PI-TP beta. To investigate the role of Ser(262) in the functioning of PI-TP beta, wtPI-TP beta and PI-TP beta(S262A) were overexpressed in NIH3T3 fibroblast cells. Two-dimensional PAGE analysis of cell lysates was used to separate PI-TP beta from its phosphorylated form. After Western blotting, wtPI-TP beta was found to be 85% phosphorylated, whereas PI-TP beta(S262A) was not phosphorylated. In the presence of the PKC inhibitor GF 109203X, the phosphorylated form of wtPI-TP beta was strongly reduced. Immunolocalization showed that wtPI-TP beta was predominantly associated with the Golgi membranes. In the presence of the PKC inhibitor, wtPI-TP beta was distributed throughout the cell similar to what was observed for PI-TP beta(S262A). In contrast to wtPI-TP beta overexpressors, cells overexpressing PI-TP beta(S262A) were unable to rapidly replenish sphingomyelin in the plasma membrane upon degradation by sphingomyelinase. This implies that PKC-dependent association with the Golgi complex is a prerequisite for PI-TP beta to express its effect on sphingomyelin metabolism.

Probing the Bioeffects of Cavitation at the Single-Cell Level

NASA Astrophysics Data System (ADS)

Yuan, Fang

The primary goal of this dissertation research is to develop an experimental system and associated techniques that can be used to investigate the bioeffects produced by cavitation bubbles at the single cell level. Such information has been lacking due to the randomness and complexity in cavitation inception and subsequent bubble-bubble interaction generated by an acoustic field typically used in therapeutic ultrasound applications. Connection between cavitation activities and bioeffects produced in cells nearby presents another challenge that has not been resolved satisfactorily. In this work, we developed a laser-based system for generating tandem bubbles with a maximum diameter about 50 microm (i.e., on the scale of a single cell) in a microfluidic channel of 25 microm in height and 800 microm in width. We further developed techniques for micropatterning of individual gold dots (15 nm thick and 6 microm in diameter) used for bubble generation, which are precisely aligned at various stand-off distances (SD) from individual islands (32 x 32 microm2) coated with fibronectin used for cell adhesion. The dynamics of tandem bubble interaction with resultant jet formation, microstreaming and vortex flow in the microfluidic channel were captured by high-speed imaging and particle image velocimetry (PIV). The deformation of the target cell was recorded by high-speed imaging as well (using a second camera) immediately after the tandem bubble interaction and assessment of membrane strain was aided with 2 microm sized polystyrene beads attached to the cell membrane. Membrane poration was characterized by uptake of fluorescent propodium iodide (PI) into the target cell, from which the normalized maximum pore size was estimated. Using this experimental system, we have observed the complete process of bubble-bubble interaction with resultant jetting flow, cell deformation, and localized pinpoint membrane rupture with progressive diffusion of macromolecules into the target cell. Furthermore, we observed a clear SD dependence in the treatment outcome produced by the tandem bubbles. At short SD of 10 microm, all treated cells underwent necrosis with high yet unsaturated level of PI uptake, indicating that the cell could not reseal the poration site. At intermediate SD of 20 ˜ 30 microm, 58% to 80% of the cells were observed to have repairable membrane poration with low to medium but saturated level of PI uptake. At long SD of 40 microm, no detectable PI uptake was observed, corresponding to no membrane compromise. Within the repairable membrane poration group, the sub-population of cells that eventually survived without apoptosis increased from about 9% at SD of 20 microm with strong adhesion to about 70% at SD of 30 microm with no adhesion at the leading edge facing the jetting flow. The maximum PI uptake, pore size, and membrane strain estimated could vary by more than an order of magnitude, which is similar to the magnitude of variations in pore size (0.2 ˜ 2 microm) produced by tandem bubbles observed by SEM. The large principal strain (> 500%) with associated high strain-rate (> 106·s -1) produced by the tandem bubbles provide a unique tool to examine the bioeffects of cavitation at the single cell level and potentially a diverse range of applications to be explored.

Optimum pelvic incidence minus lumbar lordosis value can be determined by individual pelvic incidence.

PubMed

Inami, Satoshi; Moridaira, Hiroshi; Takeuchi, Daisaku; Shiba, Yo; Nohara, Yutaka; Taneichi, Hiroshi

2016-11-01

Adult spinal deformity (ASD) classification showing that ideal pelvic incidence minus lumbar lordosis (PI-LL) value is within 10° has been received widely. But no study has focused on the optimum level of PI-LL value that reflects wide variety in PI among patients. This study was conducted to determine the optimum PI-LL value specific to an individual's PI in postoperative ASD patients. 48 postoperative ASD patients were recruited. Spino-pelvic parameters and Oswestry Disability Index (ODI) were measured at the final follow-up. Factors associated with good clinical results were determined by stepwise multiple regression model using the ODI. The patients with ODI under the 75th percentile cutoff were designated into the "good" health related quality of life (HRQOL) group. In this group, the relationship between the PI-LL and PI was assessed by regression analysis. Multiple regression analysis revealed PI-LL as significant parameters associated with ODI. Thirty-six patients with an ODI <22 points (75th percentile cutoff) were categorized into a good HRQOL group, and linear regression models demonstrated the following equation: PI-LL = 0.41PI-11.12 (r = 0.45, P = 0.0059). On the basis of this equation, in the patients with a PI = 50°, the PI-LL is 9°. Whereas in those with a PI = 30°, the optimum PI-LL is calculated to be as low as 1°. In those with a PI = 80°, PI-LL is estimated at 22°. Consequently, an optimum PI-LL is inconsistent in that it depends on the individual PI.

Ibrolipim attenuates high glucose-induced endothelial dysfunction in cultured human umbilical vein endothelial cells via PI3K/Akt pathway.

PubMed

Xiao, Guohua; Wang, Zongbao; Zeng, Huaicai; Yu, Jian; Yin, Weidong; Zhang, Sujun; Wang, Yueting; Zhang, Yali

2011-10-01

Endothelial dysfunction is a key event in the onset and progression of atherosclerosis associated with diabetes. Increasing cell apoptosis may lead to endothelial dysfunction and contribute to vascular complications. Therefore, we aimed to elucidate the possible role and mechanism of ibrolipim in preventing endothelial dysfunction induced by high glucose. Human umbilical vein endothelial cells (HUVECs) were cultured respectively under normal glucose level (5.5mM), high glucose level (33mM), and high glucose level with ibrolipim treatment. Endothelial dysfunction was identified by the expression of ET-1 and vWF through reverse transcription PCR (RT-PCR). HUVECs apoptosis was assessed by fluorescent staining with Hoechst 33258. Akt activity was analyzed by western blot. High glucose condition significantly increased the rate of apoptotic cells, weakened cell viability, and decreased the expression of ET-1 and vWF. Ibrolipim treatment significantly attenuated these alterations of endothelial dysfunction. The lower concentrations (2, 4, 8 microM) of ibrolipim inhibited apoptosis of cultured HUVECs, improved cell viability, down-regulated the mRNA levels of ET-1, vWF, and attenuated the cytotoxicity; however, higher concentration (16, 32 microM) of ibrolipim aggravated the damage of HUVECs cultured under high glucose level. Meanwhile, high glucose induced a decrease of Akt activity which led to apoptosis, and ibrolipim prevented the decrease and attenuated apoptotic effect induced by high glucose. Furthermore, the PI3K inhibitor LY294002 significantly abolished the anti-apoptotic effect of ibrolipim, and decreased Akt phosphorylation. Although, the expression of Akt mRNA and total protein were not altered in cultured HUVECs. Ibrolipim at lower concentrations can inhibit high glucose-induced apoptosis in cultured HUVECs, which might be related to the alternation of Akt activity. Ibrolipim has the potential to attenuate endothelial dysfunction and lower the risk of diabetes-associated vascular diseases. And it might be a therapeutic agent for diabetic vascular complications.

Cooperative multi-targeting of signaling networks by angiomiR-204 inhibits vasculogenic mimicry in breast cancer cells.

PubMed

Salinas-Vera, Yarely M; Marchat, Laurence A; García-Vázquez, Raúl; González de la Rosa, Claudia Haydée; Castañeda-Saucedo, Eduardo; Tito, Napoleón Navarro; Flores, Carlos Palma; Pérez-Plasencia, Carlos; Cruz-Colin, José L; Carlos-Reyes, Ángeles; López-González, José Sullivan; Álvarez-Sánchez, María Elizbeth; López-Camarillo, César

2018-06-06

RNA-based multi-target therapies focused in the blocking of signaling pathways represent an attractive approach in cancer. Here, we uncovered a miR-204 cooperative targeting of multiple signaling transducers involved in vasculogenic mimicry (VM). Our data showed that invasive triple negative MDA-MB-231 and Hs-578T breast cancer cells, but not poorly invasive MCF-7 cells, efficiently undergoes matrix-associated VM under hypoxia. Ectopic restoration of miR-204 in MDA-MB-231 cells leads to a potent inhibition of VM and reduction of number of branch points and patterned 3D channels. Further analysis of activation state of multiple signaling pathways using Phosphorylation Antibody Arrays revealed that miR-204 reduced the expression and phosphorylation levels of 13 proteins involved in PI3K/AKT, RAF1/MAPK, VEGF, and FAK/SRC signaling. In agreement with phospho-proteomic profiling, VM was impaired following pharmacological administration of PI3K and SRC inhibitors. Mechanistic studies confirmed that miR-204 exerts a negative post-transcriptional regulation of PI3K-α and c-SRC proto-oncogenes. Moreover, overall survival analysis of a large cohort of breast cancer patients indicates that low miR-204 and high FAK/SRC levels were associated with worst outcomes. In conclusion, our study provides novel lines of evidence indicating that miR-204 may exerts a fine-tuning regulation of the synergistic transduction of PI3K/AKT/FAK mediators critical in VM formation. Copyright © 2018 Elsevier B.V. All rights reserved.

Ozone and childhood respiratory disease in three US cities: evaluation of effect measure modification by neighborhood socioeconomic status using a Bayesian hierarchical approach.

PubMed

O' Lenick, Cassandra R; Chang, Howard H; Kramer, Michael R; Winquist, Andrea; Mulholland, James A; Friberg, Mariel D; Sarnat, Stefanie Ebelt

2017-04-05

Ground-level ozone is a potent airway irritant and a determinant of respiratory morbidity. Susceptibility to the health effects of ambient ozone may be influenced by both intrinsic and extrinsic factors, such as neighborhood socioeconomic status (SES). Questions remain regarding the manner and extent that factors such as SES influence ozone-related health effects, particularly across different study areas. Using a 2-stage modeling approach we evaluated neighborhood SES as a modifier of ozone-related pediatric respiratory morbidity in Atlanta, Dallas, & St. Louis. We acquired multi-year data on emergency department (ED) visits among 5-18 year olds with a primary diagnosis of respiratory disease in each city. Daily concentrations of 8-h maximum ambient ozone were estimated for all ZIP Code Tabulation Areas (ZCTA) in each city by fusing observed concentration data from available network monitors with simulations from an emissions-based chemical transport model. In the first stage, we used conditional logistic regression to estimate ZCTA-specific odds ratios (OR) between ozone and respiratory ED visits, controlling for temporal trends and meteorology. In the second stage, we combined ZCTA-level estimates in a Bayesian hierarchical model to assess overall associations and effect modification by neighborhood SES considering categorical and continuous SES indicators (e.g., ZCTA-specific levels of poverty). We estimated ORs and 95% posterior intervals (PI) for a 25 ppb increase in ozone. The hierarchical model combined effect estimates from 179 ZCTAs in Atlanta, 205 ZCTAs in Dallas, and 151 ZCTAs in St. Louis. The strongest overall association of ozone and pediatric respiratory disease was in Atlanta (OR = 1.08, 95% PI: 1.06, 1.11), followed by Dallas (OR = 1.04, 95% PI: 1.01, 1.07) and St. Louis (OR = 1.03, 95% PI: 0.99, 1.07). Patterns of association across levels of neighborhood SES in each city suggested stronger ORs in low compared to high SES areas, with some evidence of non-linear effect modification. Results suggest that ozone is associated with pediatric respiratory morbidity in multiple US cities; neighborhood SES may modify this association in a non-linear manner. In each city, children living in low SES environments appear to be especially vulnerable given positive ORs and high underlying rates of respiratory morbidity.

Cross-talk between Phosphate Starvation and Other Environmental Stress Signaling Pathways in Plants

PubMed Central

Baek, Dongwon; Chun, Hyun Jin; Yun, Dae-Jin; Kim, Min Chul

2017-01-01

The maintenance of inorganic phosphate (Pi) homeostasis is essential for plant growth and yield. Plants have evolved strategies to cope with Pi starvation at the transcriptional, post-transcriptional, and post-translational levels, which maximizes its availability. Many transcription factors, miRNAs, and transporters participate in the Pi starvation signaling pathway where their activities are modulated by sugar and phytohormone signaling. Environmental stresses significantly affect the uptake and utilization of nutrients by plants, but their effects on the Pi starvation response remain unclear. Recently, we reported that Pi starvation signaling is affected by abiotic stresses such as salt, abscisic acid, and drought. In this review, we identified transcription factors, such as MYB, WRKY, and zinc finger transcription factors with functions in Pi starvation and other environmental stress signaling. In silico analysis of the promoter regions of Pi starvation-responsive genes, including phosphate transporters, microRNAs, and phosphate starvation–induced genes, suggest that their expression may be regulated by other environmental stresses, such as hormones, drought, cold, heat, and pathogens as well as by Pi starvation. Thus, we suggest the possibility of cross-talk between Pi starvation signaling and other environmental stress signaling pathways. PMID:29047263

Kidney and Phosphate Metabolism

PubMed Central

2008-01-01

The serum phosphorus level is maintained through a complex interplay between intestinal absorption, exchange intracellular and bone storage pools, and renal tubular reabsorption. The kidney plays a major role in regulation of phosphorus homeostasis by renal tubular reabsorption. Type IIa and type IIc Na+/Pi transporters are important renal Na+-dependent inorganic phosphate (Pi) transporters, which are expressed in the brush border membrane of proximal tubular cells. Both are regulated by dietary Pi intake, vitamin D, fibroblast growth factor 23 (FGF23) and parathyroid hormone. The expression of type IIa Na+/Pi transporter result from hypophosphatemia quickly. However, type IIc appears to act more slowly. Physiological and pathophysiological alteration in renal Pi reabsorption are related to altered brush border membrane expression/content of the type II Na+/Pi cotransporter. Many studies of genetic and acquired renal phosphate wasting disorders have led to the identification of novel genes. Two novel Pi regulating genes, PHEX and FGF23, play a role in the pathophysiology of genetic and acquired renal phosphate wasting disorders and studies are underway to define their mechanism on renal Pi regulation. In recent studies, sodium-hydrogen exchanger regulatory factor 1 (NHERF1) is reported as another new regulator for Pi reabsorption mechanism. PMID:24459526

Binding of peptides with basic and aromatic residues to bilayer membranes: phenylalanine in the myristoylated alanine-rich C kinase substrate effector domain penetrates into the hydrophobic core of the bilayer.

PubMed

Zhang, Wenyi; Crocker, Evan; McLaughlin, Stuart; Smith, Steven O

2003-06-13

Electrostatic interactions with positively charged regions of membrane-associated proteins such as myristoylated alanine-rich C kinase substrate (MARCKS) may have a role in regulating the level of free phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) in plasma membranes. Both the MARCKS protein and a peptide corresponding to the effector domain (an unstructured region that contains 13 basic residues and 5 phenylalanines), MARCKS-(151-175), laterally sequester the polyvalent lipid PI(4,5)P2 in the plane of a bilayer membrane with high affinity. We used high resolution magic angle spinning NMR to establish the location of MARCKS-(151-175) in membrane bilayers, which is necessary to understand the sequestration mechanism. Measurements of cross-relaxation rates in two-dimensional nuclear Overhauser enhancement spectroscopy NMR experiments show that the five Phe rings of MARCKS-(151-175) penetrate into the acyl chain region of phosphatidylcholine bilayers containing phosphatidylglycerol or PI(4,5)P2. Specifically, we observed strong cross-peaks between the aromatic protons of the Phe rings and the acyl chain protons of the lipids, even for very short (50 ms) mixing times. The position of the Phe rings implies that the adjacent positively charged amino acids in the peptide are close to the level of the negatively charged lipid phosphates. The deep location of the MARCKS peptide in the polar head group region should enhance its electrostatic sequestration of PI(4,5)P2 by an "image charge" mechanism. Moreover, this location has interesting implications for membrane curvature and local surface pressure effects and may be relevant to a wide variety of other proteins with basic-aromatic clusters, such as phospholipase D, GAP43, SCAMP2, and the N-methyl-d-aspartate receptor.

Molecular Basis of Autophagic Cell Death in Prostate Cancer

DTIC Science & Technology

2009-03-01

lipid-binding proteinwith high affinity for phosphatidic acid (PA) and cardiolipin (CL). Previously, it has been shown that PA directly interacted...lyceride), PI (phosphatidylinositol), DAG (diacylglycerol), PI4P (PtdIns(4)P), PA ( phosphatidic acid ), PI4,5P2 (PtdIns(4,5)P2), PS (phosphatidylserine...with high affinity for phosphatidic acid and cardiolipin and less affinity for various phosphoinositides. Functional genomics analysis identified 5

High-throughput exposure modeling to support prioritization of chemicals in personal care products.

PubMed

Csiszar, Susan A; Ernstoff, Alexi S; Fantke, Peter; Meyer, David E; Jolliet, Olivier

2016-11-01

We demonstrate the application of a high-throughput modeling framework to estimate exposure to chemicals used in personal care products (PCPs). As a basis for estimating exposure, we use the product intake fraction (PiF), defined as the mass of chemical taken by an individual or population per mass of a given chemical used in a product. We calculated use- and disposal- stage PiFs for 518 chemicals for five PCP archetypes. Across all product archetypes the use- and disposal- stage PiFs ranged from 10(-5) to 1 and 0 to 10(-3), respectively. There is a distinction between the use-stage PiF for leave-on and wash-off products which had median PiFs of 0.5 and 0.02 across the 518 chemicals, respectively. The PiF is a function of product characteristics and physico-chemical properties and is maximized when skin permeability is high and volatility is low such that there is no competition between skin and air losses from the applied product. PCP chemical contents (i.e. concentrations) were available for 325 chemicals and were combined with PCP usage characteristics and PiF yielding intakes summed across a demonstrative set of products ranging from 10(-8)-30 mg/kg/d, with a median of 0.1 mg/kg/d. The highest intakes were associated with body lotion. Bioactive doses derived from high-throughput in vitro toxicity data were combined with the estimated PiFs to demonstrate an approach to estimate bioactive equivalent chemical content and to screen chemicals for risk. Copyright © 2016 Elsevier Ltd. All rights reserved.

High dietary phosphate intake induces hypertension and augments exercise pressor reflex function in rats.

PubMed

Mizuno, Masaki; Mitchell, Jere H; Crawford, Scott; Huang, Chou-Long; Maalouf, Naim; Hu, Ming-Chang; Moe, Orson W; Smith, Scott A; Vongpatanasin, Wanpen

2016-07-01

An increasing number of studies have linked high dietary phosphate (Pi) intake to hypertension. It is well established that the rise in sympathetic nerve activity (SNA) and blood pressure (BP) during physical exertion is exaggerated in many forms of hypertension, which are primarily mediated by an overactive skeletal muscle exercise pressor reflex (EPR). However, it remains unknown whether high dietary Pi intake potentiates the EPR-mediated SNA and BP response to exercise. Accordingly, we measured renal SNA (RSNA) and mean BP (MBP) in normotensive Sprague-Dawley rats fed a normal Pi diet (0.6%, n = 13) or high Pi diet (1.2%, n = 13) for 3 mo. As previously reported, we found that resting BP was significantly increased by 1.2% Pi diet in both conscious and anesthetized animals. Activation of the EPR by electrically induced hindlimb contraction triggered greater increases in ΔRSNA and ΔMBP in the 1.2% compared with 0.6% Pi group (126 ± 25 vs. 42 ± 9%; 44 ± 5 vs. 14 ± 2 mmHg, respectively, P < 0.01). Activation of the muscle mechanoreflex, a component of the EPR, by passively stretching hindlimb muscle also evoked greater increases in ΔRSNA and ΔMBP in the 1.2% compared with 0.6% Pi group (109 ± 27 vs. 24 ± 7%, 38 ± 7 vs. 8 ± 2 mmHg, respectively, P < 0.01). A similar response was produced by hindlimb intra-arterial capsaicin administration to stimulate the metaboreflex arm of the EPR. Thus, our data demonstrate a novel action of dietary Pi loading in augmenting EPR function through overactivation of both the muscle mechanoreflex and metaboreflex. Copyright © 2016 the American Physiological Society.

High-frequency electroacupuncture versus carprofen in an incisional pain model in rats.

PubMed

Teixeira, F M; Castro, L L; Ferreira, R T; Pires, P A; Vanderlinde, F A; Medeiros, M A

2012-12-01

The objective of the present study was to compare the effect of electroacupuncture (EA) and carprofen (CP) on postoperative incisional pain using the plantar incision (PI) model in rats. A 1-cm longitudinal incision was made through skin, fascia and muscles of a hind paw of male Wistar rats and the development of mechanical and thermal hypersensitivity was determined over 4 days using the von Frey and Hargreaves methods, respectively. Based on the experimental treatments received on the third postoperative day, the animals were divided into the following groups: PI+CP (CP, 2 mg/kg, po); PI+EAST36 (100-Hz EA applied bilaterally at the Zusanli point (ST36)); PI+EANP (EA applied to a non-acupoint region); PI+IMMO (immobilization only); PI (vehicle). In the von Frey test, the PI+EAST36 group had higher withdrawal force thresholds in response to mechanical stimuli than the PI, PI+IMMO and PI+EANP groups at several times studied. Furthermore, the PI+EAST36 group showed paw withdrawal thresholds in response to mechanical stimuli that were similar to those of the PI+CP group. In the Hargreaves test, all groups had latencies higher than those observed with PI. The PI+EAST36 group was similar to the PI+IMMO, PI+EANP and PI+CP groups. We conclude that 100-Hz EA at the ST36 point, but not at non-acupoints, can reduce mechanical nociception in the rat model of incisional pain, and its effectiveness is comparable to that of carprofen.

Strategic Therapeutic Targeting to Overcome Venetoclax Resistance in Aggressive B-cell Lymphomas.

PubMed

Pham, Lan V; Huang, Shengjian; Zhang, Hui; Zhang, Jun; Bell, Taylor; Zhou, Shouhao; Pogue, Elizabeth; Ding, Zhiyong; Lam, Laura; Westin, Jason; Davis, R Eric; Young, Ken H; Medeiros, L Jeffrey; Ford, Richard J; Nomie, Krystle; Zhang, Leo; Wang, Michael

2018-04-17

Purpose: B-cell lymphoma-2 (BCL-2), an antiapoptotic protein often dysregulated in B-cell lymphomas, promotes cell survival and provides protection from stress. A recent phase I first-in-human study of the BCL-2 inhibitor venetoclax in non-Hodgkin lymphoma showed an overall response rate of 44%. These promising clinical results prompted our examination of the biological effects and mechanism of action underlying venetoclax activity in aggressive B-cell lymphoma, including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). Experimental Design: MCL and DLBCL cell lines, primary patient samples, and in vivo patient-derived xenograft (PDX) models were utilized to examine venetoclax efficacy. Furthermore, the mechanisms underlying venetoclax response and the development of venetoclax resistance were evaluated using proteomics analysis and Western blotting. Results: Potential biomarkers linked to venetoclax activity and targeted combination therapies that can augment venetoclax response were identified. We demonstrate that DLBCL and MCL cell lines, primary patient samples, and PDX mouse models expressing high BCL-2 levels are extremely sensitive to venetoclax treatment. Proteomics studies showed that venetoclax substantially alters the expression levels and phosphorylation status of key proteins involved in cellular processes, including the DNA damage response, cell metabolism, cell growth/survival, and apoptosis. Short- and long-term exposure to venetoclax inhibited PTEN expression, leading to enhanced AKT pathway activation and concomitant susceptibility to PI3K/AKT inhibition. Intrinsic venetoclax-resistant cells possess high AKT activation and are highly sensitive to PI3K/AKT inhibition. Conclusions: These findings demonstrate the on-target effect of venetoclax and offer potential mechanisms to overcome acquired and intrinsic venetoclax resistance through PI3K/AKT inhibition. Clin Cancer Res; 1-14. ©2018 AACR. ©2018 American Association for Cancer Research.

Heterologous expression of proteins from Plasmodium falciparum: results from 1000 genes.

PubMed

Mehlin, Christopher; Boni, Erica; Buckner, Frederick S; Engel, Linnea; Feist, Tiffany; Gelb, Michael H; Haji, Lutfiyah; Kim, David; Liu, Colleen; Mueller, Natascha; Myler, Peter J; Reddy, J T; Sampson, Joshua N; Subramanian, E; Van Voorhis, Wesley C; Worthey, Elizabeth; Zucker, Frank; Hol, Wim G J

2006-08-01

As part of a structural genomics initiative, 1000 open reading frames from Plasmodium falciparum, the causative agent of the most deadly form of malaria, were tested in an E. coli protein expression system. Three hundred and thirty-seven of these targets were observed to express, although typically the protein was insoluble. Sixty-three of the targets provided soluble protein in yields ranging from 0.9 to 406.6 mg from one liter of rich media. Higher molecular weight, greater protein disorder (segmental analysis, SEG), more basic isoelectric point (pI), and a lack of homology to E. coli proteins were all highly and independently correlated with difficulties in expression. Surprisingly, codon usage and the percentage of adenosines and thymidines (%AT) did not appear to play a significant role. Of those proteins which expressed, high pI and a hypothetical annotation were both strongly and independently correlated with insolubility. The overwhelmingly important role of pI in both expression and solubility appears to be a surprising and fundamental issue in the heterologous expression of P. falciparum proteins in E. coli. Twelve targets which did not express in E. coli from the native gene sequence were codon-optimized through whole gene synthesis, resulting in the (insoluble) expression of three of these proteins. Seventeen targets which were expressed insolubly in E. coli were moved into a baculovirus/Sf-21 system, resulting in the soluble expression of one protein at a high level and six others at a low level. A variety of factors conspire to make the heterologous expression of P. falciparum proteins challenging, and these observations lay the groundwork for a rational approach to prioritizing and, ultimately, eliminating these impediments.

Gallic acid attenuates high-fat diet fed-streptozotocin-induced insulin resistance via partial agonism of PPARγ in experimental type 2 diabetic rats and enhances glucose uptake through translocation and activation of GLUT4 in PI3K/p-Akt signaling pathway.

PubMed

Gandhi, Gopalsamy Rajiv; Jothi, Gnanasekaran; Antony, Poovathumkal James; Balakrishna, Kedike; Paulraj, Michael Gabriel; Ignacimuthu, Savarimuthu; Stalin, Antony; Al-Dhabi, Naif Abdullah

2014-12-15

In this study, the therapeutic efficacy of gallic acid from Cyamopsis tetragonoloba (L.) Taub. (Fabaceae) beans was examined against high-fat diet fed-streptozotocin-induced experimental type 2 diabetic rats. Molecular-dockings were done to determine the putative binding modes of gallic acid into the active sites of key insulin-signaling markers. Gallic acid (20 mg/kg) given to high-fat diet fed-streptozotocin-induced rats lowered body weight gain, fasting blood glucose and plasma insulin in diabetic rats. It further restored the alterations of biochemical parameters to near normal levels in diabetic treated rats along with cytoprotective action on pancreatic β-cell. Histology of liver and adipose tissues supported the biochemical findings. Gallic acid significantly enhanced the level of peroxisome proliferator-activated receptor γ (PPARγ) expression in the adipose tissue of treated rat compared to untreated diabetic rat; it also slightly activated PPARγ expressions in the liver and skeletal muscle. Consequently, it improved insulin-dependent glucose transport in adipose tissue through translocation and activation of glucose transporter protein 4 (GLUT4) in phosphatidylinositol 3-kinase (PI3K)/phosphorylated protein kinase B (p-Akt) dependent pathway. Gallic acid docked with PPARγ; it exhibited promising interactions with the GLUT4, glucose transporter protein 1 (GLUT1), PI3K and p-Akt. These findings provided evidence to show that gallic acid could improve adipose tissue insulin sensitivity, modulate adipogenesis, increase adipose glucose uptake and protect β-cells from impairment. Hence it can be used in the management of obesity-associated type 2 diabetes mellitus. Copyright © 2014 Elsevier B.V. All rights reserved.

Construction of an 800-kb contig in the near-centromeric region of the rice blast resistance gene Pi-ta2 using a highly representative rice BAC library.

PubMed

Nakamura, S; Asakawa, S; Ohmido, N; Fukui, K; Shimizu, N; Kawasaki, S

1997-05-01

We constructed a rice Bacterial Artificial Chromosome (BAC) library from green leaf protoplasts of the cultivar Shimokita harboring the rice blast resistance gene Pi-ta. The average insert size of 155 kb and the library size of seven genome equivalents make it one of the most comprehensive BAC libraries available, and larger than many plant YAC libraries. The library clones were plated on seven high density membranes of microplate size, enabling efficient colony identification in colony hybridization experiments. Seven percent of clones carried chloroplast DNA. By probing with markers close to the blast resistance genes Pi-ta2(closely linked to Pi-ta) and Pi-b, respectively located in the centromeric region of chromosome 12 and near the telomeric end of chromosome 2, on average 2.2 +/- 1.3 and 8.0 +/- 2.6 BAC clones/marker were isolated. Differences in chromosomal structures may contribute to this wide variation in yield. A contig of about 800 kb, consisting of 19 clones, was constructed in the Pi-ta2 region. This region had a high frequency of repetitive sequences. To circumvent this difficulty, we devised a "two-step walking" method. The contig spanned a 300 kb region between markers located at 0 cM and 0.3 cM from Pi-ta. The ratio of physical to genetic distances (> 1,000 kb/cM) was more than three times larger than the average of rice (300 kb/cM). The low recombination rate and high frequency of repetitive sequences may also be related to the near centromeric character of this region. Fluorescent in situ hybridization (FISH) with a BAC clone from the Pi-b region yielded very clear signals on the long arm of chromosome 2, while a clone from the Pi-ta2 region showed various cross-hybridizing signals near the centromeric regions of all chromosomes.

Pathogen trafficking pathways and host phosphoinositide metabolism.

PubMed

Weber, Stefan S; Ragaz, Curdin; Hilbi, Hubert

2009-03-01

Phosphoinositide (PI) glycerolipids are key regulators of eukaryotic signal transduction, cytoskeleton architecture and membrane dynamics. The host cell PI metabolism is targeted by intracellular bacterial pathogens, which evolved intricate strategies to modulate uptake processes and vesicle trafficking pathways. Upon entering eukaryotic host cells, pathogenic bacteria replicate in distinct vacuoles or in the host cytoplasm. Vacuolar pathogens manipulate PI levels to mimic or modify membranes of subcellular compartments and thereby establish their replicative niche. Legionella pneumophila, Brucella abortus, Mycobacterium tuberculosis and Salmonella enterica translocate effector proteins into the host cell, some of which anchor to the vacuolar membrane via PIs or enzymatically turnover PIs. Cytoplasmic pathogens target PI metabolism at the plasma membrane, thus modulating their uptake and antiapoptotic signalling pathways. Employing this strategy, Shigella flexneri directly injects a PI-modifying effector protein, while Listeria monocytogenes exploits PI metabolism indirectly by binding to transmembrane receptors. Thus, regardless of the intracellular lifestyle of the pathogen, PI metabolism is critically involved in the interactions with host cells.

PI3K-resistant GSK3 controls adiponectin formation and protects from metabolic syndrome.

PubMed

Chen, Hong; Fajol, Abul; Hoene, Miriam; Zhang, Bingbing; Schleicher, Erwin D; Lin, Yun; Calaminus, Carsten; Pichler, Bernd J; Weigert, Cora; Häring, Hans U; Lang, Florian; Föller, Michael

2016-05-17

Metabolic syndrome is characterized by insulin resistance, obesity, and dyslipidemia. It is the consequence of an imbalance between caloric intake and energy consumption. Adiponectin protects against metabolic syndrome. Insulin-induced signaling includes activation of PI3 kinase and protein kinase B (PKB)/Akt. PKB/Akt in turn inactivates glycogen synthase kinase (GSK) 3, a major regulator of metabolism. Here, we studied the significance of PI3K-dependent GSK3 inactivation for adiponectin formation in diet-induced metabolic syndrome. Mice expressing PI3K-insensitive GSK3 (gsk3(KI)) and wild-type mice (gsk3(WT)) were fed a high-fat diet. Compared with gsk3(WT) mice, gsk3(KI) mice were protected against the development of metabolic syndrome as evident from a markedly lower weight gain, lower total body and liver fat accumulation, better glucose tolerance, stronger hepatic insulin-dependent PKB/Akt phosphorylation, lower serum insulin, cholesterol, and triglyceride levels, as well as higher energy expenditure. Serum adiponectin concentration and the activity of transcription factor C/EBPα controlling the expression of adiponectin in adipose tissue was significantly higher in gsk3(KI) mice than in gsk3(WT) mice. Treatment with GSK3 inhibitor lithium significantly decreased the serum adiponectin concentration of gsk3(KI) mice and abrogated the difference in C/EBPα activity between the genotypes. Taken together, our data demonstrate that the expression of PI3K-insensitive GSK3 stimulates the production of adiponectin and protects from diet-induced metabolic syndrome.

Effect of saw palmetto extract on PI3K cell signaling transduction in human glioma

PubMed Central

YANG, YANG; HUI, LV; YUQIN, CHE; JIE, LI; SHUAI, HOU; TIEZHU, ZHOU; WEI, WANG

2014-01-01

Saw palmetto extract can induce the apoptosis of prostate cancer cells. The aim of the present study was to investigate the effect of saw palmetto extract on the phosphatidylinositol 3-kinase (PI3K)/Akt signaling transduction pathway in human glioma U87 and U251 cell lines. Suspensions of U87 and U251 cells in a logarithmic growth phase were seeded into six-well plates at a density of 104 cells/well. In the experimental group, 1 μl/ml saw palmetto extract was added, while the control group was cultured without a drug for 24 h. The expression levels of PI3K, B-cell lymphoma-extra large (Bcl-xL) and p53 were evaluated through western blot analysis. In the experimental group, the U87 and U251 cells exhibited a lower expression level of PI3K protein as compared with the control group (t=6.849; P<0.001). In addition, the two cell lines had a higher expression level of p53 protein in the experimental group as compared with the control group (t=40.810; P<0.001). Protein expression levels of Bcl-xL decreased significantly in the experimental group as compared with the control group (t=19.640; P=0.000). Therefore, saw palmetto extract induces glioma cell growth arrest and apoptosis via decreasing PI3K/Akt signal transduction. PMID:25009620

Lactobacillus casei DG and its postbiotic reduce the inflammatory mucosal response: an ex-vivo organ culture model of post-infectious irritable bowel syndrome.

PubMed

Compare, Debora; Rocco, Alba; Coccoli, Pietro; Angrisani, Debora; Sgamato, Costantino; Iovine, Barbara; Salvatore, Umberto; Nardone, Gerardo

2017-04-14

The evidence on the role of gut microbiota in post-infectious irritable bowel syndrome (PI-IBS) is convincing. Lactobacillus spp. positively affect IBS symptoms, although the mechanisms through which probiotics exert their beneficial effects are largely unknown. The aim of the study is to evaluate the role of Lactobacillus casei DG (LC-DG) and its postbiotic (PB) in modulating the inflammatory/immune-response in PI-IBS in an ex-vivo organ culture model. Ex vivo cultures of ileal and colonic mucosa from 10 PI-IBS, diarrhea predominant subtype (D) patients, and 10 healthy controls (HC) were treated with LPS, LC-DG and PB. Interleukin (IL)-1α, IL-6, IL-8 and IL-10 mRNA levels were assessed by real-time PCR and Toll like receptor 4 (TLR-4) protein expression by Western blotting. At baseline, IL-1α, IL-6 and IL-8 mRNA levels as well as TLR-4 protein expression were significantly higher while IL-10 mRNA levels were lower in PI-IBS D than in HC in both ileum and colon. LC-DG and PB significantly reduced the mRNA levels of pro-inflammatory cytokines and TLR-4 while increased that of IL-10 after LPS stimulation. The protective effect was more pronounced for PB than LC-DG treatment. LC-DG and its PB attenuate the inflammatory mucosal response in an ex-vivo organ culture model of PI-IBS D.

CLAS N* Excitation Results from Pion and Kaon Electroproduction

DOE PAGES

Carman, Daniel S.

2018-05-24

The study of the structure of excited nucleonmore » $N^*$ states employing the electroproduction of exclusive reactions is an important avenue for exploring the nature of the non-perturbative strong interaction. The electrocouplings of $N^*$ states in the mass range below $W$=1.8~GeV have been determined from analyses of CLAS $$\\pi N$$, $$\\eta N$$, and $$\\pi \\pi N$$ data at four-momentum transfers $Q^2$ up to 5~GeV$^2$. The work has made it clear that consistent results from independent analyses of several exclusive channels with different couplings and non-resonant backgrounds but the same $N^*$ electroexcitation amplitudes, is essential to have confidence in the extracted results. In terms of hadronic couplings, many high-lying $N^*$ states preferentially decay through the $$\\pi \\pi N$$ channel, while couplings to $$\\pi N$$ final states become rather small. The resonance parameters determined from $$\\pi N$$ and $$\\pi \\pi N$$ electroproduction can be checked in independent studies of the $KY$ ($$Y = \\Lambda, \\Sigma^0$$) channels. Therefore, data from the $KY$ channels already measured with CLAS will play an important role in $N^*$ structure studies. These comparisons await the development of suitable reaction models. Starting in 2018, a program to study the structure of $N^*$ states in various exclusive electroproduction channels using the new CLAS12 spectrometer will get underway. These studies will probe the structure of $N^*$ states in the mass range up to $W$=3~GeV and $Q^2$ up to 12~GeV$^2$, thus providing a means to access $N^*$ structure information spanning a broad regime encompassing both low- and high-energy degrees of freedom.« less

CLAS N* Excitation Results from Pion and Kaon Electroproduction

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

Carman, Daniel S.

The study of the structure of excited nucleonmore » $N^*$ states employing the electroproduction of exclusive reactions is an important avenue for exploring the nature of the non-perturbative strong interaction. The electrocouplings of $N^*$ states in the mass range below $W$=1.8~GeV have been determined from analyses of CLAS $$\\pi N$$, $$\\eta N$$, and $$\\pi \\pi N$$ data at four-momentum transfers $Q^2$ up to 5~GeV$^2$. The work has made it clear that consistent results from independent analyses of several exclusive channels with different couplings and non-resonant backgrounds but the same $N^*$ electroexcitation amplitudes, is essential to have confidence in the extracted results. In terms of hadronic couplings, many high-lying $N^*$ states preferentially decay through the $$\\pi \\pi N$$ channel, while couplings to $$\\pi N$$ final states become rather small. The resonance parameters determined from $$\\pi N$$ and $$\\pi \\pi N$$ electroproduction can be checked in independent studies of the $KY$ ($$Y = \\Lambda, \\Sigma^0$$) channels. Therefore, data from the $KY$ channels already measured with CLAS will play an important role in $N^*$ structure studies. These comparisons await the development of suitable reaction models. Starting in 2018, a program to study the structure of $N^*$ states in various exclusive electroproduction channels using the new CLAS12 spectrometer will get underway. These studies will probe the structure of $N^*$ states in the mass range up to $W$=3~GeV and $Q^2$ up to 12~GeV$^2$, thus providing a means to access $N^*$ structure information spanning a broad regime encompassing both low- and high-energy degrees of freedom.« less

Doppler Audio Signal Analysis as an Additional Tool in Evaluation of Umbilical Artery Circulation.

PubMed

Thuring, Ann; Källén, Karin; Brännström, K Jonas; Jansson, Tomas; Maršál, Karel

2017-10-01

Purpose  To investigate the predictive capacity of a new method for sound spectrum analysis of Doppler signals recorded from the umbilical artery in high-risk pregnancies. Material and Methods  The retrospective study comprised 127 pregnant women with various pregnancy complications between 23 and 39 gestational weeks. Umbilical artery blood flow velocity waveforms were recorded with Doppler ultrasound and characterized by pulsatility index (PI) and blood flow class (BFC). Doppler audio signals were stored on a digital video recorder and the sound frequency at the energy level 15 dB below its peak (MAX peak-15 dB ) was estimated off-line. The prediction of probability for composite adverse pregnancy outcome (operative delivery for fetal distress, admission to neonatal intensive care unit, perinatal death) was evaluated using the area under the curve (AUC) of the receiver operating characteristics (ROC) curve. Results  With increasing umbilical artery BFC, the MAX peak-15 dB frequencies decreased (p < 0.0001) and the PI increased (p < 0.0001). The ROC AUCs for adverse outcome for MAX peak-15 dB and for PI were 0.842 and 0.836 (p = 0.88), respectively. For the combination of MAX peak-15 dB and PI, the corresponding AUC was 0.894, significantly higher than that of PI (p < 0.03) and of MAX peak-15 dB (p < 0.05). Conclusion  Umbilical artery Doppler sound spectrum analysis might be a useful supplement to PI in the clinical evaluation of fetoplacental circulation. © Georg Thieme Verlag KG Stuttgart · New York.

Silencing of Transposable Elements by piRNAs in Drosophila: An Evolutionary Perspective.

PubMed

Luo, Shiqi; Lu, Jian

2017-06-01

Transposable elements (TEs) are DNA sequences that can move within the genome. TEs have greatly shaped the genomes, transcriptomes, and proteomes of the host organisms through a variety of mechanisms. However, TEs generally disrupt genes and destabilize the host genomes, which substantially reduce fitness of the host organisms. Understanding the genomic distribution and evolutionary dynamics of TEs will greatly deepen our understanding of the TE-mediated biological processes. Most TE insertions are highly polymorphic in Drosophila melanogaster, providing us a good system to investigate the evolution of TEs at the population level. Decades of theoretical and experimental studies have well established "transposition-selection" population genetics model, which assumes that the equilibrium between TE replication and purifying selection determines the copy number of TEs in the genome. In the last decade, P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) were demonstrated to be master repressors of TE activities in Drosophila. The discovery of piRNAs revolutionized our understanding of TE repression, because it reveals that the host organisms have evolved an adaptive mechanism to defend against TE invasion. Tremendous progress has been made to understand the molecular mechanisms by which piRNAs repress active TEs, although many details in this process remain to be further explored. The interaction between piRNAs and TEs well explains the molecular mechanisms underlying hybrid dysgenesis for the I-R and P-M systems in Drosophila, which have puzzled evolutionary biologists for decades. The piRNA repression pathway provides us an unparalleled system to study the co-evolutionary process between parasites and host organisms. Copyright © 2017 Beijing Institute of Genomics, Chinese Academy of Sciences and Genetics Society of China. Production and hosting by Elsevier B.V. All rights reserved.

Pittsburgh Compound B and AV-1451 positron emission tomography assessment of molecular pathologies of Alzheimer's disease in progressive supranuclear palsy.

PubMed

Whitwell, Jennifer L; Ahlskog, J Eric; Tosakulwong, Nirubol; Senjem, Matthew L; Spychalla, Anthony J; Petersen, Ronald C; Jack, Clifford R; Lowe, Val J; Josephs, Keith A

2018-03-01

Little is known about Alzheimer's disease molecular proteins, beta-amyloid and paired helical filament (PHF) tau, in progressive supranuclear palsy (PSP). Recent techniques have been developed to allow for investigations of these proteins in PSP. We determined the frequency of beta-amyloid deposition in PSP, and whether beta-amyloid deposition in PSP is associated with PHF-tau deposition pattern, or clinical features. Thirty probable PSP participants underwent MRI, [ 18 F]AV-1451 PET and Pittsburgh compound B (PiB) PET. Apolipoprotein (APOE) genotyping was also performed. A global PiB standard-uptake value ratio (SUVR) was calculated. AV-1451 SUVRs were calculated for a set of Alzheimer's disease (AD)-related regions and a set of PSP-related regions. Voxel-level analyses were conducted to assess for differences in AV-1451 uptake patterns and MRI atrophy between PiB(+) and PiB(-) cases compared to 60 normal PiB(-) controls. Statistical testing for correlations and associations between variables of interest were also performed. Twelve subjects (40%) showed beta-amyloid deposition. Higher PiB SUVR correlated with older age but not with AV-1451 SUVR in the AD- or PSP-related regions. Higher AV-1451 SUVR in AD-related regions was associated with higher AV-1451 SUVR in PSP-related regions. We found little evidence for beta-amyloid related differences in clinical metrics, proportion of APOE e4 carriers, pattern of AV-1451 uptake, or pattern of atrophy. Beta-amyloid deposition occurs in a relatively high proportion of PSP subjects. Unlike in Alzheimer's disease, however, there is little evidence that beta-amyloid, and PHF-tau, play a significant role in neurodegeneration in PSP. Copyright © 2017 Elsevier Ltd. All rights reserved.

Transcriptomic Response of Resistant (PI613981–Malus sieversii) and Susceptible (“Royal Gala”) Genotypes of Apple to Blue Mold (Penicillium expansum) Infection

PubMed Central

Ballester, Ana-Rosa; Norelli, John; Burchard, Erik; Abdelfattah, Ahmed; Levin, Elena; González-Candelas, Luis; Droby, Samir; Wisniewski, Michael

2017-01-01

Malus sieversii from Central Asia is a progenitor of the modern domesticated apple (Malus × domestica). Several accessions of M. sieversii are highly resistant to the postharvest pathogen Penicillium expansum. A previous study identified the qM–Pe3.1 QTL on LG3 for resistance to P. expansum in the mapping population GMAL4593, developed using the resistant accession, M. sieversii –PI613981, and the susceptible cultivar “Royal Gala” (RG) (M. domestica), as parents. The goal of the present study was to characterize the transcriptomic response of susceptible RG and resistant PI613981 apple fruit to wounding and inoculation with P. expansum using RNA–Seq. Transcriptomic analyses 0–48 h post inoculation suggest a higher basal level of resistance and a more rapid and intense defense response to wounding and wounding plus inoculation with P. expansum in M. sieversii –PI613981 than in RG. Functional analysis showed that ethylene–related genes and genes involved in “jasmonate” and “MYB–domain transcription factor family” were over–represented in the resistant genotype. It is suggested that the more rapid response in the resistant genotype (Malus sieversii–PI613981) plays a major role in the resistance response. At least twenty DEGs were mapped to the qM–Pe3.1 QTL (M × d v.1: 26,848,396–28,424,055) on LG3, and represent potential candidate genes responsible for the observed resistance QTL in M. sieversii–PI613981. RT–qPCR of several of these genes was used to validate the RNA–Seq data and to confirm their higher expression in MS0. PMID:29201037

Pseudoinverse Decoding Process in Delay-Encoded Synthetic Transmit Aperture Imaging.

PubMed

Gong, Ping; Kolios, Michael C; Xu, Yuan

2016-09-01

Recently, we proposed a new method to improve the signal-to-noise ratio of the prebeamformed radio-frequency data in synthetic transmit aperture (STA) imaging: the delay-encoded STA (DE-STA) imaging. In the decoding process of DE-STA, the equivalent STA data were obtained by directly inverting the coding matrix. This is usually regarded as an ill-posed problem, especially under high noise levels. Pseudoinverse (PI) is usually used instead for seeking a more stable inversion process. In this paper, we apply singular value decomposition to the coding matrix to conduct the PI. Our numerical studies demonstrate that the singular values of the coding matrix have a special distribution, i.e., all the values are the same except for the first and last ones. We compare the PI in two cases: complete PI (CPI), where all the singular values are kept, and truncated PI (TPI), where the last and smallest singular value is ignored. The PI (both CPI and TPI) DE-STA processes are tested against noise with both numerical simulations and experiments. The CPI and TPI can restore the signals stably, and the noise mainly affects the prebeamformed signals corresponding to the first transmit channel. The difference in the overall enveloped beamformed image qualities between the CPI and TPI is negligible. Thus, it demonstrates that DE-STA is a relatively stable encoding and decoding technique. Also, according to the special distribution of the singular values of the coding matrix, we propose a new efficient decoding formula that is based on the conjugate transpose of the coding matrix. We also compare the computational complexity of the direct inverse and the new formula.

Modulation of phosphoinositide turnover by chronic nicergoline in rat brain.

PubMed

Carfagna, N; Cavanus, S; Damiani, D; Salmoiraghi, P; Fariello, R; Post, C

1996-05-17

Basal and agonist-stimulated phosphoinositide (PI) turnover and inositol 1,4,5 -trisphospate (InsP3) content in rat brain were investigated after chronic nicergoline (SERMION) treatment. Oral administration of nicergoline (5 mg/kg b.i.d. for 7 weeks) enhanced the basal turnover of PI in the cerebral cortex compared to controls. This effect was paralleled by a significant rise of cortical InsP3 levels. No significant changes of noradrenaline- or carbachol-induced accumulation of [3H]-inositol-I-phophate ([3H]-InsP1) were found in cortices from nicergoline-treated rats. On the contrary, in the striatum nicergoline significantly potentiated the responsiveness of noradrenaline- and carbachol-stimulated PI turnover, leaving unchanged the basal production of [3H]-InsP1 and InsP3 levels. The results suggest that the interaction of nicergoline with PI transducing pathway might have relevance to the mechanisms of action of nicergoline.

Theoretical study of the NO gamma system

NASA Technical Reports Server (NTRS)

Langhoff, Stephen R.; Bauschlicher, Charles W., Jr.; Partridge, Harry

1988-01-01

A systematic study of the NO gamma system with level of correlation treatment was carried out using large Gaussian basis sets to determine the potential curves for the X2Pi and A2Sigma(+) states of NO. It is shown that the A2Sigma-X2Pi electronic transition moment (gamma system) increases monotonically with decreasing internuclear distance and that the increase in the moment as r decreases is correlated with the increasing degree of diffuse character in the X2Pi state. The results of a study of the X2Pi and A2Sigma(+) dipole moment functions showed that the X2Pi vibrationally averaged dipole moments and the (1-0) and (2-0) vibration-rotation band intensities agree well with experimental data.

PI-273, a Substrate-Competitive, Specific Small-Molecule Inhibitor of PI4KIIα, Inhibits the Growth of Breast Cancer Cells.

PubMed

Li, Jiangmei; Gao, Zhen; Zhao, Dan; Zhang, Lunfeng; Qiao, Xinhua; Zhao, Yingying; Ding, Hong; Zhang, Panpan; Lu, Junyan; Liu, Jia; Jiang, Hualiang; Luo, Cheng; Chen, Chang

2017-11-15

While phosphatidylinositol 4-kinase (PI4KIIα) has been identified as a potential target for antitumor therapy, the clinical applications of PI4KIIα are limited by a lack of specific inhibitors. Here we report the first small-molecule inhibitor (SMI) of human PI4KIIα. Docking-based and ligand-based virtual screening strategies were first employed to identify promising hits, followed by two rounds of kinase activity inhibition validation. 2-(3-(4-Chlorobenzoyl)thioureido)-4-ethyl-5-methylthiophene-3-carboxamide (PI-273) exhibited the greatest inhibitory effect on PI4KIIα kinase activity (IC 50 = 0.47 μmol/L) and suppressed cell proliferation. Surface plasmon resonance and thermal shift assays indicated that PI-273 interacted directly with PI4KIIα. Kinetic analysis identified PI-273 as a reversible competitive inhibitor with respect to the substrate phosphatidylinositol (PI), which contrasted with most other PI kinase inhibitors that bind the ATP binding site. PI-273 reduced PI4P content, cell viability, and AKT signaling in wild-type MCF-7 cells, but not in PI4KIIα knockout MCF-7 cells, indicating that PI-273 is highly selective for PI4KIIα. Mutant analysis revealed a role of palmitoylation insertion in the selectivity of PI-273 for PI4KIIα. In addition, PI-273 treatment retarded cell proliferation by blocking cells in G 2 -M, inducing cell apoptosis and suppressing colony-forming ability. Importantly, PI-273 significantly inhibited MCF-7 cell-induced breast tumor growth without toxicity. PI-273 is the first substrate-competitive, subtype-specific inhibitor of PI4KIIα, the use of which will facilitate evaluations of PI4KIIα as a cancer therapeutic target. Cancer Res; 77(22); 6253-66. ©2017 AACR . ©2017 American Association for Cancer Research.

Comparative transcriptome analysis of nodules of two Mesorhizobium-chickpea associations with differential symbiotic efficiency under phosphate deficiency.

PubMed

Nasr Esfahani, Maryam; Inoue, Komaki; Chu, Ha Duc; Nguyen, Kien Huu; Van Ha, Chien; Watanabe, Yasuko; Burritt, David J; Herrera-Estrella, Luis; Mochida, Keiichi; Tran, Lam-Son Phan

2017-09-01

Phosphate (Pi) deficiency is known to be a major limitation for symbiotic nitrogen fixation (SNF), and hence legume crop productivity globally. However, very little information is available on the adaptive mechanisms, particularly in the important legume crop chickpea (Cicer arietinum L.), which enable nodules to respond to low-Pi availability. Thus, to elucidate these mechanisms in chickpea nodules at molecular level, we used an RNA sequencing approach to investigate transcriptomes of the nodules in Mesorhizobium mediterraneum SWRI9-(MmSWRI9)-chickpea and M. ciceri CP-31-(McCP-31)-chickpea associations under Pi-sufficient and Pi-deficient conditions, of which the McCP-31-chickpea association has a better SNF capacity than the MmSWRI9-chickpea association during Pi starvation. Our investigation revealed that more genes showed altered expression patterns in MmSWRI9-induced nodules than in McCP-31-induced nodules (540 vs. 225) under Pi deficiency, suggesting that the Pi-starvation-more-sensitive MmSWRI9-induced nodules required expression change in a larger number of genes to cope with low-Pi stress than the Pi-starvation-less-sensitive McCP-31-induced nodules. The functional classification of differentially expressed genes (DEGs) was examined to gain an understanding of how chickpea nodules respond to Pi starvation, caused by soil Pi deficiency. As a result, more DEGs involved in nodulation, detoxification, nutrient/ion transport, transcriptional factors, key metabolic pathways, Pi remobilization and signalling were found in Pi-starved MmSWRI9-induced nodules than in Pi-starved McCP-31-induced nodules. Our findings have enabled the identification of molecular processes that play important roles in the acclimation of nodules to Pi deficiency, ultimately leading to the development of Pi-efficient chickpea symbiotic associations suitable for Pi-deficient soils. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.

α1-Antitrypsin Protease Inhibitor MZ Heterozygosity Is Associated With Airflow Obstruction in Two Large Cohorts

PubMed Central

Sørheim, Inga-Cecilie; Bakke, Per; Gulsvik, Amund; Pillai, Sreekumar G.; Johannessen, Ane; Gaarder, Per I.; Campbell, Edward J.; Agustí, Alvar; Calverley, Peter M. A.; Donner, Claudio F.; Make, Barry J.; Rennard, Stephen I.; Vestbo, Jørgen; Wouters, Emiel F. M.; Paré, Peter D.; Levy, Robert D.; Coxson, Harvey O.; Lomas, David A.; Hersh, Craig P.

2010-01-01

Background: Severe α1-antitrypsin deficiency is a known genetic risk factor for COPD. Heterozygous (protease inhibitor [PI] MZ) individuals have moderately reduced serum levels of α1-antitrypsin, but whether they have an increased risk of COPD is uncertain. Methods: We compared PI MZ and PI MM individuals in two large populations: a case-control study from Norway (n = 1,669) and a multicenter family-based study from Europe and North America (n = 2,707). We sought to determine whether PI MZ was associated with the specific COPD-related phenotypes of lung function and quantitative CT scan measurements of emphysema and airway disease. Results: PI MZ was associated with a 3.5% lower FEV1/FVC ratio in the case-control study (P = .035) and 3.9% lower FEV1/vital capacity (VC) ratio in the family study (P = .009). In the case-control study, PI MZ also was associated with 3.7% more emphysema on quantitative analysis of chest CT scans (P = .003). The emphysema result was not replicated in the family study. PI MZ was not associated with airway wall thickness or COPD status in either population. Among subjects with low smoking exposure (< 20 pack-years), PI MZ individuals had more severe emphysema on chest CT scan than PI MM individuals in both studies. Conclusions: Compared with PI MM individuals, PI MZ heterozygotes had lower FEV1/(F)VC ratio in two independent studies. Our results suggest that PI MZ individuals may be slightly more susceptible to the development of airflow obstruction than PI MM individuals. PMID:20595457

Prenatal retinoic acid upregulates pulmonary gene expression of PI3K and AKT in nitrofen-induced pulmonary hypoplasia.

PubMed

Doi, Takashi; Sugimoto, Kaoru; Ruttenstock, Elke; Dingemann, Jens; Puri, Prem

2010-10-01

The precise mechanism of pulmonary hypoplasia associated with congenital diaphragmatic hernia (CDH) still remains unclear. Recently, prenatal treatment with retinoic acid (RA) has been reported to stimulate alveologenesis in hypoplastic lungs in the nitrofen model of CDH. The serine/threonine protein kinase B (AKT) plays a key role in lung morphogenesis through epithelial-mesenchymal interaction in phosphatidylinositide 3-kinase (PI3K)-dependent manner. It has been reported that the lung morphogenesis in explants in mice is interfered by inhibitors of PI3K-AKT signaling pathway. Furthermore, we have recently shown that nitrofen inhibits PI3K-AKT signaling during mid-to-late lung morphogenesis in the nitrofen-induced hypoplastic lung. We hypothesized that prenatal administration of RA upregulates pulmonary gene expression of PI3K and AKT in the nitrofen-induced hypoplastic lung. Pregnant rats were exposed to either olive oil or nitrofen on day 9 of gestation (D9). 5 mg/kg of RA was given on D18, D19 and D20. The fetuses were harvested on D21, and fetal lungs were obtained and divided into four groups: control, control + RA, nitrofen, nitrofen + RA. The mRNA expression levels of PI3K and AKT were analyzed in each lung by real-time RT-PCR and statistically analyzed. Immunohistochemistry was also performed to evaluate protein expression of PI3K and AKT in the fetal lungs at D21. The pulmonary gene expression levels of PI3K and AKT were significantly upregulated in nitrofen + RA group compared to nitrofen group and control + RA group (p < 0.05), whereas there were no significant differences between controls and control + RA group. Immunoreactivity of PI3K and AKT was markedly increased in nitrofen + RA lungs compared to nitrofen-induced hypoplastic lungs. Upregulation of PI3K and AKT genes after prenatal treatment with RA in the nitrofen-induced hypoplastic lung suggests that RA may have a therapeutic potential in modulating lung alveologenesis by stimulating epithelial-mesenchymal interaction via PI3K-AKT signaling.

Irisin inhibits hepatic gluconeogenesis and increases glycogen synthesis via the PI3K/Akt pathway in type 2 diabetic mice and hepatocytes.

PubMed

Liu, Tong-Yan; Shi, Chang-Xiang; Gao, Run; Sun, Hai-Jian; Xiong, Xiao-Qing; Ding, Lei; Chen, Qi; Li, Yue-Hua; Wang, Jue-Jin; Kang, Yu-Ming; Zhu, Guo-Qing

2015-11-01

Increased glucose production and reduced hepatic glycogen storage contribute to metabolic abnormalities in diabetes. Irisin, a newly identified myokine, induces the browning of white adipose tissue, but its effects on gluconeogenesis and glycogenesis are unknown. In the present study, we investigated the effects and underlying mechanisms of irisin on gluconeogenesis and glycogenesis in hepatocytes with insulin resistance, and its therapeutic role in type 2 diabetic mice. Insulin resistance was induced by glucosamine (GlcN) or palmitate in human hepatocellular carcinoma (HepG2) cells and mouse primary hepatocytes. Type 2 diabetes was induced by streptozotocin/high-fat diet (STZ/HFD) in mice. In HepG2 cells, irisin ameliorated the GlcN-induced increases in glucose production, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) expression, and glycogen synthase (GS) phosphorylation; it prevented GlcN-induced decreases in glycogen content and the phosphoinositide 3-kinase (PI3K) p110α subunit level, and the phosphorylation of Akt/protein kinase B, forkhead box transcription factor O1 (FOXO1) and glycogen synthase kinase-3 (GSK3). These effects of irisin were abolished by the inhibition of PI3K or Akt. The effects of irisin were confirmed in mouse primary hepatocytes with GlcN-induced insulin resistance and in human HepG2 cells with palmitate-induced insulin resistance. In diabetic mice, persistent subcutaneous perfusion of irisin improved the insulin sensitivity, reduced fasting blood glucose, increased GSK3 and Akt phosphorylation, glycogen content and irisin level, and suppressed GS phosphorylation and PEPCK and G6Pase expression in the liver. Irisin improves glucose homoeostasis by reducing gluconeogenesis via PI3K/Akt/FOXO1-mediated PEPCK and G6Pase down-regulation and increasing glycogenesis via PI3K/Akt/GSK3-mediated GS activation. Irisin may be regarded as a novel therapeutic strategy for insulin resistance and type 2 diabetes. © 2015 Authors; published by Portland Press Limited.

Not all intestinal traumatic injuries are the same: a comparison of surgically treated blunt vs. penetrating injuries.

PubMed

Adam, Nadir; Sorensen, Victor; Skinner, Ruby

2015-01-01

Traumatic intestinal injuries are less common with blunt compared to penetrating mechanisms of trauma and blunt injuries are often associated with diagnostic delays. The purpose of this study is to evaluate differences in the characteristics and outcomes between blunt and penetrating intestinal injuries to facilitate insight into optimal recognition and management. A retrospective analysis of trauma admissions from January 2009 to June 2011 was performed. Patient demographics, ISS, early shock, injury type, timing to OR, blood loss and transfusions, surgical management, infections, EC fistulas, enteric leaks, LOS and mortality were compared. Demographics - There was 3866 blunt admissions and 966 penetrating admissions to our level II trauma centre (Total n=4832) during this interval. The final study group comprised n=131 patients treated for intestinal injuries. Blunt n=54 (BI) vs. penetrating (PI) n=77. Age was similar between the groups: (BI 34 SD 12 vs. PI 30 SD 12). Comorbid conditions were similar as were ED hypotension and blood transfusions. Blunt mechanisms had higher ISS; BI (20 SD 14) vs. PI (16 SD 12), p=0.08 and organ specific injury scales were higher in blunt injuries. Operative Management - Time to operation was higher in BI: (500 SD 676min vs. PI 110 SD 153min, p=0.01). The use of an open abdomen technique was higher for BI: n=19 (35%) vs. PI: n=5 (6%), p=<0.001, as well as delayed intestinal repair in damage control cases. Outcomes - Anastomotic leaks were more prevalent in BI: n=4 (7%) vs. PI: n=2 (3%), p=0.38. Enteric fistulas were: (BI n=8 (15%), vs. PI n=2 (3%), p=0.02). Surgical site infections and other nosocomial infections were: (BI n=11 (20%) vs. PI n=4 (5%), p=0.02), (BI n=11 (20%) vs. PI n=2 (3%), p=0.002), respectively. Hospital and ICU LOS was: (BI=20 SD 14 vs. PI=11 SD 11, p=0.001), (BI=10 SD 10 vs. PI=5 SD 5, p=0.01) respectively. These differences were reflected in higher hospital charges in BI. Blunt and penetrating intestinal injury patterns have high injury severity. Significant operative delays occurred in the blunt injury group as well as, anastomotic failures, enteric fistulas, nosocomial infections, and higher cost. These features underscore the complexity of blunt injury patterns and warrant vigilant injury recognition to improve outcomes. Copyright © 2014 Elsevier Ltd. All rights reserved.

Regulation of the plasma membrane type III phosphatidylinositol 4-kinase by positively charged compounds.

PubMed

Yang, W; Boss, W F

1994-08-15

The effects of positively charged compounds on a plasma membrane, type III phosphatidylinositol 4-kinase were studied. To determine whether the enzyme would respond differently to the compounds in a membrane-associated versus a soluble state, both the plasma membrane and solubilized (released by 0.01% (v/v) Triton X-100) PI 4-kinase were used. Spermidine, spermine, polylysine, cardiotoxin, melittin, and histone stimulated the solubilized PI 4-kinase but had little effect on or weakly stimulated the membrane-associated PI 4-kinase. Polyarginine inhibited membrane-associated PI 4-kinase 75% and inhibited the solubilized PI 4-kinase 30%, indicating that charge alone was not sufficient for activation. Polyarginine also eliminated the activation of the solubilized PI 4-kinase by a PI 4-kinase activator protein, PIK-A49. Calmodulin, a common calcium-binding protein, at micromolar levels strongly inhibited solubilized PI 4-kinase activity but did not inhibit membrane-associated PI 4-kinase activity. The inhibition of the solubilized PI 4-kinase by calmodulin was calcium independent. Calcium alone (1 microM-0.1 mM) inhibited PI 4-kinase activity only slightly (< 30%). The differential effects of the positively charged compounds on the solubilized and membrane-associated PI 4-kinase were not due to substrate availability because both enzymes were assayed in the presence of excess PI (0.6 mM) and 0.3% (v/v) Triton X-100. The data suggest that positively charged compounds affected the enzyme activity not only by interacting with the substrates or products of the reaction but also by interacting with the PI 4-kinase or regulatory components in the plasma membrane.

Regional Fluid-Attenuated Inversion Recovery (FLAIR) at 7 Tesla correlates with amyloid beta in hippocampus and brainstem of cognitively normal elderly subjects

PubMed Central

Schreiner, Simon J.; Liu, Xinyang; Gietl, Anton F.; Wyss, Michael; Steininger, Stefanie C.; Gruber, Esmeralda; Treyer, Valerie; Meier, Irene B.; Kälin, Andrea M.; Leh, Sandra E.; Buck, Alfred; Nitsch, Roger M.; Pruessmann, Klaas P.; Hock, Christoph; Unschuld, Paul G.

2014-01-01

Background: Accumulation of amyloid beta (Aβ) may occur during healthy aging and is a risk factor for Alzheimer Disease (AD). While individual Aβ-accumulation can be measured non-invasively using Pittsburgh Compund-B positron emission tomography (PiB-PET), Fluid-attenuated inversion recovery (FLAIR) is a Magnetic Resonance Imaging (MRI) sequence, capable of indicating heterogeneous age-related brain pathologies associated with tissue-edema. In the current study cognitively normal elderly subjects were investigated for regional correlation of PiB- and FLAIR intensity. Methods: Fourteen healthy elderly subjects without known history of cognitive impairment received 11C-PiB-PET for estimation of regional Aβ-load. In addition, whole brain T1-MPRAGE and FLAIR-MRI sequences were acquired at high field strength of 7 Tesla (7T). Volume-normalized intensities of brain regions were assessed by applying an automated subcortical segmentation algorithm for spatial definition of brain structures. Statistical dependence between FLAIR- and PiB-PET intensities was tested using Spearman's rank correlation coefficient (rho), followed by Holm–Bonferroni correction for multiple testing. Results: Neuropsychological testing revealed normal cognitive performance levels in all participants. Mean regional PiB-PET and FLAIR intensities were normally distributed and independent. Significant correlation between volume-normalized PiB-PET signals and FLAIR intensities resulted for Hippocampus (right: rho = 0.86; left: rho = 0.84), Brainstem (rho = 0.85) and left Basal Ganglia vessel region (rho = 0.82). Conclusions: Our finding of a significant relationship between PiB- and FLAIR intensity mainly observable in the Hippocampus and Brainstem, indicates regional Aβ associated tissue-edema in cognitively normal elderly subjects. Further studies including clinical populations are necessary to clarify the relevance of our findings for estimating individual risk for age-related neurodegenerative processes such as AD. PMID:25249977

Neuroprotective effect of resveratrol against brain ischemia reperfusion injury in rats entails reduction of DJ-1 protein expression and activation of PI3K/Akt/GSK3b survival pathway.

PubMed

Abdel-Aleem, Ghada A; Khaleel, Eman F; Mostafa, Dalia G; Elberier, Lydia K

2016-10-01

In the current study, we aimed to investigate the mechanistic role of DJ-1/PI3K/Akt survival pathway in ischemia/reperfusion (I/R) induced cerebral damage and to investigate if the resveratrol (RES) mediates its ischemic neuroptotection through this pathway. RES administration to Sham rats boosted glutathione level and superoxide dismutase activity and downregulated inducible nitric oxide synthase expression without affecting redox levels of DJ-1 forms or components of PI3K/Akt pathway including PTEN, p-Akt or p/p-GSK3b. However, RES pre-administration to I/R rats reduced infarction area, oxidative stress, inflammation and apoptosis. Concomitantly, RES ameliorated the decreased levels of oxidized forms of DJ-1 and enhancing its reduction, increased the nuclear protein expression of Nfr-2 and led to activation of PI3K/Akt survival pathway. In conclusion, overoxidation of DJ-1 is a major factor that contributes to post-I/R cerebral damage and its reduction by RES could explain the neuroprotection offered by RES.

Epstein–Barr Virus Susceptibility in Activated PI3Kδ Syndrome (APDS) Immunodeficiency

PubMed Central

Carpier, Jean-Marie; Lucas, Carrie L.

2018-01-01

Activated PI3Kδ Syndrome (APDS) is an inherited immune disorder caused by heterozygous, gain-of-function mutations in the genes encoding the phosphoinositide 3-kinase delta (PI3Kδ) subunits p110δ or p85δ. This recently described primary immunodeficiency disease (PID) is characterized by recurrent sinopulmonary infections, lymphoproliferation, and susceptibility to herpesviruses, with Epstein–Barr virus (EBV) infection being most notable. A broad range of PIDs having disparate, molecularly defined genetic etiology can cause susceptibility to EBV, lymphoproliferative disease, and lymphoma. Historically, PID patients with loss-of-function mutations causing defective cell-mediated cytotoxicity or antigen receptor signaling were found to be highly susceptible to pathological EBV infection. By contrast, the gain of function in PI3K signaling observed in APDS patients paradoxically renders these patients susceptible to EBV, though the underlying mechanisms are incompletely understood. At a cellular level, APDS patients exhibit deranged B lymphocyte development and defects in class switch recombination, which generally lead to defective immunoglobulin production. Moreover, APDS patients also demonstrate an abnormal skewing of T cells toward terminal effectors with short telomeres and senescence markers. Here, we review APDS with a particular focus on how the altered lymphocyte biology in these patients may confer EBV susceptibility. PMID:29387064

PTP1B deficiency improves hypothalamic insulin sensitivity resulting in the attenuation of AgRP mRNA expression under high-fat diet conditions.

PubMed

Sugiyama, Mariko; Banno, Ryoichi; Mizoguchi, Akira; Tominaga, Takashi; Tsunekawa, Taku; Onoue, Takeshi; Hagiwara, Daisuke; Ito, Yoshihiro; Morishita, Yoshiaki; Iwama, Shintaro; Goto, Motomitsu; Suga, Hidetaka; Arima, Hiroshi

2017-06-17

Hypothalamic insulin receptor signaling regulates energy balance and glucose homeostasis via agouti-related protein (AgRP). While protein tyrosine phosphatase 1B (PTP1B) is classically known to be a negative regulator of peripheral insulin signaling by dephosphorylating both insulin receptor β (IRβ) and insulin receptor substrate, the role of PTP1B in hypothalamic insulin signaling remains to be fully elucidated. In the present study, we investigated the role of PTP1B in hypothalamic insulin signaling using PTP1B deficient (KO) mice in vivo and ex vivo. For the in vivo study, hypothalamic insulin resistance induced by a high-fat diet (HFD) improved in KO mice compared to wild-type (WT) mice. Hypothalamic AgRP mRNA expression levels were also significantly decreased in KO mice independent of body weight changes. In an ex vivo study using hypothalamic organotypic cultures, insulin treatment significantly increased the phosphorylation of both IRβ and Akt in the hypothalamus of KO mice compared to WT mice, and also significantly decreased AgRP mRNA expression levels in KO mice. While incubation with inhibitors of phosphatidylinositol-3 kinase (PI3K) had no effect on basal levels of Akt phosphorylation, these suppressed insulin induction of Akt phosphorylation to almost basal levels in WT and KO mice. The inhibition of the PI3K-Akt pathway blocked the downregulation of AgRP mRNA expression in KO mice treated with insulin. These data suggest that PTP1B acts on the hypothalamic insulin signaling via the PI3K-Akt pathway. Together, our results suggest a deficiency of PTP1B improves hypothalamic insulin sensitivity resulting in the attenuation of AgRP mRNA expression under HFD conditions. Copyright © 2017 Elsevier Inc. All rights reserved.

[Excitation and relaxation of metastable state NaK(1 3Pi) at high vibrational levels].

PubMed

Luan, Nan-Nan; Cai, Qin; Zhang, Li-Ping; Dai, Kang; Shen, Yi-Fan

2011-11-01

The authors have investigated collision vibrational energy transfer rate constants in NaK[1 3Pi(v)] and He system. Pump laser excitation of the spin-forbidden band was used to produce very highly vibrationally excited metastable state NaK[1 3Pi (v = 22, 21, 20)]. The probe laser was used to excite the 1 3Pi (v = 22, 21, 20) to 5 3Pi(v'). Laser induced fluorescence (LIF) from 5 3Pi --> 1 3Sigma+ transition was used to follow the collision dynamics. The semilog plots of time-resolved LIF was obtained. The slopes yielded the effective lifetimes. From such data several Stern-Volmer plots could be constructed and the relaxation rate constants could be extracted for the sum of all processes that give rise to the decay of the prepared vibrational state. The rate constants (in units of 10(-11) cm3 x s(-1)) for v being 22, 21 and 20 are 1.4 +/- 0.1, 1.2 +/- 0.1 and 1.0 +/- 0.1, respectively. The vibrational relaxation rate is increasing with vibrational quantum number. In order to determine the importance of multiquantum relaxation, it is necessary to measure the relative population of both the prepared state and collisionally populated states. By the kinetic equations governing up to Delta(v) = 2 transitions, the time dependence of populations of the vibrational states were obtained. With the help of the integrating the population equations over all time, the importance of the two-quantum relaxation could be studied experimentally. By varying the delay between the pump and the probe laser, the He pressure dependent vibrational state specific decay could be measured. The time evolutions and relative intensities of the three states v = 22, 21 and 20 by preparing v = 22 were obtained. Using experimental data the rate constants (in units of 10(-11) cm3 x s(-1)) for v = 22 --> 21 and v = 22 --> 20 are 0.67 +/- 0.15 and 0.49 +/- 0.12, respectively. The single quantum relaxation accounts for only about 48% of the total relaxation out of v = 22. Multi-quantum relaxation (Delta(v) > 1) was found to be important at high vibrational states.

Assessment of Vitamin B12 and Its Correlation with Dental Caries and Gingival Diseases in 10- to 14-year-old Children: A Cross-sectional Study.

PubMed

M Hugar, Shivayogi; S Dhariwal, Neha; Majeed, Andleeb; Badakar, Chandrashekhar; Gokhale, Niraj; Mistry, Laresh

2017-01-01

To assess the level of vitamin B 12 and correlate it with dental caries [decayed, missing, and filled permanent teeth (DMFT) score] and gingival diseases [plaque index (PI) and gingival index (GI)]. Healthy children according to the inclusion criteria were selected by the computerized randomization method from a school to assess the vitamin B 12 levels using Centaur/ Versace machine. Blood samples were collected to assess vitamin B 12 levels using automated analyzer. Oral examination was done by a single calibrated dentist. A thorough oral examination was carried out and the DMFT, PI, and GI scores of all the children were recorded and assessed. Data were analyzed using Karl Pearson's correlation test. Vitamin B 12 levels were deficient in 64% of the children. In boys, vitamin B 12 deficiency was found in about 76.2%, whereas, in girls it was 57.1%, which was not statistically significant. The vitamin B 12 deficient children showed a significantly high DMFT scores than the children with normal vitamin B 12 levels. The Pearson's correlation was -0.614 for DMFT, PI value -0.663, and GI value of -0.477. The negative correlation stated that there was a reverse relation between these indices and vitamin B 12 . In children with systemic vitamin B 12 deficiency, there is increased dental caries prevalence and associated gingival problems. Hugar SM, Dhariwal NS, Majeed A, Badakar C, Gokhale N, Mistry L. Assessment of Vitamin B 12 and Its Correlation with Dental Caries and Gingival Diseases in 10- to 14-year-old Children: A Cross-sectional Study. Int J Clin Pediatr Dent 2017;10(2):142-146.

Assessment of Vitamin B12 and Its Correlation with Dental Caries and Gingival Diseases in 10- to 14-year-old Children: A Cross-sectional Study

PubMed Central

S Dhariwal, Neha; Majeed, Andleeb; Badakar, Chandrashekhar; Gokhale, Niraj; Mistry, Laresh

2017-01-01

Aim To assess the level of vitamin B12 and correlate it with dental caries [decayed, missing, and filled permanent teeth (DMFT) score] and gingival diseases [plaque index (PI) and gingival index (GI)]. Design Healthy children according to the inclusion criteria were selected by the computerized randomization method from a school to assess the vitamin B12 levels using Centaur/ Versace machine. Materials and methods Blood samples were collected to assess vitamin B12 levels using automated analyzer. Oral examination was done by a single calibrated dentist. A thorough oral examination was carried out and the DMFT, PI, and GI scores of all the children were recorded and assessed. Data were analyzed using Karl Pearson’s correlation test. Results Vitamin B12 levels were deficient in 64% of the children. In boys, vitamin B12 deficiency was found in about 76.2%, whereas, in girls it was 57.1%, which was not statistically significant. The vitamin B12 deficient children showed a significantly high DMFT scores than the children with normal vitamin B12 levels. The Pearson’s correlation was -0.614 for DMFT, PI value -0.663, and GI value of -0.477. The negative correlation stated that there was a reverse relation between these indices and vitamin B12. Conclusion In children with systemic vitamin B12 deficiency, there is increased dental caries prevalence and associated gingival problems. How to cite this article Hugar SM, Dhariwal NS, Majeed A, Badakar C, Gokhale N, Mistry L. Assessment of Vitamin B12 and Its Correlation with Dental Caries and Gingival Diseases in 10- to 14-year-old Children: A Cross-sectional Study. Int J Clin Pediatr Dent 2017;10(2):142-146. PMID:28890613

Phosphoinositide 3-Kinase p110β Regulates Integrin αIIbβ3 Avidity and the Cellular Transmission of Contractile Forces*

PubMed Central

Schoenwaelder, Simone M.; Ono, Akiko; Nesbitt, Warwick S.; Lim, Joanna; Jarman, Kate; Jackson, Shaun P.

2010-01-01

Phosphoinositide (PI) 3-kinase (PI3K) signaling processes play an important role in regulating the adhesive function of integrin αIIbβ3, necessary for platelet spreading and sustained platelet aggregation. PI3K inhibitors are effective at reducing platelet aggregation and thrombus formation in vivo and as a consequence are currently being evaluated as novel antithrombotic agents. PI3K regulation of integrin αIIbβ3 activation (affinity modulation) primarily occurs downstream of Gi-coupled and tyrosine kinase-linked receptors linked to the activation of Rap1b, AKT, and phospholipase C. In the present study, we demonstrate an important role for PI3Ks in regulating the avidity (strength of adhesion) of high affinity integrin αIIbβ3 bonds, necessary for the cellular transmission of contractile forces. Using knock-out mouse models and isoform-selective PI3K inhibitors, we demonstrate that the Type Ia p110β isoform plays a major role in regulating thrombin-stimulated fibrin clot retraction in vitro. Reduced clot retraction induced by PI3K inhibitors was not associated with defects in integrin αIIbβ3 activation, actin polymerization, or actomyosin contractility but was associated with a defect in integrin αIIbβ3 association with the contractile cytoskeleton. Analysis of integrin αIIbβ3 adhesion contacts using total internal reflection fluorescence microscopy revealed an important role for PI3Ks in regulating the stability of high affinity integrin αIIbβ3 bonds. These studies demonstrate an important role for PI3K p110β in regulating the avidity of high affinity integrin αIIbβ3 receptors, necessary for the cellular transmission of contractile forces. These findings may provide new insight into the potential antithrombotic properties of PI3K p110β inhibitors. PMID:19940148

Pion Elastic Scattering and the (pion Pion' Proton) Reaction on HELIUM-4 in the DELTA(3,3) Region

NASA Astrophysics Data System (ADS)

Jones, Mark Kevin

This dissertation presents measurements and analyses of pi^+ and pi ^{-} elastic scattering, and ( pi^{+}, pi^ {+^'}p) and ( pi^{-},pi^{-^ '}p) reactions on ^4 He. Both experiments were done at the Los Alamos Meson Physics Facility using the Energetic Pion Channel and Spectrometer. The ^4He( pi,pi) elastic scattering cross sections were measured for pi^{+} scattering at scattering angles theta _{lab} = 110^circ -170^circ and five incident energies between T_{pi } = 90 and 180 MeV. Elastic pi ^{-} cross sections were measured only at T_{pi} = 180 MeV. The ^4He(pi, pi' p) angular correlation functions were measured for pi^{+} and pi^{-} at T_{pi} = 180 and theta_{pi^' } = 30^circ, 40 ^circ, 60^circ , 80^circ and at T _pi = 140 MeV and theta_{pi^'} = 40^circ. Using scintillators at eight angles the protons were detected in coincidence with the inelastically scattered pions. In the ^4He(pi, pi^' p) experiment unexpectedly large ratios R_{pi p} = {sigma(pi^{+}, pi^{+} p)}over{sigma( pi^{-},pi^{-} p)} of up to 50 were observed near the quasi -free angle in the angular correlation functions summed over 30.5 to 39.5 MeV in ^4He excitation energy. The (pi,pi' p) data were analyzed by a distorted wave impulse approximation code 3DEE (Ch 82), (Re 82). 3DEE models the ( pi,pi' p) reaction as a pion -induced proton knock-out and includes distortions in the incident pion, the outgoing pion, and the emitted proton waves. The calculations give R_{pi p} between 6 and 9 at all proton and pion angles. The pi^{+} calculations reproduce the absolute pi^ {+} cross sections fairly well. The pi^{-} calculations have a peak in the angular correlation function near the quasi-free angle, in contrast to the pi^ {-} data which displays a flat distribution. At proton angles near 180^circ in the center of mass of the struck mass 4 system, the measured pi^{-} cross sections are larger than the pi^ {+} cross section which is the reverse of the ratio at 0^circ. These features of the measured pi^- cross sections indicate that interference between a quasi -free process and another process is important in the ( pi,pi^' p) reaction. The measurement of ^4He( pi,pi) elastic scattering data at theta_pi = 110 ^circ-170^circ extends the angular range of previous ^4He(pi,pi) data measured at EPICS. The experiment provides high quality elastic scattering data at backward angles. The pi^{-} elastic cross section at T_pi = 180 MeV measured for this dissertation when extrapolated to theta _{cm} = 180^circ is about a factor of two smaller than the cross section measured previously at CERN (Ref. (Bi 78)). The data were analyzed using a microscopic optical model and by a phase shift fit.

Association between haptoglobin and IgM levels and the clinical progression of caseous lymphadenitis in sheep

PubMed Central

2013-01-01

Background Sheep caseous lymphadenitis (CLA), caused by Corynebacterium pseudotuberculosis (Cp), is associated with direct economic losses and presents significant zoonotic potential. Despite the importance of the disease, a satisfactory vaccine model has not been developed. Thus, this study aimed to investigate the association between haptoglobin (Hp) and IgM levels and the clinical progression of CLA in primarily infected sheep and in sheep immunized with Cp- secreted antigens adjuvanted with Quillaja saponaria saponins. These animals were kept with CLA-positive sheep to simulate natural exposure that occurs in field conditions. During the experiment, the Hp and IgM levels were monitored for 21 days, and the development of internal CLA lesions was investigated through necropsies on day182 post-immunization. Results Primarily infected sheep in Group 2 (inoculated with 2x105 Cp virulent strain) had higher Hp values between the first and ninth days post inoculation (PI) than sheep in Group 1 (control; P < 0.05). Immunized animals in Group 3 had significantly higher Hp values between the third and seventh days PI, compared with the control group (P < 0.01). Binary logistic regression (BLR) analysis of primarily infected sheep indicated an association between Hp concentration and CLA clinical progression: animals with high Hp values had 99.9% less risk of having CLA abscesses than animals with low Hp levels (Odds ratio = 0.001, P < 0.05). Both experimental groups had significantly higher IgM titers than the control group around the ninth and eleventh days PI (P < 0.05). The BLR analysis for immunized sheep indicated an association between IgM levels and clinical progression: sheep with high IgM titers had 100.0% less risk of having CLA abscesses than animals with low IgM levels (Odds ratio = 0.000, P < 0.05). Conclusions Resistance to C. pseudotuberculosis infection is supported by the early acute phase response, in which up-regulation of Hp and IgM were predictive of a lower risk of CLA lesion development. Because the immunogen used in this study induced a high production of both Hp and IgM, Q. saponaria saponin should be considered a promising candidate in vaccine formulations against sheep CLA. PMID:24330714

Multicentre evaluation of targeted and systematic biopsies using magnetic resonance and ultrasound image-fusion guided transperineal prostate biopsy in patients with a previous negative biopsy.

PubMed

Hansen, Nienke L; Kesch, Claudia; Barrett, Tristan; Koo, Brendan; Radtke, Jan P; Bonekamp, David; Schlemmer, Heinz-Peter; Warren, Anne Y; Wieczorek, Kathrin; Hohenfellner, Markus; Kastner, Christof; Hadaschik, Boris

2017-11-01

To evaluate the detection rates of targeted and systematic biopsies in magnetic resonance imaging (MRI) and ultrasound (US) image-fusion transperineal prostate biopsy for patients with previous benign transrectal biopsies in two high-volume centres. A two centre prospective outcome study of 487 patients with previous benign biopsies that underwent transperineal MRI/US fusion-guided targeted and systematic saturation biopsy from 2012 to 2015. Multiparametric MRI (mpMRI) was reported according to Prostate Imaging Reporting and Data System (PI-RADS) Version 1. Detection of Gleason score 7-10 prostate cancer on biopsy was the primary outcome. Positive (PPV) and negative (NPV) predictive values including 95% confidence intervals (95% CIs) were calculated. Detection rates of targeted and systematic biopsies were compared using McNemar's test. The median (interquartile range) PSA level was 9.0 (6.7-13.4) ng/mL. PI-RADS 3-5 mpMRI lesions were reported in 343 (70%) patients and Gleason score 7-10 prostate cancer was detected in 149 (31%). The PPV (95% CI) for detecting Gleason score 7-10 prostate cancer was 0.20 (±0.07) for PI-RADS 3, 0.32 (±0.09) for PI-RADS 4, and 0.70 (±0.08) for PI-RADS 5. The NPV (95% CI) of PI-RADS 1-2 was 0.92 (±0.04) for Gleason score 7-10 and 0.99 (±0.02) for Gleason score ≥4 + 3 cancer. Systematic biopsies alone found 125/138 (91%) Gleason score 7-10 cancers. In patients with suspicious lesions (PI-RADS 4-5) on mpMRI, systematic biopsies would not have detected 12/113 significant prostate cancers (11%), while targeted biopsies alone would have failed to diagnose 10/113 (9%). In equivocal lesions (PI-RADS 3), targeted biopsy alone would not have diagnosed 14/25 (56%) of Gleason score 7-10 cancers, whereas systematic biopsies alone would have missed 1/25 (4%). Combination with PSA density improved the area under the curve of PI-RADS from 0.822 to 0.846. In patients with high probability mpMRI lesions, the highest detection rates of Gleason score 7-10 cancer still required combined targeted and systematic MRI/US image-fusion; however, systematic biopsy alone may be sufficient in patients with equivocal lesions. Repeated prostate biopsies may not be needed at all for patients with a low PSA density and a negative mpMRI read by experienced radiologists. © 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.

Lysophosphatidic Acid Inhibits Apoptosis Induced by Cisplatin in Cervical Cancer Cells

PubMed Central

Sui, Yanxia; Yang, Ya; Wang, Ji; Li, Yi; Ma, Hongbing; Cai, Hui; Liu, Xiaoping; Zhang, Yong; Wang, Shufeng; Li, Zongfang; Zhang, Xiaozhi; Wang, Jiansheng; Liu, Rui; Yan, Yanli; Xue, Chaofan; Shi, Xiaowei; Tan, Li; Ren, Juan

2015-01-01

Cervical cancer is the second most common cause of cancer death in women worldwide. Lysophosphatidic acid (LPA) level has been found significantly increased in the serum of patients with ovarian, cervical, and colon cancers. LPA level in cervical cancer patients is significantly higher than in healthy controls. LPA receptors were found highly expressed in cervical cancer cells, suggesting LPA may play a role in the development of cervical cancer. The aim of this study is to investigate the effect of LPA on the apoptosis induced by cisplatin (DDP) in cervical cancer cell line and the underlying changes in signaling pathways. Our study found that cisplatin induced apoptosis of Hela cell through inhibiting expression of Bcl-2, upregulating the expression of Bax, Fas-L, and the enzyme activity of caspase-3 (p < 0.05); LPA significantly provided protection against the apoptosis induced by cisplatin by inhibiting the above alterations in apoptotic factor caused by cisplatin (p < 0.05). Moreover, PI3K/AKT pathway was found to be important for the LPA antiapoptosis effect, and administration of PI3K/AKT partially reversed the LPA-mediated protection against cisplatin-induced apoptosis (p < 0.05). These findings have shed new lights on the LPA bioactivity in cervical cancer cells and pointed to a possible sensitization scheme through combined administration of PI3K inhibitor and cisplatin for better treatment of cervical cancer patients, especially those with elevated LPA levels. PMID:26366416

Regulation of S-like ribonuclease levels in Arabidopsis. Antisense inhibition of RNS1 or RNS2 elevates anthocyanin accumulation

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

Bariola, P.A.; MacIntosh, G.C.; Green, P.J.

1999-01-01

The S-like ribonucleases (RNases) RNS1 and RNS2 of Arabidopsis are members of the widespread T{sub 2} ribonuclease family, whose members also include the S-RNases, involved in gametophytic self-incompatibility in plants. Both RNS1 and RNS2 mRNAs have been shown previously to be induced by inorganic phosphate (Pi) starvation. In this study the authors examined this regulation at the protein level and determined the effects of diminishing RNS1 and RNS2 expression using antisense techniques. The Pi-starvation control of RNS1 and RNS2 was confirmed using antibodies specific for each protein. These specific antibodies also demonstrated that RNS1 is secreted, whereas RNS2 is intracellular.more » By introducing antisense constructs, mRNA accumulation was inhibited by up to 90% for RNS1 and up to 65% for NS2. These plants contained abnormally high levels of anthocyanins, the production of which is often associated with several forms of stress, including Pi starvation. This effect demonstrates that diminishing the amounts of either RNS1 or RNS2 leads to effects that cannot be compensated for by the actions of other RNases, even though Arabidopsis contains a large number of different RNase activities. These results, together with the differential localization of the proteins, imply that RNS1 and RNS2 have distinct functions in the plant.« less

A novel snapshot polarimetric imager

NASA Astrophysics Data System (ADS)

Wong, Gerald; McMaster, Ciaran; Struthers, Robert; Gorman, Alistair; Sinclair, Peter; Lamb, Robert; Harvey, Andrew R.

2012-10-01

Polarimetric imaging (PI) is of increasing importance in determining additional scene information beyond that of conventional images. For very long-range surveillance, image quality is degraded due to turbulence. Furthermore, the high magnification required to create images with sufficient spatial resolution suitable for object recognition and identification require long focal length optical systems. These are incompatible with the size and weight restrictions for aircraft. Techniques which allow detection and recognition of an object at the single pixel level are therefore likely to provide advance warning of approaching threats or long-range object cueing. PI is a technique that has the potential to detect object signatures at the pixel level. Early attempts to develop PI used rotating polarisers (and spectral filters) which recorded sequential polarized images from which the complete Stokes matrix could be derived. This approach has built-in latency between frames and requires accurate registration of consecutive frames to analyze real-time video of moving objects. Alternatively, multiple optical systems and cameras have been demonstrated to remove latency, but this approach increases cost and bulk of the imaging system. In our investigation we present a simplified imaging system that divides an image into two orthogonal polarimetric components which are then simultaneously projected onto a single detector array. Thus polarimetric data is recorded without latency on a single snapshot. We further show that, for pixel-level objects, the data derived from only two orthogonal states (H and V) is sufficient to increase the probability of detection whilst reducing false alarms compared to conventional unpolarised imaging.

Combined multireference configuration interaction/ molecular dynamics approach for calculating solvatochromic shifts: application to the n(O) --> pi* electronic transition of formaldehyde.

PubMed

Xu, ZongRong; Matsika, Spiridoula

2006-11-02

A combined quantum mechanics/molecular mechanics method is described here for considering the solvatochromic shift of excited states in solution. The quantum mechanical solute is described using high level multireference configuration interaction methods (MRCI), while molecular dynamics is used for obtaining the structure of the solvent around the solute. The electrostatic effect of the solvent is included in the quantum description of the solute in an averaged way. This method is used to study solvent effects on the n(O) --> pi* electronic transition of formaldehyde in aqueous solution. The effects of solute polarization, basis sets, and dynamical correlation on the solvatochromic shift, and on dipole moments, have been investigated.

Classical and quantum analysis of repulsive singularities in four-dimensional extended supergravity

NASA Astrophysics Data System (ADS)

Gaida, I.; Hollmann, H. R.; Stewart, J. M.

1999-07-01

Non-minimal repulsive singularities (`repulsons') in extended supergravity theories are investigated. The short-distance antigravity properties of the repulsons are tested at the classical and the quantum level by a scalar test-particle. Using a partial wave expansion it is shown that the particle is totally reflected at the origin. A high-frequency incoming particle undergoes a phase shift of icons/Journals/Common/pi" ALT="pi" ALIGN="TOP"/>/2. However, the phase shift for a low-frequency particle depends upon the physical data of the repulson. The curvature singularity at a finite distance rh turns out to be transparent for the scalar test-particle and the coordinate singularity at the origin serves as the repulsive barrier to bounce back the particles.

Targeting the PI3K/Akt/mTOR axis by apigenin for cancer prevention

PubMed Central

Tong, Xin; Pelling, Jill

2013-01-01

Natural products are important sources of anti-cancer lead molecules, and high dietary consumption of fruits and vegetables is associated with a reduced risk of certain cancers. Many efforts have been devoted to identifying and developing plant-derived dietary constituents as chemopreventive agents. Among them, apigenin, a naturally occurring flavonoid found in a variety of fruits and leafy vegetables, has been shown to possess remarkable anti-oxidant, anti-inflammatory and anti-carcinogenic properties. This review summarizes the anti-cancer and chemopreventive effects of apigenin at cellular and molecular levels, its chemical structure and properties, with focus on mechanism related to apigenin’s inhibition of the PI3K/Akt/mTOR signaling pathways. PMID:23272913

Sensitivities to Early Exchange in Synchronous Computer-Supported Collaborative Learning (CSCL) Groups

ERIC Educational Resources Information Center

Kapur, Manu; Voiklis, John; Kinzer, Charles K.

2008-01-01

This study reports the impact of high sensitivity to early exchange in 11th-grade, CSCL triads solving well- and ill-structured problems in Newtonian Kinematics. A mixed-method analysis of the evolution of participation inequity (PI) in group discussions suggested that participation levels tended to get locked-in relatively early on in the…

High-frequency electroacupuncture versus carprofen in an incisional pain model in rats

PubMed Central

Teixeira, F.M.; Castro, L.L.; Ferreira, R.T.; Pires, P.A.; Vanderlinde, F.A.; Medeiros, M.A.

2012-01-01

The objective of the present study was to compare the effect of electroacupuncture (EA) and carprofen (CP) on postoperative incisional pain using the plantar incision (PI) model in rats. A 1-cm longitudinal incision was made through skin, fascia and muscles of a hind paw of male Wistar rats and the development of mechanical and thermal hypersensitivity was determined over 4 days using the von Frey and Hargreaves methods, respectively. Based on the experimental treatments received on the third postoperative day, the animals were divided into the following groups: PI+CP (CP, 2 mg/kg, po); PI+EAST36 (100-Hz EA applied bilaterally at the Zusanli point (ST36)); PI+EANP (EA applied to a non-acupoint region); PI+IMMO (immobilization only); PI (vehicle). In the von Frey test, the PI+EAST36 group had higher withdrawal force thresholds in response to mechanical stimuli than the PI, PI+IMMO and PI+EANP groups at several times studied. Furthermore, the PI+EAST36 group showed paw withdrawal thresholds in response to mechanical stimuli that were similar to those of the PI+CP group. In the Hargreaves test, all groups had latencies higher than those observed with PI. The PI+EAST36 group was similar to the PI+IMMO, PI+EANP and PI+CP groups. We conclude that 100-Hz EA at the ST36 point, but not at non-acupoints, can reduce mechanical nociception in the rat model of incisional pain, and its effectiveness is comparable to that of carprofen. PMID:22911345

Pharmaceutical industry interactions of psychiatric trainees from 20 European countries.

PubMed

Riese, F; Guloksuz, S; Roventa, C; Fair, J D; Haravuori, H; Rolko, T; Flynn, D; Giacco, D; Banjac, V; Jovanovic, N; Bayat, N; Palumbo, C; Rusaka, M; Kilic, O; Augėnaitė, J; Nawka, A; Zenger, M; Kekin, I; Wuyts, P; Barrett, E; Bausch-Becker, N; Mikaliūnas, J; Del Valle, E; Feffer, K; Lomax, G A; Marques, J G; Jauhar, S

2015-02-01

Interactions between the pharmaceutical industry (PI) and psychiatrists have been under scrutiny recently, though there is little empirical evidence on the nature of the relationship and its intensity at psychiatry trainee level. We therefore studied the level of PI interactions and the underlying beliefs and attitudes in a large sample of European psychiatric trainees. One thousand four hundred and forty-four psychiatric trainees in 20 European countries were assessed cross-sectionally, with a 62-item questionnaire. The total number of PI interactions in the preceding two months varied between countries, with least interactions in The Netherlands (M (Mean)=0.92, SD=1.44, range=0-12) and most in Portugal (M=19.06, SD=17.44, range=0-100). Trainees were more likely to believe that PI interactions have no impact on their own prescribing behaviour than that of other physicians (M=3.30, SD=1.26 vs. M=2.39, SD=1.06 on a 5-point Likert scale: 1 "completely disagree" to 5 "completely agree"). Assigning an educational role to the pharmaceutical industry was associated with more interactions and higher gift value (IRR (incidence rate ratio)=1.21, 95%CI=1.12-1.30 and OR=1.18, 95%CI=1.02-1.37). There are frequent interactions between European psychiatric trainees and the PI, with significant variation between countries. We identified several factors affecting this interaction, including attribution of an educational role to the PI. Creating alternative educational opportunities and specific training dedicated to PI interactions may therefore help to reduce the impact of the PI on psychiatric training. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Functional Trajectories, Cognition, and Subclinical Cerebrovascular Disease.

PubMed

Dhamoon, Mandip S; Cheung, Ying-Kuen; Gutierrez, Jose; Moon, Yeseon P; Sacco, Ralph L; Elkind, Mitchell S V; Wright, Clinton B

2018-03-01

Cognition and education influence functional trajectories, but whether associations differ with subclinical brain infarcts (SBI) or white matter hyperintensity volume (WMHV) is unknown. We hypothesized that SBI and WMHV moderated relationships between cognitive performance and education and functional trajectories. A total of 1290 stroke-free individuals underwent brain magnetic resonance imaging and were followed for 7.3 years (mean) with annual functional assessments with the Barthel index (range, 0-100). Magnetic resonance imaging measurements included pathology-informed SBI (PI-SBI) and WMHV (% total cranial volume). Generalized estimating equation models tested associations between magnetic resonance imaging variables and baseline Barthel index and change in Barthel index, adjusting for demographic, vascular, cognitive, and social risk factors, and stroke and myocardial infarction during follow-up. We tested interactions among education level, baseline cognitive performance (Mini-Mental State score), and functional trajectories and ran models stratified by levels of magnetic resonance imaging variables. Mean age was 70.6 (SD, 9.0) years; 19% had PI-SBI, and mean WMHV was 0.68%. Education did not modify associations between cognition and functional trajectories. PI-SBI modified associations between cognition and functional trajectories ( P =0.04) with a significant protective effect of better cognition on functional decline seen only in those without PI-SBI. There was no significant interaction for WMHV ( P =0.8). PI-SBI, and greater WMHV, were associated with 2- to 3-fold steeper functional decline, holding cognition constant. PI-SBI moderated the association between cognition and functional trajectories, with 3-fold greater decline among those with PI-SBI (compared with no PI-SBI) and normal baseline cognition. This highlights the strong and independent association between subclinical markers and patient-centered trajectories over time. © 2018 American Heart Association, Inc.

Persistent elastase/proteinase inhibitor imbalance during prolonged ventilation of infants with bronchopulmonary dysplasia: evidence for the role of nosocomial infections.

PubMed

Walti, H; Tordet, C; Gerbaut, L; Saugier, P; Moriette, G; Relier, J P

1989-10-01

Acute imbalance between elastase and alpha-1-proteinase inhibitor (alpha 1Pi) may contribute to the development of bronchopulmonary dysplasia (BPD). The question of whether such an imbalance persists in BPD infants still requiring mechanical ventilation after 4 wk of life has not been previously addressed. We studied 14 infants still on mechanical ventilation at 4 wk of age: nine had BPD and five did not. Weekly (4 to 9 wk) serum and bronchoalveolar lavage (BAL) specimens were taken. alpha 1Pi and alpha-2-macroglobulin were measured in serum and BAL by immunoturbidimetric assay. BAL elastase activity was measured by cleavage of a synthetic substrate and expressed as ng of porcine pancreatic elastase equivalent. Infants with BPD had higher levels of serum alpha 1Pi and alpha-2-macroglobulin than those without BPD. In contrast, the corresponding BAL levels were either similar or even decreased (alpha 1Pi). Moreover, there was a 3-fold increase in elastase-1Pi imbalance expressed as the BAL ng of porcine pancreatic elastase equivalent/2 alpha 1Pi ratio. The role of nosocomial infections was evident in a subgroup of 11 infected BAL aspirates in BPD infants. In such cases we found a 3-fold increase in the BAL ng of porcine pancreatic elastase equivalent/alpha 1Pi ratio as compared to 35 noninfected BAL in BPD infants. These data suggest a persistent alveolitis with imbalance between elastase and proteinase inhibitors in prolonged severe BPD. Such an imbalance is, in part, explained by a local destruction and/or inactivation of alpha 1Pi. Our results also emphasize the increase in proteolysis with nosocomial pneumonia.

Apatinib promotes apoptosis of the SMMC-7721 hepatocellular carcinoma cell line via the PI3K/Akt pathway.

PubMed

Zhang, Hua; Cao, Yumei; Chen, Yuru; Li, Guangxi; Yu, Hanshu

2018-04-01

The present study investigated the inhibitory effects of apatinib on the proliferation of the SMMC-7721 hepatocellular carcinoma cell line to explore the possible mechanism. The MTT assay was used to detect the inhibitory effects of the different concentrations of apatinib on the proliferation of SMMC-7721 cells. Annexin V/PI double staining was performed to investigate the effects of apatinib on the apoptosis of SMMC-7721 cells. Expression of the apoptosis-related genes Bcl-2, Bax and caspase-9 after apatinib treatment was detected by reverse transcription-quantitative PCR (RT-qPCR) and western blot analysis. Expression of the PI3K, p-PI3K, Akt and p-Akt proteins after apatinib treatment was detected using western blot analysis. The MTT results showed that apatinib inhibited the in vitro proliferation of SMMC-7721 cells. Annexin V/PI double staining showed that apatinib induced the apoptosis of SMMC-7721 cells in a concentration-dependent manner. Results of RT-qPCR and western blot analysis showed that apatinib was able to induce the expression of pro-apoptotic genes Bax and caspase-9 and inhibited the expression of anti-apoptotic gene Bcl-2 . In addition, the western blot analysis revealed that p-PI3K and p-Akt was significantly decreased following apatinib treatment, while no significant differences were found in the total protein levels of PI3K and Akt. The results of the present show that apatinib is capable of promoting the apoptosis of SMMC-7721 cells by inhibiting the PI3K/Akt signal transduction pathway, upregulating the expression of pro-apoptotic genes Bax and caspase-9 , and downregulating the expression level of the anti-apoptotic gene Bcl-2 .

Accurate ab initio calculations which demonstrate a 3 Pi u ground state for Al2

NASA Technical Reports Server (NTRS)

Bauschlicher, Charles W., Jr.; Partridge, Harry; Langhoff, Stephen R.; Taylor, Peter R.; Walch, Stephen P.

1986-01-01

The spectroscopic parameters and separations between the three low-lying X 3 Pi u, A 3 Sigma g -, and a 1 Sigma g + states of Al2 are studied as a function of both the one-particle and n-particle basis set. Approximate correlation treatments are calibrated against full Cl calculations correlating the six valence electrons in a double-zeta plus two d-function basis set. Since the CASSCF/MRCI 3 Pi u to 3 Sigma g - separation is in excellent agreement wtih the FCI value, the MRCI calculations were carried out in an extended (20s13p6d4f)/(6s5p3d2f) gaussian basis. Including a small correction for relativistic effects, the best estimate is that 3 Sigma g - state lies 174/cm above the 3 Pi u ground state. The 1 Sigma g + state lies at least 2000/cm higher in energy. At the CPF level, inclusion of 2s and 2p correlation has little effect on D sub e, reduces T sub e by only 26/cm, and shortens the bond lengths by about 0.02 a sub o. Further strong support for a 3 Pi u ground state comes from the experimental absorption spectra, since both observed transitions can be convincingly assigned as 3 Pi u yields 3 Pi g. The (2) 3 Pi g state is observed to be sensitive to the level of correlation treatment, and to have its minimum shifted to shorter rho values, such that the strongest experimental absorption peak probably corresponds to the 0 yields 2 transition.

The effect of pharmacological PI3Kγ inhibitor on eotaxin-induced human eosinophil functions.

PubMed

Saito, Yukiko; Takeda, Masahide; Nishikawa, Junko; Konno, Yasunori; Tamaki, Mami; Itoga, Masamichi; Kobayashi, Yoshiki; Moritoki, Yuki; Ito, Wataru; Chihara, Junichi; Ueki, Shigeharu

2014-04-01

Asthma is characterized by chronic inflammation caused by activation of immune cells including Th2 lymphocytes and eosinophils. Phosphoinositide 3-kinase (PI3K) γ deficient asthmatic mice did not develop lung eosinophilia, although the detailed mechanisms are not well known. A CC chemokine eotaxin (CCL11) plays a prominent role in developing eosinophilic inflammation through CCR3. In this study, we tested the roles of PI3Kγ in eotaxin-induced eosinophil functions using a pharmacological inhibitor. Human peripheral blood eosinophils were isolated by CD16-negative selection method. The effect of AS605240, synthetic PI3Kγ inhibitor on eotaxin-induced adhesion, chemotaxis, and degranulation were studied using intracellular adhesion molecule-1 (ICAM-1)-coated plates, Boyden chamber system, ELISA for eosinophil-derived neurotoxin (EDN) levels in the culture supernatant, respectively. CCR3 expression levels and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation were assessed by flowcytometry. Involvement of PI3Kγ in spontaneous apoptosis was studied using flowcytometry. Although AS605240 did not affect the eosinophil spontaneous apoptosis, eotaxin-induced chemotaxis, adhesion to ICAM-1 coated plate, and EDN release were inhibited by AS605240. AS605240 also inhibited the eotaxin-induced ERK1/2 phosphorylation without down-regulation of surface CCR3 expression. These results indicate that PI3Kγ inhibitor attenuates eotaxin-induced eosinophil functions by suppressing the downstream signaling of CCR3 without significant cytotoxicity. PI3Kγ plays an important role in the development of eosinophilic inflammation and blockade of PI3Kγ might be a therapeutic strategy for treatment of eosinophil-related diseases including asthma. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

Arbuscular mycorrhizal fungi differ in their ability to regulate the expression of phosphate transporters in maize (Zea mays L.).

PubMed

Tian, Hui; Drijber, Rhae A; Li, Xiaolin; Miller, Daniel N; Wienhold, Brian J

2013-08-01

Previous studies have found that some phosphate (Pi) starvation inducible transporter genes are downregulated and arbuscular mycorrhizal (AM) inducible Pi transporter genes are upregulated in maize roots associated with the fungus Glomus intraradices. However, little is known about the functional diversity of different AM fungal species in influencing the expression of Pi transporters in maize roots. Here, we studied the expression of two Pi transporter genes ZEAma:Pht1;3 (Pi starvation inducible) and ZEAma:Pht1;6 (AM inducible) in maize root colonized by different AM fungal inoculants. Non-mycorrhizal maize, maize colonized by Glomus deserticola (CA113), Glomus intraradices (IA506), Glomus mosseae (CA201), Gigaspora gigantea (MN922A) and the co-inoculation of all four species were established. The expression patterns of the two genes were quantified using real-time, reverse transcription polymerase chain reaction. The expression level of ZEAma:Pht1;6 was 26-135 times higher in AM plants than in non-mycorrhizal maize roots, whereas the expression level of ZEAma:Pht1;3 was five to 44 times lower in AM plants than in non-mycorrhizal plants. Expression of the two genes differed with inoculation treatment, and increasing the diversity of AM fungi in maize roots led to greater expression of ZEAma:Pht1;6 as well as Pi uptake in shoots. The expression of ZEAma:Pht1;6 was significantly positively correlated with AM colonization rate, concentration of AM biomarkers in maize roots, Pi uptake and dry weight of shoot, but negatively correlated with the expression of ZEAma:Pht1;3. Addition of Pi fertilizer at a low concentration significantly increased the expression of ZEAma:Pht1;6 but had no effect on the expression of ZEAma:Pht1;3.

Training of resistance to proactive interference and working memory in older adults: a randomized double-blind study.

PubMed

Loosli, Sandra V; Falquez, Rosalux; Unterrainer, Josef M; Weiller, Cornelius; Rahm, Benjamin; Kaller, Christoph P

2016-03-01

Working memory (WM) performance is often decreased in older adults. Despite the growing popularity of WM trainings, underlying mechanisms are still poorly understood. Resistance to proactive interference (PI) constitutes a candidate process that contributes to WM performance and might influence training or transfer effects. Here, we investigated whether PI resistance can be enhanced in older adults using a WM training with specifically increased PI-demands. Further, we investigated whether potential effects of such a training were stable and entailed any transfer on non-trained tasks. Healthy old adults (N = 25, 68.8 ± 5.5 years) trained with a recent-probes and an n-back task daily for two weeks. Two different training regimens (high vs. low PI-amount in the tasks) were applied as between-participants manipulation, to which participants were randomly assigned. Near transfer tasks included interference tasks; far transfer tasks assessed fluid intelligence (gF) or speed. Immediate transfer was assessed directly after training; a follow-up measurement was conducted after two months. Both groups similarly improved in PI resistance in both training tasks. Thus, PI susceptibility was generally reduced in the two training groups and there was no difference between WM training with high versus low PI demands. Further, there was no differential near or far transfer on non-trained tasks, neither immediately after the training nor in the follow-up. PI-demands in WM training tasks do not seem critical for enhancing WM performance or PI resistance in older adults. Instead, improved resistance to PI appears to be an unspecific side-effect of a WM training.

Age differences in proactive interference, working memory, and abstract reasoning

PubMed Central

Emery, Lisa; Hale, Sandra; Myerson, Joel

2008-01-01

It has been hypothesized that older adults are especially susceptible to proactive interference (PI), and that this may contribute to age differences in working memory performance. In young adults, individual differences in PI affect both working memory and reasoning ability, but the relations between PI, working memory, and reasoning in older adults have not been examined. In the current study, young, old, and very old adults performed a modified operation span task that induced several cycles of PI buildup and release, as well as two tests of abstract reasoning ability. Age differences in working memory scores increased as PI built up, consistent with the hypothesis that older adults are more susceptible to PI, but both young and older adults showed complete release from PI. Young adults' reasoning ability was best predicted by working memory performance under high-PI conditions, replicating Bunting (2006). In contrast, older adults' reasoning ability was best predicted by their working memory performance under low-PI conditions, thereby raising questions regarding the general role of susceptibility to PI in differences in higher cognitive function among older adults. PMID:18808252

Simultaneous polarization-insensitive phase-space trans-multiplexing and wavelength multicasting via cross-phase modulation in a photonic crystal fiber at 10 GBd

NASA Astrophysics Data System (ADS)

Cannon, Brice M.

This thesis investigates the all-optical combination of amplitude and phase modulated signals into one unified multi-level phase modulated signal, utilizing the Kerr nonlinearity of cross-phase modulation (XPM). Predominantly, the first experimental demonstration of simultaneous polarization-insensitive phase-transmultiplexing and multicasting (PI-PTMM) will be discussed. The PI-PTMM operation combines the data of a single 10-Gbaud carrier-suppressed return-to-zero (CSRZ) on-off keyed (OOK) pump signal and 4x10-Gbaud return-to-zero (RZ) binary phase-shift keyed (BPSK) probe signals to generate 4x10-GBd RZ-quadrature phase-shift keyed (QPSK) signals utilizing a highly nonlinear, birefringent photonic crystal fiber (PCF). Since XPM is a highly polarization dependent nonlinearity, a polarization sensitivity reduction technique was used to alleviate the fluctuations due to the remotely generated signals' unpredictable states of polarization (SOP). The measured amplified spontaneous emission (ASE) limited receiver sensitivity optical signal-to-noise ratio (OSNR) penalty of the PI-PTMM signal relative to the field-programmable gate array (FPGA) pre-coded RZ-DQPSK baseline at a forward-error correction (FEC) limit of 10-3 BER was ≈ 0.3 dB. In addition, the OSNR of the remotely generated CSRZ-OOK signal could be degraded to ≈ 29 dB/0.1nm, before the bit error rate (BER) performance of the PI-PTMM operation began to exponentially degrade. A 138-km dispersion-managed recirculating loop system with a 100-GHz, 13-channel mixed-format dense-wavelength-division multiplexed (DWDM) transmitter was constructed to investigate the effect of metro/long-haul transmission impairments. The PI-PTMM DQPSK and the FPGA pre-coded RZ-DQPSK baseline signals were transmitted 1,900 km and 2,400 km in the nonlinearity-limited transmission regime before reaching the 10-3 BER FEC limit. The relative reduction in transmission distance for the PI-PTMM signal was due to the additional transmitter impairments in the PCF that interact negatively with the transmission fiber.

Effect of microRNA-135a on Cell Proliferation, Migration, Invasion, Apoptosis and Tumor Angiogenesis Through the IGF-1/PI3K/Akt Signaling Pathway in Non-Small Cell Lung Cancer.

PubMed

Zhou, Yufei; Li, Shaoxia; Li, Jiangtao; Wang, Dongfeng; Li, Quanxing

2017-01-01

This study explored the ability of microRNA-135a (miR-135a) to influence cell proliferation, migration, invasion, apoptosis and tumor angiogenesis through the IGF-1/PI3K/Akt signaling pathway in non-small cell lung cancer (NSCLC). NSCLC tissues and adjacent normal tissues were collected from 138 NSCLC patients. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression levels of miR-135a and IGF-1, PI3K, Akt, VEGF, bFGF and IL-8 mRNA; western blotting was used to determine the expression levels of IGF-1, PI3K and Akt protein; and enzyme-linked immunosorbent assay (ELISA) was used to analyze the expression levels of VEGF, bFGF and IL-8 protein. Human NSCLC cell lines (A549, H460, and H1299) and the human bronchial epithelial cell line (HBE) were selected. A549 cells were assigned to blank, negative control (NC), miR-135a mimics, miR-135a inhibitors, IGF-1 siRNA and miR-135a inhibitors + IGF-1 siRNA groups. The following were performed: an MTT assay to assess cell proliferation, a scratch test to detect cell migration, a Transwell assay to measure cell invasion, and a flow cytometry to analyze cell apoptosis. The expression level of miR-135a was lower while those of IGF-1, PI3K and Akt mRNA were higher in NSCLC tissues than in the adjacent normal tissues. Dual-luciferase reporter assay indicated IGF-1 as a target of miR-135a. The in vitro results showed that compared with the blank group, cell proliferation, migration and invasion were suppressed, mRNA and protein levels of IGF-1, PI3K, Akt, VEGF, bFGF and IL-8 were reduced, and cell apoptosis was enhanced in the miR-135a mimics and IGF-1 siRNA groups. Compared with the IGF-1 siRNA group, cells in the miR-135a inhibitors + IGF-1 siRNA group demonstrated increased cell proliferation, migration and invasion, elevated mRNA and protein levels of IGF-1, PI3K, Akt, VEGF, bFGF and IL-8 and reduced cell apoptosis. These findings indicated that miR-135a promotes cell apoptosis and inhibits cell proliferation, migration, invasion and tumor angiogenesis by targeting IGF-1 gene through the IGF-1/PI3K/Akt signaling pathway in NSCLC. © 2017 The Author(s). Published by S. Karger AG, Basel.

Regulation of Head and Neck Squamous Cancer Stem Cells by PI3K and SOX2

PubMed Central

Keysar, Stephen B.; Le, Phuong N.; Miller, Bettina; Jackson, Brian C.; Eagles, Justin R.; Nieto, Cera; Kim, Jihye; Tang, Binwu; Glogowska, Magdalena J.; Morton, J. Jason; Padilla-Just, Nuria; Gomez, Karina; Warnock, Emily; Reisinger, Julie; Arcaroli, John J.; Messersmith, Wells A.; Wakefield, Lalage M.; Gao, Dexiang; Tan, Aik-Choon; Serracino, Hilary

2017-01-01

Background: We have an incomplete understanding of the differences between cancer stem cells (CSCs) in human papillomavirus–positive (HPV-positive) and –negative (HPV-negative) head and neck squamous cell cancer (HNSCC). The PI3K pathway has the most frequent activating genetic events in HNSCC (especially HPV-positive driven), but the differential signaling between CSCs and non-CSCs is also unknown. Methods: We addressed these unresolved questions using CSCs identified from 10 HNSCC patient-derived xenografts (PDXs). Sored populations were serially passaged in nude mice to evaluate tumorigenicity and tumor recapitulation. The transcription profile of HNSCC CSCs was characterized by mRNA sequencing, and the susceptibility of CSCs to therapy was investigated using an in vivo model. SOX2 transcriptional activity was used to follow the asymmetric division of PDX-derived CSCs. All statistical tests were two-sided. Results: CSCs were enriched by high aldehyde dehydrogenase (ALDH) activity and CD44 expression and were similar between HPV-positive and HPV-negative cases (percent tumor formation injecting ≤ 1x103 cells: ALDH+CD44high = 65.8%, ALDH-CD44high = 33.1%, ALDH+CD44high = 20.0%; and injecting 1x105 cells: ALDH-CD44low = 4.4%). CSCs were resistant to conventional therapy and had PI3K/mTOR pathway overexpression (GSEA pathway enrichment, P < .001), and PI3K inhibition in vivo decreased their tumorigenicity (40.0%–100.0% across cases). PI3K/mTOR directly regulated SOX2 protein levels, and SOX2 in turn activated ALDH1A1 (P < .001 013C and 067C) expression and ALDH activity (ALDH+ [%] empty-control vs SOX2, 0.4% ± 0.4% vs 14.5% ± 9.8%, P = .03 for 013C and 1.7% ± 1.3% vs 3.6% ± 3.4%, P = .04 for 067C) in 013C and 067 cells. SOX2 enhanced sphere and tumor growth (spheres/well, 013C P < .001 and 067C P = .04) and therapy resistance. SOX2 expression prompted mesenchymal-to-epithelial transition (MET) by inducing CDH1 (013C P = .002, 067C P = .01), followed by asymmetric division and proliferation, which contributed to tumor formation. Conclusions: The molecular link between PI3K activation and CSC properties found in this study provides insights into therapeutic strategies for HNSCC. Constitutive expression of SOX2 in HNSCC cells generates a CSC-like population that enables CSC studies. PMID:27634934

Na+-independent phosphate transport in Caco2BBE cells

PubMed Central

Candeal, Eduardo; Caldas, Yupanqui A.; Guillén, Natalia; Levi, Moshe

2014-01-01

Pi transport in epithelia has both Na+-dependent and Na+-independent components, but so far only Na+-dependent transporters have been characterized in detail and molecularly identified. Consequently, in the present study, we initiated the characterization and analysis of intestinal Na+-independent Pi transport using an in vitro model, Caco2BBE cells. Only Na+-independent Pi uptake was observed in these cells, and Pi uptake was dramatically increased when cells were incubated in high-Pi DMEM (4 mM) from 1 day to several days. No response to low-Pi medium was observed. The increased Pi transport was mainly caused by Vmax changes, and it was prevented by actinomycin D and cycloheximide. Pi transport in cells grown in 1 mM Pi (basal DMEM) decreased at pH > 7.5, and it was inhibited with proton ionophores. Pi transport in cells incubated with 4 mM Pi increased with alkaline pH, suggesting a preference for divalent phosphate. Pi uptake in cells in 1 mM Pi was completely inhibited only by Pi and partially inhibited by phosphonoformate, oxalate, DIDS, SITS, SO42−, HCO3−, and arsenate. This inhibition pattern suggests that more than one Pi transporter is active in cells maintained with 1 mM Pi. Phosphate transport from cells maintained at 4 mM Pi was only partially inhibited by phosphonoformate, oxalate, and arsenate. Attempts to identify the responsible transporters showed that multifunctional anion exchangers of the Slc26 family as well as members of Slc17, Slc20, and Slc37 and the Pi exporter xenotropic and polytropic retrovirus receptor 1 are not involved. PMID:25298422

Cultural and Contextual Determinants of Alcohol Use Among African American Women: A Multidisciplinary Approach to Breast Cancer Risk

DTIC Science & Technology

2007-09-01

attend lectures, seminars and short courses on a variety of topics , and to apply for seed grants for research proposals. The PI also collaborates with...target low income consumers.11,12 Indeed, research shows that neighborhoods with high percentages of families below the poverty level and with less... research indicates that high concentrations of alcohol density (sales and advertising) are perceived as disorder.17 Thus, it is possible that high ad space

Quantitative characterization of brain β-amyloid using a joint PiB/FDG PET image histogram

NASA Astrophysics Data System (ADS)

Camp, Jon J.; Hanson, Dennis P.; Holmes, David R.; Kemp, Bradley J.; Senjem, Matthew L.; Murray, Melissa E.; Dickson, Dennis W.; Parisi, Joseph; Petersen, Ronald C.; Lowe, Val J.; Robb, Richard A.

2014-03-01

A complex analysis performed by spatial registration of PiB and MRI patient images in order to localize the PiB signal to specific cortical brain regions has been proven effective in identifying imaging characteristics associated with underlying Alzheimer's Disease (AD) and Lewy Body Disease (LBD) pathology. This paper presents an original method of image analysis and stratification of amyloid-related brain disease based on the global spatial correlation of PiB PET images with 18F-FDG PET images (without MR images) to categorize the PiB signal arising from the cortex. Rigid registration of PiB and 18F-FDG images is relatively straightforward, and in registration the 18F-FDG signal serves to identify the cortical region in which the PiB signal is relevant. Cortical grey matter demonstrates the highest levels of amyloid accumulation and therefore the greatest PiB signal related to amyloid pathology. The highest intensity voxels in the 18F-FDG image are attributed to the cortical grey matter. The correlation of the highest intensity PiB voxels with the highest 18F-FDG values indicates the presence of β-amyloid protein in the cortex in disease states, while correlation of the highest intensity PiB voxels with mid-range 18F-FDG values indicates only nonspecific binding in the white matter.

The Effect of Blood Alcohol Level and Pre-Injury Chronic Alcohol Use on Outcome from Severe Traumatic Brain Injury in Hispanics, Anglo-Caucasians, and African Americans

PubMed Central

O’Dell, Keira M.; Hannay, H. Julia; Biney, Fedora O.; Robertson, Claudia S.; Tian, T. Siva

2012-01-01

Objective To examine a) ethnic differences in blood alcohol level (BAL) and pre-injury chronic alcohol use (PI-ETOH) within a severe closed head injury (CHI) sample, and b) the main and interaction effects of BAL, PI-ETOH, and ethnicity on functional outcome following severe CHI. Participants 434 Hispanic, Anglo-Caucasian, and African American individuals with severe CHI. Design Retrospective cohort study. Setting Consecutive admissions to a level one trauma center. Main measures BAL upon admission to the trauma center was collected for each patient. Additional information regarding PI-ETOH was collected in a subset of patients (N=116). Functional outcome was measured using the Disability Rating Scale (DRS) at 6 months post-injury. Results A one-way ANOVA revealed ethnic differences in mean BAL. Hierarchical multiple regression indicated that BAL did not predict DRS outcomes after controlling for pertinent covariates. An interaction effect between PI-ETOH and ethnicity was observed, such that presence of chronic alcohol use predicted worse functional outcome for Anglo-Caucasians and African Americans, but more favorable outcome for Hispanics. Conclusions Ethnic differences in BALs within our severe TBI sample mirrored ethnic drinking patterns observed in the general population, with Hispanics having the highest BALs. A paradoxical relationship between PI-ETOH and functional outcome was observed for Hispanics. PMID:22955101

Characteristics of low-latitude TEC during solar cycles 23 and 24 using global ionospheric maps (GIMs) over Indian sector

NASA Astrophysics Data System (ADS)

Dashora, N.; Suresh, Sunanda

2015-06-01

The characteristics of quiet time equatorial and low-latitude total electron content over the Indian sector using global ionospheric map (GIM) data (1998-2014) are obtained filtering out the solar flare and storm effects. The results are examined and interpreted in the context of large number of previous studies. The newly found features from this study are as follows. Marked difference in nature of equinoctial asymmetry is noted between solar cycles 23 and 24. Long absence of winter anomaly both during low and high solar activity (HSA) in LL (low-latitude) regions is found. Climatology of the diurnal cycle is provided in four categories using new criteria for demarcation of solar activity levels. Highest correlation (~77%) between GIM ionospheric electron content (IEC) and PI (solar EUV proxy index) is noted over equator in contrast to previous studies. The minimum positive contribution of PI in variation of IEC requires minimum of 2 years of data, and if more than 7-8 years of data are used, it saturates. Root-mean-square width of PI can be used to define the HSA. Strong QBO (quasi-biennial oscillations) in IEC is noted in tune with the one in PI over both LL locations but QBO remains surprisingly subdued over equator. The semiannual oscillations in GIM-IEC are found to be stronger at all locations during high solar activity and weaker between 2005 and 2011, whereas the annual oscillations are found to be substantially stronger only during HSA-23 and weakest over southern LL location throughout 17 years.