Ventricular structure, function, and mechanics at high altitude: chronic remodeling in Sherpa vs. short-term lowlander adaptation.

PubMed

Stembridge, Mike; Ainslie, Philip N; Hughes, Michael G; Stöhr, Eric J; Cotter, James D; Nio, Amanda Q X; Shave, Rob

2014-08-01

Short-term, high-altitude (HA) exposure raises pulmonary artery systolic pressure (PASP) and decreases left-ventricular (LV) volumes. However, relatively little is known of the long-term cardiac consequences of prolonged exposure in Sherpa, a highly adapted HA population. To investigate short-term adaptation and potential long-term cardiac remodeling, we studied ventricular structure and function in Sherpa at 5,050 m (n = 11; 31 ± 13 yr; mass 68 ± 10 kg; height 169 ± 6 cm) and lowlanders at sea level (SL) and following 10 ± 3 days at 5,050 m (n = 9; 34 ± 7 yr; mass 82 ± 10 kg; height 177 ± 6 cm) using conventional and speckle-tracking echocardiography. At HA, PASP was higher in Sherpa and lowlanders compared with lowlanders at SL (both P < 0.05). Sherpa had smaller right-ventricular (RV) and LV stroke volumes than lowlanders at SL with lower RV systolic strain (P < 0.05) but similar LV systolic mechanics. In contrast to LV systolic mechanics, LV diastolic, untwisting velocity was significantly lower in Sherpa compared with lowlanders at both SL and HA. After partial acclimatization, lowlanders demonstrated no change in the RV end-diastolic area; however, both RV strain and LV end-diastolic volume were reduced. In conclusion, short-term hypoxia induced a reduction in RV systolic function that was also evident in Sherpa following chronic exposure. We propose that this was consequent to a persistently higher PASP. In contrast to the RV, remodeling of LV volumes and normalization of systolic mechanics indicate structural and functional adaptation to HA. However, altered LV diastolic relaxation after chronic hypoxic exposure may reflect differential remodeling of systolic and diastolic LV function. Copyright © 2014 the American Physiological Society.

Ventricular structure, function, and mechanics at high altitude: chronic remodeling in Sherpa vs. short-term lowlander adaptation

PubMed Central

Ainslie, Philip N.; Hughes, Michael G.; Stöhr, Eric J.; Cotter, James D.; Nio, Amanda Q. X.; Shave, Rob

2014-01-01

Short-term, high-altitude (HA) exposure raises pulmonary artery systolic pressure (PASP) and decreases left-ventricular (LV) volumes. However, relatively little is known of the long-term cardiac consequences of prolonged exposure in Sherpa, a highly adapted HA population. To investigate short-term adaptation and potential long-term cardiac remodeling, we studied ventricular structure and function in Sherpa at 5,050 m (n = 11; 31 ± 13 yr; mass 68 ± 10 kg; height 169 ± 6 cm) and lowlanders at sea level (SL) and following 10 ± 3 days at 5,050 m (n = 9; 34 ± 7 yr; mass 82 ± 10 kg; height 177 ± 6 cm) using conventional and speckle-tracking echocardiography. At HA, PASP was higher in Sherpa and lowlanders compared with lowlanders at SL (both P < 0.05). Sherpa had smaller right-ventricular (RV) and LV stroke volumes than lowlanders at SL with lower RV systolic strain (P < 0.05) but similar LV systolic mechanics. In contrast to LV systolic mechanics, LV diastolic, untwisting velocity was significantly lower in Sherpa compared with lowlanders at both SL and HA. After partial acclimatization, lowlanders demonstrated no change in the RV end-diastolic area; however, both RV strain and LV end-diastolic volume were reduced. In conclusion, short-term hypoxia induced a reduction in RV systolic function that was also evident in Sherpa following chronic exposure. We propose that this was consequent to a persistently higher PASP. In contrast to the RV, remodeling of LV volumes and normalization of systolic mechanics indicate structural and functional adaptation to HA. However, altered LV diastolic relaxation after chronic hypoxic exposure may reflect differential remodeling of systolic and diastolic LV function. PMID:24876358

Effect of gender on training-induced vascular remodeling in SHR.

PubMed

Amaral, S L; Michelini, L C

2011-09-01

There is accumulating evidence that physical inactivity, associated with the modern sedentary lifestyle, is a major determinant of hypertension. It represents the most important modifiable risk factor for cardiovascular diseases, which are the leading cause of morbidity and mortality for both men and women. In addition to involving sympathetic overactivity that alters hemodynamic parameters, hypertension is accompanied by several abnormalities in the skeletal muscle circulation including vessel rarefaction and increased arteriole wall-to-lumen ratio, which contribute to increased total peripheral resistance. Low-intensity aerobic training is a promising tool for the prevention, treatment and control of high blood pressure, but its efficacy may differ between men and women and between male and female animals. This review focuses on peripheral training-induced adaptations that contribute to a blood pressure-lowering effect, with special attention to differential responses in male and female spontaneously hypertensive rats (SHR). Heart, diaphragm and skeletal muscle arterioles (but not kidney arterioles) undergo eutrophic outward remodeling in trained male SHR, which contributed to a reduction of peripheral resistance and to a pressure fall. In contrast, trained female SHR showed no change in arteriole wall-to-lumen ratio and no pressure fall. On the other hand, training-induced adaptive changes in capillaries and venules (increased density) were similar in male and female SHR, supporting a similar hyperemic response to exercise.

Adaptive remodeling at the pedicle due to pars fracture: a finite element analysis study.

PubMed

İnceoğlu, Serkan; Mageswaran, Prasath; Modic, Michael T; Benzel, Edward C

2014-09-01

Spondylolysis is a common condition among the general population and a major cause of back pain in young athletes. This condition can be difficult to detect with plain radiography and has been reported to lead to contralateral pars fracture or pedicle fracture in the terminal stages. Interestingly, some patients with late-stage spondylolysis are observed to have radiographic or CT evidence of a sclerotic pedicle on the side contralateral to the spondylolysis. Although computational studies have shown stress elevation in the contralateral pedicle after a pars fracture, it is not known if these changes would cause sclerotic changes in the contralateral pedicle. The objective of this study was to investigate the adaptive remodeling process at the pedicle due to a contralateral spondylolysis using finite element analysis. A multiscale finite element model of a vertebra was obtained by combining a continuum model of the posterior elements with a voxel-based pedicle section. Extension loading conditions were applied with or without a fracture at the contralateral pars to analyze the stresses in the contralateral pedicle. A remodeling algorithm was used to simulate and assess density changes in the contralateral pedicle. The remodeling algorithm demonstrated an increase in bone formation around the perimeter of the contralateral pedicle with some localized loss of mass in the region of cancellous bone. The authors' results indicated that a pars fracture results in sclerotic changes in the contralateral pedicle. Such a remodeling process could increase overall bone mass. However, focal bone loss in the region of the cancellous bone of the pedicle might predispose the pedicle to microfractures. This phenomenon explains, at least in part, the origin of pedicle stress fractures in the sclerotic contralateral pedicles of patients with unilateral spondylolysis.

Frontiers in growth and remodeling

PubMed Central

Menzel, Andreas; Kuhl, Ellen

2012-01-01

Unlike common engineering materials, living matter can autonomously respond to environmental changes. Living structures can grow stronger, weaker, larger, or smaller within months, weeks, or days as a result of a continuous microstructural turnover and renewal. Hard tissues can adapt by increasing their density and grow strong. Soft tissues can adapt by increasing their volume and grow large. For more than three decades, the mechanics community has actively contributed to understand the phenomena of growth and remodeling from a mechanistic point of view. However, to date, there is no single, unified characterization of growth, which is equally accepted by all scientists in the field. Here we shed light on the continuum modeling of growth and remodeling of living matter, and give a comprehensive overview of historical developments and trends. We provide a state-of-the-art review of current research highlights, and discuss challenges and potential future directions. Using the example of volumetric growth, we illustrate how we can establish and utilize growth theories to characterize the functional adaptation of soft living matter. We anticipate this review to be the starting point for critical discussions and future research in growth and remodeling, with a potential impact on life science and medicine. PMID:22919118

Girls Leading Outward

ERIC Educational Resources Information Center

Hamed, Heather; Reyes, Jazmin; Moceri, Dominic C.; Morana, Laura; Elias, Maurice J.

2011-01-01

The authors describe a program implemented in Red Bank Middle School in New Jersey to help at-risk, minority middle school girls realize their leadership potential. The GLO (Girls Leading Outward) program was developed by the Developing Safe and Civil Schools Project at Rutgers University and is facilitated by university students. Selected middle…

Outward foreign direct investments and home country's economic growth

NASA Astrophysics Data System (ADS)

Ciesielska, Dorota; Kołtuniak, Marcin

2017-09-01

The study examines the time stability of the causality direction and cross-correlations between the home country's economic growth and pace of growth of its outward foreign direct investment (OFDI) stocks within the complex system of the Polish national economy. The research has been performed in order to verify, using both the time and frequency domains time series analyses, if economic agents' long term decisions on outward foreign direct investments, leading to cross-border value chains and production fragmentation processes, are of adaptive or predictive character. Consequently, the aim was to check if the home country's economic growth leads the internationalization processes of domestic enterprises, which stays in line with Dunning's Investment Development Path (IDP) paradigm, or if these complex processes, thanks to entrepreneurs' ability to formulate relevant rational expectations, precede the home country's economic growth, which would be supported with the introduction of the policy on reinforcing the internationalization processes of domestic enterprises. The presence of the unidirectional economic growth-led internationalization, consistent with the IDP concept's base assumptions, has been ascertained by the results of the short term Granger causality tests. Nevertheless, the results of the wavelet analyses, supported with the results of the econometric block exogeneity long term causality Wald tests, have revealed that in the long term the OFDI stocks' growth permanently precedes the home country's economic growth, which stays in the unequivocal contrast with the IDP paradigm's premises, as well as with the indicated above short term Granger causality tests' outcomes and indicates that economic agents' choices are not strictly of adaptive but also of predictive character, which influences the current state of knowledge on economic complex systems' characteristics. Such a result is of a great importance in the light of the existence of the significant

Exercise-Induced Skeletal Muscle Remodeling and Metabolic Adaptation: Redox Signaling and Role of Autophagy

PubMed Central

Giammarioli, Anna Maria; Chiandotto, Sergio; Spoletini, Ilaria

2014-01-01

Abstract Significance: Skeletal muscle is a highly plastic tissue. Exercise evokes signaling pathways that strongly modify myofiber metabolism and physiological and contractile properties of skeletal muscle. Regular physical activity is beneficial for health and is highly recommended for the prevention of several chronic conditions. In this review, we have focused our attention on the pathways that are known to mediate physical training-induced plasticity. Recent Advances: An important role for redox signaling has recently been proposed in exercise-mediated muscle remodeling and peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) activation. Still more currently, autophagy has also been found to be involved in metabolic adaptation to exercise. Critical Issues: Both redox signaling and autophagy are processes with ambivalent effects; they can be detrimental and beneficial, depending on their delicate balance. As such, understanding their role in the chain of events induced by exercise and leading to skeletal muscle remodeling is a very complicated matter. Moreover, the study of the signaling induced by exercise is made even more difficult by the fact that exercise can be performed with several different modalities, with this having different repercussions on adaptation. Future Directions: Unraveling the complexity of the molecular signaling triggered by exercise on skeletal muscle is crucial in order to define the therapeutic potentiality of physical training and to identify new pharmacological compounds that are able to reproduce some beneficial effects of exercise. In evaluating the effect of new “exercise mimetics,” it will also be necessary to take into account the involvement of reactive oxygen species, reactive nitrogen species, and autophagy and their controversial effects. Antioxid. Redox Signal. 21, 154–176. PMID:24450966

Outward Migration of Giant Planets in Orbital Resonance

NASA Astrophysics Data System (ADS)

D'Angelo, G.; Marzari, F.

2013-05-01

A pair of giant planets interacting with a gaseous disk may be subject to convergent orbital migration and become locked into a mean motion resonance. If the orbits are close enough, the tidal gaps produced by the planets in the disk may overlap. This represents a necessary condition to activate the outward migration of the pair. However, a number of other conditions must also be realized in order for this mechanism to operate. We have studied how disk properties, such as turbulence viscosity, temperature, surface density gradient, mass, and age, may affect the outcome of the outward migration process. We have also investigated the implications on this mechanism of the planets' gas accretion. If the pair resembles Jupiter and Saturn, the 3:2 orbital resonance may drive them outward until they reach stalling radii for migration, which are within ~10 AU of the star for disks representative of the early proto-solar nebula. However, planet post-formation conditions in the disk indicate that such planets become typically locked in the 1:2 orbital resonance, which does not lead to outward migration. Planet growth via gas accretion tends to alter the planets' mass-ratio and/or the disk accretion rate toward the star, reducing or inhibiting outward migration. Support from NASA Outer Planets Research Program and NASA Origins of Solar Systems Program is gratefully acknowledged.

Outward Bound Outcome Model Validation and Multilevel Modeling

ERIC Educational Resources Information Center

Luo, Yuan-Chun

2011-01-01

This study was intended to measure construct validity for the Outward Bound Outcomes Instrument (OBOI) and to predict outcome achievement from individual characteristics and course attributes using multilevel modeling. A sample of 2,340 participants was collected by Outward Bound USA between May and September 2009 using the OBOI. Two phases of…

ADAPTIVE MECHANISMS CONTROLLING UTERINE SPIRAL ARTERY REMODELING DURING THE ESTABLISHMENT OF PREGNANCY

PubMed Central

Soares, Michael J.; Chakraborty, Damayanti; Kubota, Kaiyu; Renaud, Stephen J.; Rumi, M.A. Karim

2015-01-01

Implantation of the embryo into the uterus triggers the initiation of hemochorial placentation. The hemochorial placenta facilitates the acquisition of maternal resources required for embryo/fetal growth. Uterine spiral arteries form the nutrient supply line for the placenta and fetus. This vascular conduit undergoes gestation stage-specific remodeling directed by maternal natural killer cells and embryo-derived invasive trophoblast lineages. The placentation site, including remodeling of the uterine spiral arteries, is shaped by environmental challenges. In this review, we discuss the cellular participants controlling pregnancy-dependent uterine spiral artery remodeling and mechanisms responsible for their development and function. PMID:25023691

Activation of outward K+ currents: effect of VIP in oesophagus

PubMed Central

Jury, Jennifer; Daniel, Edwin E

1999-01-01

Electrical field stimulations (EFS) of the opossum and canine lower oesophageal sphincters (OLOS and CLOS respectively) and opossum oesophageal body circular muscle (OOBCM) induce non-adrenergic, non-cholinergic (NANC) relaxations of any active tension and NO-mediated hyperpolarization. VIP relaxes the OLOS and CLOS and any tone in OOBCM without major electrophysiological effects. These relaxations are not blocked by NOS inhibitors. Using isolated smooth muscle cells, we tested whether VIP acted through myogenic NO production.Outward currents were similar in OOBCM and OLOS and NO increased them regardless of pipette Ca2+i, from 50–8000 nM. L-NAME or L-NOARG did not block outward currents in OLOS at 200 nM pipette Ca2+.Outward currents in CLOS cells decreased at 200 nM pipette Ca2+ or less but NO donors still increased them. VIP had no effect on outward currents in cells from OOBCM, OLOS or CLOS under conditions of pipette Ca2+ at which NO donors increased outward K+ currents.We conclude, VIP does not mimic electrophysiological effects of NO donors on isolated cells of OOBCM, OLOS or CLOS. VIP relaxes the OLOS and CLOS and inhibits contraction of OOBCM by a mechanism unrelated to release of myogenic NO or an increase in outward current.Also, the different dependence of outward currents of OOBCM and OLOS on pipette Ca2+ from those of CLOS suggests that different K+ channels are involved and that myogenic NO production contributes to K+ channel activity in CLOS but not in OLOS or OOBCM. PMID:10385258

Outward Bound--An Adjunctive Psychiatric Therapy: Preliminary Research Findings.

ERIC Educational Resources Information Center

Stich, Thomas F.; Sussman, Lewis R.

According to a small study, Outward Bound can enhance the treatment of hospitalized psychiatric patients. Researchers measured the effect of a therapeutic Outward Bound program of prescribed physical and social tasks on the contentment and self-esteem of seven patients undergoing short-term treatment at the Veterans Administration Hospital in…

Role of 5-HTTLPR polymorphism in the development of the inward/outward personality organization: a genetic association study.

PubMed

Nardi, Bernardo; Marini, Alessandra; Turchi, Chiara; Arimatea, Emidio; Tagliabracci, Adriano; Bellantuono, Cesario

2013-01-01

Reciprocity with primary caregivers affects subjects' adaptive abilities toward the construction of the most useful personal meaning organization (PMO) with respect to their developmental environment. Within cognitive theory the post-rationalist approach has outlined two basic categories of identity construction and of regulation of cognitive and emotional processes: the Outward and the Inward PMO. The presence of different, consistent clinical patterns in Inward and Outward subjects is paralleled by differences in cerebral activation during emotional tasks on fMRI and by different expression of some polymorphisms in serotonin pathways. Since several lines of evidence support a role for the 5-HTTLPR polymorphism in mediating individual susceptibility to environmental emotional stimuli, this study was conducted to investigate its influence in the development of the Inward/Outward PMO. PMO was assessed and the 5-HTTLPR polymorphism investigated in 124 healthy subjects who were subdivided into an Inward (n = 52) and an Outward (n = 72) group. Case-control comparisons of short allele (S) frequencies showed significant differences between Inwards and Outwards (p = 0.036, χ2 test; p = 0.026, exact test). Genotype frequencies were not significantly different although values slightly exceeded p ≤ 0.05 (p = 0.056, χ2 test; p = 0.059, exact test). Analysis of the 5-HTTLPR genotypes according to the recessive inheritance model showed that the S/S genotype increased the likelihood of developing an Outward PMO (p = 0.0178, χ2 test; p = 0.0143, exact test; OR = 3.43, CI (95%) = 1.188-9.925). A logistic regression analysis confirmed the association between short allele and S/S genotypes with the Outward PMO also when gender and age were considered. However none of the differences remained significant after correction for multiple testing, even though using the recessive model they approach significance. Overall our data seem to suggest a putative genetic basis for

Role of 5-HTTLPR Polymorphism in the Development of the Inward/Outward Personality Organization: A Genetic Association Study

PubMed Central

Nardi, Bernardo; Marini, Alessandra; Turchi, Chiara; Arimatea, Emidio; Tagliabracci, Adriano; Bellantuono, Cesario

2013-01-01

Reciprocity with primary caregivers affects subjects' adaptive abilities toward the construction of the most useful personal meaning organization (PMO) with respect to their developmental environment. Within cognitive theory the post-rationalist approach has outlined two basic categories of identity construction and of regulation of cognitive and emotional processes: the Outward and the Inward PMO. The presence of different, consistent clinical patterns in Inward and Outward subjects is paralleled by differences in cerebral activation during emotional tasks on fMRI and by different expression of some polymorphisms in serotonin pathways. Since several lines of evidence support a role for the 5-HTTLPR polymorphism in mediating individual susceptibility to environmental emotional stimuli, this study was conducted to investigate its influence in the development of the Inward/Outward PMO. PMO was assessed and the 5-HTTLPR polymorphism investigated in 124 healthy subjects who were subdivided into an Inward (n = 52) and an Outward (n = 72) group. Case-control comparisons of short allele (S) frequencies showed significant differences between Inwards and Outwards (p = 0.036, χ2 test; p = 0.026, exact test). Genotype frequencies were not significantly different although values slightly exceeded p≤0.05 (p = 0.056, χ2 test; p = 0.059, exact test). Analysis of the 5-HTTLPR genotypes according to the recessive inheritance model showed that the S/S genotype increased the likelihood of developing an Outward PMO (p = 0.0178, χ2 test; p = 0.0143, exact test; OR = 3.43, CI (95%) = 1.188–9.925). A logistic regression analysis confirmed the association between short allele and S/S genotypes with the Outward PMO also when gender and age were considered. However none of the differences remained significant after correction for multiple testing, even though using the recessive model they approach significance. Overall our data seem to suggest

Hsp90 Orchestrates Transcriptional Regulation by Hsf1 and Cell Wall Remodelling by MAPK Signalling during Thermal Adaptation in a Pathogenic Yeast

PubMed Central

Leach, Michelle D.; Budge, Susan; Walker, Louise; Munro, Carol; Cowen, Leah E.; Brown, Alistair J. P.

2012-01-01

Thermal adaptation is essential in all organisms. In yeasts, the heat shock response is commanded by the heat shock transcription factor Hsf1. Here we have integrated unbiased genetic screens with directed molecular dissection to demonstrate that multiple signalling cascades contribute to thermal adaptation in the pathogenic yeast Candida albicans. We show that the molecular chaperone heat shock protein 90 (Hsp90) interacts with and down-regulates Hsf1 thereby modulating short term thermal adaptation. In the longer term, thermal adaptation depends on key MAP kinase signalling pathways that are associated with cell wall remodelling: the Hog1, Mkc1 and Cek1 pathways. We demonstrate that these pathways are differentially activated and display cross talk during heat shock. As a result ambient temperature significantly affects the resistance of C. albicans cells to cell wall stresses (Calcofluor White and Congo Red), but not osmotic stress (NaCl). We also show that the inactivation of MAP kinase signalling disrupts this cross talk between thermal and cell wall adaptation. Critically, Hsp90 coordinates this cross talk. Genetic and pharmacological inhibition of Hsp90 disrupts the Hsf1-Hsp90 regulatory circuit thereby disturbing HSP gene regulation and reducing the resistance of C. albicans to proteotoxic stresses. Hsp90 depletion also affects cell wall biogenesis by impairing the activation of its client proteins Mkc1 and Hog1, as well as Cek1, which we implicate as a new Hsp90 client in this study. Therefore Hsp90 modulates the short term Hsf1-mediated activation of the classic heat shock response, coordinating this response with long term thermal adaptation via Mkc1- Hog1- and Cek1-mediated cell wall remodelling. PMID:23300438

Inflammatory Regulation of Valvular Remodeling: The Good(?), the Bad, and the Ugly

PubMed Central

Mahler, Gretchen J.; Butcher, Jonathan T.

2011-01-01

Heart valve disease is unique in that it affects both the very young and very old, and does not discriminate by financial affluence, social stratus, or global location. Research over the past decade has transformed our understanding of heart valve cell biology, yet still more remains unclear regarding how these cells respond and adapt to their local microenvironment. Recent studies have identified inflammatory signaling at nearly every point in the life cycle of heart valves, yet its role at each stage is unclear. While the vast majority of evidence points to inflammation as mediating pathological valve remodeling and eventual destruction, some studies suggest inflammation may provide key signals guiding transient adaptive remodeling. Though the mechanisms are far from clear, inflammatory signaling may be a previously unrecognized ally in the quest for controlled rapid tissue remodeling, a key requirement for regenerative medicine approaches for heart valve disease. This paper summarizes the current state of knowledge regarding inflammatory mediation of heart valve remodeling and suggests key questions moving forward. PMID:21792386

Colorado Outward Bound School Rafting Manual.

ERIC Educational Resources Information Center

Brown, Al

River rafting trips at the Colorado Outward Bound School (COBS) present participants with an opportunity for developing self-confidence, self-awareness, and concern for others through challenging and adventuresome group effort, combined with a program of instruction in rafting skills, safety consciousness, and awareness of the natural environment.…

[Bone remodeling and modeling/mini-modeling.

PubMed

Hasegawa, Tomoka; Amizuka, Norio

Modeling, adapting structures to loading by changing bone size and shapes, often takes place in bone of the fetal and developmental stages, while bone remodeling-replacement of old bone into new bone-is predominant in the adult stage. Modeling can be divided into macro-modeling(macroscopic modeling)and mini-modeling(microscopic modeling). In the cellular process of mini-modeling, unlike bone remodeling, bone lining cells, i.e., resting flattened osteoblasts covering bone surfaces will become active form of osteoblasts, and then, deposit new bone onto the old bone without mediating osteoclastic bone resorption. Among the drugs for osteoporotic treatment, eldecalcitol(a vitamin D3 analog)and teriparatide(human PTH[1-34])could show mini-modeling based bone formation. Histologically, mature, active form of osteoblasts are localized on the new bone induced by mini-modeling, however, only a few cell layer of preosteoblasts are formed over the newly-formed bone, and accordingly, few osteoclasts are present in the region of mini-modeling. In this review, histological characteristics of bone remodeling and modeling including mini-modeling will be introduced.

Outward Bound Goes to the Inner City.

ERIC Educational Resources Information Center

Buchanan, David

1993-01-01

A program at the Thompson Island Outward Bound Education Center in Boston (Massachusetts) supplements the traditional program of ropes and rocks with community service, giving urban students opportunities to try out new leadership skills in local neighborhoods. (MLF)

Regulation and impairments of dynamic desmosome and corneodesmosome remodeling.

PubMed

Kitajima, Yasuo

2013-04-30

Desmosomes and corneodesmosomes are the most important adhering junctions to provide strength for the epidermal sheet structure made of living keratinocytes and enucleated corneocytes, respectively. These junctions are connected directly with transmembrane desmosomal cadherins, desmogleins (Dsgs) and desmocollins (Dscs), mainly Dsg1/Dsc1 and Dsg3/Dsc3 in desmosomes and Dsg1/Dsc1 with corneodesmosin in corneodesmosomes. Dsgs and Dscs are associated with several proteins at their inner cytoplasmic domains to anchor keratin intermediate filaments. Desmosomes are not static, but dynamic units that undergo regular remodeling to allow for keratinocyte outward-migration in the epidermis. Recently, two mutually-reversible desmosomal adhesion states have been recognized, i.e., "stable hyper-adhesion (Ca 2+ -independent)" and "dynamic weak-adhesion (Ca 2+ -dependent)". A remarkable impairment of this remodeling is observed in pemphigus vulgaris (an autoimmune blistering disease), caused by anti-Dsg3 antibodies, generating a weak-adhesion desmosome state. Immediately after formation, corneodesmosomes normally commit to degradation, which is complicatedly regulated by proteolytic cleavage of their respective extracellular portion(s), via kallikrein-regulated peptidases and cathepsins. This proteolytic activity is in turn controlled by a variety of inhibitory agents, including protease inhibitors, cholesterol sulfate, and an acidic gradient. The impairment of protease control causes keratinization disorders. This review focuses on the dynamic regulation of desmosomes and corneodesmosomes in relation to keratinization disorders.

Skeletal Muscle Remodeling in Response to Eccentric vs. Concentric Loading: Morphological, Molecular, and Metabolic Adaptations

PubMed Central

Franchi, Martino V.; Reeves, Neil D.; Narici, Marco V.

2017-01-01

Skeletal muscle contracts either by shortening or lengthening (concentrically or eccentrically, respectively); however, the two contractions substantially differ from one another in terms of mechanisms of force generation, maximum force production and energy cost. It is generally known that eccentric actions generate greater force than isometric and concentric contractions and at a lower metabolic cost. Hence, by virtue of the greater mechanical loading involved in active lengthening, eccentric resistance training (ECC RT) is assumed to produce greater hypertrophy than concentric resistance training (CON RT). Nonetheless, prevalence of either ECC RT or CON RT in inducing gains in muscle mass is still an open issue, with some studies reporting greater hypertrophy with eccentric, some with concentric and some with similar hypertrophy within both training modes. Recent observations suggest that such hypertrophic responses to lengthening vs. shortening contractions are achieved by different adaptations in muscle architecture. Whilst the changes in muscle protein synthesis in response to acute and chronic concentric and eccentric exercise bouts seem very similar, the molecular mechanisms regulating the myogenic adaptations to the two distinct loading stimuli are still incompletely understood. Thus, the present review aims to, (a) critically discuss the literature on the contribution of eccentric vs. concentric loading to muscular hypertrophy and structural remodeling, and, (b) clarify the molecular mechanisms that may regulate such adaptations. We conclude that, when matched for either maximum load or work, similar increase in muscle size is found between ECC and CON RT. However, such hypertrophic changes appear to be achieved through distinct structural adaptations, which may be regulated by different myogenic and molecular responses observed between lengthening and shortening contractions. PMID:28725197

Effects of age, blood pressure and antihypertensive treatments on retinal arterioles remodeling assessed by adaptive optics.

PubMed

Rosenbaum, David; Mattina, Alessandro; Koch, Edouard; Rossant, Florence; Gallo, Antonio; Kachenoura, Nadjia; Paques, Michel; Redheuil, Alban; Girerd, Xavier

2016-06-01

In humans, adaptive optics camera enables precise large-scale noninvasive retinal microcirculation evaluation to assess ageing, blood pressure and antihypertensive treatments respective roles on retinal arterioles anatomy. We used adaptive optics camera rtx1 (Imagine-Eyes, Orsay, France) to measure wall thickness, internal diameter and to calculate wall-to-lumen ratio (WLR) and wall cross-sectional area of retinal arterioles. This assessment was repeated within a short period in two subgroups of hypertensive individuals without or with a drug-induced blood pressure drop. In 1000 individuals, mean wall thickness, lumen diameter and WLR were 23.2 ± 3.9, 78.0 ± 10.9 and 0.300 ± 0.054 μm, respectively. Blood pressure and age both independently increased WLR by thickening arterial wall. In opposite, hypertension narrowed lumen in younger as compared to older individuals (73.2 ± 9.0 vs. 81.7 ± 10.2 μm; P < 0.001), whereas age exerted no influence on lumen diameter. Short-term blood pressure drop (-29.3 ± 17.3/-14.4 ± 10.0 mmHg) induced a WLR decrease (-6.0 ± 8.0%) because of lumen dilatation (+4.4 ± 5.9%) without wall thickness changes. By contrast, no modifications were observed in individuals with stable blood pressure. In treated and controlled hypertensives under monotherapy WLR normalization was observed because of combined wall decrease and lumen dilatation independently of antihypertensive pharmacological classes. In multivariate analysis, hypertension drug regimen was not an independent predictor of any retinal anatomical indices. Retinal arteriolar remodeling comprised blood pressure and age-driven wall thickening as well as blood pressure-triggered lumen narrowing in younger individuals. Remodeling reversal observed in controlled hypertensives seems to include short-term functional and long-term structural changes.

Immune remodeling: lessons from repertoire alterations during chronological aging and in immune-mediated disease.

PubMed

Vallejo, Abbe N

2007-03-01

Immunological studies of aging and of patients with chronic immune-mediated diseases document overlap of immune phenotypes. Here, the term "immune remodeling" refers to these phenotypes that are indicative of biological processes of deterioration and repair. This concept is explored through lessons from studies about the changes in the T-cell repertoire and the functional diversity of otherwise oligoclonal, senescent T cells. Immune remodeling suggests a gradual process that occurs throughout life. However, similar but more drastic remodeling occurs disproportionately among young patients with chronic disease. In this article, I propose that immune remodeling is a beneficial adaptation of aging to promote healthy survival beyond reproductive performance, but acute remodeling poses risk of premature exhaustion of the immune repertoire and, thus, is detrimental in young individuals.

Outward Bound Giwaykiwin: Connecting to Land and Culture through Indigenous Outdoor Education

ERIC Educational Resources Information Center

Lowan, Greg

2007-01-01

Outward Bound Canada's (OBC) Giwaykiwin Program was founded in 1985 in response to a recognized need for programming specific to students from Indigenous backgrounds. The Giwaykiwin program aims to integrate Outward Bound (OB) and Indigenous philosophies and traditions. Giwaykiwin means "coming home" in Ojibwa and signifies the program's…

Computational biomechanics of bone's responses to dental prostheses - osseointegration, remodeling and resorption

NASA Astrophysics Data System (ADS)

Li, Wei; Rungsiyakull, Chaiy; Field, Clarice; Lin, Daniel; Zhang, Leo; Li, Qing; Swain, Michael

2010-06-01

Clinical and experimental studies showed that human bone has the ability to remodel itself to better adapt to its biomechanical environment by changing both its material properties and geometry. As a consequence of the rapid development and extensive applications of major dental restorations such as implantation and fixed partial denture (FPD), the effect of bone remodeling on the success of a dental restorative surgery is becoming critical for prosthetic design and pre-surgical assessment. This paper aims to provide a computational biomechanics framework to address dental bone's responses as a result of dental restoration. It explored three important issues of resorption, apposition and osseointegration in terms of remodeling simulation. The published remodeling data in long bones were regulated to drive the computational remodeling prediction for the dental bones by correlating the results to clinical data. It is anticipated that the study will provide a more predictive model of dental bone response and help develop a new design methodology for patient-specific dental prosthetic restoration.

Outward Bound...Into the Mainstream of Education.

ERIC Educational Resources Information Center

Outward Bound, Inc., Andover, MA.

Outward Bound schools have instituted advanced courses designed specifically for adults engaged in education and youth work. Benefits for teachers include greater development of capacitites and potentialities, greater confidence in their abilities, and the ability to relate more effectively to others. Some of the specific training elements in an…

Logistics Handbook, 1976. Colorado Outward Bound School.

ERIC Educational Resources Information Center

Colorado Outward Bound School, Denver.

Logistics, a support mission, is vital to the successful operation of the Colorado Outward Bound School (COBS) courses. Logistics is responsible for purchasing, maintaining, transporting, and replenishing a wide variety of items, i.e., food, mountaineering and camping equipment, medical and other supplies, and vehicles. The Logistics coordinator…

Bone remodelling: its local regulation and the emergence of bone fragility.

PubMed

Martin, T John; Seeman, Ego

2008-10-01

Bone modelling prevents the occurrence of damage by adapting bone structure - and hence bone strength - to its loading circumstances. Bone remodelling removes damage, when it inevitably occurs, in order to maintain bone strength. This cellular machinery is successful during growth, but fails during advancing age because of the development of a negative balance between the volumes of bone resorbed and formed during remodelling by the basic multicellular unit (BMU), high rates of remodelling during midlife in women and late in life in both sexes, and a decline in periosteal bone formation. together resulting in bone loss and structural decay each time a remodelling event occurs. The two steps in remodelling - resorption of a volume of bone by osteoclasts and formation of a comparable volume by osteoblasts - are sequential, but the regulatory events leading to these two fully differentiated functions are not. Reparative remodelling is initiated by damage producing osteocyte apoptosis, which signals the location of damage via the osteocyte canalicular system to endosteal lining cells which forms the canopy of a bone-remodelling compartment (BRC). Within the BRC, local recruitment of osteoblast precursors from the lining cells, the marrow and circulation, direct contact with osteoclast precursors, osteoclastogenesis and molecular cross-talk between precursors, mature cells, cells of the immune system, and products of the resorbed matrix, titrate the birth, work and lifespan of the cells of this multicellular remodelling machinery to either remove or form a net volume of bone appropriate to the mechanical requirements.

Adaptive remodeling of skeletal muscle energy metabolism in high-altitude hypoxia: Lessons from AltitudeOmics.

PubMed

Chicco, Adam J; Le, Catherine H; Gnaiger, Erich; Dreyer, Hans C; Muyskens, Jonathan B; D'Alessandro, Angelo; Nemkov, Travis; Hocker, Austin D; Prenni, Jessica E; Wolfe, Lisa M; Sindt, Nathan M; Lovering, Andrew T; Subudhi, Andrew W; Roach, Robert C

2018-05-04

Metabolic responses to hypoxia play important roles in cell survival strategies and disease pathogenesis in humans. However, the homeostatic adjustments that balance changes in energy supply and demand to maintain organismal function under chronic low oxygen conditions remain incompletely understood, making it difficult to distinguish adaptive from maladaptive responses in hypoxia-related pathologies. We integrated metabolomic and proteomic profiling with mitochondrial respirometry and blood gas analyses to comprehensively define the physiological responses of skeletal muscle energy metabolism to 16 days of high-altitude hypoxia (5260 m) in healthy volunteers from the AltitudeOmics project. In contrast to the view that hypoxia down-regulates aerobic metabolism, results show that mitochondria play a central role in muscle hypoxia adaptation by supporting higher resting phosphorylation potential and enhancing the efficiency of long-chain acylcarnitine oxidation. This directs increases in muscle glucose toward pentose phosphate and one-carbon metabolism pathways that support cytosolic redox balance and help mitigate the effects of increased protein and purine nucleotide catabolism in hypoxia. Muscle accumulation of free amino acids favor these adjustments by coordinating cytosolic and mitochondrial pathways to rid the cell of excess nitrogen, but might ultimately limit muscle oxidative capacity in vivo Collectively, these studies illustrate how an integration of aerobic and anaerobic metabolism is required for physiological hypoxia adaptation in skeletal muscle, and highlight protein catabolism and allosteric regulation as unexpected orchestrators of metabolic remodeling in this context. These findings have important implications for the management of hypoxia-related diseases and other conditions associated with chronic catabolic stress. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Colorado Outward Bound School River Rafters' Manual.

ERIC Educational Resources Information Center

Leachman, Mark

Instructional sequences, safety rules, duties of crew members, and procedures for Colorado Outward Bound School river rafting trips are summarized in this manual. Designed to acquaint instructors with the duties expected of them on the trips, the information in the manual is presented in outline form and is intended for those with prior river…

Fibrous tissues growth and remodeling: Evolutionary micro-mechanical theory

NASA Astrophysics Data System (ADS)

Lanir, Yoram

2017-10-01

Living fibrous tissues are composite materials having the unique ability to adapt their size, shape, structure and mechanical properties in response to external loading. This adaptation, termed growth and remodeling (G&R), occurs throughout life and is achieved via cell-induced turnover of tissue constituents where some are degraded and new ones are produced. Realistic mathematical modeling of G&R provides insight into the basic processes, allows for hypotheses testing, and constitutes an essential tool for establishing clinical thresholds of pathological remodeling and for the production of tissue substitutes aimed to achieve target structure and properties. In this study, a general 3D micro-mechanical multi-scale theory of G&R in fibrous tissue was developed which connects between the evolution of the tissue structure and properties, and the underlying mechano-biological turnover events of its constituents. This structural approach circumvents a fundamental obstacle in modeling growth mechanics since the growth motion is not bijective. The model was realized for a flat tissue under two biaxial external loadings using data-based parameter values. The predictions show close similarity to characteristics of remodeled adult tissue including its structure, anisotropic and non-linear mechanical properties, and the onset of in situ pre-strain and pre-stress. The results suggest that these important features of living fibrous tissues evolve as they grow.

Pharmacological Conversion of a Cardiac Inward Rectifier into an Outward Rectifier Potassium Channel.

PubMed

Moreno-Galindo, Eloy G; Sanchez-Chapula, Jose A; Tristani-Firouzi, Martin; Navarro-Polanco, Ricardo A

2016-09-01

Potassium (K(+)) channels are crucial for determining the shape, duration, and frequency of action-potential firing in excitable cells. Broadly speaking, K(+) channels can be classified based on whether their macroscopic current outwardly or inwardly rectifies, whereby rectification refers to a change in conductance with voltage. Outwardly rectifying K(+) channels conduct greater current at depolarized membrane potentials, whereas inward rectifier channels conduct greater current at hyperpolarized membrane potentials. Under most circumstances, outward currents through inwardly rectifying K(+) channels are reduced at more depolarized potentials. However, the acetylcholine-gated K(+) channel (KACh) conducts current that inwardly rectifies when activated by some ligands (such as acetylcholine), and yet conducts current that outwardly rectifies when activated by other ligands (for example, pilocarpine and choline). The perplexing and paradoxical behavior of KACh channels is due to the intrinsic voltage sensitivity of the receptor that activates KACh channels, the M2 muscarinic receptor (M2R). Emerging evidence reveals that the affinity of M2R for distinct ligands varies in a voltage-dependent and ligand-specific manner. These intrinsic receptor properties determine whether current conducted by KACh channels inwardly or outwardly rectifies. This review summarizes the most recent concepts regarding the intrinsic voltage sensitivity of muscarinic receptors and the consequences of this intriguing behavior on cardiac physiology and pharmacology of KACh channels. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Site-specific adaptive remodeling of Greyhound metacarpal cortical bone subjected to asymmetrical cyclic loading.

PubMed

Johnson, K A; Skinner, G A; Muir, P

2001-05-01

To quantify geometric, inertial, and histomorphometric properties at the mid-diaphyseal level of left and right metacarpal bones (MCB) of racing Greyhounds. MCB from 7 racing Greyhounds euthanatized for reasons unrelated to MCB abnormalities. Mid-diaphyseal transverse sections of left and right MCB were stained with H&E or microradiographed. Images of stained sections were digitized, and cross-sectional area, cortical area, and maximum and minimum area moments of inertia of each bone were determined. Histomorphometric data (osteonal density, osteonal birefringence, and endosteal new lamellar bone thickness) were collected in 4 quadrants (dorsal, palmar, lateral, medial). Values were compared between limbs and among bones and quadrants. Cross-sectional area, cortical area, and maximum and minimum moments of inertia of left MCB-IV and -V were significantly greater, compared with contralateral bones. Overall osteonal densities in the dorsal quadrants of left MCB were greater, compared with lateral and medial quadrants. Also, percentage of birefringent osteons was significantly greater in the dorsal quadrant of left MCB-III, -IV, and -V, compared with the palmar quadrant. Thickness of new endosteal lamellar bone was not significantly influenced by limb, bone, or quadrant. Increased cortical thickness and geometric properties of left MCB-IV and -V of Greyhounds, together with altered turnover and orientation of osteons in the dorsal quadrants of left MCB, are site-specific adaptive responses associated with asymmetric cyclic loading as a result of racing on circular tracks. Site-specific adaptive remodeling may be important in the etiopathogenesis of fatigue fractures in racing Greyhounds.

A Means-End Investigation of Outcomes Associated with Outward Bound and NOLS Programs

ERIC Educational Resources Information Center

Goldenberg, Marni; Pronsolino, Dan

2008-01-01

This study compares outcomes associated with participation in Outward Bound (OB) and National Outdoor Leadership Schools (NOLS) courses in the United States. OB and NOLS (two of the largest providers of outdoor adventure education [OAE] courses) combined saw more than 30,000 students in 2006 (NOLS, n.d.; Outward Bound, n.d.). Comparing these two…

Helical unwinding and side-chain unlocking unravel the outward open conformation of the melibiose transporter

NASA Astrophysics Data System (ADS)

Wang, Li-Ying; Ravi, Vidhya M.; Leblanc, Gérard; Padrós, Esteve; Cladera, Josep; Perálvarez-Marín, Alex

2016-09-01

Molecular dynamics simulations have been used to study the alternate access mechanism of the melibiose transporter from Escherichia coli. Starting from the outward-facing partially occluded form, 2 out of 12 simulations produced an outward full open form and one partially open, whereas the rest yielded fully or partially occluded forms. The shape of the outward-open form resembles other outward-open conformations of secondary transporters. During the transporter opening, conformational changes in some loops are followed by changes in the periplasm region of transmembrane helix 7. Helical curvature relaxation and unlocking of hydrophobic and ionic locks promote the outward opening of the transporter making accessible the substrate binding site. In particular, FRET studies on mutants of conserved aromatic residues of extracellular loop 4 showed lack of substrate binding, emphasizing the importance of this loop for making crucial interactions that control the opening of the periplasmic side. This study indicates that the alternate access mechanism for the melibiose transporter fits better into a flexible gating mechanism rather than the archetypical helical rigid-body rocker-switch mechanism.

Cardiac remodeling in preterm infants with prolonged exposure to a patent ductus arteriosus.

PubMed

de Waal, Koert; Phad, Nilkant; Collins, Nick; Boyle, Andrew

2017-05-01

Sustained volume load due to a patent ductus arteriosus (PDA) leads to cardiac remodeling. Remodeling changes can become pathological and are associated with cardiovascular disease progression. Data on remodeling changes in preterm infants is not available. Clinical and echocardiography data were collected in preterm infants <30 weeks gestation on postnatal day 3 and then every 7-14 days until closure of the ductus arteriosus. Images were analyzed using conventional techniques and speckle tracking. Remodeling changes of infants with prolonged (>14 days) exposure to a PDA were compared to control infants without a PDA. Thirty out of 189 infants had prolonged exposure to a PDA. The left heart remodeled to a larger and more spherical shape and thus significantly increased in volume. Most changes occurred in the first 4 weeks, plateaued, and then returned to control values. Systolic function and estimates of filling pressure increased and effective arterial elastance reduced with a PDA, however contractility was unchanged. Wall thickness increased after 4 weeks of increased volume exposure. The preterm PDA induces early and significant remodeling of the left heart. A compensated cardiac physiology was seen with preserved systolic function, suggesting adaptive rather than pathological remodeling changes with prolonged exposure to a PDA. © 2017 Wiley Periodicals, Inc.

Instructor's Field Manual: North Carolina Outward Bound School.

ERIC Educational Resources Information Center

Outward Bound, Morganton, NC.

A supplement to the North Carolina Outward Bound School's Instructor's Handbook, this field manual presents useful, but not required, information gleaned from old timers and resource books which may enable the instructor to conduct a better course. Section one considers advantages and disadvantages and provides directions and topographical maps…

Restraint stress delays endometrial adaptive remodeling during mouse embryo implantation.

PubMed

Liu, Guanhui; Dong, Yulan; Wang, Zixu; Cao, Jing; Chen, Yaoxing

2015-01-01

In mice, previously, we showed that restraint stress reduces the number of embryo implantation sites in the endometrium. Here, we hypothesized that the uterine microenvironment is altered by restraint stress and consequently is suboptimal for embryo implantation. On embryonic day 1 (E1), 60 of 154 pregnant CD1 mice underwent restraint stress (4 h), repeated daily to E3, E5 or E7 (n = 10 mice per group). Restraint stress decreased food intake and suppressed body weight gain on E3, E5 and E7. Restraint stress decreased the actual and relative weight (percent body weight) of uterus and ovary on E5 (by 14.9%, p = 0.03; 16.1%, p = 0.004) and E7 (by 16.8%, p = 0.03; 20.0%, p = 0.01). Morphologically, restraint stress decreased relative endometrial area (by 8.94-18.8%, p = 0.003-0.021) and uterine gland area (by 30.6%, p < 0.01 on E3 and 44.5%, p < 0.01 on E5). Immunohistochemistry showed that restraint stress decreased microvessel density (by 12.9-70.5%, p < 0.01) and vascular endothelial growth factor expression (by 14.6-45.9%, p = 0.007-0.02). Restraint stress decreased by 32.4-39.8% (p = 0.002-0.01) the mean optical density ratio for proliferating cell nuclear antigen/terminal deoxynucleotidyl transferase dUTP nick end labeling. Methyl thiazolyl tetrazolium assay showed a dose-dependent decrease in proliferative activity of endometrial stromal cells (from 52 of 154 pregnant E5 control mice) incubated with H2O2 (100-1000 μM) in vitro. These findings supported the hypothesis that restraint stress negatively influences endometrial adaptive remodeling via an oxidative stress pathway, which resulted in fewer implantation sites.

Extensive Intestinal Resection Triggers Behavioral Adaptation, Intestinal Remodeling and Microbiota Transition in Short Bowel Syndrome

PubMed Central

Mayeur, Camille; Gillard, Laura; Le Beyec, Johanne; Bado, André; Joly, Francisca; Thomas, Muriel

2016-01-01

Extensive resection of small bowel often leads to short bowel syndrome (SBS). SBS patients develop clinical mal-absorption and dehydration relative to the reduction of absorptive area, acceleration of gastrointestinal transit time and modifications of the gastrointestinal intra-luminal environment. As a consequence of severe mal-absorption, patients require parenteral nutrition (PN). In adults, the overall adaptation following intestinal resection includes spontaneous and complex compensatory processes such as hyperphagia, mucosal remodeling of the remaining part of the intestine and major modifications of the microbiota. SBS patients, with colon in continuity, harbor a specific fecal microbiota that we called “lactobiota” because it is enriched in the Lactobacillus/Leuconostoc group and depleted in anaerobic micro-organisms (especially Clostridium and Bacteroides). In some patients, the lactobiota-driven fermentative activities lead to an accumulation of fecal d/l-lactates and an increased risk of d-encephalopathy. Better knowledge of clinical parameters and lactobiota characteristics has made it possible to stratify patients and define group at risk for d-encephalopathy crises. PMID:27681910

An Investigation of the Outward Bound Final Expedition

ERIC Educational Resources Information Center

Bobilya, Andrew J.; Kalisch, Ken; Daniel, Brad

2011-01-01

Research of wilderness programs indicates a clear need for additional investigation of specific program components and their influence on participant outcomes. This study examines one component of the Outward Bound wilderness program--the Final Expedition. The Final Expedition is a student-led wilderness expedition and is also referred to as an…

To Know By Experience: Outward Bound, North Carolina.

ERIC Educational Resources Information Center

Meyer, Dan; Meyer, Diane

Directed at discovering one's inner resources and the dignity of one's fellow man, the Outward Bound experience seeks to instill self-reliance, physical fitness, and compassion as fundamental values recognizing there are few opportunities to formulate such values in an increasingly technological and urbanized society. For 3 1/2 weeks, people from…

Innovative Adolescent Chemical Dependency Treatment and Its Outcome: A Model Based on Outward Bound Programming.

ERIC Educational Resources Information Center

McPeake, John D.; And Others

1991-01-01

Describes adolescent chemical dependency treatment model developed at Beech Hill Hospital (New Hampshire) which integrated Twelve Step-oriented alcohol and drug rehabilitation program with experiential education school, Hurricane Island Outward Bound School. Describes Beech Hill Hurricane Island Outward Bound School Adolescent Chemical Dependency…

Connecting mechanics and bone cell activities in the bone remodeling process: an integrated finite element modeling.

PubMed

Hambli, Ridha

2014-01-01

Bone adaptation occurs as a response to external loadings and involves bone resorption by osteoclasts followed by the formation of new bone by osteoblasts. It is directly triggered by the transduction phase by osteocytes embedded within the bone matrix. The bone remodeling process is governed by the interactions between osteoblasts and osteoclasts through the expression of several autocrine and paracrine factors that control bone cell populations and their relative rate of differentiation and proliferation. A review of the literature shows that despite the progress in bone remodeling simulation using the finite element (FE) method, there is still a lack of predictive models that explicitly consider the interaction between osteoblasts and osteoclasts combined with the mechanical response of bone. The current study attempts to develop an FE model to describe the bone remodeling process, taking into consideration the activities of osteoclasts and osteoblasts. The mechanical behavior of bone is described by taking into account the bone material fatigue damage accumulation and mineralization. A coupled strain-damage stimulus function is proposed, which controls the level of autocrine and paracrine factors. The cellular behavior is based on Komarova et al.'s (2003) dynamic law, which describes the autocrine and paracrine interactions between osteoblasts and osteoclasts and computes cell population dynamics and changes in bone mass at a discrete site of bone remodeling. Therefore, when an external mechanical stress is applied, bone formation and resorption is governed by cells dynamic rather than adaptive elasticity approaches. The proposed FE model has been implemented in the FE code Abaqus (UMAT routine). An example of human proximal femur is investigated using the model developed. The model was able to predict final human proximal femur adaptation similar to the patterns observed in a human proximal femur. The results obtained reveal complex spatio-temporal bone

Simulated Microgravity and Recovery-Induced Remodeling of the Left and Right Ventricle

PubMed Central

Zhong, Guohui; Li, Yuheng; Li, Hongxing; Sun, Weijia; Cao, Dengchao; Li, Jianwei; Zhao, Dingsheng; Song, Jinping; Jin, Xiaoyan; Song, Hailin; Yuan, Xinxin; Wu, Xiaorui; Li, Qi; Xu, Qing; Kan, Guanghan; Cao, Hongqing; Ling, Shukuan; Li, Yingxian

2016-01-01

Physiological adaptations to microgravity involve alterations in cardiovascular systems. These adaptations result in cardiac remodeling and orthostatic hypotension. However, the response of the left ventricle (LV) and right ventricle (RV) following hindlimb unloading (HU) and hindlimb reloading (HR) is not clear and the underlying mechanism remains to be understood. In this study, three groups of mice were subjected to HU by tail suspension for 28 days. Following this, two groups were allowed to recover for 7 or 14 days. The control group was treated equally, with the exception of tail suspension. Echocardiography was performed to detect the structure and function changes of heart. Compared with the control, the HU group of mice showed reduced LV-EF (ejection fraction), and LV-FS (fractional shortening). However, mice that were allowed to recover for 7 days after HU (HR-7d) showed increased LVIDs (systolic LV internal diameter) and LV Vols (systolic LV volume). Mice that recovered for 14 days (HR-14d) returned to the normal state. In comparison, RV-EF and RV-FS didn't recover to the normal conditions till being reloaded for 14 days. Compared with the control, RVIDd (diastolic RV internal diameter), and RV Vold (diastolic RV volume) were reduced in HU group and recovered to the normal conditions in HR-7d and HR-14d groups, in which groups RVIDs (systolic RV internal diameter) and RV Vols (systolic RV volume) were increased. Histological analysis and cardiac remodeling gene expression results indicated that HU induces left and right ventricular remodeling. Western blot demonstrated that the phosphorylation of HDAC4 and ERK1/2 and the ratio of LC3-II / LC3-I, were increased following HU and recovered following HR in both LV and RV, and the phosphorylation of AMPK was inhibited in both LV and RV following HU, but only restored in LV following HR for 14 days. These results indicate that simulated microgravity leads to cardiac remodeling, and the remodeling changes can

Supply-demand balance in outward-directed networks and Kleiber's law

PubMed Central

Painter, Page R

2005-01-01

Background Recent theories have attempted to derive the value of the exponent α in the allometric formula for scaling of basal metabolic rate from the properties of distribution network models for arteries and capillaries. It has recently been stated that a basic theorem relating the sum of nutrient currents to the specific nutrient uptake rate, together with a relationship claimed to be required in order to match nutrient supply to nutrient demand in 3-dimensional outward-directed networks, leads to Kleiber's law (b = 3/4). Methods The validity of the supply-demand matching principle and the assumptions required to prove the basic theorem are assessed. The supply-demand principle is evaluated by examining the supply term and the demand term in outward-directed lattice models of nutrient and water distribution systems and by applying the principle to fractal-like models of mammalian arterial systems. Results Application of the supply-demand principle to bifurcating fractal-like networks that are outward-directed does not predict 3/4-power scaling, and evaluation of water distribution system models shows that the matching principle does not match supply to demand in such systems. Furthermore, proof of the basic theorem is shown to require that the covariance of nutrient uptake and current path length is 0, an assumption unlikely to be true in mammalian arterial systems. Conclusion The supply-demand matching principle does not lead to a satisfactory explanation for the approximately 3/4-power scaling of mammalian basal metabolic rate. PMID:16283939

Supply-demand balance in outward-directed networks and Kleiber's law.

PubMed

Painter, Page R

2005-11-10

Recent theories have attempted to derive the value of the exponent alpha in the allometric formula for scaling of basal metabolic rate from the properties of distribution network models for arteries and capillaries. It has recently been stated that a basic theorem relating the sum of nutrient currents to the specific nutrient uptake rate, together with a relationship claimed to be required in order to match nutrient supply to nutrient demand in 3-dimensional outward-directed networks, leads to Kleiber's law (b = 3/4). The validity of the supply-demand matching principle and the assumptions required to prove the basic theorem are assessed. The supply-demand principle is evaluated by examining the supply term and the demand term in outward-directed lattice models of nutrient and water distribution systems and by applying the principle to fractal-like models of mammalian arterial systems. Application of the supply-demand principle to bifurcating fractal-like networks that are outward-directed does not predict 3/4-power scaling, and evaluation of water distribution system models shows that the matching principle does not match supply to demand in such systems. Furthermore, proof of the basic theorem is shown to require that the covariance of nutrient uptake and current path length is 0, an assumption unlikely to be true in mammalian arterial systems. The supply-demand matching principle does not lead to a satisfactory explanation for the approximately 3/4-power scaling of mammalian basal metabolic rate.

No-Regrets Remodeling, 2nd Edition

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

None

2013-12-01

No-Regrets Remodeling, sponsored by Oak Ridge National Laboratory, is an informative publication that walks homeowners and/or remodelers through various home remodeling projects. In addition to remodeling information, the publication provides instruction on how to incorporate energy efficiency into the remodeling process. The goal of the publication is to improve homeowner satisfaction after completing a remodeling project and to provide the homeowner with a home that saves energy and is comfortable and healthy.

Changes of vessel-cells complex in zones of adaptive remodeling of the bone tissue under microgravity conditions

NASA Astrophysics Data System (ADS)

Rodionova, N.; Oganov, V.; Nosova, L.

The development and differentiation of osteogenic cells in organism happen in closely topographical and functional connection with blood capillaries. We formerly proofed, that small-differentiated cells, which are in the population of perivascular cells are osteogenic cells -precursors . At the present time it is actually to clear up, how these biostructures react on conditions of less of biomechanical load on skeleton bones. We researched peculiarities of blood-bed structure and perivascular cells in metaphises of thighbones and tibial bones in rats, which were onboard the American space station SLS-2 and in experiments of modeling hypokinesia. There were used methods of cytochemistry, histology and electron microscopy. We established, that under the support and functional load decreasing in zones of bones adaptive remodeling, comparatively to control, on histosections the own volume of sinusoid capillaries reduces. The small vessels prevail here. The spaces of sinusoid capillaries are limited by 1 2 cells of the endothelia. Endotheliocytes in- general have the typical ultrastructure. Basal membranes are expressed not-distinctly. Perivascular cells don't create the unbroken layer. The population of these cells is not-homogeneous. It includes enclosed to endothelia small-differentiated forms and separating cells with sings of fibroblastic differentiation (the own volume of rough endoplasmic reticulum in cytoplasm induces). The part of these cells reacts on the alkaline phosphatase (the marker of the osteogenic differentiation). Under the conditions of support load decreasing (especially under the microgravity) there is a tendency to reducing of separating osteogenic cells number. We noted the priority of differentiating fibroblasts. It leads to further development in zones of bone remodeling of hearths of fibrous tissue, that doesn't mineralize. The obtained data are seen as one of mechanisms of osteoporosis and osteopenia development under the deficite of support

Substrate transport pathway inside outward open conformation of EmrD: a molecular dynamics simulation study.

PubMed

Xianwei, Tan; Diannan, Lu; Boxiong, Wang

2016-07-19

The EmrD transporter, which is a classical major facilitator superfamily (MFS) protein, can extrude a range of drug molecules out of E. coil. The drug molecules transport through the channel of MFS in an outward open state, an important issue in research about bacterial drug resistance, which however, is still unknown. In this paper, we construct a starting outward-open model of the EmrD transporter using a state transition method. The starting model is refined by a conventional molecular dynamics simulation. Locally enhanced sampling simulation (LES) is used to validate the outward-open model of EmrD. In the locally enhanced sampling simulation, ten substrates are placed along the channel of the outward-open EmrD, and these substrates are sampled in the outward-open center cavity. It is found that the translocation pathway of these substrates from the inside to the outside of the cell through the EmrD transporter is composed of two sub-pathways, one sub-pathway, including H2, H4, and H5, and another sub-pathway, including H8, H10, and H11. The results give us have a further insight to the ways of substrate translocation of an MFS protein. The model method is based on common features of an MFS protein, so this modeling method can be used to construct various MFS protein models which have a desired state with other conformations not known in the alternating-access mechanism.

Academic Perspectives on the Outcomes of Outward Student Mobility

ERIC Educational Resources Information Center

Bridger, Kath

2015-01-01

This research project was commissioned by the UK Higher Education International Unit (IU) and the Higher Education Academy (HEA) in June 2014 to explore academic perspectives on the outcomes of outward mobility at undergraduate, postgraduate and research levels for UK domiciled students, and to consider how best to facilitate the take up as well…

Chromatin Remodeling and Plant Immunity.

PubMed

Chen, W; Zhu, Q; Liu, Y; Zhang, Q

Chromatin remodeling, an important facet of the regulation of gene expression in eukaryotes, is performed by two major types of multisubunit complexes, covalent histone- or DNA-modifying complexes, and ATP-dependent chromosome remodeling complexes. Snf2 family DNA-dependent ATPases constitute the catalytic subunits of ATP-dependent chromosome remodeling complexes, which accounts for energy supply during chromatin remodeling. Increasing evidence indicates a critical role of chromatin remodeling in the establishment of long-lasting, even transgenerational immune memory in plants, which is supported by the findings that DNA methylation, histone deacetylation, and histone methylation can prime the promoters of immune-related genes required for disease defense. So what are the links between Snf2-mediated ATP-dependent chromosome remodeling and plant immunity, and what mechanisms might support its involvement in disease resistance? © 2017 Elsevier Inc. All rights reserved.

Outward Motions of SiO Masers around VX Sgr

NASA Astrophysics Data System (ADS)

Su, J. B.; Shen, Z.-Q.; Chen, X.; Jiang, D. R.

2014-09-01

We report the proper motions of SiO maser features around VX Sgr from the two-epoch VLBA observations (2006 December 15 and 2007 August 19). The majority of maser feature activities show a trend of outward motions. It is consistent with our previous finding that the outflow may play an important role for SiO maser pumping.

Pay attention to cardiac remodeling in cancer cachexia.

PubMed

Zheng, Yawen; Chen, Han; Li, Xiaoqing; Sun, Yuping

2016-07-01

Cancer cachexia is a complex and multifaceted disease state characterized by fatigue, weakness, and loss of skeletal muscle and adipose tissue. Recently, the profound negative effects of cancer cachexia on cardiac tissue draw much attention, which is likely to contribute to mortality in tumor-bearing animals. The mechanism of cardiac remodeling is not so clear and involved with a series of molecular alterations. In cancer cachexia model, progressive loss of left ventricular mass and decrease in myocardial function is observed and cardiac autonomic functions are altered. Levels of several emerging cardiovascular neurohormones are found elevating in patients with cancer, but it is still controversial whether the changes could reflect the heart injury accurately. The remedy for cardiac remodeling has been explored. It is showed that exercise can modulate signaling pathways activated by wasting cytokines and impact on the resulting outcomes on heart adaptation. Some drugs, such as bisoprolol, spironolactone, perindopril, tandospirone, and simvastatin, can mitigate adverse effects of the tumor on the heart and prolong survival.

Adaptation of the membrane in Archaea.

PubMed

Oger, Philippe M; Cario, Anaïs

2013-12-15

Microbes often face contrasted and fluctuating environmental conditions, to which they need to adapt or die. Because membranes play a central role in regulating fluxes inward and outward from the cells, maintaining the appropriate structure of the membrane is crucial to maintain cellular integrity and functions. This is achieved in bacteria and eucarya by a modification of the membrane lipid compositions, a strategy termed homeoviscous adaptation. We review here evidence for homeoviscous adaptation in Archaea, and discuss the limits of this strategy and our knowledge in this very peculiar domain of life. © 2013 Elsevier B.V. All rights reserved.

Pulsatile Fluid Shear in Bone Remodeling

NASA Technical Reports Server (NTRS)

Frangos, John A.

1997-01-01

The objective of this investigation was to elucidate the sensitivity to transients in fluid shear stress in bone remodeling. Bone remodeling is clearly a function of the local mechanical environment which includes interstitial fluid flow. Traditionally, load-induced remodeling has been associated with low frequency (1-2 Hz) signals attributed to normal locomotion. McLeod and Rubin, however, demonstrated in vivo remodeling events associated with high frequency (15-30 Hz) loading. Likewise, other in vivo studies demonstrated that slowly applied strains did not trigger remodeling events. We therefore hypothesized that the mechanosensitive pathways which control bone maintenance and remodeling are differentially sensitive to varying rates of applied fluid shear stress.

Outward transport of high-temperature materials around the midplane of the solar nebula.

PubMed

Ciesla, Fred J

2007-10-26

The Stardust samples collected from Comet 81P/Wild 2 indicate that large-scale mixing occurred in the solar nebula, carrying materials from the hot inner regions to cooler environments far from the Sun. Similar transport has been inferred from telescopic observations of protoplanetary disks around young stars. Models for protoplanetary disks, however, have difficulty explaining the observed levels of transport. Here I report the results of a new two-dimensional model that shows that outward transport of high-temperature materials in protoplanetary disks is a natural outcome of disk formation and evolution. This outward transport occurs around the midplane of the disk.

Perspectives on biomechanical growth and remodeling mechanisms in glaucoma⋆

PubMed Central

Grytz, Rafael; Girkin, Christopher A.; Libertiaux, Vincent; Downs, J. Crawford

2012-01-01

Glaucoma is a blinding diseases in which damage to the axons results in loss of retinal ganglion cells. Experimental evidence indicates that chronic intraocular pressure elevation initiates axonal insult at the level of the lamina cribrosa. The lamina cribrosa is a porous collagen structure through which the axons pass on their path from the retina to the brain. Recent experimental studies revealed the extensive structural changes of the lamina cribrosa and its surrounding tissues during the development and progression of glaucoma. In this perspective paper we review the experimental evidence for growth and remodeling mechanisms in glaucoma including adaptation of tissue anisotropy, tissue thickening/thinning, tissue elongation/shortening and tissue migration. We discuss the existing predictive computational approaches that try to elucidate the potential biomechanical basis of theses growth and remodeling mechanisms and highlight open questions, challenges, and avenues for further development. PMID:23109748

Seasonal and post-trauma remodeling in cone-dominant ground squirrel retina

PubMed Central

Merriman, Dana K.; Sajdak, Benjamin S.; Li, Wei; Jones, Bryan W.

2016-01-01

With a photoreceptor mosaic containing ~85% cones, the ground squirrel is one of the richest known mammalian sources of these important retinal cells. It also has a visual ecology much like the human’s. While the ground squirrel retina is understandably prominent in the cone biochemistry, physiology, and circuitry literature, far less is known about the remodeling potential of its retinal pigment epithelium, neurons, macroglia, or microglia. This review aims to summarize the data from ground squirrel retina to this point in time, and to relate them to data from other brain areas where appropriate. We begin with a survey of the ground squirrel visual system, making comparisons with traditional rodent models and with human. Because this animal’s status as a hibernator often goes unnoticed in the vision literature, we then present a brief primer on hibernation biology. Next we review what is known about ground squirrel retinal remodeling concurrent with deep torpor and with rapid recovery upon re-warming. Notable here is rapidly-reversible, temperature-dependent structural plasticity of cone ribbon synapses, as well as pre- and post-synaptic plasticity throughout diverse brain regions. It is not yet clear if retinal cell types other than cones engage in torpor-associated synaptic remodeling. We end with the small but intriguing literature on the ground squirrel retina’s remodeling responses to insult by retinal detachment. Notable for widespread loss of (cone) photoreceptors, there is surprisingly little remodeling of the RPE or Müller cells. Microglial activation appears minimal, and remodeling of surviving second- and third-order neurons seems absent, but both require further study. In contrast, traumatic brain injury in the ground squirrel elicits typical macroglial and microglial responses. Overall, the data to date strongly suggest a heretofore unrecognized, natural checkpoint between retinal deafferentiation and RPE and Müller cell remodeling events. As

Haloperidol Selectively Remodels Striatal Indirect Pathway Circuits

PubMed Central

Sebel, Luke E; Graves, Steven M; Chan, C Savio; Surmeier, D James

2017-01-01

Typical antipsychotic drugs are widely thought to alleviate the positive symptoms of schizophrenia by antagonizing dopamine D2 receptors expressed by striatal spiny projection neurons (SPNs). What is less clear is why antipsychotics have a therapeutic latency of weeks. Using a combination of physiological and anatomical approaches in ex vivo brain slices from transgenic mice, it was found that 2 weeks of haloperidol treatment induced both intrinsic and synaptic adaptations specifically within indirect pathway SPNs (iSPNs). Perphenazine treatment had similar effects. Some of these adaptations were homeostatic, including a drop in intrinsic excitability and pruning of excitatory corticostriatal glutamatergic synapses. However, haloperidol treatment also led to strengthening of a subset of excitatory corticostriatal synapses. This slow remodeling of corticostriatal iSPN circuitry is likely to play a role in mediating the delayed therapeutic action of neuroleptics. PMID:27577602

Outward Bound Leadership Model: An Exploratory Study of Leadership Variables.

ERIC Educational Resources Information Center

Bartley, Natalie L.

A field study of 29 mountain-course instructors at the Colorado Outward Bound School (COBS) explored the relationships of gender-related personality traits and soft skills to outdoor leadership styles and course outcomes. Soft skills are competencies necessary for effective interpersonal helping skills, as opposed to hard skills, which are…

Callus remodelling model

NASA Astrophysics Data System (ADS)

Miodowska, Justyna; Bielski, Jan; Kromka-Szydek, Magdalena

2018-01-01

The objective of this paper is to investigate the healing process of the callus using bone remodelling approach. A new mathematical model of bone remodelling is proposed including both underload and overload resorption, as well as equilibrium and bone growth states. The created model is used to predict the stress-stimulated change in the callus density. The permanent and intermittent loading programs are considered. The analyses indicate that obtaining a sufficiently high values of the callus density (and hence the elasticity) modulus is only possible using time-varying load parameters. The model predictions also show that intermittent loading program causes delayed callus healing. Understanding how mechanical conditions influence callus remodelling process may be relevant in the bone fracture treatment and initial bone loading during rehabilitation.

Revealing an outward-facing open conformational state in a CLC Cl–/H+ exchange transporter

PubMed Central

Khantwal, Chandra M; Abraham, Sherwin J; Han, Wei; Jiang, Tao; Chavan, Tanmay S; Cheng, Ricky C; Elvington, Shelley M; Liu, Corey W; Mathews, Irimpan I; Stein, Richard A; Mchaourab, Hassane S; Tajkhorshid, Emad; Maduke, Merritt

2016-01-01

CLC secondary active transporters exchange Cl- for H+. Crystal structures have suggested that the conformational change from occluded to outward-facing states is unusually simple, involving only the rotation of a conserved glutamate (Gluex) upon its protonation. Using 19F NMR, we show that as [H+] is increased to protonate Gluex and enrich the outward-facing state, a residue ~20 Å away from Gluex, near the subunit interface, moves from buried to solvent-exposed. Consistent with functional relevance of this motion, constriction via inter-subunit cross-linking reduces transport. Molecular dynamics simulations indicate that the cross-link dampens extracellular gate-opening motions. In support of this model, mutations that decrease steric contact between Helix N (part of the extracellular gate) and Helix P (at the subunit interface) remove the inhibitory effect of the cross-link. Together, these results demonstrate the formation of a previously uncharacterized 'outward-facing open' state, and highlight the relevance of global structural changes in CLC function. DOI: http://dx.doi.org/10.7554/eLife.11189.001 PMID:26799336

Disorders of Bone Remodeling

PubMed Central

Feng, Xu; McDonald, Jay M.

2013-01-01

The skeleton provides mechanical support for stature and locomotion, protects vital organs, and controls mineral homeostasis. A healthy skeleton must be maintained by constant bone modeling to carry out these crucial functions throughout life. Bone remodeling involves the removal of old or damaged bone by osteoclasts (bone resorption) and the subsequent replacement of new bone formed by osteoblasts (bone formation). Normal bone remodeling requires a tight coupling of bone resorption to bone formation to guarantee no alteration in bone mass or quality after each remodeling cycle. However, this important physiological process can be derailed by a variety of factors, including menopause-associated hormonal changes, age-related factors, changes in physical activity, drugs, and secondary diseases, which lead to the development of various bone disorders in both women and men. We review the major diseases of bone remodeling, emphasizing our current understanding of the underlying pathophysiological mechanisms. PMID:20936937

Dynamics of Lung Defense in Pneumonia: Resistance, Resilience, and Remodeling

PubMed Central

Quinton, Lee J.; Mizgerd, Joseph P.

2015-01-01

Pneumonia is initiated by microbes in the lung, but physiological processes integrating responses across diverse cell types and organ systems dictate the outcome of respiratory infection. Resistance, or actions of the host to eradicate living microbes, in the lungs involves a combination of innate and adaptive immune responses triggered by air-space infection. Resilience, or the ability of the host tissues to withstand the physiologically damaging effects of microbial and immune activities, is equally complex, precisely regulated, and determinative. Both immune resistance and tissue resilience are dynamic and change throughout the lifetime, but we are only beginning to understand such remodeling and how it contributes to the incidence of severe pneumonias, which diminishes as childhood progresses and then increases again among the elderly. Here, we review the concepts of resistance, resilience, and remodeling as they apply to pneumonia, highlighting recent advances and current significant knowledge gaps. PMID:25148693

Growth and Remodeling in Blood Vessels Studied In Vivo With Fractal Analysis

NASA Technical Reports Server (NTRS)

Parsons-Wingerter, Patricia A.

2003-01-01

Every cell in the human body must reside in close proximity to a blood vessel (within approximately 200 mm) because blood vessels provide the oxygen, metabolite, and fluid exchanges required for cellular existence. The growth and remodeling of blood vessels are required to support the normal physiology of embryonic development, reproductive biology, wound healing and adaptive remodeling to exercise, as well as abnormal tissue change in diseases such as cancer, diabetes, and coronary heart disease. Cardiovascular and hemodynamic (blood flow dynamics) alterations experienced by astronauts during long-term spaceflight, including orthostatic intolerance, fluid shifts in the body, and reduced numbers of red (erythrocyte) and white (immune) blood cells, are identified as risk factors of very high priority in the NASA task force report on risk reduction for human spaceflight, the "Critical Path Roadmap."

An Evaluation of Dropouts from Outward Bound Programs for the Unemployed

ERIC Educational Resources Information Center

Maxwell, Robert; Perry, Martin; Martin, Andrew John

2008-01-01

Outward Bound New Zealand provides 21-day residential motivational intervention courses (Catalyst courses) to long-term unemployed clients approved by the Ministry of Social Development. During the period 2002/03, 20% of participants starting the course dropped out before course completion; which was double the contracted acceptable level set by…

The Cooperstown Outward Bound Summer Program: An Informal Look at the Program's Impact on the Lives of Students.

ERIC Educational Resources Information Center

Sakofs, Mitchell S.; And Others

During the summer of 1987, 29 students from the Cooperstown High School in New York received scholarships and participated in an Outward Bound course. This report presents the results of a study assessing the impact of the Outward Bound experience on these students. Data gathering instruments included: the Self Report Survey (SRS), developed by…

The turbulent generation of outward traveling Alfvenic fluctuations in the solar wind

NASA Technical Reports Server (NTRS)

Matthaeus, W. H.; Goldstein, M. L.; Montgomery, D. C.

1983-01-01

From an analysis of the incompressible MHD equations, it is concluded that the frequent observation of outward propagating Alfvenic fluctuations in the solar wind can arise from early stages of in situ turbulent evolution, and need not reflect coronal processes.

Outwardly Propagating Flames at Elevated Pressures

NASA Technical Reports Server (NTRS)

Law, C. K.; Rozenchan, G.; Tse, S. D.; Zhu, D. L.

2001-01-01

Spherical, outwardly-propagating flames of CH4-O2-inert and H2-O2-inert mixtures were experimentally studied in a high pressure apparatus. Stretch-free flame speeds and Markstein lengths were extracted for a wide range of pressures and equivalence ratios for spherically-symmetric, smooth flamefronts and compared to numerical computations with detailed chemistry and transport, as well as existing data in the literature. Wrinkle development was examined for propagating flames that were unstable under our experimental conditions. Hydrodynamic cells developed for most H2-air and CH4-air flames at elevated pressures, while thermal-diffusive instabilities were also observed for lean and near-stoichiometric hydrogen flames at pressures above atmospheric. Strategies in suppressing or delaying the onset of cell formation have been assessed. Buoyancy effects affected sufficiently off-stoichiometric CH4 mixtures at high pressures.

Revealing an outward-facing open conformational state in a CLC Cl –/H + exchange transporter

DOE PAGES

Khantwal, Chandra M.; Abraham, Sherwin J.; Han, Wei; ...

2016-01-22

CLC secondary active transporters exchange Cl - for H + . Crystal structures have suggested that the conformational change from occluded to outward-facing states is unusually simple, involving only the rotation of a conserved glutamate (Glu ex ) upon its protonation. Using 19 F NMR, we show that as [H + ] is increased to protonate Glu ex and enrich the outward-facing state, a residue ~20 Å away from Glu ex , near the subunit interface, moves from buried to solvent-exposed. Consistent with functional relevance of this motion, constriction via inter-subunit cross-linking reduces transport. Molecular dynamics simulations indicate that themore » cross-link dampens extracellular gate-opening motions. In support of this model, mutations that decrease steric contact between Helix N (part of the extracellular gate) and Helix P (at the subunit interface) remove the inhibitory effect of the cross-link. Together, these results demonstrate the formation of a previously uncharacterized 'outward-facing open' state, and highlight the relevance of global structural changes in CLC function.« less

Modeling Slab-Slab Interactions: Dynamics of Outward Dipping Double-Sided Subduction Systems

NASA Astrophysics Data System (ADS)

Király, Ágnes; Holt, Adam F.; Funiciello, Francesca; Faccenna, Claudio; Capitanio, Fabio A.

2018-03-01

Slab-slab interaction is a characteristic feature of tectonically complex areas. Outward dipping double-sided subduction is one of these complex cases, which has several examples on Earth, most notably the Molucca Sea and Adriatic Sea. This study focuses on developing a framework for linking plate kinematics and slab interactions in an outward dipping subduction geometry. We used analog and numerical models to better understand the underlying subduction dynamics. Compared to a single subduction model, double-sided subduction exhibits more time-dependent and vigorous toroidal flow cells that are elongated (i.e., not circular). Because both the Molucca and Adriatic Sea exhibit an asymmetric subduction configuration, we also examine the role that asymmetry plays in the dynamics of outward dipping double-sided subduction. We introduce asymmetry in two ways; with variable initial depths for the two slabs ("geometric" asymmetry), and with variable buoyancy within the subducting plate ("mechanical" asymmetry). Relative to the symmetric case, we probe how asymmetry affects the overall slab kinematics, whether asymmetric behavior intensifies or equilibrates as subduction proceeds. While initial geometric asymmetry disappears once the slabs are anchored to the 660 km discontinuity, the mechanical asymmetry can cause more permanent differences between the two subduction zones. In the most extreme case, the partly continental slab stops subducting due to the unequal slab pull force. The results show that the slab-slab interaction is most effective when the two trenches are closer than 10-8 cm in the laboratory, which is 600-480 km when scaled to the Earth.

Left ventricular remodeling and hypertrophy in patients with aortic stenosis: insights from cardiovascular magnetic resonance

PubMed Central

2012-01-01

Background Cardiovascular magnetic resonance (CMR) is the gold standard non-invasive method for determining left ventricular (LV) mass and volume but has not been used previously to characterise the LV remodeling response in aortic stenosis. We sought to investigate the degree and patterns of hypertrophy in aortic stenosis using CMR. Methods Patients with moderate or severe aortic stenosis, normal coronary arteries and no other significant valve lesions or cardiomyopathy were scanned by CMR with valve severity assessed by planimetry and velocity mapping. The extent and patterns of hypertrophy were investigated using measurements of the LV mass index, indexed LV volumes and the LV mass/volume ratio. Asymmetric forms of remodeling and hypertrophy were defined by a regional wall thickening ≥13 mm and >1.5-fold the thickness of the opposing myocardial segment. Results Ninety-one patients (61±21 years; 57 male) with aortic stenosis (aortic valve area 0.93±0.32cm2) were recruited. The severity of aortic stenosis was unrelated to the degree (r2=0.012, P=0.43) and pattern (P=0.22) of hypertrophy. By univariate analysis, only male sex demonstrated an association with LV mass index (P=0.02). Six patterns of LV adaption were observed: normal ventricular geometry (n=11), concentric remodeling (n=11), asymmetric remodeling (n=11), concentric hypertrophy (n=34), asymmetric hypertrophy (n=14) and LV decompensation (n=10). Asymmetric patterns displayed considerable overlap in appearances (wall thickness 17±2mm) with hypertrophic cardiomyopathy. Conclusions We have demonstrated that in patients with moderate and severe aortic stenosis, the pattern of LV adaption and degree of hypertrophy do not closely correlate with the severity of valve narrowing and that asymmetric patterns of wall thickening are common. Trial registration ClinicalTrials.gov Reference Number: NCT00930735 PMID:22839417

X-ray structures of LeuT in substrate-free outward-open and apo inward-open states

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

Krishnamurthy, Harini; Gouaux, Eric

2012-08-09

Neurotransmitter sodium symporters are integral membrane proteins that remove chemical transmitters from the synapse and terminate neurotransmission mediated by serotonin, dopamine, noradrenaline, glycine and GABA ({gamma}-aminobutyric acid). Crystal structures of the bacterial homologue, LeuT, in substrate-bound outward-occluded and competitive inhibitor-bound outward-facing states have advanced our mechanistic understanding of neurotransmitter sodium symporters but have left fundamental questions unanswered. Here we report crystal structures of LeuT mutants in complexes with conformation-specific antibody fragments in the outward-open and inward-open states. In the absence of substrate but in the presence of sodium the transporter is outward-open, illustrating how the binding of substrate closes themore » extracellular gate through local conformational changes: hinge-bending movements of the extracellular halves of transmembrane domains 1, 2 and 6, together with translation of extracellular loop 4. The inward-open conformation, by contrast, involves large-scale conformational changes, including a reorientation of transmembrane domains 1, 2, 5, 6 and 7, a marked hinge bending of transmembrane domain 1a and occlusion of the extracellular vestibule by extracellular loop 4. These changes close the extracellular gate, open an intracellular vestibule, and largely disrupt the two sodium sites, thus providing a mechanism by which ions and substrate are released to the cytoplasm. The new structures establish a structural framework for the mechanism of neurotransmitter sodium symporters and their modulation by therapeutic and illicit substances.« less

Orthogonal decomposition of left ventricular remodeling in myocardial infarction.

PubMed

Zhang, Xingyu; Medrano-Gracia, Pau; Ambale-Venkatesh, Bharath; Bluemke, David A; Cowan, Brett R; Finn, J Paul; Kadish, Alan H; Lee, Daniel C; Lima, Joao A C; Young, Alistair A; Suinesiaputra, Avan

2017-03-01

Left ventricular size and shape are important for quantifying cardiac remodeling in response to cardiovascular disease. Geometric remodeling indices have been shown to have prognostic value in predicting adverse events in the clinical literature, but these often describe interrelated shape changes. We developed a novel method for deriving orthogonal remodeling components directly from any (moderately independent) set of clinical remodeling indices. Six clinical remodeling indices (end-diastolic volume index, sphericity, relative wall thickness, ejection fraction, apical conicity, and longitudinal shortening) were evaluated using cardiac magnetic resonance images of 300 patients with myocardial infarction, and 1991 asymptomatic subjects, obtained from the Cardiac Atlas Project. Partial least squares (PLS) regression of left ventricular shape models resulted in remodeling components that were optimally associated with each remodeling index. A Gram-Schmidt orthogonalization process, by which remodeling components were successively removed from the shape space in the order of shape variance explained, resulted in a set of orthonormal remodeling components. Remodeling scores could then be calculated that quantify the amount of each remodeling component present in each case. A one-factor PLS regression led to more decoupling between scores from the different remodeling components across the entire cohort, and zero correlation between clinical indices and subsequent scores. The PLS orthogonal remodeling components had similar power to describe differences between myocardial infarction patients and asymptomatic subjects as principal component analysis, but were better associated with well-understood clinical indices of cardiac remodeling. The data and analyses are available from www.cardiacatlas.org. © The Author 2017. Published by Oxford University Press.

Orthogonal decomposition of left ventricular remodeling in myocardial infarction

PubMed Central

Zhang, Xingyu; Medrano-Gracia, Pau; Ambale-Venkatesh, Bharath; Bluemke, David A.; Cowan, Brett R; Finn, J. Paul; Kadish, Alan H.; Lee, Daniel C.; Lima, Joao A. C.; Young, Alistair A.; Suinesiaputra, Avan

2017-01-01

Abstract Left ventricular size and shape are important for quantifying cardiac remodeling in response to cardiovascular disease. Geometric remodeling indices have been shown to have prognostic value in predicting adverse events in the clinical literature, but these often describe interrelated shape changes. We developed a novel method for deriving orthogonal remodeling components directly from any (moderately independent) set of clinical remodeling indices. Results: Six clinical remodeling indices (end-diastolic volume index, sphericity, relative wall thickness, ejection fraction, apical conicity, and longitudinal shortening) were evaluated using cardiac magnetic resonance images of 300 patients with myocardial infarction, and 1991 asymptomatic subjects, obtained from the Cardiac Atlas Project. Partial least squares (PLS) regression of left ventricular shape models resulted in remodeling components that were optimally associated with each remodeling index. A Gram–Schmidt orthogonalization process, by which remodeling components were successively removed from the shape space in the order of shape variance explained, resulted in a set of orthonormal remodeling components. Remodeling scores could then be calculated that quantify the amount of each remodeling component present in each case. A one-factor PLS regression led to more decoupling between scores from the different remodeling components across the entire cohort, and zero correlation between clinical indices and subsequent scores. Conclusions: The PLS orthogonal remodeling components had similar power to describe differences between myocardial infarction patients and asymptomatic subjects as principal component analysis, but were better associated with well-understood clinical indices of cardiac remodeling. The data and analyses are available from www.cardiacatlas.org. PMID:28327972

OUTWARD MOTION OF POROUS DUST AGGREGATES BY STELLAR RADIATION PRESSURE IN PROTOPLANETARY DISKS

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

Tazaki, Ryo; Nomura, Hideko, E-mail: rtazaki@kusastro.kyoto-u.ac.jp

2015-02-01

We study the dust motion at the surface layer of protoplanetary disks. Dust grains in the surface layer migrate outward owing to angular momentum transport via gas-drag force induced by the stellar radiation pressure. In this study we calculate the mass flux of the outward motion of compact grains and porous dust aggregates by the radiation pressure. The radiation pressure force for porous dust aggregates is calculated using the T-Matrix Method for the Clusters of Spheres. First, we confirm that porous dust aggregates are forced by strong radiation pressure even if they grow to be larger aggregates, in contrast tomore » homogeneous and spherical compact grains, for which radiation pressure efficiency becomes lower when their sizes increase. In addition, we find that the outward mass flux of porous dust aggregates with monomer size of 0.1 μm is larger than that of compact grains by an order of magnitude at the disk radius of 1 AU, when their sizes are several microns. This implies that large compact grains like calcium-aluminum-rich inclusions are hardly transported to the outer region by stellar radiation pressure, whereas porous dust aggregates like chondritic-porous interplanetary dust particles are efficiently transported to the comet formation region. Crystalline silicates are possibly transported in porous dust aggregates by stellar radiation pressure from the inner hot region to the outer cold cometary region in the protosolar nebula.« less

Behavioural and cognitive-behavioural interventions for outwardly-directed aggressive behaviour in people with intellectual disabilities.

PubMed

Ali, Afia; Hall, Ian; Blickwedel, Jessica; Hassiotis, Angela

2015-04-07

Outwardly-directed aggressive behaviour is a significant part of problem behaviours presented by people with intellectual disabilities. Prevalence rates of up to 50% have been reported in the literature, depending on the population sampled. Such behaviours often run a long-term course and are a major cause of social exclusion. This is an update of a previously published systematic review (see Hassiotis 2004; Hassiotis 2008). To evaluate the efficacy of behavioural and cognitive-behavioural interventions on outwardly-directed aggressive behaviour in people with intellectual disabilities when compared to standard intervention or wait-list controls. In April 2014 we searched CENTRAL, Ovid MEDLINE, Embase, and eight other databases. We also searched two trials registers, checked reference lists, and handsearched relevant journals to identify any additional trials. We included studies if more than four participants (children or adults) were allocated by random or quasi-random methods to either intervention, standard treatment, or wait-list control groups. Two review authors independently identified studies and extracted and assessed the quality of the data. We deemed six studies (309 participants), based on adult populations with intellectual disabilities, suitable for inclusion in the current version of this review. These studies examined a range of cognitive-behavioural therapy (CBT) approaches: anger management (three studies (n = 235); one individual therapy and two group-based); relaxation (one study; n = 12), mindfulness based on meditation (one study; n = 34), problem solving and assertiveness training (one study; n = 28). We were unable to include any studies using behavioural interventions. There were no studies of children.Only one study reported moderate quality of evidence for outcomes of interest as assessed by the Grades of Recommendations, Assessment, Development and Evaluation (GRADE) approach. We judged the evidence for the remaining studies to be of

To Remodel or To Build?

ERIC Educational Resources Information Center

Rosenblum, Todd

2009-01-01

The question of remodeling an existing house to make it wheelchair accessible or building a new barrier-free house is a difficult decision. This article presents some initial questions and considerations followed by a list of pros and cons for remodeling an existing house vs. building a new house.

Distinct right ventricle remodeling in response to pressure overload in the rat.

PubMed

Mendes-Ferreira, P; Santos-Ribeiro, D; Adão, R; Maia-Rocha, C; Mendes-Ferreira, M; Sousa-Mendes, C; Leite-Moreira, A F; Brás-Silva, C

2016-07-01

Pulmonary arterial hypertension (PAH), the most serious chronic disorder of the pulmonary circulation, is characterized by pulmonary vasoconstriction and remodeling, resulting in increased afterload on the right ventricle (RV). In fact, RV function is the main determinant of prognosis in PAH. The most frequently used experimental models of PAH include monocrotaline- and chronic hypoxia-induced PAH, which primarily affect the pulmonary circulation. Alternatively, pulmonary artery banding (PAB) can be performed to achieve RV overload without affecting the pulmonary vasculature, allowing researchers to determine the RV-specific effects of their drugs/interventions. In this work, using two different degrees of pulmonary artery constriction, we characterize, in full detail, PAB-induced adaptive and maladaptive remodeling of the RV at 3 wk after PAB surgery. Our results show that application of a mild constriction resulted in adaptive hypertrophy of the RV, with preserved systolic and diastolic function, while application of a severe constriction resulted in maladaptive hypertrophy, with chamber dilation and systolic and diastolic dysfunction up to the isolated cardiomyocyte level. By applying two different degrees of constriction, we describe, for the first time, a reliable and short-duration PAB model in which RV adaptation can be distinguished at 3 wk after surgery. We characterize, in full detail, structural and functional changes of the RV in its response to moderate and severe constriction, allowing researchers to better study RV physiology and transition to dysfunction and failure, as well as to determine the effects of new therapies. Copyright © 2016 the American Physiological Society.

Outward Foreign Direct Investment and Human Capital Development: A Small Country Perspective

ERIC Educational Resources Information Center

McDonnell, Anthony

2008-01-01

Purpose: The purpose of this paper is to examine the pattern of outward foreign direct investment (FDI) by Irish MNCs, and more specifically, to investigate their approach to human capital development and how these correspond to foreign MNCs in Ireland. In particular, it seeks to investigate training and development expenditure, adoption of…

Epigenomic regulation of oncogenesis by chromatin remodeling.

PubMed

Kumar, R; Li, D-Q; Müller, S; Knapp, S

2016-08-25

Disruption of the intricate gene expression program represents one of major driving factors for the development, progression and maintenance of human cancer, and is often associated with acquired therapeutic resistance. At the molecular level, cancerous phenotypes are the outcome of cellular functions of critical genes, regulatory interactions of histones and chromatin remodeling complexes in response to dynamic and persistent upstream signals. A large body of genetic and biochemical evidence suggests that the chromatin remodelers integrate the extracellular and cytoplasmic signals to control gene activity. Consequently, widespread dysregulation of chromatin remodelers and the resulting inappropriate expression of regulatory genes, together, lead to oncogenesis. We summarize the recent developments and current state of the dysregulation of the chromatin remodeling components as the driving mechanism underlying the growth and progression of human tumors. Because chromatin remodelers, modifying enzymes and protein-protein interactions participate in interpreting the epigenetic code, selective chromatin remodelers and bromodomains have emerged as new frontiers for pharmacological intervention to develop future anti-cancer strategies to be used either as single-agent or in combination therapies with chemotherapeutics or radiotherapy.

Housing Adaptability Guidelines: A Concept to Make All Housing Accessible.

ERIC Educational Resources Information Center

Peoples Housing, Inc., Topanga, CA.

Specifications for making adaptable dwelling units, minimally accessible designs which can later be inexpensively remodeled for the disabled, are presented. Advantages to providing many adaptable units rather than a few accessible ones are outlined, including eliminating the marketing problem, providing a disabled person with a wider choice of…

Cholinergically-induced changes in outward currents in hair cells isolated from the semicircular canal of the frog.

PubMed

Housley, G D; Norris, C H; Guth, P S

1990-01-01

Two cholinergically-induced modulations of membrane conductances have been identified in hair cells isolated from the crista ampullaris of the leopard frog (Rana pipiens), using the whole cell recording configuration of the patch clamp technique. Of 56 crista hair cells tested, 28 showed drug-induced changes in membrane current or membrane potential which were repeatable and could be reversed with washout of drug. The predominant effect (observed in 20 hair cells) of acetylcholine (Ach, 100 microM) to 1mM) or carbachol (1 microM to 50 microM) applied to these hair cells was the reduction of an outward current corresponding to a change in conductance of approximately -0.22 nS. This action by Ach on hair cells has been inferred from previous studies of afferent fiber discharge which reported an increase in firing rate with stimulation of efferent fibers or exogenous application of cholinomimetics (Bernard et al., 1985; Valli et al., 1986; Guth et al., 1986; Norris et al., 1988a). The Ach-induced reduction in outward current was associated with a depolarization of the zero-current membrane potential by approximately +2.5 mV. In a total of 8 hair cells, an Ach-induced reversible increase in outward current was recorded. Changes in conductance were approximately +0.13 nS and were associated with a hyperpolarization of the zero-current membrane potential by approximately -2.2 mV. This current increase is likely to be responsible for the inhibitory post-synaptic potentials (IPSPs) which have previously been recorded intracellularly from acoustico-lateralis hair cells during stimulation of the efferent innervation (Flock and Russell, 1976; Ashmore and Russell, 1982; Art et al., 1984, 1985). Of the remaining 28 hair cells, six cells failed to exhibit any change in membrane conductance or membrane potential in the presence of cholinomimetics while an additional 15 cells exhibited decreases, and 7 cells exhibited increases in outward conductance, during application of Ach or

An Analysis of the Impact of Outward Bound on Twelve High Schools.

ERIC Educational Resources Information Center

Schulze, Joseph R.

Describing and analyzing the impact of Outward Bound (OB) programs on 12 high schools which reflect OB involvement varying from 1 to 5 years and include urban, suburban, and rural (public, private, boarding, and day) schools, this 1970-71 report is aimed at furthering OB philosophy and method. The report presents OB program: background; evaluation…

Classical confinement and outward convection of impurity ions in the MST RFP

NASA Astrophysics Data System (ADS)

Kumar, S. T. A.; Den Hartog, D. J.; Mirnov, V. V.; Caspary, K. J.; Magee, R. M.; Brower, D. L.; Chapman, B. E.; Craig, D.; Ding, W. X.; Eilerman, S.; Fiksel, G.; Lin, L.; Nornberg, M.; Parke, E.; Reusch, J. A.; Sarff, J. S.

2012-05-01

Impurity ion dynamics measured with simultaneously high spatial and temporal resolution reveal classical ion transport in the reversed-field pinch. The boron, carbon, oxygen, and aluminum impurity ion density profiles are obtained in the Madison Symmetric Torus [R. N. Dexter et al., Fusion Technol. 19, 131 (1991)] using a fast, active charge-exchange-recombination-spectroscopy diagnostic. Measurements are made during improved-confinement plasmas obtained using inductive control of tearing instability to mitigate stochastic transport. At the onset of the transition to improved confinement, the impurity ion density profile becomes hollow, with a slow decay in the core region concurrent with an increase in the outer region, implying an outward convection of impurities. Impurity transport from Coulomb collisions in the reversed-field pinch is classical for all collisionality regimes, and analysis shows that the observed hollow profile and outward convection can be explained by the classical temperature screening mechanism. The profile agrees well with classical expectations. Experiments performed with impurity pellet injection provide further evidence for classical impurity ion confinement.

Differentiation potentials of perivascular cells in the bone tissue remodeling zones under microgravity

NASA Astrophysics Data System (ADS)

Rodionova, Natalia; Katkova, Olena

Adaptive remodeling processes in the skeleton bones occur in the close topographical interconnection with blood capillaries followed by perivascular cells. Radioautographic studies with 3H- thymidine (Kimmel D.B., Fee W.S., 1980; Rodionova N.V., 1989, 2006) has shown that in osteogenesis zones there is sequential differentiation process of the perivascular cells into osteogenic ones. Using electron microscopy and cytochemistry we studied perivsacular cells in metaphysis of the rats femoral bones under conditions of modeling microgravity (28 days duration) and in femoral bones metaphyses of rats flown on board of the space laboratory (Spacelab - 2) It was revealed that population of the perivascular cells is not homogeneous in adaptive zones of the remodeling in both control and test groups (lowering support loading). This population comprises adjacent to endothelium little differentiated forms and isolated cells with differentiation features (specific volume of rough endoplasmic reticulum in cytoplasm is increased). Majority of the perivascular cells in the control group reveals reaction to alkaline phosphatase (marker of the osteogenic differentiation). In little differentiated cells this reaction is registered in nucleolus, nucleous and cytoplasm. In differentiating cells activity of the alkaline phosphatase is also detected on the outer surface of the cellular membrane. Unlike the control group in the bones of animals under microgravitaty reaction to the alkaline phosphatase is registered not for all cells of perivascular population. Part of the differentiating perivascular cells does not contain a product of the reaction. There is also visible trend of individual alkaline phosphatase containing perivascular cells amounts decrease (i.e. osteogenic cells-precursors). Under microgravity some little differentiated perivascular cells reveal destruction signs. Found decrease trend of the alkaline phosphatase containing cells (i.e. osteogenic cells) number in

A multi-block adaptive solving technique based on lattice Boltzmann method

NASA Astrophysics Data System (ADS)

Zhang, Yang; Xie, Jiahua; Li, Xiaoyue; Ma, Zhenghai; Zou, Jianfeng; Zheng, Yao

2018-05-01

In this paper, a CFD parallel adaptive algorithm is self-developed by combining the multi-block Lattice Boltzmann Method (LBM) with Adaptive Mesh Refinement (AMR). The mesh refinement criterion of this algorithm is based on the density, velocity and vortices of the flow field. The refined grid boundary is obtained by extending outward half a ghost cell from the coarse grid boundary, which makes the adaptive mesh more compact and the boundary treatment more convenient. Two numerical examples of the backward step flow separation and the unsteady flow around circular cylinder demonstrate the vortex structure of the cold flow field accurately and specifically.

Severity of structural and functional right ventricular remodeling depends on training load in an experimental model of endurance exercise.

PubMed

Sanz-de la Garza, Maria; Rubies, Cira; Batlle, Montserrat; Bijnens, Bart H; Mont, Lluis; Sitges, Marta; Guasch, Eduard

2017-09-01

Arrhythmogenic right ventricular (RV) remodeling has been reported in response to regular training, but it remains unclear how exercise intensity affects the presence and extent of such remodeling. We aimed to assess the relationship between RV remodeling and exercise load in a long-term endurance training model. Wistar rats were conditioned to run at moderate (MOD; 45 min, 30 cm/s) or intense (INT; 60 min, 60 cm/s) workloads for 16 wk; sedentary rats served as controls. Cardiac remodeling was assessed with standard echocardiographic and tissue Doppler techniques, sensor-tip pressure catheters, and pressure-volume loop analyses. After MOD training, both ventricles similarly dilated (~16%); the RV apical segment deformation, but not the basal segment deformation, was increased [apical strain rate (SR): -2.9 ± 0.5 vs. -3.3 ± 0.6 s -1 , SED vs. MOD]. INT training prompted marked RV dilatation (~26%) but did not further dilate the left ventricle (LV). A reduction in both RV segments' deformation in INT rats (apical SR: -3.3 ± 0.6 vs. -3.0 ± 0.4 s -1 and basal SR: -3.3 ± 0.7 vs. -2.7 ± 0.6 s -1 , MOD vs. INT) led to decreased global contractile function (maximal rate of rise of LV pressure: 2.53 ± 0.15 vs. 2.17 ± 0.116 mmHg/ms, MOD vs. INT). Echocardiography and hemodynamics consistently pointed to impaired RV diastolic function in INT rats. LV systolic and diastolic functions remained unchanged in all groups. In conclusion, we showed a biphasic, unbalanced RV remodeling response with increasing doses of exercise: physiological adaptation after MOD training turns adverse with INT training, involving disproportionate RV dilatation, decreased contractility, and impaired diastolic function. Our findings support the existence of an exercise load threshold beyond which cardiac remodeling becomes maladaptive. NEW & NOTEWORTHY Exercise promotes left ventricular eccentric hypertrophy with no changes in systolic or diastolic function in healthy rats. Conversely, right

The skeleton in the closet: actin cytoskeletal remodeling in β-cell function.

PubMed

Arous, Caroline; Halban, Philippe A

2015-10-01

Over the last few decades, biomedical research has considered not only the function of single cells but also the importance of the physical environment within a whole tissue, including cell-cell and cell-extracellular matrix interactions. Cytoskeleton organization and focal adhesions are crucial sensors for cells that enable them to rapidly communicate with the physical extracellular environment in response to extracellular stimuli, ensuring proper function and adaptation. The involvement of the microtubular-microfilamentous cytoskeleton in secretion mechanisms was proposed almost 50 years ago, since when the evolution of ever more sensitive and sophisticated methods in microscopy and in cell and molecular biology have led us to become aware of the importance of cytoskeleton remodeling for cell shape regulation and its crucial link with signaling pathways leading to β-cell function. Emerging evidence suggests that dysfunction of cytoskeletal components or extracellular matrix modification influences a number of disorders through potential actin cytoskeleton disruption that could be involved in the initiation of multiple cellular functions. Perturbation of β-cell actin cytoskeleton remodeling could arise secondarily to islet inflammation and fibrosis, possibly accounting in part for impaired β-cell function in type 2 diabetes. This review focuses on the role of actin remodeling in insulin secretion mechanisms and its close relationship with focal adhesions and myosin II. Copyright © 2015 the American Physiological Society.

Low-affinity spermine block mediating outward currents through Kir2.1 and Kir2.2 inward rectifier potassium channels

PubMed Central

Ishihara, Keiko; Yan, Ding-Hong

2007-01-01

The outward component of the strong inward rectifier K+ current (IKir) plays a pivotal role in polarizing the membranes of excitable and non-excitable cells and is regulated by voltage-dependent channel block by internal cations. Using the Kir2.1 channel, we previously showed that a small fraction of the conductance susceptible only to a low-affinity mode of block likely carries a large portion of the outward current. To further examine the relevance of the low-affinity block to outward IKir and to explore its molecular mechanism, we studied the block of the Kir2.1 and Kir2.2 channels by spermine, which is the principal Kir2 channel blocker. Current–voltage relations of outward Kir2.2 currents showed a peak, a plateau and two peaks in the presence of 10, 1 and 0.1 μm spermine, respectively, which was explained by the presence of two conductances that differ in their susceptibility to spermine block. When the current–voltage relations showed one peak, like those of native IKir, outward Kir2.2 currents were mediated mostly by the conductance susceptible to the low-affinity block. They also flowed in a narrower range than the corresponding Kir2.1 currents, because of 3- to 4-fold greater susceptibility to the low-affinity block than in Kir2.1. Reducing external [K+] shifted the voltage dependences of both the high- and low-affinity block of Kir2.1 in parallel with the shift in the reversal potential, confirming the importance of the low-affinity block in mediating outward IKir. When Kir2.1 mutants known to have reduced sensitivity to internal blockers were examined, the D172N mutation in the transmembrane pore region made almost all of the conductance susceptible only to low-affinity block, while the E224G mutation in the cytoplasmic pore region reduced the sensitivity to low-affinity block without markedly altering that to the high-affinity block or the high/low conductance ratio. The effects of these mutations support the hypothesis that Kir2 channels exist in

Pulmonary arterial remodeling induced by a Th2 immune response

PubMed Central

Daley, Eleen; Emson, Claire; Guignabert, Christophe; de Waal Malefyt, Rene; Louten, Jennifer; Kurup, Viswanath P.; Hogaboam, Cory; Taraseviciene-Stewart, Laimute; Voelkel, Norbert F.; Rabinovitch, Marlene; Grunig, Ekkehard; Grunig, Gabriele

2008-01-01

Pulmonary arterial remodeling characterized by increased vascular smooth muscle density is a common lesion seen in pulmonary arterial hypertension (PAH), a deadly condition. Clinical correlation studies have suggested an immune pathogenesis of pulmonary arterial remodeling, but experimental proof has been lacking. We show that immunization and prolonged intermittent challenge via the airways with either of two different soluble antigens induced severe muscularization in small- to medium-sized pulmonary arteries. Depletion of CD4+ T cells, antigen-specific T helper type 2 (Th2) response, or the pathogenic Th2 cytokine interleukin 13 significantly ameliorated pulmonary arterial muscularization. The severity of pulmonary arterial muscularization was associated with increased numbers of epithelial cells and macrophages that expressed a smooth muscle cell mitogen, resistin-like molecule α, but surprisingly, there was no correlation with pulmonary hypertension. Our data are the first to provide experimental proof that the adaptive immune response to a soluble antigen is sufficient to cause severe pulmonary arterial muscularization, and support the clinical observations in pediatric patients and in companion animals that muscularization represents one of several injurious events to the pulmonary artery that may collectively contribute to PAH. PMID:18227220

Modification of a Volume-Overload Heart Failure Model to Track Myocardial Remodeling and Device-Related Reverse Remodeling

PubMed Central

Tuzun, Egemen; Bick, Roger; Kadipasaoglu, Cihan; Conger, Jeffrey L.; Poindexter, Brian J.; Gregoric, Igor D.; Frazier, O. H.; Towbin, Jeffrey A.; Radovancevic, Branislav

2011-01-01

Purpose. To provide an ovine model of ventricular remodeling and reverse remodeling by creating congestive heart failure (CHF) and then treating it by implanting a left ventricular assist device (LVAD). Methods. We induced volume-overload heart failure in 2 sheep; 20 weeks later, we implanted an LVAD and assessed recovery 11 weeks thereafter. We examined changes in histologic and hemodynamic data and levels of cellular markers of CHF. Results. After CHF induction, we found increases in LV end-diastolic pressure, LV systolic and diastolic dimensions, wall thickness, left atrial diameter, and atrial natriuretic protein (ANP) and endothelin-1 (ET-1) levels; β-adrenergic receptor (BAR) and dystrophin expression decreased markedly. Biopsies confirmed LV remodeling. After LVAD support, LV systolic and diastolic dimensions, wall thickness, and mass, and ANP and ET-1 levels decreased. Histopathologic and hemodynamic markers improved, and BAR and dystrophin expression normalized. Conclusions. We describe a successful sheep model for ventricular and reverse remodeling. PMID:22347659

Ecological genomics of adaptation and speciation in fungi.

PubMed

Leducq, Jean-Baptiste

2014-01-01

Fungi play a central role in both ecosystems and human societies. This is in part because they have adopted a large diversity of life history traits to conquer a wide variety of ecological niches. Here, I review recent fungal genomics studies that explored the molecular origins and the adaptive significance of this diversity. First, macro-ecological genomics studies revealed that fungal genomes were highly remodelled during their evolution. This remodelling, in terms of genome organization and size, occurred through the proliferation of non-coding elements, gene compaction, gene loss and the expansion of large families of adaptive genes. These features vary greatly among fungal clades, and are correlated with different life history traits such as multicellularity, pathogenicity, symbiosis, and sexual reproduction. Second, micro-ecological genomics studies, based on population genomics, experimental evolution and quantitative trait loci approaches, have allowed a deeper exploration of early evolutionary steps of the above adaptations. Fungi, and especially budding yeasts, were used intensively to characterize early mutations and chromosomal rearrangements that underlie the acquisition of new adaptive traits allowing them to conquer new ecological niches and potentially leading to speciation. By uncovering the ecological factors and genomic modifications that underline adaptation, these studies showed that Fungi are powerful models for ecological genomics (eco-genomics), and that this approach, so far mainly developed in a few model species, should be expanded to the whole kingdom.

Effects of nucleosome stability on remodeler-catalyzed repositioning

NASA Astrophysics Data System (ADS)

Morgan, Aaron M.; LeGresley, Sarah E.; Briggs, Koan; Al-Ani, Gada; Fischer, Christopher J.

2018-03-01

Chromatin remodelers are molecular motors that play essential roles in the regulation of nucleosome positioning and chromatin accessibility. These machines couple the energy obtained from the binding and hydrolysis of ATP to the mechanical work of manipulating chromatin structure through processes that are not completely understood. Here we present a quantitative analysis of nucleosome repositioning by the imitation switch (ISWI) chromatin remodeler and demonstrate that nucleosome stability significantly impacts the observed activity. We show how DNA damage induced changes in the affinity of DNA wrapping within the nucleosome can affect ISWI repositioning activity and demonstrate how assay-dependent limitations can bias studies of nucleosome repositioning. Together, these results also suggest that some of the diversity seen in chromatin remodeler activity can be attributed to the variations in the thermodynamics of interactions between the remodeler, the histones, and the DNA, rather than reflect inherent properties of the remodeler itself.

Control of bone remodelling by applied dynamic loads

NASA Technical Reports Server (NTRS)

Lanyon, L. E.; Rubin, C. T.

1984-01-01

The data showing the relationship between bone mass and peak strain magnitude prepared and submitted for publication. The data from experiments relating remodelling activity with static or dynamic loads were prepared and submitted for publication. Development of programs to relate the location of remodelling activity with he natural and artificial dynamic strain distributions continued. Experiments on the effect of different strain rates on the remodelling response continued.

Exploring Familial Relationship Growth and Negotiation: A Case Study of Outward Bound Family Courses

ERIC Educational Resources Information Center

Overholt, Jillisa R.

2013-01-01

This study explored the phenomenon of father-child relationship development within the context of an Outward Bound (OB) family course, an environment that may both disrupt the ordinary aspects of an established relationship, and provide activities to purposefully encourage relationship development through a variety of aspects inherent to the…

Valve sparing aortic replacement - root remodeling.

PubMed

Lausberg, Henning F; Schäfers, Hans-Joachim

2006-01-01

Aortic root remodeling restores aortic root geometry and improves valve competence. We have used this technique whenever aorto-ventricular diameter is preserved. The operative technique is detained in this presentation. As a result of our 10-year experience with root remodeling we propose this operation as a reproducible option for patients with dilatation of the aortic root.

Potassium channels cloned from neuroblastoma cells display slowly inactivating outward currents in Xenopus oocytes.

PubMed

Ito, Y; Yokoyama, S; Higashida, H

1992-05-22

Messenger RNAs (mRNAs) specific for NGK1 and NGK2 potassium channels were synthesized from complementary DNAs (cDNAs) that had been cloned from mouse neuroblastoma x rat glioma hybrid NG108-15 cells. Outward pottasium currents were evoked by 5 s depolarizing voltage commands in Xenopus oocytes injected with NGK1- or NGK2-specific mRNAs. The NGK1 or NGK2 currents showed different activation and inactivation kinetics, and different pharmacological sensitivities. The threshold potential for activation of the NGK2 current (-14 mV) was more positive than that for the NGK1 (-36 mV). The NGK2 current showed faster inactivation during a 5 s depolarizing pulse than did the NGK1 current. Inactivation was best fit by time constants of 0.37, 1.5 and 19 s for the NGK2 current and 4.4 and 19 s for NGK1. Extracellularly applied tetraethylammonium chloride (TEA) was 1000 times more potent on the NGK2 current than the NGK1 current. Furthermore we examined outward current following co-injection of an equal amount of mRNAs for NGK1 and NGK2. The timecourse of inactivation differed from either alone or from a simple sum of the two individual currents. TEA sensitivity could not be explained by summation of the two homomultimeric channels. These findings suggest that both NGK1 and NGK2 proteins assemble to form heteromultimeric K+ channels in addition to homomultimeric K+ channels. NGK2 channels and the heteromultimeric channels may be responsible for the native transient outward current with slow inactivation in NG108-15 hybrid cells.

Vascular remodeling: A redox-modulated mechanism of vessel caliber regulation.

PubMed

Tanaka, Leonardo Y; Laurindo, Francisco R M

2017-08-01

Vascular remodeling, i.e. whole-vessel structural reshaping, determines lumen caliber in (patho)physiology. Here we review mechanisms underlying vessel remodeling, with emphasis in redox regulation. First, we discuss confusing terminology and focus on strictu sensu remodeling. Second, we propose a mechanobiological remodeling paradigm based on the concept of tensional homeostasis as a setpoint regulator. We first focus on shear-mediated models as prototypes of remodeling closely dominated by highly redox-sensitive endothelial function. More detailed discussions focus on mechanosensors, integrins, extracellular matrix, cytoskeleton and inflammatory pathways as potential of mechanisms potentially coupling tensional homeostasis to redox regulation. Further discussion of remodeling associated with atherosclerosis and injury repair highlights important aspects of redox vascular responses. While neointima formation has not shown consistent responsiveness to antioxidants, vessel remodeling has been more clearly responsive, indicating that despite the multilevel redox signaling pathways, there is a coordinated response of the whole vessel. Among mechanisms that may orchestrate redox pathways, we discuss roles of superoxide dismutase activity and extracellular protein disulfide isomerase. We then discuss redox modulation of aneurysms, a special case of expansive remodeling. We propose that the redox modulation of vascular remodeling may reflect (1) remodeling pathophysiology is dominated by a particularly redox-sensitive cell type, e.g., endothelial cells (2) redox pathways are temporospatially coordinated at an organ level across distinct cellular and acellular structures or (3) the tensional homeostasis setpoint is closely connected to redox signaling. The mechanobiological/redox model discussed here can be a basis for improved understanding of remodeling and helps clarifying mechanisms underlying prevalent hard-to-treat diseases. Copyright © 2017 Elsevier Inc. All

A dynamical system that describes vein graft adaptation and failure.

PubMed

Garbey, Marc; Berceli, Scott A

2013-11-07

Adaptation of vein bypass grafts to the mechanical stresses imposed by the arterial circulation is thought to be the primary determinant for lesion development, yet an understanding of how the various forces dictate local wall remodeling is lacking. We develop a dynamical system that summarizes the complex interplay between the mechanical environment and cell/matrix kinetics, ultimately dictating changes in the vein graft architecture. Based on a systematic mapping of the parameter space, three general remodeling response patterns are observed: (1) shear stabilized intimal thickening, (2) tension induced wall thinning and lumen expansion, and (3) tension stabilized wall thickening. Notable is our observation that the integration of multiple feedback mechanisms leads to a variety of non-linear responses that would be unanticipated by an analysis of each system component independently. This dynamic analysis supports the clinical observation that the majority of vein grafts proceed along an adaptive trajectory, where grafts dilate and mildly thicken in response to the increased tension and shear, but a small portion of the grafts demonstrate a maladaptive phenotype, where progressive inward remodeling and accentuated wall thickening lead to graft failure. © 2013 The Authors. Published by Elsevier Ltd. All rights reserved.

Convergent evolution and adaptation of Pseudomonas aeruginosa within patients with cystic fibrosis.

PubMed

Marvig, Rasmus Lykke; Sommer, Lea Mette; Molin, Søren; Johansen, Helle Krogh

2015-01-01

Little is known about how within-host evolution compares between genotypically different strains of the same pathogenic species. We sequenced the whole genomes of 474 longitudinally collected clinical isolates of Pseudomonas aeruginosa sampled from 34 children and young individuals with cystic fibrosis. Our analysis of 36 P. aeruginosa lineages identified convergent molecular evolution in 52 genes. This list of genes suggests a role in host adaptation for remodeling of regulatory networks and central metabolism, acquisition of antibiotic resistance and loss of extracellular virulence factors. Furthermore, we find an ordered succession of mutations in key regulatory networks. Accordingly, mutations in downstream transcriptional regulators were contingent upon mutations in upstream regulators, suggesting that remodeling of regulatory networks might be important in adaptation. The characterization of genes involved in host adaptation may help in predicting bacterial evolution in patients with cystic fibrosis and in the design of future intervention strategies.

Mitochondrial remodeling in the liver following chronic alcohol feeding to rats.

PubMed

Han, Derick; Johnson, Heather S; Rao, Madhuri P; Martin, Gary; Sancheti, Harsh; Silkwood, Kai H; Decker, Carl W; Nguyen, Kim Tho; Casian, Joseph G; Cadenas, Enrique; Kaplowitz, Neil

2017-01-01

the liver. Our findings suggest that mitochondrial dysfunction represents an incomplete picture of mitochondrial dynamics that occur in the liver following alcohol feeding. While alcohol feeding causes some mitochondrial dysfunction (i.e. succinate-driven respiration), our work suggests that the major consequence of alcohol feeding is mitochondrial remodeling in the liver as an adaptation. This mitochondrial remodeling may play an important role in the enhanced alcohol metabolism and other adaptations in the liver that develop with alcohol intake. Copyright © 2016 Elsevier Inc. All rights reserved.

19 CFR 192.14 - Electronic information for outward cargo required in advance of departure.

Code of Federal Regulations, 2014 CFR

2014-04-01

... Information Through the Automated Export System (AES) § 192.14 Electronic information for outward cargo... Automated Export System (AES)). (b) Presentation of data—(1) Time for presenting data. USPPIs or their... regulatory authority to do so. The CBP will also continue to require 72-hour advance notice for used vehicle...

19 CFR 192.14 - Electronic information for outward cargo required in advance of departure.

Code of Federal Regulations, 2013 CFR

2013-04-01

... Information Through the Automated Export System (AES) § 192.14 Electronic information for outward cargo... Automated Export System (AES)). (b) Presentation of data—(1) Time for presenting data. USPPIs or their... regulatory authority to do so. The CBP will also continue to require 72-hour advance notice for used vehicle...

19 CFR 192.14 - Electronic information for outward cargo required in advance of departure.

Code of Federal Regulations, 2012 CFR

2012-04-01

... Information Through the Automated Export System (AES) § 192.14 Electronic information for outward cargo... Automated Export System (AES)). (b) Presentation of data—(1) Time for presenting data. USPPIs or their... regulatory authority to do so. The CBP will also continue to require 72-hour advance notice for used vehicle...

19 CFR 192.14 - Electronic information for outward cargo required in advance of departure.

Code of Federal Regulations, 2011 CFR

2011-04-01

... Information Through the Automated Export System (AES) § 192.14 Electronic information for outward cargo... Automated Export System (AES)). (b) Presentation of data—(1) Time for presenting data. USPPIs or their... regulatory authority to do so. The CBP will also continue to require 72-hour advance notice for used vehicle...

New predictive model for monitoring bone remodeling.

PubMed

Bougherara, Habiba; Klika, Václav; Marsík, Frantisek; Marík, Ivo A; Yahia, L'hocine

2010-10-01

The aim of this article was to present a new thermodynamic-based model for bone remodeling which is able to predict the functional adaptation of bone in response to changes in both mechanical and biochemical environments. The model was based on chemical kinetics and irreversible thermodynamic principles, in which bone is considered as a self-organizing system that exchanges matter, energy and entropy with its surroundings. The governing equations of the mathematical model have been numerically solved using Matlab software and implemented in ANSYS software using the Finite Element Method. With the aid of this model, the whole inner structure of bone was elucidated. The current model suggested that bone remodeling was a dynamic process which was driven by mechanical loading, metabolic factors and other external contributions. The model clearly indicated that in the absence of mechanical stimulus, the bone was not completely resorbed and reaches a new steady state after about 50% of bone loss. This finding agreed with previous clinical studies. Furthermore, results of virtual computations of bone density in a composite femur showed the development of a dense cortical bone around the medullary canal and a dense trabeculae bone between the femoral head and the calcar region of the medial cortex due to compressive stresses. The comparison of the predicted bone density with the structure of the proximal femur obtained from X-rays and using strain energy density gave credibility to the current model. Copyright 2010 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2010.

The relationship of outwardly-directed aggression to suicidal ideation and suicide attempts across two high-risk samples

PubMed Central

Swogger, Marc T.; Van Orden, Kimberly A.; Conner, Kenneth R.

2014-01-01

Objective While research has established some relationships between risk factors and specific suicide-related outcomes, in large part the extent to which suicidal ideation and attempts have different risk profiles is unclear. Using two theories of suicidal behavior to guide our hypotheses, we studied the relationship of outwardly-directed aggression to suicidal ideation and attempts in two high-risk samples. Method Participants in study one were 271 criminal offenders in a pretrial diversion program. Participants in study two were 892 psychiatric inpatients who participated in the MacArthur Violence Risk Assessment Study. Results In both studies, after controlling for relevant covariates, outwardly-directed aggression was associated with suicide attempts, but not ideation. Among psychiatric patients, further analyses revealed that outwardly-directed aggression was associated with planned, but not unplanned, suicide attempts. Conclusions That aggression is related to suicide attempts and not ideation is consistent with hypotheses based on both Joiner's (2005) interpersonal theory of suicidal behavior and theories based on a diathesis toward behavioral dysregulation (e.g., Mann, 2009). That aggression was associated with planned suicide attempts is consistent with Joiner's theory. Competing explanations for the results include a potential role of proactive aggression in suicide attempts, particularly planned attempts. PMID:26180654

Chromatin remodelling: the industrial revolution of DNA around histones.

PubMed

Saha, Anjanabha; Wittmeyer, Jacqueline; Cairns, Bradley R

2006-06-01

Chromatin remodellers are specialized multi-protein machines that enable access to nucleosomal DNA by altering the structure, composition and positioning of nucleosomes. All remodellers have a catalytic ATPase subunit that is similar to known DNA-translocating motor proteins, suggesting DNA translocation as a unifying aspect of their mechanism. Here, we explore the diversity and specialization of chromatin remodellers, discuss how nucleosome modifications regulate remodeller activity and consider a model for the exposure of nucleosomal DNA that involves the use of directional DNA translocation to pump 'DNA waves' around the nucleosome.

Properties of the late transient outward current in isolated intestinal smooth muscle cells of the guinea-pig.

PubMed

Zholos, A V; Baidan, L V; Shuba, M F

1991-11-01

1. Whole-cell membrane currents in voltage-clamped single isolated cells of longitudinal smooth muscle of guinea-pig ileum were studied at room temperature using patch pipettes filled with either high-K+ solution or high-Cs+ solution, to suppress K+ outward current, and containing 0.3 mM-EGTA. 2. In the presence of high-K+ solution in the pipette, membrane depolarization from the holding potential of -50 mV evoked an initial inward calcium current (ICa) followed by a large initial transient outward current and a sustained outward current with spontaneous oscillations superimposed. Prolonged depolarization above -20 mV produced a late transient outward current which reached a maximum (up to several nanoamps at +10 mV) within approximately 1 s and lasted several seconds. 3. The late outward current (ILTO) was voltage dependent and reversed at the EK (potassium equilibrium potential) in cells exposed to high-K+ external solution. It was blocked by TEA+ (tetraethylammonium) or Ba2+ applied externally (calculated Kd (dissociation constant) values were 0.67 and 4.43 mM, respectively) or by high-Cs+ solution perfusing the cell. The removal of extracellular Ca2+, application of Ca2+ channel blockers (3 mM-Co2+, 0.2 mM-Cd2+ or 1 microM-nifedipine) or perfusion of 5 mM-EGTA inside the cell also abolished the current. Thus, the current seems to be a Ca(2+)-activated K+ current. 4. There is a great discrepancy between the time course of the ICa and that of the late ILTO, which suggests that Ca2+ release from intracellular storage sites may contribute to the generation of the ILTO. 5. Bath application of caffeine (10 mM) during the development of ILTO enhanced the current. However, in the presence of caffeine ILTO was inhibited. Moderate inhibition of ICa by caffeine was also observed. 6. Ryanodine (5 microM) applied to the bathing solution completely inhibited ILTO within 3.5 min; however, it had no or little effect on the ICa. 7. Ruthenium Red (10 microM) completely blocked

An exploratory study of the changes in benefits sought during an outward bound experience

Treesearch

Frederick Kacprzynski

1992-01-01

Participants in an eight-day Outward Bound program were asked about their motivations for participation before the experience began and at the mid-point of the actual experience. Although more anticipated differences were expected, based on motivational theory, only one of the twelve motivational domains was significantly different at the .001 level.

Adipose extracellular matrix remodelling in obesity and insulin resistance☆

PubMed Central

Lin, De; Chun, Tae-Hwa; Kang, Li

2016-01-01

The extracellular matrix (ECM) of adipose tissues undergoes constant remodelling to allow adipocytes and their precursor cells to change cell shape and function in adaptation to nutritional cues. Abnormal accumulation of ECM components and their modifiers in adipose tissues has been recently demonstrated to cause obesity-associated insulin resistance, a hallmark of type 2 diabetes. Integrins and other ECM receptors (e.g. CD44) that are expressed in adipose tissues have been shown to regulate insulin sensitivity. It is well understood that a hypoxic response is observed in adipose tissue expansion during obesity progression and that hypoxic response accelerates fibrosis and inflammation in white adipose tissues. The expansion of adipose tissues should require angiogenesis; however, the excess deposition of ECM limits the angiogenic response of white adipose tissues in obesity. While recent studies have focused on the metabolic consequences and the mechanisms of adipose tissue expansion and remodelling, little attention has been paid to the role played by the interaction between peri-adipocyte ECM and their cognate cell surface receptors. This review will address what is currently known about the roles played by adipose ECM, their modifiers, and ECM receptors in obesity and insulin resistance. Understanding how excess ECM deposition in the adipose tissue deteriorates insulin sensitivity would provide us hints to develop a new therapeutic strategy for the treatment of insulin resistance and type 2 diabetes. PMID:27179976

Outward current produced by somatostatin (SRIF) in rat anterior cingulate pyramidal cells in vitro

PubMed Central

Hicks, G A; Feniuk, W; Humphrey, P P A

1998-01-01

A high density of receptors for somatostatin (SRIF) exists in the anterior cingulate cortex but their function is unknown. Whole-cell patch clamp recordings were made from visualized deep layer pyramidal cells of the rat anterior cingulate cortex contained in isolated brain slices to investigate the putative effects of SRIF and to identify the receptor subtype(s) involved.SRIF (1–1000 nM) produced a concentration-dependent outward current which was associated with an increased membrane conductance, was sensitive to Ba2+ (300 μM–1 mM), and was absent in the presence of a maximal concentration of the GABAB receptor agonist, baclofen (100 μM). These observations suggest the outward current was carried by K+ ions.SRIF analogues also elicited outward currents with a rank potency order of (EC50, nM): octreotide (1.8)>BIM-23027 (3.7)>SRIF (20)=L-362,855 (20). BIM-23056 was without agonist or antagonist activity. Responses to L-362,855 were unlike those to the other agonists since they were sustained for the duration of the application.The sst2 receptor antagonist, L-Tyr8Cyanamid 154806 (1 μM), had no effect alone but partially reversed responses to submaximal concentrations of SRIF (100 nM, 44±6% reversal) and L-362,855 (100 nM, 70±6% reversal) and fully reversed the response to BIM-23027 (10 nM). In contrast, L-Tyr8Cyanamid 154806 did not antagonize the response to baclofen (10 μM).We conclude that SRIF activates a K+ conductance in anterior cingulate pyramidal neurones via an action predominantly at sst2 receptors. PMID:9630367

The chromatin remodeler SPLAYED regulates specific stress signaling pathways.

PubMed

Walley, Justin W; Rowe, Heather C; Xiao, Yanmei; Chehab, E Wassim; Kliebenstein, Daniel J; Wagner, Doris; Dehesh, Katayoon

2008-12-01

Organisms are continuously exposed to a myriad of environmental stresses. Central to an organism's survival is the ability to mount a robust transcriptional response to the imposed stress. An emerging mechanism of transcriptional control involves dynamic changes in chromatin structure. Alterations in chromatin structure are brought about by a number of different mechanisms, including chromatin modifications, which covalently modify histone proteins; incorporation of histone variants; and chromatin remodeling, which utilizes ATP hydrolysis to alter histone-DNA contacts. While considerable insight into the mechanisms of chromatin remodeling has been gained, the biological role of chromatin remodeling complexes beyond their function as regulators of cellular differentiation and development has remained poorly understood. Here, we provide genetic, biochemical, and biological evidence for the critical role of chromatin remodeling in mediating plant defense against specific biotic stresses. We found that the Arabidopsis SWI/SNF class chromatin remodeling ATPase SPLAYED (SYD) is required for the expression of selected genes downstream of the jasmonate (JA) and ethylene (ET) signaling pathways. SYD is also directly recruited to the promoters of several of these genes. Furthermore, we show that SYD is required for resistance against the necrotrophic pathogen Botrytis cinerea but not the biotrophic pathogen Pseudomonas syringae. These findings demonstrate not only that chromatin remodeling is required for selective pathogen resistance, but also that chromatin remodelers such as SYD can regulate specific pathways within biotic stress signaling networks.

Acetylcholine beyond bronchoconstriction: roles in inflammation and remodeling.

PubMed

Kistemaker, Loes E M; Gosens, Reinoud

2015-03-01

Acetylcholine is the primary parasympathetic neurotransmitter in the airways, where it not only induces bronchoconstriction and mucus secretion, but also regulates airway inflammation and remodeling. In this review, we propose that these effects are all primarily mediated via the muscarinic M3 receptor. Acetylcholine promotes inflammation and remodeling via direct effects on airway cells, and via mechanical stress applied to the airways sequential to bronchoconstriction. The effects on inflammation and remodeling are regulated by both neuronal and non-neuronal acetylcholine. Taken together, we believe that the combined effects of anticholinergic therapy on M3-mediated bronchoconstriction, mucus secretion, inflammation, and remodeling may account for the positive outcome of treatment with these drugs for patients with chronic pulmonary obstructive disease (COPD) or asthma. Copyright © 2014 Elsevier Ltd. All rights reserved.

An Analysis of the Residential Remodeling Occupation.

ERIC Educational Resources Information Center

Scruggs, Kenneth

The general purpose of the occupational analysis is to provide workable, basic information dealing with the many and varied duties performed in the residential remodeling occupation. The analysis only briefly covers the many areas of residential remodeling. The document opens with a brief introduction followed by a job description. The bulk of the…

Participants' Perceptions of Their Outward Bound Final Expedition and the Relationship to Instructor Supervisory Position

ERIC Educational Resources Information Center

Bobilya, Andrew J.; Kalisch, Kenneth R.; Daniel, Brad

2014-01-01

The purpose of this mixed-method study was to understand participants' perceptions of their Outward Bound Final Expedition experience and more specifically the relationship between the instructor supervisory position and participant's perception of learning. A sample of 331 students consented to participate and completed a survey at the conclusion…

Adaptive plasticity in the mouse mandible.

PubMed

Anderson, Philip S L; Renaud, Sabrina; Rayfield, Emily J

2014-04-18

Plasticity, i.e. non-heritable morphological variation, enables organisms to modify the shape of their skeletal tissues in response to varying environmental stimuli. Plastic variation may also allow individuals to survive in the face of new environmental conditions, enabling the evolution of heritable adaptive traits. However, it is uncertain whether such a plastic response of morphology constitutes an evolutionary adaption itself. Here we investigate whether shape differences due to plastic bone remodelling have functionally advantageous biomechanical consequences in mouse mandibles. Shape characteristics of mandibles from two groups of inbred laboratory mice fed either rodent pellets or ground pellets mixed with jelly were assessed using geometric morphometrics and mechanical advantage measurements of jaw adductor musculature. Mandibles raised on diets with differing food consistency showed significant differences in shape, which in turn altered their biomechanical profile. Mice raised on a soft food diet show a reduction in mechanical advantage relative to mice of the same inbred strain raised on a typical hard food diet. Further, the soft food eaters showed lower levels of integration between jaw regions, particularly between the molar and angular region relative to hard food eaters. Bone remodelling in mouse mandibles allows for significant shifts in biomechanical ability. Food consistency significantly influences this process in an adaptive direction, as mice raised on hard food develop jaws better suited to handle hard foods. This remodelling also affects the organisation of the mandible, as mice raised on soft food appear to be released from developmental constraints showing less overall integration than those raised on hard foods, but with a shift of integration towards the most solicited regions of the mandible facing such a food, namely the incisors. Our results illustrate how environmentally driven plasticity can lead to adaptive functional changes that

Radio-Adaptive Responses of Mouse Myocardiocytes

NASA Technical Reports Server (NTRS)

Seawright, John W.; Westby, Christian M.

2011-01-01

One of the most significant occupational hazards to an astronaut is the frequent exposure to radiation. Commonly associated with increased risk for cancer related morbidity and mortality, radiation is also known to increase the risk for cardiovascular related disorders including: pericarditis, hypertension, and heart failure. It is believed that these radiation-induced disorders are a result of abnormal tissue remodeling. It is unknown whether radiation exposure promotes remodeling through fibrotic changes alone or in combination with programmed cell death. Furthermore, it is not known whether it is possible to mitigate the hazardous effects of radiation exposure. As such, we assessed the expression and mechanisms of radiation-induced tissue remodeling and potential radio-adaptive responses of p53-mediated apoptosis and fibrosis pathways along with markers for oxidative stress and inflammation in mice myocardium. 7 week old, male, C57Bl/6 mice were exposed to 6Gy (H) or 5cGy followed 24hr later with 6Gy (LH) Cs-137 gamma radiation. Mice were sacrificed and their hearts extirpated 4, 24, or 72hr after final irradiation. Real Time - Polymerase Chain Reaction was used to evaluate target genes. Pro-apoptotic genes Bad and Bax, pro-cell survival genes Bcl2 and Bcl2l2, fibrosis gene Vegfa, and oxidative stress genes Sod2 and GPx4 showed a reduced fold regulation change (Bad,-6.18; Bax,-6.94; Bcl2,-5.09; Bcl2l2,-4.03; Vegfa, -11.84; Sod2,-5.97; GPx4*,-28.72; * = Bonferroni adjusted p-value . 0.003) 4hr after H, but not after 4hr LH when compared to control. Other p53-mediated apoptosis genes Casp3, Casp9, Trp53, and Myc exhibited down-regulation but did not achieve a notable level of significance 4hr after H. 24hr after H, genetic down-regulation was no longer present compared to 24hr control. These data suggest a general reduction in genetic expression 4hrs after a high dose of gamma radiation. However, pre-exposure to 5cGy gamma radiation appears to facilitate a radio-adaptive

The Chromatin Remodeler SPLAYED Regulates Specific Stress Signaling Pathways

PubMed Central

Walley, Justin W.; Rowe, Heather C.; Xiao, Yanmei; Chehab, E. Wassim; Kliebenstein, Daniel J.; Wagner, Doris; Dehesh, Katayoon

2008-01-01

Organisms are continuously exposed to a myriad of environmental stresses. Central to an organism's survival is the ability to mount a robust transcriptional response to the imposed stress. An emerging mechanism of transcriptional control involves dynamic changes in chromatin structure. Alterations in chromatin structure are brought about by a number of different mechanisms, including chromatin modifications, which covalently modify histone proteins; incorporation of histone variants; and chromatin remodeling, which utilizes ATP hydrolysis to alter histone-DNA contacts. While considerable insight into the mechanisms of chromatin remodeling has been gained, the biological role of chromatin remodeling complexes beyond their function as regulators of cellular differentiation and development has remained poorly understood. Here, we provide genetic, biochemical, and biological evidence for the critical role of chromatin remodeling in mediating plant defense against specific biotic stresses. We found that the Arabidopsis SWI/SNF class chromatin remodeling ATPase SPLAYED (SYD) is required for the expression of selected genes downstream of the jasmonate (JA) and ethylene (ET) signaling pathways. SYD is also directly recruited to the promoters of several of these genes. Furthermore, we show that SYD is required for resistance against the necrotrophic pathogen Botrytis cinerea but not the biotrophic pathogen Pseudomonas syringae. These findings demonstrate not only that chromatin remodeling is required for selective pathogen resistance, but also that chromatin remodelers such as SYD can regulate specific pathways within biotic stress signaling networks. PMID:19079584

RosettaRemodel: A Generalized Framework for Flexible Backbone Protein Design

PubMed Central

Huang, Po-Ssu; Ban, Yih-En Andrew; Richter, Florian; Andre, Ingemar; Vernon, Robert; Schief, William R.; Baker, David

2011-01-01

We describe RosettaRemodel, a generalized framework for flexible protein design that provides a versatile and convenient interface to the Rosetta modeling suite. RosettaRemodel employs a unified interface, called a blueprint, which allows detailed control over many aspects of flexible backbone protein design calculations. RosettaRemodel allows the construction and elaboration of customized protocols for a wide range of design problems ranging from loop insertion and deletion, disulfide engineering, domain assembly, loop remodeling, motif grafting, symmetrical units, to de novo structure modeling. PMID:21909381

Characteristics of action potentials and their underlying outward currents in rat taste receptor cells.

PubMed

Chen, Y; Sun, X D; Herness, S

1996-02-01

1. Taste receptor cells produce action potentials as a result of transduction mechanisms that occur when these cells are stimulated with tastants. These action potentials are thought to be key signaling events in relaying information to the central nervous system. We explored the ionic basis of action potentials from dissociated posterior rat taste cells using the patch-clamp recording technique in both voltage-clamp and current-clamp modes. 2. Action potentials were evoked by intracellular injection of depolarizing current pulses from a holding potential of -80 mV. The threshold potential for firing of action potentials was approximately -35 mV; the input resistance of these cells averaged 6.9 G omega. With long depolarizing pulses, two or three action potentials could be elicited with successive attenuation of the spike height. Afterhyperpolarizations were observed often. 3. Both sodium and calcium currents contribute to depolarizing phases of the action potential. Action potentials were blocked completely in the presence of the sodium channel blocker tetrodotoxin. Calcium contributions could be visualized as prolonged calcium plateaus when repolarizing potassium currents were blocked and barium was used as a charge carrier. 4. Outward currents were composed of sustained delayed rectifier current, transient potassium current, and calcium-activated potassium current. Transient and sustained potassium currents activated close to -30 mV and increased monotonically with further depolarization. Up to half the outward current inactivated with decay constants on the order of seconds. Sustained and transient currents displayed steep voltage dependence in conductance and inactivation curves. Half inactivation occurred at -20 +/- 3.1 mV (mean +/- SE) with a decrease of 11.2 +/- 0.5 mV per e-fold. Half maximal conductance occurred at 3.6 +/- 1.8 mV and increased 12.2 +/- 0.6 mV per e-fold. Calcium-activated potassium current was evidenced by application of apamin and the

A tissue adaptation model based on strain-dependent collagen degradation and contact-guided cell traction.

PubMed

Heck, T A M; Wilson, W; Foolen, J; Cilingir, A C; Ito, K; van Donkelaar, C C

2015-03-18

Soft biological tissues adapt their collagen network to the mechanical environment. Collagen remodeling and cell traction are both involved in this process. The present study presents a collagen adaptation model which includes strain-dependent collagen degradation and contact-guided cell traction. Cell traction is determined by the prevailing collagen structure and is assumed to strive for tensional homeostasis. In addition, collagen is assumed to mechanically fail if it is over-strained. Care is taken to use principally measurable and physiologically meaningful relationships. This model is implemented in a fibril-reinforced biphasic finite element model for soft hydrated tissues. The versatility and limitations of the model are demonstrated by corroborating the predicted transient and equilibrium collagen adaptation under distinct mechanical constraints against experimental observations from the literature. These experiments include overloading of pericardium explants until failure, static uniaxial and biaxial loading of cell-seeded gels in vitro and shortening of periosteum explants. In addition, remodeling under hypothetical conditions is explored to demonstrate how collagen might adapt to small differences in constraints. Typical aspects of all essentially different experimental conditions are captured quantitatively or qualitatively. Differences between predictions and experiments as well as new insights that emerge from the present simulations are discussed. This model is anticipated to evolve into a mechanistic description of collagen adaptation, which may assist in developing load-regimes for functional tissue engineered constructs, or may be employed to improve our understanding of the mechanisms behind physiological and pathological collagen remodeling. Copyright © 2014 Elsevier Ltd. All rights reserved.

Load-adaptive bone remodeling simulations reveal osteoporotic microstructural and mechanical changes in whole human vertebrae.

PubMed

Badilatti, Sandro D; Christen, Patrik; Parkinson, Ian; Müller, Ralph

2016-12-08

Osteoporosis is a major medical burden and its impact is expected to increase in our aging society. It is associated with low bone density and microstructural deterioration. Treatments are available, but the critical factor is to define individuals at risk from osteoporotic fractures. Computational simulations investigating not only changes in net bone tissue volume, but also changes in its microstructure where osteoporotic deterioration occur might help to better predict the risk of fractures. In this study, bone remodeling simulations with a mechanical feedback loop were used to predict microstructural changes due to osteoporosis and their impact on bone fragility from 50 to 80 years of age. Starting from homeostatic bone remodeling of a group of seven, mixed sex whole vertebrae, five mechanostat models mimicking different biological alterations associated with osteoporosis were developed, leading to imbalanced bone formation and resorption with a total net loss of bone tissue. A model with reduced bone formation rate and cell sensitivity led to the best match of morphometric indices compared to literature data and was chosen to predict postmenopausal osteoporotic bone loss in the whole group. Thirty years of osteoporotic bone loss were predicted with changes in morphometric indices in agreement with experimental measurements, and only showing major deviations in trabecular number and trabecular separation. In particular, although being optimized to match to the morphometric indices alone, the predicted bone loss revealed realistic changes on the organ level and on biomechanical competence. While the osteoporotic bone was able to maintain the mechanical stability to a great extent, higher fragility towards error loads was found for the osteoporotic bones. Copyright © 2016 Elsevier Ltd. All rights reserved.

Multiscale mechanobiology of de novo bone generation, remodeling and adaptation of autograft in a common ovine femur model.

PubMed

Knothe Tate, Melissa L; Dolejs, Scott; McBride, Sarah H; Matthew Miller, R; Knothe, Ulf R

2011-08-01

The link between mechanics and biology in the generation and the adaptation of bone has been studied for more than a century in the context of skeletal development and fracture healing. However, the interplay between mechanics and biology in de novo generation of bone in postnatal defects as well as healing of morcellized bone graft or massive cortical bone autografts is less well understood. To address this, here we integrate insights from our previously published studies describing the mechanobiology on both de novo bone generation and graft healing in a common ovine femoral defect model. Studying these effects in a common experimental model provides a unique opportunity to elucidate factors conducive to harnessing the regenerative power of the periosteum, and ultimately, to provide mechanistic insights into the multiscale mechanobiology of bone generation, remodeling and adaptation. Taken together, the studies indicate that, as long as adequate, directional transport of cells and molecules can be insured (e.g. with periosteum in situ or a delivery device), biological factors intrinsic to the periosteum suffice to bridge critical sized bone defects, even in the absence of a patent blood supply. Furthermore, mechanical stimuli are crucial for the success of periosteal bone generation and bone graft healing. Interestingly, areas of highest periosteal strain around defects correlate with greatest amounts albeit not greatest mineralization of newly generated bone. This may indicate a role for convection enhanced transport of cells and molecules in modulation of tissue generation by pluripotent cells that ingress into the defect center, away from the periosteum and toward the surface of the intramedullary nail that fills the medullary cavity. These insights bring us much closer to understanding the mechanobiological environment and stimuli that stimulate the proliferation and differentiation of periosteum-derived progenitor cells and ultimately drive the generation of

Changes in the population of perivascular cells in the bone tissue remodeling zones under microgravity

NASA Astrophysics Data System (ADS)

Katkova, Olena; Rodionova, Natalia; Shevel, Ivan

2016-07-01

Microgravity and long-term hypokinesia induce reduction both in bone mass and mineral saturation, which can lead to the development of osteoporosis and osteopenia. (Oganov, 2003). Reorganizations and adaptive remodeling processes in the skeleton bones occur in the topographical interconnection with blood capillaries and perivascular cells. Radioautographic studies with 3H- thymidine (Kimmel, Fee, 1980; Rodionova, 1989, 2006) have shown that in osteogenesis zones there is sequential differentiation process of the perivascular cells into osteogenic. Hence the study of populations of perivascular stromal cells in areas of destructive changes is actual. Perivascular cells from metaphysis of the rat femoral bones under conditions of modeling microgravity were studied using electron microscopy and cytochemistry (hindlimb unloading, 28 days duration) and biosatellite «Bion-M1» (duration of flight from April 19 till May 19, 2013 on C57, black mice). It was revealed that both control and test groups populations of the perivascular cells are not homogeneous in remodeling adaptive zones. These populations comprise of adjacent to endothelium poorly differentiated forms and isolated cells with signs of differentiation (specific increased volume of rough endoplasmic reticulum in cytoplasm). Majority of the perivascular cells in the control group (modeling microgravity) reveals reaction to alkaline phosphatase (marker of the osteogenic differentiation). In poorly differentiated cells this reaction is registered in nucleolus, nucleous and cytoplasm. In differentiating cells activity of the alkaline phosphatase is also detected on the outer surface of the cellular membrane. Unlike the control group in the bones of experimental animals reaction to the alkaline phosphatase is registered not in all cells of perivascular population. Part of the differentiating perivascular cells does not contain a product of the reaction. Under microgravity some poorly differentiated perivascular

ATP-dependent chromatin assembly is functionally distinct from chromatin remodeling

PubMed Central

Torigoe, Sharon E; Patel, Ashok; Khuong, Mai T; Bowman, Gregory D; Kadonaga, James T

2013-01-01

Chromatin assembly involves the combined action of ATP-dependent motor proteins and histone chaperones. Because motor proteins in chromatin assembly also function as chromatin remodeling factors, we investigated the relationship between ATP-driven chromatin assembly and chromatin remodeling in the generation of periodic nucleosome arrays. We found that chromatin remodeling-defective Chd1 motor proteins are able to catalyze ATP-dependent chromatin assembly. The resulting nucleosomes are not, however, spaced in periodic arrays. Wild-type Chd1, but not chromatin remodeling-defective Chd1, can catalyze the conversion of randomly-distributed nucleosomes into periodic arrays. These results reveal a functional distinction between ATP-dependent nucleosome assembly and chromatin remodeling, and suggest a model for chromatin assembly in which randomly-distributed nucleosomes are formed by the nucleosome assembly function of Chd1, and then regularly-spaced nucleosome arrays are generated by the chromatin remodeling activity of Chd1. These findings uncover an unforeseen level of specificity in the role of motor proteins in chromatin assembly. DOI: http://dx.doi.org/10.7554/eLife.00863.001 PMID:23986862

ATP-dependent chromatin remodeling in T cells

PubMed Central

Wurster, Andrea L.; Pazin, Michael J.

2012-01-01

One of the best studied systems for mammalian chromatin remodeling is transcriptional regulation during T cell development. The variety of these studies have led to important findings in T cell gene regulation and cell fate determination. Importantly, these findings have also advanced our knowledge of the function of remodeling enzymes in mammalian gene regulation. In this review, first we briefly present biochemical/cell-free analysis of 3 types of ATP dependent remodeling enzymes (SWI/SNF, Mi2, and ISWI), to construct an intellectual framework to understand how these enzymes might be working. Second, we compare and contrast the function of these enzymes, during early (thymic) and late (peripheral) T cell development. Finally, we examine some of the gaps in our present understanding. PMID:21999456

ATP-dependent chromatin remodeling in T cells.

PubMed

Wurster, Andrea L; Pazin, Michael J

2012-02-01

One of the best studied systems for mammalian chromatin remodeling is transcriptional regulation during T cell development. The variety of these studies have led to important findings in T cell gene regulation and cell fate determination. Importantly, these findings have also advanced our knowledge of the function of remodeling enzymes in mammalian gene regulation. First we briefly present biochemical and cell-free analysis of 3 types of ATP dependent remodeling enzymes (SWI/SNF, Mi2, and ISWI) to construct an intellectual framework to understand how these enzymes might be working. Second, we compare and contrast the function of these enzymes during early (thymic) and late (peripheral) T cell development. Finally, we examine some of the gaps in our present understanding.

Coupling of Outward Radial Diffusion and Losses at the Magnetopause in the Outer Radiation Belt

NASA Astrophysics Data System (ADS)

Castillo Tibocha, A. M.; Shprits, Y.; Drozdov, A.; Kellerman, A. C.; Aseev, N.

2017-12-01

Sudden dropouts observed in relativistic electron fluxes within the radiation belts are one the most studied and yet poorly understood features of the dynamics of radiation belts. A number of physical processes contributing to these dropout events are triggered by solar wind drivers. Magnetopause losses are one of the most effective mechanisms involved here and usually occur when drifting particles reach the boundary or when inward motion of the magnetopause crosses closed particle drift shells. In both cases, particles are rapidly transported into interplanetary space generating sharp gradients in electron PSD that will promote further outward radial diffusion of particles due to adiabatic transport and the influence of outward ULF waves. Studies suggest that the coupling of these two mechanisms explains nearly all the depletion of MeV electrons observed in the outer region of the radiation belts (L*>5). In this study, we present a simple approach to model electron losses at the magnetopause and outward radial diffusion in the outer radiation belt during geomagnetic storm time. Measured upstream solar wind parameters were used to calculate the radial distance of the subsolar point as proposed by Shue et al. (1997), which was defined as the radial extent of our assumed dipole field configuration. Radial diffusion was modelled using the empirical Kp-dependent DLL [Brautigam and Albert, JGR 2000] diffusion coefficient, which is included in the 3D Versatile Electron Radiation Belt (VERB) code. Simulations of geomagnetic storms were performed in order to evaluate the effects of the integrated mechanisms and the results were compared with Van Allen probe satellite data. Our simulation results reproduce well the observed loss at the magnetopause and electron depletion in the outer radiation belt.

'Oxytocin' for the outwardly oriented: Evidence for interactive effects in placebo responding.

PubMed

Darragh, Margot; Booth, Roger J; Consedine, Nathan S

2016-04-01

In order to harness the placebo effect for clinical benefit, more research is needed to determine who might be responsive to a placebo treatment. Recently, a two-faceted Transactional Model of Placebo Responding (TMPR) was offered, which suggests different personality types might respond to different contextual cues. The current study directly tested this model by manipulating treatment descriptors to match the two purported facets of responsiveness. Physically healthy volunteers (N=77) experiencing life stress were randomised to either the: (1) wait-list control, (2) 'serotonin treatment' group; or (3) 'oxytocin treatment' group. Both treatment groups received an 'antistress' intranasal spray (placebo). The 'serotonin' and 'oxytocin' treatments were described to appeal to the two purported facets responsiveness set out in the TMPR, inward and outward orientation. The BIS/BAS scale was used as proxies for inward (BIS) and outward (BAS) orientation. It was hypothesised that high BAS types would be more responsive to the 'oxytocin' and high BIS types would be more responsive to the 'serotonin'. Findings provide partial support for hypotheses, with high but not low BAS types having a greater response to the 'oxytocin' placebo; but the pattern of responses from high BIS types were contrary to predictions. Findings indicate interactions between personality type and environmental cues may contribute to placebo responding, but more research is needed to investigate possible operationalisations of responsiveness and the contextual cues to which different types may respond. Copyright © 2016 Elsevier Inc. All rights reserved.

TRIP13 is a protein-remodeling AAA+ ATPase that catalyzes MAD2 conformation switching

DOE PAGES

Ye, Qiaozhen; Rosenberg, Scott C.; Moeller, Arne; ...

2015-04-28

The AAA+ family ATPase TRIP13 is a key regulator of meiotic recombination and the spindle assembly checkpoint, acting on signaling proteins of the conserved HORMA domain family. Here we present the structure of the Caenorhabditis elegans TRIP13 ortholog PCH-2, revealing a new family of AAA+ ATPase protein remodelers. PCH-2 possesses a substrate-recognition domain related to those of the protein remodelers NSF and p97, while its overall hexameric architecture and likely structural mechanism bear close similarities to the bacterial protein unfoldase ClpX. We find that TRIP13, aided by the adapter protein p31(comet), converts the HORMA-family spindle checkpoint protein MAD2 from amore » signaling-active ‘closed’ conformer to an inactive ‘open’ conformer. We propose that TRIP13 and p31(comet) collaborate to inactivate the spindle assembly checkpoint through MAD2 conformational conversion and disassembly of mitotic checkpoint complexes. A parallel HORMA protein disassembly activity likely underlies TRIP13's critical regulatory functions in meiotic chromosome structure and recombination.« less

Novel pathogenetic mechanisms and structural adaptations in ischemic mitral regurgitation.

PubMed

Silbiger, Jeffrey J

2013-10-01

Ischemic mitral regurgitation (MR) is a common complication of myocardial infarction thought to result from leaflet tethering caused by displacement of the papillary muscles that occurs as the left ventricle remodels. The author explores the possibility that left atrial remodeling may also play a role in the pathogenesis of ischemic MR, through a novel mechanism: atriogenic leaflet tethering. When ischemic MR is hemodynamically significant, the left ventricle compensates by dilating to preserve forward output using the Starling mechanism. Left ventricular dilatation, however, worsens MR by increasing the mitral valve regurgitant orifice, leading to a vicious cycle in which MR begets more MR. The author proposes that several structural adaptations play a role in reducing ischemic MR. In contrast to the compensatory effects of left ventricular enlargement, these may reduce, rather than increase, its severity. The suggested adaptations involve the mitral valve leaflets, the papillary muscles, the mitral annulus, and the left ventricular false tendons. This review describes the potential role each may play in reducing ischemic MR. Therapies that exploit these adaptations are also discussed. Copyright © 2013 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.

Left ventricular remodeling in preclinical experimental mitral regurgitation of dogs.

PubMed

Dillon, A Ray; Dell'Italia, Louis J; Tillson, Michael; Killingsworth, Cheryl; Denney, Thomas; Hathcock, John; Botzman, Logan

2012-03-01

Dogs with experimental mitral regurgitation (MR) provide insights into the left ventricular remodeling in preclinical MR. The early preclinical left ventricular (LV) changes after mitral regurgitation represent progressive dysfunctional remodeling, in that no compensatory response returns the functional stroke volume (SV) to normal even as total SV increases. The gradual disease progression leads to mitral annulus stretch and enlargement of the regurgitant orifice, further increasing the regurgitant volume. Remodeling with loss of collagen weave and extracellular matrix (ECM) is accompanied by stretching and hypertrophy of the cross-sectional area and length of the cardiomyocyte. Isolated ventricular cardiomyocytes demonstrate dysfunction based on decreased cell shortening and reduced intracellular calcium transients before chamber enlargement or decreases in contractility in the whole heart can be clinically appreciated. The genetic response to increased end-diastolic pressure is down-regulation of genes associated with support of the collagen and ECM and up-regulation of genes associated with matrix remodeling. Experiments have not demonstrated any beneficial effects on remodeling from treatments that decrease afterload via blocking the renin-angiotensin system (RAS). Beta-1 receptor blockade and chymase inhibition have altered the progression of the LV remodeling and have supported cardiomyocyte function. The geometry of the LV during the remodeling provides insight into the importance of regional differences in responses to wall stress. Copyright © 2012 Elsevier B.V. All rights reserved.

Remodeling of ribosomal genes in somatic cells by Xenopus egg extract

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

Ostrup, Olga, E-mail: osvarcova@gmail.com; Stem Cell Epigenetics Laboratory, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo; Norwegian Center for Stem Cell Research, Oslo

Highlights: {yields} Xenopus egg extract remodels nuclei and alter cell growth characteristics. {yields} Ribosomal genes are reprogrammed within 6 h after extract exposure. {yields} rDNA reprogramming involves promoter targeting of SNF2H remodeling complex. {yields} Xenopus egg extract does not initiate stress-related response in somatic cells. {yields} Aza-cytidine elicits a stress-induced response in reprogrammed cells. -- Abstract: Extracts from Xenopus eggs can reprogram gene expression in somatic nuclei, however little is known about the earliest processes associated with the switch in the transcriptional program. We show here that an early reprogramming event is the remodeling of ribosomal chromatin and gene expression.more » This occurs within hours of extract treatment and is distinct from a stress response. Egg extract elicits remodeling of the nuclear envelope, chromatin and nucleolus. Nucleolar remodeling involves a rapid and stable decrease in ribosomal gene transcription, and promoter targeting of the nucleolar remodeling complex component SNF2H without affecting occupancy of the transcription factor UBF and the stress silencers SUV39H1 and SIRT1. During this process, nucleolar localization of UBF and SIRT1 is not altered. On contrary, azacytidine pre-treatment has an adverse effect on rDNA remodeling induced by extract and elicits a stress-type nuclear response. Thus, an early event of Xenopus egg extract-mediated nuclear reprogramming is the remodeling of ribosomal genes involving nucleolar remodeling complex. Condition-specific and rapid silencing of ribosomal genes may serve as a sensitive marker for evaluation of various reprogramming methods.« less

Retinal Remodeling in Human Retinitis Pigmentosa

PubMed Central

Jones, B.W.; Pfeiffer, R.L.; Ferrell, W. D.; Watt, C.B.; Marmor, M.; Marc, R.E.

2016-01-01

Retinitis Pigmentosa (RP) in the human is a progressive, currently irreversible neural degenerative disease usually caused by gene defects that disrupt the function or architecture of the photoreceptors. While RP can initially be a disease of photoreceptors, there is increasing evidence that the inner retina becomes progressively disorganized as the outer retina degenerates. These alterations have been extensively described in animal models, but remodeling in humans has not been as well characterized. This study, using computational molecular phenotyping (CMP) seeks to advance our understanding of the retinal remodeling process in humans. We describe cone mediated preservation of overall topology, retinal reprogramming in the earliest stages of the disease in retinal bipolar cells, and alterations in both small molecule and protein signatures of neurons and glia. Furthermore, while Müller glia appear to be some of the last cells left in the degenerate retina, they are also one of the first cell classes in the neural retina to respond to stress which may reveal mechanisms related to remodeling and cell death in other retinal cell classes. Also fundamentally important is the finding that retinal network topologies are altered. Our results suggest interventions that presume substantial preservation of the neural retina will likely fail in late stages of the disease. Even early intervention offers no guarantee that the interventions will be immune to progressive remodeling. Fundamental work in the biology and mechanisms of disease progression are needed to support vision rescue strategies. PMID:27020758

Extracellular Matrix Degradation and Remodeling in Development and Disease

PubMed Central

Lu, Pengfei; Takai, Ken; Weaver, Valerie M.; Werb, Zena

2011-01-01

The extracellular matrix (ECM) serves diverse functions and is a major component of the cellular microenvironment. The ECM is a highly dynamic structure, constantly undergoing a remodeling process where ECM components are deposited, degraded, or otherwise modified. ECM dynamics are indispensible during restructuring of tissue architecture. ECM remodeling is an important mechanism whereby cell differentiation can be regulated, including processes such as the establishment and maintenance of stem cell niches, branching morphogenesis, angiogenesis, bone remodeling, and wound repair. In contrast, abnormal ECM dynamics lead to deregulated cell proliferation and invasion, failure of cell death, and loss of cell differentiation, resulting in congenital defects and pathological processes including tissue fibrosis and cancer. Understanding the mechanisms of ECM remodeling and its regulation, therefore, is essential for developing new therapeutic interventions for diseases and novel strategies for tissue engineering and regenerative medicine. PMID:21917992

mAKAP – A Master Scaffold for Cardiac Remodeling

PubMed Central

Passariello, Catherine L.; Li, Jinliang; Dodge-Kafka, Kimberly; Kapiloff, Michael S.

2014-01-01

Cardiac remodeling is regulated by an extensive intracellular signal transduction network. Each of the many signaling pathways in this network contributes uniquely to the control of cellular adaptation. In the last few years, it has become apparent that multimolecular signaling complexes or ‘signalosomes’ are important for fidelity in intracellular signaling and for mediating crosstalk between the different signaling pathways. These complexes integrate upstream signals and control downstream effectors. In the cardiac myocyte, the protein mAKAPβ serves as a scaffold for a large signalosome that is responsive to cAMP, calcium, hypoxia, and mitogen-activated protein kinase signaling. The main function of mAKAPβ signalosomes is to modulate stress-related gene expression regulated by the transcription factors NFATc, MEF2 and HIF-1α and type II histone deacetylases that control pathological cardiac hypertrophy. PMID:25551320

Fibrin Networks Support Recurring Mechanical Loads by Adapting their Structure across Multiple Scales.

PubMed

Kurniawan, Nicholas A; Vos, Bart E; Biebricher, Andreas; Wuite, Gijs J L; Peterman, Erwin J G; Koenderink, Gijsje H

2016-09-06

Tissues and cells sustain recurring mechanical loads that span a wide range of loading amplitudes and timescales as a consequence of exposure to blood flow, muscle activity, and external impact. Both tissues and cells derive their mechanical strength from fibrous protein scaffolds, which typically have a complex hierarchical structure. In this study, we focus on a prototypical hierarchical biomaterial, fibrin, which is one of the most resilient naturally occurring biopolymers and forms the structural scaffold of blood clots. We show how fibrous networks composed of fibrin utilize irreversible changes in their hierarchical structure at different scales to maintain reversible stress stiffening up to large strains. To trace the origin of this paradoxical resilience, we systematically tuned the microstructural parameters of fibrin and used a combination of optical tweezers and fluorescence microscopy to measure the interactions of single fibrin fibers for the first time, to our knowledge. We demonstrate that fibrin networks adapt to moderate strains by remodeling at the network scale through the spontaneous formation of new bonds between fibers, whereas they adapt to high strains by plastic remodeling of the fibers themselves. This multiscale adaptation mechanism endows fibrin gels with the remarkable ability to sustain recurring loads due to shear flows and wound stretching. Our findings therefore reveal a microscopic mechanism by which tissues and cells can balance elastic nonlinearity and plasticity, and thus can provide microstructural insights into cell-driven remodeling of tissues. Copyright © 2016 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Masturbation, sexuality, and adaptation: normalization in adolescence.

PubMed

Shapiro, Theodore

2008-03-01

During adolescence the central masturbation fantasy that is formulated during childhood takes its final form and paradoxically must now be directed outward for appropriate object finding and pair matching in the service of procreative aims. This is a step in adaptation that requires a further developmental landmark that I have called normalization. The path toward airing these private fantasies is facilitated by chumship relationships as a step toward further exposure to the social surround. Hartmann's structuring application of adaptation within psychoanalysis is used as a framework for understanding the process that simultaneously serves intrapsychic and social demands and permits goals that follow evolutionary principles. Variations in the normalization process from masturbatory isolation to a variety of forms of sexual socialization are examined in sociological data concerning current adolescent sexual behavior and in case examples that indicate some routes to normalized experience and practice.

Outward Rectification of Voltage-Gated K+ Channels Evolved at Least Twice in Life History.

PubMed

Riedelsberger, Janin; Dreyer, Ingo; Gonzalez, Wendy

2015-01-01

Voltage-gated potassium (K+) channels are present in all living systems. Despite high structural similarities in the transmembrane domains (TMD), this K+ channel type segregates into at least two main functional categories-hyperpolarization-activated, inward-rectifying (Kin) and depolarization-activated, outward-rectifying (Kout) channels. Voltage-gated K+ channels sense the membrane voltage via a voltage-sensing domain that is connected to the conduction pathway of the channel. It has been shown that the voltage-sensing mechanism is the same in Kin and Kout channels, but its performance results in opposite pore conformations. It is not known how the different coupling of voltage-sensor and pore is implemented. Here, we studied sequence and structural data of voltage-gated K+ channels from animals and plants with emphasis on the property of opposite rectification. We identified structural hotspots that alone allow already the distinction between Kin and Kout channels. Among them is a loop between TMD S5 and the pore that is very short in animal Kout, longer in plant and animal Kin and the longest in plant Kout channels. In combination with further structural and phylogenetic analyses this finding suggests that outward-rectification evolved twice and independently in the animal and plant kingdom.

Outward Rectification of Voltage-Gated K+ Channels Evolved at Least Twice in Life History

PubMed Central

Riedelsberger, Janin; Dreyer, Ingo; Gonzalez, Wendy

2015-01-01

Voltage-gated potassium (K+) channels are present in all living systems. Despite high structural similarities in the transmembrane domains (TMD), this K+ channel type segregates into at least two main functional categories—hyperpolarization-activated, inward-rectifying (Kin) and depolarization-activated, outward-rectifying (Kout) channels. Voltage-gated K+ channels sense the membrane voltage via a voltage-sensing domain that is connected to the conduction pathway of the channel. It has been shown that the voltage-sensing mechanism is the same in Kin and Kout channels, but its performance results in opposite pore conformations. It is not known how the different coupling of voltage-sensor and pore is implemented. Here, we studied sequence and structural data of voltage-gated K+ channels from animals and plants with emphasis on the property of opposite rectification. We identified structural hotspots that alone allow already the distinction between Kin and Kout channels. Among them is a loop between TMD S5 and the pore that is very short in animal Kout, longer in plant and animal Kin and the longest in plant Kout channels. In combination with further structural and phylogenetic analyses this finding suggests that outward-rectification evolved twice and independently in the animal and plant kingdom. PMID:26356684

Characterization of constitutive and acid-induced outwardly rectifying chloride currents in immortalized mouse distal tubular cells.

PubMed

Valinsky, William C; Touyz, Rhian M; Shrier, Alvin

2017-08-01

Thiazides block Na + reabsorption while enhancing Ca 2+ reabsorption in the kidney. As previously demonstrated in immortalized mouse distal convoluted tubule (MDCT) cells, chlorothiazide application induced a robust plasma membrane hyperpolarization, which increased Ca 2+ uptake. This essential thiazide-induced hyperpolarization was prevented by the Cl - channel inhibitor 5-Nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), implicating NPPB-sensitive Cl - channels, however the nature of these Cl - channels has been rarely described in the literature. Here we show that MDCT cells express a dominant, outwardly rectifying Cl - current at extracellular pH7.4. This constitutive Cl - current was more permeable to larger anions (Eisenman sequence I; I - >Br - ≥Cl - ) and was substantially inhibited by >100mM [Ca 2+ ] o , which distinguished it from ClC-K2/barttin. Moreover, the constitutive Cl - current was blocked by NPPB, along with other Cl - channel inhibitors (4,4'-diisothiocyanatostilbene-2,2'-disulfonate, DIDS; flufenamic acid, FFA). Subjecting the MDCT cells to an acidic extracellular solution (pH<5.5) induced a substantially larger outwardly rectifying NPPB-sensitive Cl - current. This acid-induced Cl - current was also anion permeable (I - >Br - >Cl - ), but was distinguished from the constitutive Cl - current by its rectification characteristics, ion sensitivities, and response to FFA. In addition, we have identified similar outwardly rectifying and acid-sensitive currents in immortalized cells from the inner medullary collecting duct (mIMCD-3 cells). Expression of an acid-induced Cl - current would be particularly relevant in the acidic IMCD (pH<5.5). To our knowledge, the properties of these Cl - currents are unique and provide the mechanisms to account for the Cl - efflux previously speculated to be present in MDCT cells. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Muscle remodeling in relation to blood supply: implications for seasonal changes in mitochondrial enzymes.

PubMed

McClelland, G B; Dalziel, A C; Fragoso, N M; Moyes, C D

2005-02-01

We investigated if seasonal changes in rainbow trout muscle energetics arise in response to seasonal changes in erythrocyte properties. We assessed if skeletal muscle mitochondrial enzymes changed (1) acutely in response to changes in erythrocyte abundance, or (2) seasonally when we altered the age profile of erythrocytes. Rainbow trout were treated with pheynylhydrazine, causing a 75% reduction in hematocrit within 4 days. After erythropoiesis had returned hematocrit to normal, treated and control fish were subjected to a seasonal cold acclimation regime to assess the impact of erythrocyte age on skeletal muscle remodeling. Anemia (i.e. phenylhydrazine treatment) did not alter the specific activities (U g(-1) tissue) of mitochondrial enzymes in white or red muscle. Anemic pretreatment did not alter the normal pattern of cold-induced mitochondrial proliferation in skeletal muscle, suggesting erythrocyte age was not an important influence on seasonal remodeling of muscle. Anemia and cold acclimation both induced a 25-30% increase in relative ventricular mass. The increase in relative ventricular mass with phenylhydrazine treatment was accompanied by a 35% increase in DNA content (mg DNA per ventricle), suggesting an increase in number of cells. In contrast, the increase in ventricular mass with cold temperature acclimation occurred without a change in DNA content (mg DNA per ventricle), suggesting an increase in cell size. Despite the major increases in relative ventricular mass, neither anemia nor seasonal acclimation had a major influence on the specific activities of a suite of mitochondrial enzymes in heart. Collectively, these studies argue against a role for erythrocyte dynamics in seasonal adaptive remodeling of skeletal muscle energetics.

Neural circuit rewiring: insights from DD synapse remodeling.

PubMed

Kurup, Naina; Jin, Yishi

2016-01-01

Nervous systems exhibit many forms of neuronal plasticity during growth, learning and memory consolidation, as well as in response to injury. Such plasticity can occur across entire nervous systems as with the case of insect metamorphosis, in individual classes of neurons, or even at the level of a single neuron. A striking example of neuronal plasticity in C. elegans is the synaptic rewiring of the GABAergic Dorsal D-type motor neurons during larval development, termed DD remodeling. DD remodeling entails multi-step coordination to concurrently eliminate pre-existing synapses and form new synapses on different neurites, without changing the overall morphology of the neuron. This mini-review focuses on recent advances in understanding the cellular and molecular mechanisms driving DD remodeling.

Mechanical factors direct mouse aortic remodelling during early maturation

PubMed Central

Le, Victoria P.; Cheng, Jeffrey K.; Kim, Jungsil; Staiculescu, Marius C.; Ficker, Shawn W.; Sheth, Saahil C.; Bhayani, Siddharth A.; Mecham, Robert P.; Yanagisawa, Hiromi; Wagenseil, Jessica E.

2015-01-01

Numerous diseases have been linked to genetic mutations that lead to reduced amounts or disorganization of arterial elastic fibres. Previous work has shown that mice with reduced amounts of elastin (Eln+/−) are able to live a normal lifespan through cardiovascular adaptations, including changes in haemodynamic stresses, arterial geometry and arterial wall mechanics. It is not known if the timeline and presence of these adaptations are consistent in other mouse models of elastic fibre disease, such as those caused by the absence of fibulin-5 expression (Fbln5−/−). Adult Fbln5−/− mice have disorganized elastic fibres, decreased arterial compliance and high blood pressure. We examined mechanical behaviour of the aorta in Fbln5−/− mice through early maturation when the elastic fibres are being assembled. We found that the physiologic circumferential stretch, stress and modulus of Fbln5−/− aorta are maintained near wild-type levels. Constitutive modelling suggests that elastin contributions to the total stress are decreased, whereas collagen contributions are increased. Understanding how collagen fibre structure and mechanics compensate for defective elastic fibres to meet the mechanical requirements of the maturing aorta may help to better understand arterial remodelling in human elastinopathies. PMID:25652465

Postexercise Dietary Protein Strategies to Maximize Skeletal Muscle Repair and Remodeling in Masters Endurance Athletes: A Review.

PubMed

Doering, Thomas M; Reaburn, Peter R; Phillips, Stuart M; Jenkins, David G

2016-04-01

Participation rates of masters athletes in endurance events such as long-distance triathlon and running continue to increase. Given the physical and metabolic demands of endurance training, recovery practices influence the quality of successive training sessions and, consequently, adaptations to training. Research has suggested that, after muscle-damaging endurance exercise, masters athletes experience slower recovery rates in comparison with younger, similarly trained athletes. Given that these discrepancies in recovery rates are not observed after non-muscle-damaging exercise, it is suggested that masters athletes have impairments of the protein remodeling mechanisms within skeletal muscle. The importance of postexercise protein feeding for endurance athletes is increasingly being acknowledged, and its role in creating a positive net muscle protein balance postexercise is well known. The potential benefits of postexercise protein feeding include elevating muscle protein synthesis and satellite cell activity for muscle repair and remodeling, as well as facilitating muscle glycogen resynthesis. Despite extensive investigation into age-related anabolic resistance in sedentary aging populations, little is known about how anabolic resistance affects postexercise muscle protein synthesis and thus muscle remodeling in aging athletes. Despite evidence suggesting that physical training can attenuate but not eliminate age-related anabolic resistance, masters athletes are currently recommended to consume the same postexercise dietary protein dose (approximately 20 g or 0.25 g/kg/meal) as younger athletes. Given the slower recovery rates of masters athletes after muscle-damaging exercise, which may be due to impaired muscle remodeling mechanisms, masters athletes may benefit from higher doses of postexercise dietary protein, with particular attention directed to the leucine content of the postexercise bolus.

Clinical Implications and Pathogenesis of Esophageal Remodeling in Eosinophilic Esophagitis

PubMed Central

Hirano, Ikuo; Aceves, Seema S.

2014-01-01

In eosinophilic esophagitis (EoE), remodeling changes are manifest histologically in both the epithelium as well as in the subepithelium where lamina propria (LP) fibrosis, expansion of the muscularis propria and increased vascularity occur. The major clinical symptoms and complications of EoE are largely consequences of esophageal remodeling. Important mediators of the process include IL-5, IL-13, TGFβ1, mast cells, fibroblasts and eosinophils. Methods to detect remodeling effects include upper endoscopy, histopathology, barium esophagram, endoscopic ultrasonography, esophageal manometry, and functional luminal imaging. These modalities provide evidence of organ dysfunction that include focal and diffuse esophageal strictures, expansion of the mucosa and subepithelium, esophageal motor abnormalities and reduced esophageal distensibility. Complications of food impaction and perforations of the esophageal wall have been associated with reduction in esophageal caliber and increased esophageal mural stiffness. The therapeutic benefits of topical corticosteroids and elimination diet therapy in resolving mucosal eosinophilic inflammation of the esophagus are evident. Available therapies, however, have demonstrated variable ability to reverse existing remodeling changes of the esophagus. Systemic therapies that include novel, targeted biologic agents have the potential of addressing subepithelial remodeling. Esophageal dilation remains a useful, adjunctive therapeutic maneuver in symptomatic adults with esophageal stricture. As novel treatments emerge, it is essential that therapeutic endpoints account for the fundamental contributions of esophageal remodeling to overall disease activity. PMID:24813517

Energy Efficiency Measures to Incorporate into Remodeling Projects

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

Liaukus, C.

2014-12-01

Energy improvements in a home are often approached as one concerted effort, beginning with a simple walk-through assessment or more in-depth energy audit and followed by the installation of recommended energy measures. While this approach allows for systems thinking to guide the efforts, comprehensive energy improvements of this nature are undertaken by a relatively small number of U.S. households compared to piecemeal remodeling efforts. In this report, the U.S Department of Energy Building America Retrofit Alliance research team examines the improvement of a home’s energy performance in an opportunistic way by examining what can be done to incorporate energy efficiencymore » measures into general remodeling work and home repair projects. This allows for energy efficiency upgrades to occur at the same time as remodeling proejcts. There are challenges to this approach, not the least of which being that the work will take place over time in potentially many separate projects. The opportunity to improve a home’s energy efficiency at one time expands or contracts with the scope of the remodel. As such, guidance on how to do each piece thoughtfully and with consideration for potential future projects, is critical.« less

OUTWARD MIGRATION OF JUPITER AND SATURN IN 3:2 OR 2:1 RESONANCE IN RADIATIVE DISKS: IMPLICATIONS FOR THE GRAND TACK AND NICE MODELS

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

Pierens, Arnaud; Raymond, Sean N.; Nesvorny, David

Embedded in the gaseous protoplanetary disk, Jupiter and Saturn naturally become trapped in 3:2 resonance and migrate outward. This serves as the basis of the Grand Tack model. However, previous hydrodynamical simulations were restricted to isothermal disks, with moderate aspect ratio and viscosity. Here we simulate the orbital evolution of the gas giants in disks with viscous heating and radiative cooling. We find that Jupiter and Saturn migrate outward in 3:2 resonance in modest-mass (M {sub disk} ≈ M {sub MMSN}, where MMSN is the {sup m}inimum-mass solar nebula{sup )} disks with viscous stress parameter α between 10{sup –3} andmore » 10{sup –2}. In disks with relatively low-mass (M {sub disk} ≲ M {sub MMSN}), Jupiter and Saturn get captured in 2:1 resonance and can even migrate outward in low-viscosity disks (α ≤ 10{sup –4}). Such disks have a very small aspect ratio (h ∼ 0.02-0.03) that favors outward migration after capture in 2:1 resonance, as confirmed by isothermal runs which resulted in a similar outcome for h ∼ 0.02 and α ≤ 10{sup –4}. We also performed N-body runs of the outer solar system starting from the results of our hydrodynamical simulations and including 2-3 ice giants. After dispersal of the gaseous disk, a Nice model instability starting with Jupiter and Saturn in 2:1 resonance results in good solar systems analogs. We conclude that in a cold solar nebula, the 2:1 resonance between Jupiter and Saturn can lead to outward migration of the system, and this may represent an alternative scenario for the evolution of the solar system.« less

Endothelial Msx1 transduces hemodynamic changes into an arteriogenic remodeling response

PubMed Central

Vandersmissen, Ine; Craps, Sander; Depypere, Maarten; Coppiello, Giulia; van Gastel, Nick; Maes, Frederik; Carmeliet, Geert; Schrooten, Jan; Jones, Elizabeth A.V.; Umans, Lieve; Devlieger, Roland; Koole, Michel; Gheysens, Olivier; Zwijsen, An; Aranguren, Xabier L.

2015-01-01

Collateral remodeling is critical for blood flow restoration in peripheral arterial disease and is triggered by increasing fluid shear stress in preexisting collateral arteries. So far, no arterial-specific mediators of this mechanotransduction response have been identified. We show that muscle segment homeobox 1 (MSX1) acts exclusively in collateral arterial endothelium to transduce the extrinsic shear stimulus into an arteriogenic remodeling response. MSX1 was specifically up-regulated in remodeling collateral arteries. MSX1 induction in collateral endothelial cells (ECs) was shear stress driven and downstream of canonical bone morphogenetic protein–SMAD signaling. Flow recovery and collateral remodeling were significantly blunted in EC-specific Msx1/2 knockout mice. Mechanistically, MSX1 linked the arterial shear stimulus to arteriogenic remodeling by activating the endothelial but not medial layer to a proinflammatory state because EC but not smooth muscle cellMsx1/2 knockout mice had reduced leukocyte recruitment to remodeling collateral arteries. This reduced leukocyte infiltration in EC Msx1/2 knockout mice originated from decreased levels of intercellular adhesion molecule 1 (ICAM1)/vascular cell adhesion molecule 1 (VCAM1), whose expression was also in vitro driven by promoter binding of MSX1. PMID:26391659

The Chd1 Chromatin Remodeler Shifts Nucleosomal DNA Bidirectionally as a Monomer

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

Qiu, Yupeng; Levendosky, Robert F.; Chakravarthy, Srinivas

Chromatin remodelers catalyze dynamic packaging of the genome by carrying out nucleosome assembly/disassembly, histone exchange, and nucleosome repositioning. Remodeling results in evenly spaced nucleosomes, which requires probing both sides of the nucleosome, yet the way remodelers organize sliding activity to achieve this task is not understood. Here, we show that the monomeric Chd1 remodeler shifts DNA back and forth by dynamically alternating between different segments of the nucleosome. During sliding, Chd1 generates unstable remodeling intermediates that spontaneously relax to a pre-remodeled position. We demonstrate that nucleosome sliding is tightly controlled by two regulatory domains: the DNA-binding domain, which interferes withmore » sliding when its range is limited by a truncated linking segment, and the chromodomains, which play a key role in substrate discrimination. We propose that active interplay of the ATPase motor with the regulatory domains may promote dynamic nucleosome structures uniquely suited for histone exchange and chromatin reorganization during transcription.« less

Soft skills turned into hard facts: nucleosome remodelling at developmental switches.

PubMed

Chioda, M; Becker, P B

2010-07-01

Nucleosome remodelling factors are regulators of DNA accessibility in chromatin and lubricators of all major functions of eukaryotic genomes. Their action is transient and reversible, yet can be decisive for irreversible cell-fate decisions during development. In addition to the well-known local actions of nucleosome remodelling factors during transcription initiation, more global and fundamental roles for remodelling complexes in shaping the epigenome during development are emerging.

ECM remodeling and its plasticity

NASA Astrophysics Data System (ADS)

Feng, Jingchen; Jones, Christopher A. R.; Cibula, Matthew; Mao, Xiaoming; Sander, Leonard M.; Levine, Herbert; Sun, Bo

The mechanical interactions between cells and Extracellular Matrix (ECM) are of great importance in many cellular processes. These interactions are reciprocal, i.e. contracting cells pull and reorganize the surrounding matrix, while the remodeled matrix feeds back to regulate cell activities. Recent experiments show in collagen gels with densely distributed cells, aligned fiber bundles are formed in the direction between neighboring cells. Fibers flow into the center region between contracting cell pairs in this process, which causes the concentration of fibers in the fiber bundles to become significantly enhanced. Using an extended lattice-based model, we show that viscoelasticity plays an essential role in ECM remodeling and contributes to the enhanced concentration in fiber bundles. We further characterize ECM plasticity within our model and verify our results with rheometer experiments.

Remodelling the extracellular matrix in development and disease

PubMed Central

Bonnans, Caroline; Chou, Jonathan; Werb, Zena

2015-01-01

The extracellular matrix (ECM) is a highly dynamic structure that is present in all tissues and continuously undergoes controlled remodelling. This process involves quantitative and qualitative changes in the ECM, mediated by specific enzymes that are responsible for ECM degradation, such as metalloproteinases. The ECM interacts with cells to regulate diverse functions, including proliferation, migration and differentiation. ECM remodelling is crucial for regulating the morphogenesis of the intestine and lungs, as well as of the mammary and submandibular glands. Dysregulation of ECM composition, structure, stiffness and abundance contributes to several pathological conditions, such as fibrosis and invasive cancer. A better understanding of how the ECM regulates organ structure and function and of how ECM remodelling affects disease progression will contribute to the development of new therapeutics. PMID:25415508

Visual cues that are effective for contextual saccade adaptation.

PubMed

Azadi, Reza; Harwood, Mark R

2014-06-01

The accuracy of saccades, as maintained by saccade adaptation, has been shown to be context dependent: able to have different amplitude movements to the same retinal displacement dependent on motor contexts such as orbital starting location. There is conflicting evidence as to whether purely visual cues also effect contextual saccade adaptation and, if so, what function this might serve. We tested what visual cues might evoke contextual adaptation. Over 5 experiments, 78 naive subjects made saccades to circularly moving targets, which stepped outward or inward during the saccade depending on target movement direction, speed, or color and shape. To test if the movement or context postsaccade were critical, we stopped the postsaccade target motion (experiment 4) or neutralized the contexts by equating postsaccade target speed to an intermediate value (experiment 5). We found contextual adaptation in all conditions except those defined by color and shape. We conclude that some, but not all, visual cues before the saccade are sufficient for contextual adaptation. We conjecture that this visual contextuality functions to allow for different motor states for different coordinated movement patterns, such as coordinated saccade and pursuit motor planning. Copyright © 2014 the American Physiological Society.

Visual cues that are effective for contextual saccade adaptation

PubMed Central

Azadi, Reza

2014-01-01

The accuracy of saccades, as maintained by saccade adaptation, has been shown to be context dependent: able to have different amplitude movements to the same retinal displacement dependent on motor contexts such as orbital starting location. There is conflicting evidence as to whether purely visual cues also effect contextual saccade adaptation and, if so, what function this might serve. We tested what visual cues might evoke contextual adaptation. Over 5 experiments, 78 naive subjects made saccades to circularly moving targets, which stepped outward or inward during the saccade depending on target movement direction, speed, or color and shape. To test if the movement or context postsaccade were critical, we stopped the postsaccade target motion (experiment 4) or neutralized the contexts by equating postsaccade target speed to an intermediate value (experiment 5). We found contextual adaptation in all conditions except those defined by color and shape. We conclude that some, but not all, visual cues before the saccade are sufficient for contextual adaptation. We conjecture that this visual contextuality functions to allow for different motor states for different coordinated movement patterns, such as coordinated saccade and pursuit motor planning. PMID:24647429

[Numeric simulation of functional remodeling of the anterior alveolar bone].

PubMed

Wang, Wei-feng; Xin, Hai-tao; Zang, Shun-lai; Ding, Jie

2012-04-01

To study the remodeling of the anterior alveolar bone with parodontium under physiology loading using finite element method (FEM) and theory of bone remodeling. A FEM model of the maxillary central incisor with parodontium was established, and the change of bone density during the remodeling of alveolar bone was investigated under physiology loading (60 - 150 N) based on the theory of bone remodeling about strain energy density (SED). The finite element analysis software Abaqus user material subroutine (UMAT) were used. With the increase of physiology loading, the pressure stress on the buccal cervical margin increased gradually while the density was decreased gradually. The cortical bone was lower than its initial density 1.74 g/cm(3), which was 1.74 - 1.63 g/cm(3). The density of cancellous bone was 0.90 - 0.77 g/cm(3), which was lower than its intial density 0.90 g/cm(3). The lingual cervical margin was under tensile stress which also increased with loading, the density had no significant change. When the achieve to 120 N, the density of cortical bone was 1.74 - 1.73 g/cm(3). No significant change was found in the cancellous bone. The simulation of the perodontium remodeling is achieved and proved to be effective by the relevant research based on the method of the study. And the result will be helpful to form the basis of analysis bone remodeling process and predict the results in the clinical work.

Structural and functional remodeling of skeletal muscle microvasculature is induced by simulated microgravity

NASA Technical Reports Server (NTRS)

Delp, M. D.; Colleran, P. N.; Wilkerson, M. K.; McCurdy, M. R.; Muller-Delp, J.

2000-01-01

Hindlimb unloading of rats results in a diminished ability of skeletal muscle arterioles to constrict in vitro and elevate vascular resistance in vivo. The purpose of the present study was to determine whether alterations in the mechanical environment (i.e., reduced fluid pressure and blood flow) of the vasculature in hindlimb skeletal muscles from 2-wk hindlimb-unloaded (HU) rats induces a structural remodeling of arterial microvessels that may account for these observations. Transverse cross sections were used to determine media cross-sectional area (CSA), wall thickness, outer perimeter, number of media nuclei, and vessel luminal diameter of feed arteries and first-order (1A) arterioles from soleus and the superficial portion of gastrocnemius muscles. Endothelium-dependent dilation (ACh) was also determined. Media CSA of resistance arteries was diminished by hindlimb unloading as a result of decreased media thickness (gastrocnemius muscle) or reduced vessel diameter (soleus muscle). ACh-induced dilation was diminished by 2 wk of hindlimb unloading in soleus 1A arterioles, but not in gastrocnemius 1A arterioles. These results indicate that structural remodeling and functional adaptations of the arterial microvasculature occur in skeletal muscles of the HU rat; the data suggest that these alterations may be induced by reductions in transmural pressure (gastrocnemius muscle) and wall shear stress (soleus muscle).

Cultivating Environmental Virtue among 7th and 8th Graders in an Expeditionary Learning Outward Bound School

ERIC Educational Resources Information Center

Martin, Bruce; Bright, Alan; Cafaro, Philip; Mittelstaedt, Robin; Bruyere, Brett

2008-01-01

This study attempted to assess the development of environmental virtue in 7th and 8th grade students in an Expeditionary Learning Outward Bound school. The purpose of this study was twofold. First, the researchers were interested in introducing a virtue ethics perspective into their teaching of environmental ethics. Second, the researchers were…

City Kids in the Wilderness: A Pilot-Test of Outward Bound for Foster Care Group Home Youth.

ERIC Educational Resources Information Center

Fischer, Robert L.; Attah, E. B.

2001-01-01

A study examined perceptions of a 7-day Outward Bound program among 23 urban youths, foster parents, and foster care workers from group homes in Atlanta (Georgia). Foster parents reported improved self-esteem and behavior among the teens, but foster care workers reported worse behavior. Negative program impressions lessened among male youths but…

National Remodelling Team: Evaluation Study (Year 2). Final Report

ERIC Educational Resources Information Center

Easton, Claire; Wilson, Rebekah; Sharp, Caroline

2005-01-01

This report sets out to provide the National Remodelling Team (NRT) with comprehensive details on stakeholders' views about the second year of the remodelling programme. This report is divided into nine chapters: (1) Introduction; (2) outlines the aims of the evaluation and the methodology used; (3) describes the findings from the survey of local…

DNA Looping Facilitates Targeting of a Chromatin Remodeling Enzyme

PubMed Central

Yadon, Adam N; Singh, Badri Nath; Hampsey, Michael; Tsukiyama, Toshio

2013-01-01

Summary ATP-dependent chromatin remodeling enzymes are highly abundant and play pivotal roles regulating DNA-dependent processes. The mechanisms by which they are targeted to specific loci have not been well understood on a genome-wide scale. Here we present evidence that a major targeting mechanism for the Isw2 chromatin remodeling enzyme to specific genomic loci is through sequence-specific transcription factor (TF)-dependent recruitment. Unexpectedly, Isw2 is recruited in a TF-dependent fashion to a large number of loci without TF binding sites. Using the 3C assay, we show that Isw2 can be targeted by Ume6- and TFIIB-dependent DNA looping. These results identify DNA looping as a previously unknown mechanism for the recruitment of a chromatin remodeling enzyme and defines a novel function for DNA looping. We also present evidence suggesting that Ume6-dependent DNA looping is involved in chromatin remodeling and transcriptional repression, revealing a mechanism by which the three-dimensional folding of chromatin affects DNA-dependent processes. PMID:23478442

Matrix Metalloproteinases in Bone Resorption, Remodeling, and Repair.

PubMed

Paiva, Katiucia B S; Granjeiro, José M

2017-01-01

Matrix metalloproteinases (MMPs) are the major protease family responsible for the cleavage of the matrisome (global composition of the extracellular matrix (ECM) proteome) and proteins unrelated to the ECM, generating bioactive molecules. These proteins drive ECM remodeling, in association with tissue-specific and cell-anchored inhibitors (TIMPs and RECK, respectively). In the bone, the ECM mediates cell adhesion, mechanotransduction, nucleation of mineralization, and the immobilization of growth factors to protect them from damage or degradation. Since the first description of an MMP in bone tissue, many other MMPs have been identified, as well as their inhibitors. Numerous functions have been assigned to these proteins, including osteoblast/osteocyte differentiation, bone formation, solubilization of the osteoid during bone resorption, osteoclast recruitment and migration, and as a coupling factor in bone remodeling under physiological conditions. In turn, a number of pathologies, associated with imbalanced bone remodeling, arise mainly from MMP overexpression and abnormalities of the ECM, leading to bone osteolysis or bone formation. In this review, we will discuss the functions of MMPs and their inhibitors in bone cells, during bone remodeling, pathological bone resorption (osteoporosis and bone metastasis), bone repair/regeneration, and emergent roles in bone bioengineering. © 2017 Elsevier Inc. All rights reserved.

Phenotypic plasticity and remodeling in the stress-induced Caenorhabditis elegans dauer.

PubMed

Androwski, Rebecca J; Flatt, Kristen M; Schroeder, Nathan E

2017-09-01

Organisms are often capable of modifying their development to better suit their environment. Under adverse conditions, the nematode Caenorhabditis elegans develops into a stress-resistant alternative larval stage called dauer. The dauer stage is the primary survival stage for C. elegans in nature. Large-scale tissue remodeling during dauer conveys resistance to harsh environments. The environmental and genetic regulation of the decision to enter dauer has been extensively studied. However, less is known about the mechanisms regulating tissue remodeling. Changes to the cuticle and suppression of feeding in dauers lead to an increased resistance to external stressors. Meanwhile reproductive development arrests during dauer while preserving the ability to reproduce once favorable environmental conditions return. Dramatic remodeling of neurons, glia, and muscles during dauer likely facilitate dauer-specific behaviors. Dauer-specific pulsation of the excretory duct likely mediates a response to osmotic stress. The power of C. elegans genetics has uncovered some of the molecular pathways regulating dauer tissue remodeling. In addition to genes that regulate single remodeling events, several mutants result in pleiotropic defects in dauer remodeling. This review details the individual aspects of morphological changes that occur during dauer formation and discusses molecular mechanisms regulating these processes. The dauer stage provides us with an excellent model for understanding phenotypic plasticity and remodeling from the individual cell to an entire animal. WIREs Dev Biol 2017, 6:e278. doi: 10.1002/wdev.278 For further resources related to this article, please visit the WIREs website. © 2017 Wiley Periodicals, Inc.

Perinatal outcomes associated with abnormal cardiac remodeling in women with treated chronic hypertension.

PubMed

Ambia, Anne M; Morgan, Jamie L; Wells, C Edward; Roberts, Scott W; Sanghavi, Monika; Nelson, David B; Cunningham, F Gary

2018-05-01

Adverse maternal outcomes associated with chronic hypertension include accelerated hypertension and resultant target organ damage. One example is long-standing hypertension leading to maternal cardiac dysfunction. Our group has previously identified that features of such injury manifest as cardiac remodeling with left ventricular hypertrophy. Moreover, these features of cardiac remodeling identified in women with chronic hypertension during pregnancy were associated with adverse perinatal outcomes. Recent definitions of maternal cardiac remodeling using echocardiography have been expanded to include measurements of wall thickness. We hypothesized that these new features characterizing cardiac remodeling in women with chronic hypertension may also be associated with adverse perinatal outcomes. There were 3 aims in this study of women with treated chronic hypertension during pregnancy: to (1) apply the updated definitions of maternal cardiac remodeling; (2) elucidate whether these features of cardiac remodeling were associated with adverse perinatal outcomes; and (3) determine which, if any, of the newly defined cardiac remodeling strata were most damaging when compared to women with normal cardiac geometry. This was a retrospective study of women with treated chronic hypertension during pregnancy delivered from January 2009 through January 2016. Cardiac remodeling was categorized by left ventricular mass index and relative wall thickness into 4 groups determined using the 2015 American Society of Echocardiography guidelines: normal geometry, concentric remodeling, eccentric hypertrophy, and concentric hypertrophy. Perinatal outcomes were analyzed according to each category of cardiac remodeling compared with outcomes in women with normal geometry. A total of 314 women with treated chronic hypertension underwent echocardiography at a mean gestational age of 17.9 weeks. There were no differences between maternal age (P = .896), habitus (P = .36), or duration of

Helical image reconstruction of the outward-open human erythrocyte band 3 membrane domain in tubular crystals.

PubMed

Yamaguchi, Tomohiro; Fujii, Takashi; Abe, Yoshito; Hirai, Teruhisa; Kang, Dongchon; Namba, Keiichi; Hamasaki, Naotaka; Mitsuoka, Kaoru

2010-03-01

The C-terminal membrane domain of erythrocyte band 3 functions as an anion exchanger. Here, we report the three-dimensional (3D) structure of the membrane domain in an inhibitor-stabilized, outward-open conformation at 18A resolution. Unstained, frozen-hydrated tubular crystals containing the membrane domain of band 3 purified from human red blood cells (hB3MD) were examined using cryo-electron microscopy and iterative helical real-space reconstruction (IHRSR). The 3D image reconstruction of the tubular crystals showed the molecular packing of hB3MD dimers with dimensions of 60 x 110 A in the membrane plane and a thickness of 70A across the membrane. Immunoelectron microscopy and carboxyl-terminal digestion demonstrated that the intracellular surface of hB3MD was exposed on the outer surface of the tubular crystal. A 3D density map revealed that hB3MD consists of at least two subdomains and that the outward-open form is characterized by a large hollow area on the extracellular surface and continuous density on the intracellular surface. (c) 2009 Elsevier Inc. All rights reserved.

Intervertebral disc adaptation to wedging deformation.

PubMed

Stokes, Ian A F; Aronsson, David D; Clark, Katherine C; Roemhildt, Maria L

2006-01-01

Although scoliosis includes wedge deformities of both vertebrae and discs, little is known about the causes of the discal changes, and whether they result from mechanical influences on growth and/or remodelling. An external apparatus attached to transvertebral pins applied compression and 15 degrees of angulation to each of two adjacent young rat caudal intervertebral discs for 5 weeks (four animals), or for 10 weeks (four animals). Each week, micro-CT scanning documented the in vivo discal wedging. After euthanasia, tail segments (three vertebrae and the 2 angulated discs) were excised and their flexibility was measured over a range of lateral bending. The angle of maximum flexibility was recorded. Then discs were fixed in situ (with the external apparatus in place) and sectioned for polarized light microscopy. The disc-wedging deformity averaged 15 degrees initially, it averaged 20 degrees after 5 weeks, and then reduced to 10 degrees (in 10 week animals). The lateral bending flexibility showed a distinct maximum at an average of 1.1 degrees from the in vivo position in the 5-week animals, indicating structural remodeling of the discs almost to the deformed geometry. The 10-week animals had maximum flexibility at 1.4 degrees from the in vivo position (no significant difference between 5 and 10-week animals.) Collagen crimp angles [Cassidy et al., Conn Tiss Res 1989, 23:75-88] were not significantly different between convex and concave sides, again suggesting that remodeling had occurred. In a mechanically induced scoliosis deformity in skeletally immature rats, the intervertebral discs underwent remodeling within 5 weeks. This indicates that this animal model is suitable for studying adaptive wedging changes in human scoliosis.

MMPs-Mediated ECM Remodeling

PubMed

Mali, Aniket V; Joshi, Asavari A; Hegde, Mahabaleshwar V; Kadam, Shivajirao S

2017-04-01

Background: To enhance their own survival, tumor cells can manipulate their microenvironment through remodeling of the extra cellular matrix (ECM). The urokinase-type plasminogen activator (uPA) system catalyzes plasmin production which further mediates activation of matrix metalloproteinases (MMPs) and plays an important role in breast cancer invasion and metastasis through ECM remodeling. This provides a potential target for therapeutic intervention of breast cancer treatment. Enterolactone (EL) is derived from dietary flax lignans in the human body and is known to have anti-breast cancer activity. We here investigated molecular and cellular mechanisms of EL action on the uPA-plasmin- MMPs system. Methods: MTT and trypan blue dye exclusion assays, anchorage-dependent clonogenic assays and wound healing assays were carried out to study effects on cell proliferation and viability, clonogenicity and migration capacity, respectively. Real-time PCR was employed to study gene expression and gelatin zymography was used to assess MMP-2 and MMP-9 activities. All data were statistically analysed and presented as mean ± SEM values. Results: All the findings collectively demonstrated anticancer and antimetastatic potential of EL with antiproliferative, antimigratory and anticlonogenic cellular mechanisms. EL was found to exhibit multiple control of plasmin activation by down-regulating uPA expression and also up-regulating its natural inhibitor, PAI-1, at the mRNA level. Further, EL was found to down-regulate expression of MMP-2 and MMP-9 genes, and up-regulate TIMP-1 and TIMP-2; natural inhibitors of MMP-2 and MMP-9, respectively. This may be as a consequence of inhibition of plasmin activation, resulting in robust control over migration and invasion of breast cancer cells during metastasis. Conclusions: EL suppresses proliferation, migration and metastasis of MDA-MB-231 breast cancer cells by inhibiting induced ECM remodeling by the ‘uPA-plasmin-MMPs system’. Creative

Bone modeling and remodeling: potential as therapeutic targets for the treatment of osteoporosis.

PubMed

Langdahl, Bente; Ferrari, Serge; Dempster, David W

2016-12-01

The adult skeleton is renewed by remodeling throughout life. Bone remodeling is a process where osteoclasts and osteoblasts work sequentially in the same bone remodeling unit. After the attainment of peak bone mass, bone remodeling is balanced and bone mass is stable for one or two decades until age-related bone loss begins. Age-related bone loss is caused by increases in resorptive activity and reduced bone formation. The relative importance of cortical remodeling increases with age as cancellous bone is lost and remodeling activity in both compartments increases. Bone modeling describes the process whereby bones are shaped or reshaped by the independent action of osteoblast and osteoclasts. The activities of osteoblasts and osteoclasts are not necessarily coupled anatomically or temporally. Bone modeling defines skeletal development and growth but continues throughout life. Modeling-based bone formation contributes to the periosteal expansion, just as remodeling-based resorption is responsible for the medullary expansion seen at the long bones with aging. Existing and upcoming treatments affect remodeling as well as modeling. Teriparatide stimulates bone formation, 70% of which is remodeling based and 20-30% is modeling based. The vast majority of modeling represents overflow from remodeling units rather than de novo modeling. Denosumab inhibits bone remodeling but is permissive for modeling at cortex. Odanacatib inhibits bone resorption by inhibiting cathepsin K activity, whereas modeling-based bone formation is stimulated at periosteal surfaces. Inhibition of sclerostin stimulates bone formation and histomorphometric analysis demonstrated that bone formation is predominantly modeling based. The bone-mass response to some osteoporosis treatments in humans certainly suggests that nonremodeling mechanisms contribute to this response and bone modeling may be such a mechanism. To date, this has only been demonstrated for teriparatide, however, it is clear that

Electronegative LDL-mediated cardiac electrical remodeling in a rat model of chronic kidney disease

PubMed Central

Lee, An-Sheng; Chen, Wei-Yu; Chan, Hua-Chen; Chung, Ching-Hu; Peng, Hsien-Yu; Chang, Chia-Ming; Su, Ming-Jai; Chen, Chu-Huang; Chang, Kuan-Cheng

2017-01-01

The mechanisms underlying chronic kidney disease (CKD)–associated higher risks for life-threatening ventricular tachyarrhythmias remain poorly understood. In rats subjected to unilateral nephrectomy (UNx), we examined cardiac electrophysiological remodeling and relevant mechanisms predisposing to ventricular arrhythmias. Adult male Sprague-Dawley rats underwent UNx (n = 6) or sham (n = 6) operations. Eight weeks later, the UNx group had higher serum blood urea nitrogen and creatinine levels and a longer electrocardiographic QTc interval than did the sham group. Patch-clamp studies revealed epicardial (EPI)-predominant prolongation of the action potential duration (APD) at 50% and 90% repolarization in UNx EPI cardiomyocytes compared to sham EPI cardiomyocytes. A significant reduction of the transient outward potassium current (Ito) in EPI but not in endocardial (ENDO) cardiomyocytes of UNx rats led to a decreased transmural gradient of Ito. The reduction of Ito currents in UNx EPI cardiomyocytes was secondary to downregulation of KChIP2 but not Kv4.2, Kv4.3, and Kv1.4 protein expression. Incubation of plasma electronegative low-density lipoprotein (LDL) from UNx rats with normal EPI and ENDO cardiomyocytes recapitulated the electrophysiological phenotype of UNx rats. In conclusion, CKD disrupts the physiological transmural gradient of Ito via downregulation of KChIP2 proteins in the EPI region, which may promote susceptibility to ventricular tachyarrhythmias. Electronegative LDL may underlie downregulation of KChIP2 in CKD. PMID:28094801

Comparison of different hip prosthesis shapes considering micro-level bone remodeling and stress-shielding criteria using three-dimensional design space topology optimization.

PubMed

Boyle, Christopher; Kim, Il Yong

2011-06-03

Since the late 1980s, computational analysis of total hip arthroplasty (THA) prosthesis components has been completed using macro-level bone remodeling algorithms. The utilization of macro-sized elements requires apparent bone densities to predict cancellous bone strength, thereby, preventing visualization and analysis of realistic trabecular architecture. In this study, we utilized a recently developed structural optimization algorithm, design space optimization (DSO), to perform a micro-level three-dimensional finite element bone remodeling simulation on the human proximal femur pre- and post-THA. The computational simulation facilitated direct performance comparison between two commercially available prosthetic implant stems from Zimmer Inc.: the Alloclassic and the Mayo conservative. The novel micro-level approach allowed the unique ability to visualize the trabecular bone adaption post-operation and to quantify the changes in bone mineral content by region. Stress-shielding and strain energy distribution were also quantified for the immediate post-operation and the stably fixated, post-remodeling conditions. Stress-shielding was highest in the proximal region and remained unchanged post-remodeling; conversely, the mid and distal portions show large increases in stress, suggesting a distal shift in the loadpath. The Mayo design conserves bone mass, while simultaneously reducing the incidence of stress-shielding compared to the Alloclassic, revealing a key benefit of the distinctive geometry. Several important factors for stable fixation, determined in clinical evaluations from the literature, were evident in both designs: high levels of proximal bone loss and distal bone densification. The results suggest this novel computational framework can be utilized for comparative hip prosthesis shape, uniquely considering the post-operation bone remodeling as a design criterion. Copyright © 2011 Elsevier Ltd. All rights reserved.

RAMCO Remodel America Corp.Information Sheet

EPA Pesticide Factsheets

RAMCO Remodel America Corp. (the Company) is located in Memphis, Tennessee. The settlement involves renovation activities conducted at a property constructed prior to 1978, located in Memphis, Tennessee.

Gender-related differences in β-adrenergic receptor-mediated cardiac remodeling.

PubMed

Zhu, Baoling; Liu, Kai; Yang, Chengzhi; Qiao, Yuhui; Li, Zijian

2016-12-01

Cardiac remodeling is the pathological basis of various cardiovascular diseases. In this study, we found gender-related differences in β-adrenergic receptor (AR)-mediated pathological cardiac remodeling. Cardiac remodeling model was established by subcutaneous injection of isoprenaline (ISO) for 14 days. Heart rate (HR), mean arterial pressure (MAP), and echocardiography were obtained on 7th and 14th days during ISO administration. Myocardial cross-sectional area and the ratio of heart mass to tibia length (HM/TL) were detected to assess cardiac hypertrophy. Picro-Sirius red staining (picric acid + Sirius red F3B) was used to evaluate cardiac fibrosis. Myocardial capillary density was assessed by immunohistochemistry for von Willebrand factor. Further, real-time PCR was used to measure the expression of β1-AR and β2-AR. Results showed that ISO induced cardiac remodeling, the extent of which was different between female and male mice. The extent of increase in cardiac wall thickness, myocardial cross-sectional area, and collagen deposition in females was less than that in males. However, no gender-related difference was observed in HR, MAP, cardiac function, and myocardial capillary density. The distinctive decrease of β2-AR expression, rather than a decrease of β1-AR expression, seemed to result in gender-related differences in cardiac remodeling.

Study on post occupancy evaluation after remodeling in accordance with the `green remodeling certification standards of existing non-residential buildings'- Focusing on the case of H building

NASA Astrophysics Data System (ADS)

Cho, Kyungjoo; Cho, Dongwoo; Yoon, Yosun

2018-06-01

South Korea has adopted the Paris Convention and promised to reduce greenhouse gas emissions by 37% from business-as-usual (BAU) levels in the `First Basic Plan to Respond to Climate Change'. The reduction goal of greenhouse gas cannot be achieved considering only new buildings; the analysis results shows that the reduction of greenhouse gas emissions from existing buildings is essential. `The Green Remodeling Certification Standards', established in South Korea in 2016, is in line with the above plan. The post-occupancy evaluation (POE) of remodeled buildings after applying the `Green Remodeling Certification Standards of Existing Buildings' must be studied for expansion of this scheme. The study results are expected to be used as foundational data for the promotion of remodeling existing buildings.

Outward Bound in the Professional Education of Teachers. A Study of an Experimental Component in Field Experiences.

ERIC Educational Resources Information Center

Smathers, Keener M.

In an effort to measure the impact of Outward Bound (OB) education on teacher candidates, an 18-day stress experience was arranged for 12 Appalachian State University students and then compared with the effects of the normal 11-week student teacher experiences of two other groups. The OB group underwent a series of individual and group wilderness…

Effects of adaptive servo-ventilation therapy on cardiac function and remodeling in patients with chronic heart failure (SAVIOR-C): study protocol for a randomized controlled trial.

PubMed

Seino, Yoshihiko; Momomura, Shin-Ichi; Kihara, Yasuki; Adachi, Hitoshi; Yasumura, Yoshio; Yokoyama, Hiroyuki

2015-01-16

Adaptive servo-ventilation (ASV) therapy, which is a form of noninvasive positive pressure ventilation therapy and uses an innovative ventilator that has simple operability and provides good patient adherence, potentially has therapeutic benefits-suppression of the deterioration and progression of chronic heart failure (CHF) and a reduction in the number of repeated hospitalizations. Therefore, ASV therapy draws attention as a novel, noninvasive nonpharmacotherapy for patients with CHF owing to its hemodynamics-improving effect, and it is currently being accepted in real-world clinical settings in Japan. However, clinical evidence sufficient for treatment recommendation is lacking because a multicenter, randomized, controlled study of ASV therapy has never been conducted. The present study is a confirmatory, prospective, multicenter, collaborative, open-label, blinded-endpoint, parallel-group, randomized, controlled study. At 40 medical institutions in Japan, 200 Japanese outpatients with mild to severe CHF (age: ≥ 20 years; New York Heart Association classification: greater than or equal to class II) will be randomly assigned to either of the following two study groups: the ASV group, in which 100 outpatients undergo guideline-directed medical therapy and ASV therapy for 24 weeks; and the control group, in which 100 outpatients undergo only guideline-directed medical therapy for 24 weeks. The objective of the present study is to confirm whether the ASV group is superior to the control group concerning the improvement of left ventricular contractility and remodeling, both assessed by two-dimensional echocardiography. Furthermore, the present study will also secondarily examine the effects of ASV therapy on the prognosis and quality of life of patients with CHF. ASV therapy using the device has the potential to provide therapeutic benefits based on its simple operability and good patient adherence and possesses the potential to improve left ventricular

Trefoil factor-2 reverses airway remodeling changes in allergic airways disease.

PubMed

Royce, Simon G; Lim, Clarice; Muljadi, Ruth C; Samuel, Chrishan S; Ververis, Katherine; Karagiannis, Tom C; Giraud, Andrew S; Tang, Mimi L K

2013-01-01

Trefoil factor 2 (TFF2) is a small peptide with an important role in mucosal repair. TFF2 is up-regulated in asthma, suggesting a role in asthma pathogenesis. Given its known biological role in promoting epithelial repair, TFF2 might be expected to exert a protective function in limiting the progression of airway remodeling in asthma. The contribution of TFF2 to airway remodeling in asthma was investigated by examining the expression of TFF2 in the airway and lung, and evaluating the effects of recombinant TFF2 treatment on established airway remodeling in a murine model of chronic allergic airways disease (AAD). BALB/c mice were sensitized and challenged with ovalbumin (OVA) or saline for 9 weeks, whereas mice with established OVA-induced AAD were treated with TFF2 or vehicle control (intranasally for 14 d). Effects on airway remodeling, airway inflammation, and airway hyperresponsiveness were then assessed, whereas TFF2 expression was determined by immunohistochemistry. TFF2 expression was significantly increased in the airways of mice with AAD, compared with expression levels in control mice. TFF2 treatment resulted in reduced epithelial thickening, subepithelial collagen deposition, goblet-cell metaplasia, bronchial epithelium apoptosis, and airway hyperresponsiveness (all P < 0.05, versus vehicle control), but TFF2 treatment did not influence airway inflammation. The increased expression of endogenous TFF2 in response to chronic allergic inflammation is insufficient to prevent the progression of airway inflammation and remodeling in a murine model of chronic AAD. However, exogenous TFF2 treatment is effective in reversing aspects of established airway remodeling. TFF2 has potential as a novel treatment for airway remodeling in asthma.

B.B. Contracting & Remodeling Information Sheet

EPA Pesticide Factsheets

B.B. Contracting & Remodeling (the Company) is located in St. Louis, Missouri. The settlement involves renovation activities conducted at property constructed prior to 1978, located in St. Louis, Missouri.

Matrix remodeling between cells and cellular interactions with collagen bundle

NASA Astrophysics Data System (ADS)

Kim, Jihan; Sun, Bo

When cells are surrounded by complex environment, they continuously probe and interact with it by applying cellular traction forces. As cells apply traction forces, they can sense rigidity of their local environment and remodel the matrix microstructure simultaneously. Previous study shows that single human carcinoma cell (MDA-MB-231) remodeled its surrounding extracellular matrix (ECM) and the matrix remodeling was reversible. In this study we examined the matrix microstructure between cells and cellular interaction between them using quantitative confocal microscopy. The result shows that the matrix microstructure is the most significantly remodeled between cells consisting of aligned, and densified collagen fibers (collagen bundle)., the result shows that collagen bundle is irreversible and significantly change micromechanics of ECM around the bundle. We further examined cellular interaction with collagen bundle by analyzing dynamics of actin and talin formation along with the direction of bundle. Lastly, we analyzed dynamics of cellular protrusion and migrating direction of cells along the bundle.

Drosophila Brahma complex remodels nucleosome organizations in multiple aspects.

PubMed

Shi, Jiejun; Zheng, Meizhu; Ye, Youqiong; Li, Min; Chen, Xiaolong; Hu, Xinjie; Sun, Jin; Zhang, Xiaobai; Jiang, Cizhong

2014-09-01

ATP-dependent chromatin remodeling complexes regulate nucleosome organizations. In Drosophila, gene Brm encodes the core Brahma complex, the ATPase subunit of SWI/SNF class of chromatin remodelers. Its role in modulating the nucleosome landscape in vivo is unclear. In this study, we knocked down Brm in Drosophila third instar larvae to explore the changes in nucleosome profiles and global gene transcription. The results show that Brm knockdown leads to nucleosome occupancy changes throughout the entire genome with a bias in occupancy decrease. In contrast, the knockdown has limited impacts on nucleosome position shift. The knockdown also alters another important physical property of nucleosome positioning, fuzziness. Nucleosome position shift, gain or loss and fuzziness changes are all enriched in promoter regions. Nucleosome arrays around the 5' ends of genes are reorganized in five patterns as a result of Brm knockdown. Intriguingly, the concomitant changes in the genes adjacent to the Brahma-dependent remodeling regions have important roles in development and morphogenesis. Further analyses reveal abundance of AT-rich motifs for transcription factors in the remodeling regions. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Thymosin β4 has a major role in dermal burn wound healing that involves actin cytoskeletal remodelling via heat-shock protein 70.

PubMed

Kim, Sokho; Kwon, Jungkee

2017-04-01

Rapid vascular remodelling of damaged dermal tissue is required to heal burn wounds. Thymosin β4 (Tβ4) is a growth factor that has been shown to promote angiogenesis and dermal wound repair. However, the underlying mechanisms based on Tβ4 function have not yet been fully investigated. In the present study, we investigated how Tβ4 improves dermal burn wound healing via actin cytoskeletal remodelling and the action of heat-shock proteins (HSPs), which are a vital set of chaperone proteins that respond to heat shock. Our in vitro results achieved with the use of human umbilical vein endothelial cells (HUVECs) revealed a possible signal between Tβ4 and HSP70. Moreover, we confirmed that remodelling of filamentous actin (F-actin) was regulated by Tβ4-induced HSP70 in HUVECs. Based on these in vitro results, we confirmed the healing effects of Tβ4 in an adapted dermal burn wound in vivo model. Tβ4 improved wound-healing markers, such as wound closure and vascularization. Moreover, Tβ4 maintained the long-term expression of HSP70, which is associated with F-actin regulation during the wound-healing period. These results suggest that an association between Tβ4 and HSP70 is responsible for the healing of burn wounds, and that this association may regulate F-actin remodelling. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

A homeostatic-driven turnover remodelling constitutive model for healing in soft tissues

PubMed Central

Gasser, T. Christian; Bellomo, Facundo J.

2016-01-01

Remodelling of soft biological tissue is characterized by interacting biochemical and biomechanical events, which change the tissue's microstructure, and, consequently, its macroscopic mechanical properties. Remodelling is a well-defined stage of the healing process, and aims at recovering or repairing the injured extracellular matrix. Like other physiological processes, remodelling is thought to be driven by homeostasis, i.e. it tends to re-establish the properties of the uninjured tissue. However, homeostasis may never be reached, such that remodelling may also appear as a continuous pathological transformation of diseased tissues during aneurysm expansion, for example. A simple constitutive model for soft biological tissues that regards remodelling as homeostatic-driven turnover is developed. Specifically, the recoverable effective tissue damage, whose rate is the sum of a mechanical damage rate and a healing rate, serves as a scalar internal thermodynamic variable. In order to integrate the biochemical and biomechanical aspects of remodelling, the healing rate is, on the one hand, driven by mechanical stimuli, but, on the other hand, subjected to simple metabolic constraints. The proposed model is formulated in accordance with continuum damage mechanics within an open-system thermodynamics framework. The numerical implementation in an in-house finite-element code is described, particularized for Ogden hyperelasticity. Numerical examples illustrate the basic constitutive characteristics of the model and demonstrate its potential in representing aspects of remodelling of soft tissues. Simulation results are verified for their plausibility, but also validated against reported experimental data. PMID:27009177

A homeostatic-driven turnover remodelling constitutive model for healing in soft tissues.

PubMed

Comellas, Ester; Gasser, T Christian; Bellomo, Facundo J; Oller, Sergio

2016-03-01

Remodelling of soft biological tissue is characterized by interacting biochemical and biomechanical events, which change the tissue's microstructure, and, consequently, its macroscopic mechanical properties. Remodelling is a well-defined stage of the healing process, and aims at recovering or repairing the injured extracellular matrix. Like other physiological processes, remodelling is thought to be driven by homeostasis, i.e. it tends to re-establish the properties of the uninjured tissue. However, homeostasis may never be reached, such that remodelling may also appear as a continuous pathological transformation of diseased tissues during aneurysm expansion, for example. A simple constitutive model for soft biological tissues that regards remodelling as homeostatic-driven turnover is developed. Specifically, the recoverable effective tissue damage, whose rate is the sum of a mechanical damage rate and a healing rate, serves as a scalar internal thermodynamic variable. In order to integrate the biochemical and biomechanical aspects of remodelling, the healing rate is, on the one hand, driven by mechanical stimuli, but, on the other hand, subjected to simple metabolic constraints. The proposed model is formulated in accordance with continuum damage mechanics within an open-system thermodynamics framework. The numerical implementation in an in-house finite-element code is described, particularized for Ogden hyperelasticity. Numerical examples illustrate the basic constitutive characteristics of the model and demonstrate its potential in representing aspects of remodelling of soft tissues. Simulation results are verified for their plausibility, but also validated against reported experimental data. © 2016 The Author(s).

Cardiac structural changes and electrical remodeling in a thiamine-deficiency model in rats.

PubMed

Roman-Campos, D; Campos, A C; Gioda, C R; Campos, P P; Medeiros, M A A; Cruz, J S

2009-06-05

Thiamine is an important cofactor present in many biochemical reactions, and its deprivation can lead to heart dysfunction. Little is known about the influence of thiamine deprivation on the electrophysiological behavior of the isolated heart cells and information about thiamine deficiency in heart morphology is controversial. Thus, we decided to investigate the major repolarizing conductances and their influence in the action potential (AP) waveform as well as the changes in the heart structure in a set of thiamine deficiency in rats. Using the patch-clamp technique, we investigated inward (I(K1)) and outward K(+) currents (I(to)), T-type and L-type Ca(2+) currents and APs. To evaluate heart morphology we used hematoxylin and eosin in transversal heart sections. Thiamine deficiency caused a marked decrease in left ventricle thickness, cardiomyocyte number, cell length and width, and membrane capacitance. When evaluating I(to) we did not find difference in current amplitude; however an acceleration of I(to) inactivation was observed. I(K1) showed a reduction in the amplitude and slope conductance, which implicated a less negative resting membrane potential in cardiac myocytes isolated from thiamine-deficient rats. We did not find any difference in L-type Ca(2+) current density. T-type Ca(2+) current was not observed. In addition, we did not observe significant changes in AP repolarization. Based on our study we can conclude that thiamine deficiency causes heart hypotrophy and not heart hypertrophy. Moreover, we provided evidence that there is no major electrical remodeling during thiamine deficiency, a feature of heart failure models.

Cell Wall Remodeling by a Synthetic Analog Reveals Metabolic Adaptation in Vancomycin Resistant Enterococci.

PubMed

Pidgeon, Sean E; Pires, Marcos M

2017-07-21

Drug-resistant bacterial infections threaten to overburden our healthcare system and disrupt modern medicine. A large class of potent antibiotics, including vancomycin, operate by interfering with bacterial cell wall biosynthesis. Vancomycin-resistant enterococci (VRE) evade the blockage of cell wall biosynthesis by altering cell wall precursors, rendering them drug insensitive. Herein, we reveal the phenotypic plasticity and cell wall remodeling of VRE in response to vancomycin in live bacterial cells via a metabolic probe. A synthetic cell wall analog was designed and constructed to monitor cell wall structural alterations. Our results demonstrate that the biosynthetic pathway for vancomycin-resistant precursors can be hijacked by synthetic analogs to track the kinetics of phenotype induction. In addition, we leveraged this probe to interrogate the response of VRE cells to vancomycin analogs and a series of cell wall-targeted antibiotics. Finally, we describe a proof-of-principle strategy to visually inspect drug resistance induction. Based on our findings, we anticipate that our metabolic probe will play an important role in further elucidating the interplay among the enzymes involved in the VRE biosynthetic rewiring.

Delayed expression of cytokines after reperfused myocardial infarction: possible trigger for cardiac dysfunction and ventricular remodeling.

PubMed

Moro, Cécile; Jouan, Marie-Gabrielle; Rakotovao, Andry; Toufektsian, Marie-Claire; Ormezzano, Olivier; Nagy, Norbert; Tosaki, Arpad; de Leiris, Joël; Boucher, François

2007-11-01

Previous studies have shown that 1 wk after permanent coronary artery ligation in rats, some cellular mechanisms involving TNF-alpha occur and contribute to the development of cardiac dysfunction and subsequent heart failure. The aim of the present study was to determine whether similar phenomena also occur after ischemia-reperfusion and whether cytokines other than TNF-alpha can also be involved. Anesthetized male Wistar rats were subjected to 1 h coronary occlusion followed by reperfusion. Cardiac geometry and function were assessed by echocardiography at days 5, 7, 8, and 10 postligation. Before death, heart function was assessed in vivo under basal conditions, as well as after volume overload. Finally, hearts were frozen for histoenzymologic assessment of infarct size and remodeling. The profile of cardiac cytokines was determined by ELISA and ChemiArray on heart tissue extracts. As expected, ischemia-reperfusion induced a progressive remodeling of the heart, characterized by left ventricular free-wall thinning and cavity dilation. Heart function was also decreased in ischemic rats during the first week after surgery. Interestingly, a transient and marked increase in TNF-alpha, IL-1beta, IL-6, cytokine-induced neutrophil chemoattractant (CINC) 2, CINC3, and macrophage inflammatory protein-3alpha was also observed in the myocardium of myocardial ischemia (MI) animals at day 8, whereas the expression of anti-inflammatory interleukins IL-4 and IL-10 remained unchanged. These results suggest that overexpression of proinflammatory cytokines occurring during the first week after ischemia-reperfusion may play a role in the adaptative process in the myocardium and contribute to early dysfunction and remodeling.

Profilin-1 Promotes the Development of Hypertension-induced Artery Remodeling

PubMed Central

Wang, Yan; Zhang, Jun; Gao, Haiqing; Zhao, Shaohua; Ji, Xiang; Liu, Xiangju; You, Beian; Li, Xiao

2014-01-01

Hypertension is associated with the structural remodeling and stiffening of arteries and is known to increase cardiovascular risk. In the present study, we investigated the effects of overexpression and knock down of profilin-1 on the vascular structural remodeling in spontaneous hypertensive rats (SHRs) using an adenovirus injection to knock down or overexpress profilin-1 mRNA. As a control, blank adenovirus was injected into age-matched SHRs and Wistar-Kyoto rats (WKYs). We quantified arterial structural remodeling through morphological methods, with thoracic aortas stained with hematoxylin–eosin and picosirius red. Western blotting was performed to measure the protein expression of inducible nitric oxide synthase (iNOS) and p38 mitogen-activated protein kinase (p38), and peroxynitrite was quantified by immunohistochemical staining. Overexpression of profilin-1 significantly promoted aortic remodeling, including an increase in vessel size, wall thickness, and collagen content, whereas the knockdown of profilin-1 could reverse these effects. In addition, the expression of phosphorylated p38, iNOS and peroxynitrite was significantly upregulated in SHRs with profilin-1 overexpression along with an increased level of interleukin- 6 (IL-6). These changes could be reversed by knockdown of profilin-1. Our results demonstrate a crucial role for profilin-1 in hypertension-induced arterial structural remodeling at least in part through the p38–iNOS–peroxynitrite pathway. PMID:24399041

Dynamic microtubules drive circuit rewiring in the absence of neurite remodeling

PubMed Central

Kurup, Naina; Yan, Dong; Goncharov, Alexandr; Jin, Yishi

2015-01-01

A striking neuronal connectivity change in C. elegans involves the coordinated elimination of existing synapses and formation of synapses at new locations, without altering neuronal morphology. Here, we investigate the tripartite interaction between dynamic microtubules (MTs), kinesin-1, and vesicular cargo during this synapse remodeling. We find that a reduction in the dynamic MT population in motor neuron axons, resulting from genetic interaction between loss of function in the conserved MAPKKK dlk-1 and an α-tubulin mutation, specifically blocks synapse remodeling. Using live imaging and pharmacological modulation of the MT cytoskeleton, we show that dynamic MTs are increased at the onset of remodeling and are critical for new synapse formation. DLK-1 acts during synapse remodeling, and its function involves MT catastrophe factors including kinesin-13/KLP-7 and spastin/SPAS-1. Through a forward genetic screen, we identify gain-of-function mutations in kinesin-1 that can compensate for reduced dynamic MTs to promote synaptic vesicle transport during remodeling. Our data provide in vivo evidence supporting the requirement of dynamic MTs for kinesin-1 dependent axonal transport and shed insight on the role of the MT cytoskeleton in facilitating neural circuit plasticity. PMID:26051896

Myonuclear domains in muscle adaptation and disease

NASA Technical Reports Server (NTRS)

Allen, D. L.; Roy, R. R.; Edgerton, V. R.

1999-01-01

Adult skeletal muscle fibers are among the few cell types that are truly multinucleated. Recently, evidence has accumulated supporting a role for the modulation of myonuclear number during muscle remodeling in response to injury, adaptation, and disease. These studies have demonstrated that muscle hypertrophy is associated with, and is dependent on, the addition of newly formed myonuclei via the fusion of myogenic cells to the adult myofiber, whereas muscle atrophy and disease appear to be associated with the loss of myonuclei, possibly through apoptotic-like mechanisms. Moreover, these studies also have demonstrated that myonuclear domain size, i. e., the amount of cytoplasm per myonucleus, is unchanged following the acute phase of hypertrophy but is reduced following atrophy. Together these data demonstrate that modulation of myonuclear number or myonuclear domain size (or both) is a mechanism contributing to the remodeling of adult skeletal muscle in response to alterations in the level of normal neuromuscular activity. Copyright 1999 John Wiley & Sons, Inc.

Impact of positive and negative lesion site remodeling on clinical outcomes: insights from PROSPECT.

PubMed

Inaba, Shinji; Mintz, Gary S; Farhat, Naim Z; Fajadet, Jean; Dudek, Dariusz; Marzocchi, Antonio; Templin, Barry; Weisz, Giora; Xu, Ke; de Bruyne, Bernard; Serruys, Patrick W; Stone, Gregg W; Maehara, Akiko

2014-01-01

This study investigated coronary artery remodeling patterns associated with clinical outcomes. In the prospective, multicenter PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree: An Imaging Study in Patients With Unstable Atherosclerotic Lesions) study, reported predictors of nonculprit lesion (NCL) major adverse cardiac events (MACE) were an intravascular ultrasound (IVUS) minimal lumen area (MLA) ≤4 mm(2), a plaque burden ≥70%, and a IVUS-virtual histology (VH) thin-cap fibroatheroma (TCFA), but not lesion site remodeling. Overall, 697 consecutive patients with an acute coronary syndrome were enrolled and underwent 3-vessel gray-scale and IVUS-VH; 3,223 NCLs were identified by IVUS. The remodeling index (RI) was calculated as the external elastic membrane area at the MLA site divided by the average of the proximal and distal reference external elastic membrane areas. First, one third of the patients were randomly selected to determine RI cutoffs related to NCL MACE (development cohort). Receiver-operating characteristic analysis showed that there were 2 separate cut points that predicted NCL MACE: RI = 0.8789 and RI = 1.0046 (area under the curve = 0.663). These cut points were used to define negative remodeling as an RI <0.88, intermediate remodeling as an RI of 0.88 to 1.00, and positive remodeling as an RI >1.00. Second, we used the remaining two-thirds of patients to validate these cut points with respect to lesion morphology and clinical outcomes (validation cohort). Kaplan-Meier curve analysis in the validation cohort showed that NCL MACE occurred more frequent (and equally) in negative and positive remodeling lesions compared with intermediate remodeling lesions. In this cohort, negative remodeling lesions had the smallest MLA, positive remodeling lesions had the largest plaque burden, and VH TCFA, especially VH TCFA with multiple necrotic cores, was most common in negatively remodeling lesions. The present

Mechanisms of Post-Infarct Left Ventricular Remodeling

PubMed Central

French, Brent A.; Kramer, Christopher M.

2008-01-01

Heart failure secondary to myocardial infarction (MI) remains a major source of morbidity and mortality. Long-term outcome after MI can be largely be defined in terms of its impact on the size and shape of the left ventricle (i.e., LV remodeling). Three major mechanisms contribute to LV remodeling: 1) early infarct expansion, 2) subsequent infarct extension into adjacent noninfarcted myocardium, and 3) late hypertrophy in the remote LV. Future developments in preventing post-MI heart failure will depend not only on identifying drugs targeting each of these individual mechanisms, but also on diagnostic techniques capable of assessing efficacy against each mechanism. PMID:18690295

Phase field approaches of bone remodeling based on TIP

NASA Astrophysics Data System (ADS)

Ganghoffer, Jean-François; Rahouadj, Rachid; Boisse, Julien; Forest, Samuel

2016-01-01

The process of bone remodeling includes a cycle of repair, renewal, and optimization. This adaptation process, in response to variations in external loads and chemical driving factors, involves three main types of bone cells: osteoclasts, which remove the old pre-existing bone; osteoblasts, which form the new bone in a second phase; osteocytes, which are sensing cells embedded into the bone matrix, trigger the aforementioned sequence of events. The remodeling process involves mineralization of the bone in the diffuse interface separating the marrow, which contains all specialized cells, from the newly formed bone. The main objective advocated in this contribution is the setting up of a modeling and simulation framework relying on the phase field method to capture the evolution of the diffuse interface between the new bone and the marrow at the scale of individual trabeculae. The phase field describes the degree of mineralization of this diffuse interface; it varies continuously between the lower value (no mineral) and unity (fully mineralized phase, e.g. new bone), allowing the consideration of a diffuse moving interface. The modeling framework is the theory of continuous media, for which field equations for the mechanical, chemical, and interfacial phenomena are written, based on the thermodynamics of irreversible processes. Additional models for the cellular activity are formulated to describe the coupling of the cell activity responsible for bone production/resorption to the kinetics of the internal variables. Kinetic equations for the internal variables are obtained from a pseudo-potential of dissipation. The combination of the balance equations for the microforce associated to the phase field and the kinetic equations lead to the Ginzburg-Landau equation satisfied by the phase field with a source term accounting for the dissipative microforce. Simulations illustrating the proposed framework are performed in a one-dimensional situation showing the evolution of

Potential adverse cardiac remodelling in highly trained athletes: still unknown clinical significance.

PubMed

Gabrielli, Luigi; Sitges, Marta; Chiong, Mario; Jalil, Jorge; Ocaranza, María; Llevaneras, Silvana; Herrera, Sebastian; Fernandez, Rodrigo; Saavedra, Rodrigo; Yañez, Fernando; Vergara, Luis; Diaz, Alexis; Lavandero, Sergio; Castro, Pablo

2018-06-12

Moderate endurance exercise has long been considered an essential element to maintain cardiovascular health, and sedentary behaviour in the general population has been related to a significant increase in all-causes of mortality, cardiovascular disease mortality and cardiovascular disease incidence. However, a growing group of people performs an intense exercise that leads to multiple heart adaptive changes that are collectively called "athlete's heart". In this review, we discussed the evidence of cardiac remodelling process secondary to repetitive and strenuous exercise in some predisposed athletes that produces intense and probably deleterious changes in cardiac morphology and function with no clear clinical significance in long-term follow-up. Moreover, we also discussed the individual biological response to exercise assessed by myocardial damage, inflammation, oxidative stress, fibrosis and ventricular hypertrophy biomarkers showing different intensities with equivalent exertion.

Periprosthetic bone remodelling of short-stem total hip arthroplasty: a systematic review.

PubMed

Yan, Shuang G; Weber, Patrick; Steinbrück, Arnd; Hua, Xingyi; Jansson, Volkmar; Schmidutz, Florian

2017-11-27

Short-stem hip arthroplasty (SHA) was designed to preserve bone stock and provide an improved load transfer. To gain more evidence regarding the load transfer, this review analysed the periprosthetic bone remodelling of SHA in comparison to standard hip arthroplasty (THA). PubMed and ScienceDirect were screened to extract dual-energy X-ray absorptiometry (DXA) studies evaluating the periprosthetic bone remodelling of SHA and two proven THA designs. From the studies included, the postoperative change in periprosthetic bone mineral density (BMD) after one year and the trend over two years was determined. Fifteen studies with four SHAs (CFP, Metha, Nanos, Fitmore) and two THAs (CLS and Bicontact) designs were included. All SHA and THA stems revealed an initial decrease at the calcar and major trochanter (Gruen 1 and 7) with the Metha, Nanos and Fitmore showing a smaller and more balanced remodelling compared to THA. The pattern after one year and the trend over two years argue for a methaphyseal anchorage of the Metha and Nanos, whereas the Fitmore and CFP seem to anchor metha-diaphyseal. Clearly different pattern of bone remodelling were observed between all four SHAs. Periprosthetic bone remodelling is also present in SHA, with the main bone reduction observed proximally. However, certain SHA stems show a more balanced remodelling compared to THA, arguing for a favourable load transfer. Also, the femoral length where bone remodelling occurs is clearly shorter in SHA. As distinctively different pattern between the SHA designs were observed, they should not be judged as a single implant group.

IRAK4 deficiency promotes cardiac remodeling induced by pressure overload

PubMed Central

Yuan, Yuan; Gan, Huawen; Dai, Jia; Zhou, Heng; Deng, Wei; Zong, Jing; Bian, Zhouyan; Liao, Haihan; Li, Hongliang; Tang, Qizhu

2015-01-01

Background: Interluekin1 receptor-associated kinase-4 (IRAK4) plays an essential role in the innate immune system. The aim of this study was to investigate the role of IRAK4 in cardiac remodeling induced by pressure overload and elucidate the underlying mechanisms. Methods: In vivo studies were performed using IRAK4 heterozygous knockout (HET) mice and wild type (WT) mice. Models of cardiac remodeling were induced by aortic banding (AB). Cardiac remodeling was evaluated by Echocardiography and histological analysis. Results: IRAK4 was upregulated in hearts of dilated cardiomyopathy (DCM) patients and also pressure overload-induced mice hearts. IRAK4 HET mice exhibited exacerbated cardiac hypertrophy, dysfunction and fibrosis after 4 weeks of AB compared with that in WT mice. Furthermore, enhanced activation of the MEK-ERK1/2, p38 and NFκB pathways was found in IRAK4 HET mice compared to WT mice. Conclusion: Our results suggest that IRAK4 may play a crucial role in the development of cardiac remodeling via negative regulation of multiple signaling pathways. PMID:26884959

Polycyclic aromatic hydrocarbons, tobacco smoke, and epigenetic remodeling in asthma

PubMed Central

Klingbeil, E. C.; Hew, K. M.; Nygaard, U. C.; Nadeau, K. C.

2014-01-01

Environmental determinants including aerosolized pollutants such as polycyclic aromatic hydrocarbons (PAHs) and tobacco smoke have been associated with exacerbation and increased incidence of asthma. The influence of aerosolized pollutants on the development of immune dysfunction in asthmatics has been suggested to be mediated through epigenetic remodeling. Genome accessibility and transcription are regulated primarily through DNA methylation, histone modification, and microRNA transcript silencing. Epigenetic remodeling has been shown in studies to be associated with Th2 polarization and associated cytokine and chemokine regulation in the development of asthma. This review will present evidence for the contribution of the aerosolized pollutants PAH and environmental tobacco smoke to epigenetic remodeling in asthma. PMID:24760221

Differential remodelling of peroxisome function underpins the environmental and metabolic adaptability of diplonemids and kinetoplastids.

PubMed

Morales, Jorge; Hashimoto, Muneaki; Williams, Tom A; Hirawake-Mogi, Hiroko; Makiuchi, Takashi; Tsubouchi, Akiko; Kaga, Naoko; Taka, Hikari; Fujimura, Tsutomu; Koike, Masato; Mita, Toshihiro; Bringaud, Frédéric; Concepción, Juan L; Hashimoto, Tetsuo; Embley, T Martin; Nara, Takeshi

2016-05-11

The remodelling of organelle function is increasingly appreciated as a central driver of eukaryotic biodiversity and evolution. Kinetoplastids including Trypanosoma and Leishmania have evolved specialized peroxisomes, called glycosomes. Glycosomes uniquely contain a glycolytic pathway as well as other enzymes, which underpin the physiological flexibility of these major human pathogens. The sister group of kinetoplastids are the diplonemids, which are among the most abundant eukaryotes in marine plankton. Here we demonstrate the compartmentalization of gluconeogenesis, or glycolysis in reverse, in the peroxisomes of the free-living marine diplonemid, Diplonema papillatum Our results suggest that peroxisome modification was already under way in the common ancestor of kinetoplastids and diplonemids, and raise the possibility that the central importance of gluconeogenesis to carbon metabolism in the heterotrophic free-living ancestor may have been an important selective driver. Our data indicate that peroxisome modification is not confined to the kinetoplastid lineage, but has also been a factor in the success of their free-living euglenozoan relatives. © 2016 The Author(s).

Molecular Imaging of Activated Matrix Metalloproteinases in Vascular Remodeling

PubMed Central

Zhang, Jiasheng; Nie, Lei; Razavian, Mahmoud; Ahmed, Masood; Dobrucki, Lawrence W.; Asadi, Abolfazl; Edwards, D. Scott; Azure, Michael; Sinusas, Albert J.; Sadeghi, Mehran M.

2008-01-01

Background Matrix metalloproteinase (MMP) activation plays a key role in vascular remodeling. RP782 is a novel 111In –labeled tracer with specificity for activated MMPs. We hypothesized that RP782 can detect injury-induced vascular remodeling in vivo. Methods and Results Left common carotid artery injury was induced using a guide wire in apolipoprotein E-/- mice. Sham surgery was performed on the contralateral artery, which served as control for imaging experiments. Carotid wire injury led to significant hyperplasia and expansive remodeling over a period of 4 weeks. MMP activity detected by in-situ zymography, increased in response to injury and was maximal by 3-4 weeks after injury. RP782 (11.1 MBq) was injected intravenously to apolipoprotein E-/- mice at 1, 2, 3, and 4 weeks after left carotid injury. MicroSPECT imaging was performed at 2 hours and was followed by CT angiography to localize the carotid arteries. In vivo images revealed focal uptake of RP782 in the injured carotid artery at 2, 3 and 4 weeks. Increased tracer uptake in the injured artery was confirmed by quantitative autoradiography. Pretreatment with 50-fold excess non-labeled tracer significantly reduced RP782 uptake in injured carotids, demonstrating uptake specificity. Weekly changes in the vessel wall area closely paralleled and correlated with RP782 uptake (Spearman r=0.95, p=0.001). Conclusions Injury-induced MMP activation in the vessel wall can be detected by RP782 microSPECT/CT imaging in vivo. RP782 uptake tracks the hyperplastic process in vascular remodeling, and provides an opportunity to track the remodeling process in vivo. PMID:18936327

Regulator of calcineurin 1 mediates pathological vascular wall remodeling

PubMed Central

Esteban, Vanesa; Méndez-Barbero, Nerea; Jesús Jiménez-Borreguero, Luis; Roqué, Mercè; Novensá, Laura; Belén García-Redondo, Ana; Salaices, Mercedes; Vila, Luis; Arbonés, María L.

2011-01-01

Artery wall remodeling, a major feature of diseases such as hypertension, restenosis, atherosclerosis, and aneurysm, involves changes in the tunica media mass that reduce or increase the vessel lumen. The identification of molecules involved in vessel remodeling could aid the development of improved treatments for these pathologies. Angiotensin II (AngII) is a key effector of aortic wall remodeling that contributes to aneurysm formation and restenosis through incompletely defined signaling pathways. We show that AngII induces vascular smooth muscle cell (VSMC) migration and vessel remodeling in mouse models of restenosis and aneurysm. These effects were prevented by pharmacological inhibition of calcineurin (CN) or lentiviral delivery of CN-inhibitory peptides. Whole-genome analysis revealed >1,500 AngII-regulated genes in VSMCs, with just 11 of them requiring CN activation. Of these, the most sensitive to CN activation was regulator of CN 1 (Rcan1). Rcan1 was strongly activated by AngII in vitro and in vivo and was required for AngII-induced VSMC migration. Remarkably, Rcan1−/− mice were resistant to AngII-induced aneurysm and restenosis. Our results indicate that aneurysm formation and restenosis share mechanistic elements and identify Rcan1 as a potential therapeutic target for prevention of aneurysm and restenosis progression. PMID:21930771

Age-related motor unit remodeling in the Tibialis Anterior.

PubMed

Siddiqi, Ariba; Kumar, Dinesh; Arjunan, Sridhar

2015-01-01

Limited studies exist on the use of surface electromyogram (EMG) signal features to detect age-related motor unit remodeling in the Tibialis Anterior. Motor unit remodeling leads to declined muscle strength and force steadiness during submaximal contractions which are factors for risk of falls in the elderly. This study investigated the remodeling phenomena in the Tibialis Anterior using sample entropy and higher order statistics. Eighteen young (26.1 ± 2.9 years) and twelve elderly (68.7 ± 9.0 years) participants performed isometric dorsiflexion of the ankle at 20% maximal voluntary contraction (MVC) and their Tibialis Anterior (TA) EMG was recorded. Sample entropy, Gaussianity and Linearity Test statistics were calculated from the recorded EMG for each MVC. Shapiro-Wilk test was used to determine normality, and either a two-tail student t-test or Wilcoxon rank sum test was performed to determine significant difference in the EMG features between the young and old cohorts. Results show age-related motor unit remodeling to be depicted by decreased sample entropy (p <; 0.1), increased non-Gaussianity (p <; 0.05) and lesser degree of linearity in the elderly. This is due to the increased sparsity of the MUAPs as a result of the denervation-reinnervation process, and the decrease in total number of motor units.

Non-Equilibrium Cytoquake Dynamics in Cytoskeletal Remodeling and Stabilization

PubMed Central

Alencar, Adriano Mesquita; Ferraz, Mariana Sacrini Ayres; Park, Chan Young; Millet, Emil; Trepat, Xavier; Butler, James P.; Fredberg, Jeffrey J.

2016-01-01

The cytoskeleton (CSK) is a tensed fiber framework that supports, shapes and stabilizes the cell. The CSK is in a constant state of remodeling, moreover, which is an active non-equilibrium thermodynamic process. We report here that cytoskeletal remodeling involves reconfigurations that are not only sudden but also are transmitted to great distances within the cell in a fashion reminiscent of quakes in the Earth's crust. Remarkably, these events in the cell conform both qualitatively and quantitatively to empirical laws typical of earthquakes, including hierarchical fault structures, cumulative energy distributions following the Gutenberg-Richter law, and rate of after-shocks following Omori's law. While it is well-established that remodeling and stabilization of the cytoskeleton are non-equilibrium process, these new unanticipated observations establish that these processes are also remarkably non-local and strongly cooperative. PMID:27722665

Glucocorticoid suppression of osteocyte perilacunar remodeling is associated with subchondral bone degeneration in osteonecrosis

DOE PAGES

Fowler, Tristan W.; Acevedo, Claire; Mazur, Courtney M.; ...

2017-03-22

Through a process called perilacunar remodeling, bone-embedded osteocytes dynamically resorb and replace the surrounding perilacunar bone matrix to maintain mineral homeostasis. The vital canalicular networks required for osteocyte nourishment and communication, as well as the exquisitely organized bone extracellular matrix, also depend upon perilacunar remodeling. Nonetheless, many questions remain about the regulation of perilacunar remodeling and its role in skeletal disease. We find that suppression of osteocyte-driven perilacunar remodeling, a fundamental cellular mechanism, plays a critical role in the glucocorticoid-induced osteonecrosis. In glucocorticoid-treated mice, we find that glucocorticoids coordinately suppress expression of several proteases required for perilacunar remodeling while causingmore » degeneration of the osteocyte lacunocanalicular network, collagen disorganization, and matrix hypermineralization; all of which are apparent in human osteonecrotic lesions. Therefore, osteocyte-mediated perilacunar remodeling maintains bone homeostasis, is dysregulated in skeletal disease, and may represent an attractive therapeutic target for the treatment of osteonecrosis.« less

Glucocorticoid suppression of osteocyte perilacunar remodeling is associated with subchondral bone degeneration in osteonecrosis

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

Fowler, Tristan W.; Acevedo, Claire; Mazur, Courtney M.

Through a process called perilacunar remodeling, bone-embedded osteocytes dynamically resorb and replace the surrounding perilacunar bone matrix to maintain mineral homeostasis. The vital canalicular networks required for osteocyte nourishment and communication, as well as the exquisitely organized bone extracellular matrix, also depend upon perilacunar remodeling. Nonetheless, many questions remain about the regulation of perilacunar remodeling and its role in skeletal disease. We find that suppression of osteocyte-driven perilacunar remodeling, a fundamental cellular mechanism, plays a critical role in the glucocorticoid-induced osteonecrosis. In glucocorticoid-treated mice, we find that glucocorticoids coordinately suppress expression of several proteases required for perilacunar remodeling while causingmore » degeneration of the osteocyte lacunocanalicular network, collagen disorganization, and matrix hypermineralization; all of which are apparent in human osteonecrotic lesions. Therefore, osteocyte-mediated perilacunar remodeling maintains bone homeostasis, is dysregulated in skeletal disease, and may represent an attractive therapeutic target for the treatment of osteonecrosis.« less

Transient outward currents and changes of their gating properties after cell activation in thrombocytes of the newt.

PubMed Central

Kawa, K

1987-01-01

1. The electrical properties of the cell membrane of thrombocytes in the newt, Triturus pyrrhogaster, were studied using the whole-cell variation of the patch-electrode voltage-clamp technique. 2. In medium containing Ca2+ (1.8 mM), activated thrombocytes became round and then spread on the glass. Activation of thrombocytes was inhibited by the removal of external Ca2+ and addition of 1 w/v% albumin to the external media. 3. For thrombocytes kept in the resting state, depolarizations more positive than -30 mV evoked transient outward currents which decayed completely during the duration of the depolarization (150 ms). The half-decay time of the currents became smaller as the depolarizing pulse strengthened, reaching about 20 ms at +30 mV (20 degrees C). 4. The outward currents are identified as K+ currents, since (1) their reversal potential depended on extracellular K+ concentration and (2) the outward currents were suppressed either by external application of 4-aminopyridine (1 mM) or by internal application of Cs+ (120 mM). The monovalent cation selectivities of the K+ channels were evaluated from the reversal potential as Tl (1.68) greater than K(1.0) greater than Rb (0.89) greater than NH4 (0.13) greater than Na(less than 0.03). 5. When the thrombocytes had been activated, depolarization again evoked K+ currents. The currents, however, showed negligible or small decay during the duration of the depolarization (150 ms). The rate of recovery from preceding depolarization was also reduced to about one-sixth. 6. The sensitivity to 4-aminopyridine and the selectivity of the K+ channels were not changed by cell activation. 7. We conclude that during activation of thrombocytes the inactivation of the K+ channels is almost eliminated. Removal of inactivation of the K+ channels was also induced in resting thrombocytes by intracellular application of 4-bromoacetamide (50 microM). PMID:2443665

Mechanical remodeling of normally sized mammalian cells under a gravity vector.

PubMed

Zhang, Chen; Zhou, Lüwen; Zhang, Fan; Lü, Dongyuan; Li, Ning; Zheng, Lu; Xu, Yanhong; Li, Zhan; Sun, Shujin; Long, Mian

2017-02-01

Translocation of the dense nucleus along a gravity vector initiates mechanical remodeling of a cell, but the underlying mechanisms of cytoskeletal network and focal adhesion complex (FAC) reorganization in a mammalian cell remain unclear. We quantified the remodeling of an MC3T3-E1 cell placed in upward-, downward-, or edge-on-orientated substrate. Nucleus longitudinal translocation presents a high value in downward orientation at 24 h or in edge-on orientation at 72 h, which is consistent with orientation-dependent distribution of perinuclear actin stress fibers and vimentin cords. Redistribution of total FAC area and fractionized super mature adhesion number coordinates this dependence at short duration. This orientation-dependent remodeling is associated with nucleus flattering and lamin A/C phosphorylation. Actin depolymerization or Rho-associated protein kinase signaling inhibition abolishes the orientation dependence of nucleus translocation, whereas tubulin polymerization inhibition or vimentin disruption reserves the dependence. A biomechanical model is therefore proposed for integrating the mechanosensing of nucleus translocation with cytoskeletal remodeling and FAC reorganization induced by a gravity vector.-Zhang, C., Zhou, L., Zhang, F., Lü, D., Li, N., Zheng, L., Xu, Y., Li, Z., Sun, S., Long, M. Mechanical remodeling of normally sized mammalian cells under a gravity vector. © FASEB.

The effects of the spatial influence function on orthotropic femur remodelling.

PubMed

Shang, Y; Bai, J; Peng, L

2008-07-01

The morphology and internal structure of bone are modulated by the mechanical stimulus. The osteocytes can sense the stimulus signals from the adjacent regions and respond to them through bone growth or bone absorption. This mechanism can be modelled as the spatial influence function (SIF) in bone adaptation algorithm. In this paper, the remodelling process was simulated in human femurs using an adaptation algorithm with and without SIF, and the trabecular bone was assumed to be orthotropic. A different influence radius and weighting factor were adopted to study the effects of the SIF on the bone density distribution and trabecular alignment. The results have shown that the mean density and L-T ratio (the ratio of longitudinal modulus to transverse modulus) had an excellent linear relationship with the weighting factor when the influence radius was small. The characteristics of density distribution and L-T ratio accorded with the actual observation or measurement when a small weighting factor was used. The large influence radius and weighting factor led to unrealistic results. In contrast, the SIF hardly affected the trabecular alignment, as the mean variation angles of principal axes were less than 1.0 degree for any influence radius and weighting factor.

Disruption of TGF-β signaling in smooth muscle cell prevents flow-induced vascular remodeling

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

Gao, Fu; Chambon, Pierre; Tellides, George

Highlights: • TGF-β signaling in SMC contributes to the flow-induced vascular remodeling. • Disruption of TGF-β signaling in SMC can prevent this process. • Targeting SM-specific Tgfbr2 could be a novel therapeutic strategy for vascular remodeling. - Abstract: Transforming growth factor-β (TGF-β) signaling has been prominently implicated in the pathogenesis of vascular remodeling, especially the initiation and progression of flow-induced vascular remodeling. Smooth muscle cells (SMCs) are the principal resident cells in arterial wall and are critical for arterial remodeling. However, the role of TGF-β signaling in SMC for flow-induced vascular remodeling remains unknown. Therefore, the goal of our studymore » was to determine the effect of TGF-β pathway in SMC for vascular remodeling, by using a genetical smooth muscle-specific (SM-specific) TGF-β type II receptor (Tgfbr2) deletion mice model. Mice deficient in the expression of Tgfbr2 (MyhCre.Tgfbr2{sup f/f}) and their corresponding wild-type background mice (MyhCre.Tgfbr2{sup WT/WT}) underwent partial ligation of left common carotid artery for 1, 2, or 4 weeks. Then the carotid arteries were harvested and indicated that the disruption of Tgfbr2 in SMC provided prominent inhibition of vascular remodeling. And the thickening of carotid media, proliferation of SMC, infiltration of macrophage, and expression of matrix metalloproteinase (MMP) were all significantly attenuated in Tgfbr2 disruption mice. Our study demonstrated, for the first time, that the TGF-β signaling in SMC plays an essential role in flow-induced vascular remodeling and disruption can prevent this process.« less

Evidence for immune cell involvement in decidual spiral arteriole remodeling in early human pregnancy.

PubMed

Smith, Samantha D; Dunk, Caroline E; Aplin, John D; Harris, Lynda K; Jones, Rebecca L

2009-05-01

Decidual artery remodeling is essential for a healthy pregnancy. This process involves loss of vascular smooth muscle cells and endothelium, which are replaced by endovascular trophoblasts (vEVTs) embedded in fibrinoid. Remodeling is impaired during pre-eclampsia, a disease of pregnancy that results in maternal and fetal mortality and morbidity. Early vascular changes occur in the absence of vEVTs, suggesting that another cell type is involved; evidence from animal models indicates that decidual leukocytes play a role. We hypothesized that leukocytes participate in remodeling through the triggering of apoptosis or extracellular matrix degradation. Decidua basalis samples (8 to 12 weeks gestation) were examined by immunohistochemistry to elucidate associations between leukocytes, vEVTs, and key remodeling events. Trophoblast-independent and -dependent phases of remodeling were identified. Based on a combination of morphological attributes, vessel profiles were classified into a putative temporal series of four stages. In early stages of remodeling, vascular smooth muscle cells showed dramatic disruption and disorganization before vEVT presence. Leukocytes (identified as uterine natural killer cells and macrophages) were apparent infiltrating vascular smooth muscle cells layers and were matrix metalloproteinase-7 and -9 immunopositive. A proportion of vascular smooth muscle cells and endothelial cells were terminal deoxynucleotidyl transferase dUTP nick-end labeling positive, suggesting remodeling involves apoptosis. We thus confirm that vascular remodeling occurs in distinct trophoblast-independent and -dependent stages and provide the first evidence of decidual leukocyte involvement in trophoblast-independent stages.

Regulation of bone remodeling by vitamin K2.

PubMed

Myneni, V D; Mezey, E

2017-11-01

All living tissues require essential nutrients such as amino acids, fatty acids, carbohydrates, minerals, vitamins, and water. The skeleton requires nutrients for development, maintaining bone mass and density. If the skeletal nutritional requirements are not met, the consequences can be quite severe. In recent years, there has been growing interest in promotion of bone health and inhibition of vascular calcification by vitamin K2. This vitamin regulates bone remodeling, an important process necessary to maintain adult bone. Bone remodeling involves removal of old or damaged bone by osteoclasts and its replacement by new bone formed by osteoblasts. The remodeling process is tightly regulated, when the balance between bone resorption and bone formation shifts to a net bone loss results in the development of osteoporosis in both men and women. In this review, we focus on our current understanding of the effects of vitamin K2 on bone cells and its role in prevention and treatment of osteoporosis. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Thyroid-stimulating hormone and adverse left ventricular remodeling following ST-segment elevation myocardial infarction.

PubMed

Reindl, Martin; Feistritzer, Hans-Josef; Reinstadler, Sebastian Johannes; Mueller, Lukas; Tiller, Christina; Brenner, Christoph; Mayr, Agnes; Henninger, Benjamin; Mair, Johannes; Klug, Gert; Metzler, Bernhard

2018-04-01

Adverse left ventricular remodeling is one of the major determinants of heart failure and mortality in patients surviving ST-segment elevation myocardial infarction (STEMI). The hypothalamic-pituitary-thyroid axis is a key cardiovascular regulator; however, the relationship between hypothalamic-pituitary-thyroid status and post-STEMI left ventricular remodeling is unclear. We aimed to investigate the association between thyroid-stimulating hormone concentrations and the development of left ventricular remodeling following reperfused STEMI. In this prospective observational study of 102 consecutive STEMI patients, thyroid-stimulating hormone levels were measured at the first day after infarction and 4 months thereafter. Cardiac magnetic resonance scans were performed within the first week as well as at 4 months follow-up to determine infarct characteristics, myocardial function and as primary endpoint left ventricular remodeling, defined as a 20% or greater increase in left ventricular end-diastolic volume. Patients with left ventricular remodeling ( n=15, 15%) showed significantly lower concentrations of baseline (1.20 [0.92-1.91] vs. 1.73 [1.30-2.60] mU/l; P=0.02) and follow-up (1.11 [0.86-1.28] vs. 1.51 [1.15-2.02] mU/l; P=0.002) thyroid-stimulating hormone. The association between baseline thyroid-stimulating hormone and left ventricular remodeling remained significant after adjustment for major clinical (peak high-sensitivity cardiac troponin T and C-reactive protein, heart rate; odds ratio (OR) 5.33, 95% confidence interval (CI) 1.52-18.63; P=0.01) and cardiac magnetic resonance predictors of left ventricular remodeling (infarct size, microvascular obstruction, ejection fraction; OR 4.59, 95% CI 1.36-15.55; P=0.01). Furthermore, chronic thyroid-stimulating hormone was related to left ventricular remodeling independently of chronic left ventricular remodeling correlates (infarct size, ejection fraction, left ventricular end-diastolic volume, left ventricular

Re-Modelling as De-Professionalisation

ERIC Educational Resources Information Center

Thompson, Meryl

2006-01-01

The article sets out the consequences of the British Government's remodelling agenda and its emphasis on less demarcation, for the professional status of teachers in England. It describes how the National Agreement on Raising Standards and Tackling Workload, reached between five of the six trade unions for teachers and headteachers paves the way…

Remodeling of legacy systems in health care using UML.

PubMed

Garde, Sebastian; Knaup, Petra; Herold, Ralf

2002-01-01

Research projects in the field of Medical Informatics often involve the development of application systems. Usually they are developed over a longer period of time, so that at a certain point of time a systematically planned reimplementation is necessary. The first step of reimplementation should be a systematic and comprehensive remodeling. When using UML for this task a systematic approach for remodeling activities is missing. Therefore, we developed a method for remodeling of legacy systems (Qumquad) and applied it to DOSPO, a documentation and therapy planning system for pediatric oncology. Qumquad helps to systematically carry out three steps: the modeling of the current actual state of the application system, the systematic identification of weak points and the development of a target concept for reimplementation considering the identified weak points. Results show that this approach is valuable and feasible and could be applied to various application systems in health care.

Energy Efficiency Measures to Incorporate into Remodeling Projects

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

Liaukus, C.

2014-12-01

Energy improvements in a home are often approached as one concerted effort, beginning with a simple walk-through assessment or more in-depth energy audit and followed by the installation of recommended energy measures. While this approach allows for systems thinking to guide the efforts, comprehensive energy improvements of this nature are undertaken by a relatively small number of the households in our nation compared to more piecemeal remodeling efforts. Even when programs like the Weatherization Assistance Program and Home Performance with ENERGY STAR are considered, homes that have had a comprehensive energy makeover still represent a small fraction of the 111.1more » million households. In this report, the U.S Department of Energy Building America Retrofit Alliance research team looks at the improvement of a home's energy performance in an opportunistic way: it examines what can be done to incorporate energy efficiency measures into general remodeling work and home repair projects. This allows for the possibility for people who would not normally pursue energy efficiency but will remodel their kitchen or re-side their home to improve their home's performance at the same time. There are challenges to this approach, not the least of which being that the work will take place over time in potentially many separate projects. The opportunity to improve a home's energy efficiency at one time expands or contracts with the scope of the remodel. As such, guidance on how to do each piece thoughtfully and with consideration for potential future projects, is critical.« less

A-kinase anchoring proteins that regulate cardiac remodeling.

PubMed

Carnegie, Graeme K; Burmeister, Brian T

2011-11-01

In response to injury or stress, the adult heart undergoes maladaptive changes, collectively defined as pathological cardiac remodeling. Here, we focus on the role of A-kinase anchoring proteins (AKAPs) in 3 main areas associated with cardiac remodeling and the progression of heart failure: excitation-contraction coupling, sarcomeric regulation, and induction of pathological hypertrophy. AKAPs are a diverse family of scaffold proteins that form multiprotein complexes, integrating cAMP signaling with protein kinases, phosphatases, and other effector proteins. Many AKAPs have been characterized in the heart, where they play a critical role in modulating cardiac function.

A-Kinase Anchoring Proteins That Regulate Cardiac Remodeling

PubMed Central

Carnegie, Graeme K.; Burmeister, Brian T.

2012-01-01

In response to injury or stress, the adult heart undergoes maladaptive changes, collectively defined as pathological cardiac remodeling. Here, we focus on the role of A-kinase anchoring proteins (AKAPs) in 3 main areas associated with cardiac remodeling and the progression of heart failure: excitation–contraction coupling, sarcomeric regulation, and induction of pathological hypertrophy. AKAPs are a diverse family of scaffold proteins that form multi-protein complexes, integrating cAMP signaling with protein kinases, phosphatases, and other effector proteins. Many AKAPs have been characterized in the heart, where they play a critical role in modulating cardiac function. PMID:22075671

[Impacts of physical exercise on remodeling and hypertrophy of skeletal muscle.

PubMed

Sakashita, Yoshihiro; Uchida, Takayuki; Nikawa, Takeshi

The skeletal muscle has high sensitivity for the mechanical stress. Because it is enlarged by training, whereas it is easily withered by lack of exercise. When we exercise, skeletal muscle cells per se sense mechanical loading, and muscular remodeling and the muscular hypertrophy occur. It has been revealed that the intracellular signaling through PGC-1α participates in the remodeling of the skeletal muscle, while PGC-1α4, an isoform of PGC-1α, and the dystrophin-glycoprotein complex play important roles in muscular hypertrophy. This review describes the impact of physical exercise gives on the remodeling and hypertrophy of muscle through the signaling.

Lymph node biophysical remodeling is associated with melanoma lymphatic drainage

PubMed Central

Rohner, Nathan Andrew; McClain, Jacob; Tuell, Sara Lydia; Warner, Alex; Smith, Blair; Yun, Youngho; Mohan, Abhinav; Sushnitha, Manuela; Thomas, Susan Napier

2015-01-01

Tissue remodeling is a characteristic of many solid tumor malignancies including melanoma. By virtue of tumor lymphatic transport, remodeling pathways active within the local tumor microenvironment have the potential to be operational within lymph nodes (LNs) draining the tumor interstitium. Here, we show that lymphatic drainage from murine B16 melanomas in syngeneic, immune-competent C57Bl/6 mice is associated with LN enlargement as well as nonuniform increases in bulk tissue elasticity and viscoelasticity, as measured by the response of whole LNs to compression. These remodeling responses, which quickly manifest in tumor-draining lymph nodes (TDLNs) after tumor inoculation and before apparent metastasis, were accompanied by changes in matrix composition, including up to 3-fold increases in the abundance of soluble collagen and hyaluronic acid. Intranodal pressures were also significantly increased in TDLNs (+1 cmH2O) relative to both non-tumor-draining LNs (−1 cmH2O) and LNs from naive animals (−1 to 2 cmH2O). These data suggest that the reorganization of matrix structure, composition, and fluid microenvironment within LNs associated with tumor lymphatic drainage parallels remodeling seen in primary malignancies and has the potential to regulate the adhesion, proliferation, and signaling function of LN-resident cells involved in directing melanoma disease progression.—Rohner, N. A., McClain, J., Tuell, S. L., Warner, A., Smith, B., Yun, Y., Mohan, A., Sushnitha, M., Thomas, S. N. Lymph node biophysical remodeling is associated with melanoma lymphatic drainage. PMID:26178165

Association between atrial fibrillation, atrial enlargement, and left ventricular geometric remodeling.

PubMed

Seko, Yuta; Kato, Takao; Haruna, Tetsuya; Izumi, Toshiaki; Miyamoto, Shoichi; Nakane, Eisaku; Inoko, Moriaki

2018-04-23

This study investigated the relationship between atrial fibrillation (AF) and left ventricular (LV) geometric patterns in a hospital-based population in Japan. We retrospectively analyzed 4444 patients who had undergone simultaneous scheduled transthoracic echocardiography (TTE) and electrocardiography during 2013. A total of 430 patients who had findings of previous myocardial infarctions (n = 419) and without the data on body surface area (n = 11) were excluded from the study. We calculated the LV mass index (LVMI) and relative wall (RWT) and categorized 4014 patients into four groups as follows: normal geometry (n = 3046); concentric remodeling (normal LVMI and high RWT, n = 437); concentric hypertrophy (high LVMI and high RWT, n = 149); and eccentric remodeling (high LVMI and normal RWT, n = 382). The mean left atrial volume indices (LAVI) were 22.5, 23.8, 33.3, and 37.0 mm/m 2 in patients with normal geometry, concentric remodeling, concentric hypertrophy, and eccentric hypertrophy, respectively. The mean LV ejection fractions (LVEF) were 62.7, 62.6, 60.8, and 53.8%, respectively, whereas the prevalence of AF was 10.4%, 10.5%, 14.8%, and 16.8% in patients with normal geometry, concentric remodeling, concentric hypertrophy, and eccentric hypertrophy, respectively. In conclusion, the prevalence of AF was increasing according to LV geometric remodeling patterns in association with LA size and LVEF.

Mapping protein-DNA and protein-protein interactions of ATP-dependent chromatin remodelers.

PubMed

Hota, Swetansu K; Dechassa, Mekonnen Lemma; Prasad, Punit; Bartholomew, Blaine

2012-01-01

Chromatin plays a key regulatory role in several DNA-dependent processes as it regulates DNA access to different protein factors. Several multisubunit protein complexes interact, modify, or mobilize nucleosomes: the basic unit of chromatin, from its original location in an ATP-dependent manner to facilitate processes, such as transcription, replication, repair, and recombination. Knowledge of the interactions of chromatin remodelers with nucleosomes is a crucial requirement to understand the mechanism of chromatin remodeling. Here, we describe several methods to analyze the interactions of multisubunit chromatin-remodeling enzymes with nucleosomes.

Vitamin D receptor (VDR) promoter targeting through a novel chromatin remodeling complex.

PubMed

Kato, Shigeaki; Fujiki, Ryoji; Kitagawa, Hirochika

2004-05-01

We have purified nuclear complexes for Vitamin D receptor (VDR), and identified one of them as a novel ATP-dependent chromatine remodeling containing Williams syndrome transcription factor (WSTF), that is supposed to be responsible for Williams syndrome. This complex (WSTF including nucleosome assembly complex (WINAC)) exhibited an ATP-dependent chromatin remodeling activity in vitro. Transient expression assays revealed that WINAC potentiates ligand-induced function of VDR in gene activation and repression. Thus, this study describes a molecular basis of the VDR function on chromosomal DNA through chromatine remodeling.

Dilation and Hypertrophy: A Cell-Based Continuum Mechanics Approach Towards Ventricular Growth and Remodeling

NASA Astrophysics Data System (ADS)

Ulerich, J.; Göktepe, S.; Kuhl, E.

This manuscript presents a continuum approach towards cardiac growth and remodeling that is capable to predict chronic maladaptation of the heart in response to changes in mechanical loading. It is based on the multiplicative decomposition of the deformation gradient into and elastic and a growth part. Motivated by morphological changes in cardiomyocyte geometry, we introduce an anisotropic growth tensor that can capture both hypertrophic wall thickening and ventricular dilation within one generic concept. In agreement with clinical observations, we propose wall thickening to be a stress-driven phenomenon whereas dilation is introduced as a strain-driven process. The features of the proposed approach are illustrated in terms of the adaptation of thin heart slices and in terms overload-induced dilation in a generic bi-ventricular heart model.

The role of echocardiography in the evaluation of cardiac re-modelling and differentiation between physiological and pathological hypertrophy in teenagers engaged in competitive amateur sports.

PubMed

Sulovic, Ljiljana S; Mahmutovic, Meho; Lazic, Snezana; Sulovic, Nenad

2017-05-01

Aims "Athlete's heart" is a cardiac adaptation to long-term intensive training. The aims of this study were to show the prevalence of left ventricular hypertrophy in teenagers who participate in sports, to define the different types of cardiac re-modelling, and to differentiate between physiological and pathological hypertrophy. Echocardiographic measurements were obtained by M-mode, two dimensional, and Doppler techniques of participants from sports and control groups. The echocardiographic examinations included 100 healthy teenagers taking part in dynamic sports such as football and basketball and 100 healthy teenagers taking part in static sports such as karate and judo. The control group (n=100) included healthy, sedentary teenagers. Sports participants had significantly higher left ventricular mass when compared with the control group, (p0.05). Respondents from both groups had E/A ratios (transmitral flow velocity ratio)>1, preserved diastolic function, and statistically they did not differ from the control group. Echocardiographic parameters show that physiological hypertrophy and cardiac re-modelling are present in teenagers who play sports. Unexpectedly, the prevalence of concentric and eccentric types of re-modelling is equally possible in the group of static sports participants.

Remodelling of a Lycee in Grenoble. Programme on Educational Building 14.

ERIC Educational Resources Information Center

Roche, G.

The 1973 remodeling of the Emmanuel Mounier Lycee in Grenoble, France, shows how a secondary educational facility can respond to expanding school offerings. As background to the lycee's expansion, the author, who was principal of the school during its remodeling, provides general information on the French educational system and on the consequent…

Cardiovascular remodeling induced by passive smoking.

PubMed

Minicucci, Marcos F; Azevedo, Paula S; Paiva, Sergio A R; Zornoff, Leonardo A M

2009-12-01

Coronary heart disease (CHD) is the most common cause of death in many developed countries. The major risk factors for CHD are smoking, high blood pressure, diabetes, high cholesterol levels, and lack of physical activity. Importantly, passive smoke also increases the risk for CHD. The mechanisms involved in the effects of passive smoke in CHD are complex and include endothelial dysfunction, lipoprotein modification, increased inflammation and platelet activation. Recently, several studies have shown that exposure to tobacco smoke can result in cardiac remodeling and compromised cardiac function. Potential mechanisms for these alterations are neurohumoral activation, oxidative stress, and MAPK activation. Although the vascular effects of cigarette smoke exposure are well known, the effects of tobacco smoking on the heart have received less attention. Therefore, this review will focus on the recent findings as to the effects of passive smoking in acute and chronic phases of vascular and cardiac remodeling.

Drosophila transcription factor Tramtrack69 binds MEP1 to recruit the chromatin remodeler NuRD.

PubMed

Reddy, B Ashok; Bajpe, Prashanth Kumar; Bassett, Andrew; Moshkin, Yuri M; Kozhevnikova, Elena; Bezstarosti, Karel; Demmers, Jeroen A A; Travers, Andrew A; Verrijzer, C Peter

2010-11-01

ATP-dependent chromatin-remodeling complexes (remodelers) are essential regulators of chromatin structure and gene transcription. How remodelers can act in a gene-selective manner has remained enigmatic. A yeast two-hybrid screen for proteins binding the Drosophila transcription factor Tramtrack69 (TTK69) identified MEP1. Proteomic characterization revealed that MEP1 is a tightly associated subunit of the NuRD remodeler, harboring the Mi2 enzymatic core ATPase. In addition, we identified the fly homolog of human Deleted in oral cancer 1 (DOC1), also known as CDK2-associated protein 1 (CDK2AP1), as a bona fide NuRD subunit. Biochemical and genetic assays supported the functional association between MEP1, Mi2, and TTK69. Genomewide expression analysis established that TTK69, MEP1, and Mi2 cooperate closely to control transcription. The TTK69 transcriptome profile correlates poorly with remodelers other than NuRD, emphasizing the selectivity of remodeler action. On the genes examined, TTK69 is able to bind chromatin in the absence of NuRD, but targeting of NuRD is dependent on TTK69. Thus, there appears to be a hierarchical relationship in which transcription factor binding precedes remodeler recruitment.

Chymase-producing cells of the innate immune system are required for decidual vascular remodeling and fetal growth

PubMed Central

Meyer, Nicole; Woidacki, Katja; Knöfler, Martin; Meinhardt, Gudrun; Nowak, Désirée; Velicky, Philipp; Pollheimer, Jürgen; Zenclussen, Ana C.

2017-01-01

Intrauterine growth restriction (IUGR) is caused by insufficient remodeling of spiral arteries (SAs). The mechanism underlying the relevance of natural killer cells (NKs) and mast cells (MCs) for SA remodeling and its effects on pregnancy outcome are not well understood. We show that NK depletion arrested SA remodeling without affecting pregnancy. MC depletion resulted in abnormally remodeled SAs and IUGR. Combined absence of NKs and MCs substantially affected SA remodeling and impaired fetal growth. We found that α-chymase mast cell protease (Mcpt) 5 mediates apoptosis of uterine smooth muscle cells, a key feature of SA remodeling. Additionally, we report a previously unknown source for Mcpt5: uterine (u) NKs. Mice with selective deletion of Mcpt5+ cells had un-remodeled SAs and growth-restricted progeny. The human α-chymase CMA1, phylogenetic homolog of Mcpt5, stimulated the ex vivo migration of human trophoblasts, a pre-requisite for SA remodeling. Our results show that chymases secreted by uMCs and uNKs are pivotal to the vascular changes required to support pregnancy. Understanding the mechanisms underlying pregnancy-induced vascular changes is essential for developing therapeutic options against pregnancy complications associated with poor vascular remodeling. PMID:28327604

Association of Lipidome Remodeling in the Adipocyte Membrane with Acquired Obesity in Humans

PubMed Central

Gopalacharyulu, Peddinti; Tang, Jing; Rodriguez-Cuenca, Sergio; Maciejewski, Arkadiusz; Naukkarinen, Jussi; Ruskeepää, Anna-Liisa; Niemelä, Perttu S.; Yetukuri, Laxman; Tan, Chong Yew; Velagapudi, Vidya; Castillo, Sandra; Nygren, Heli; Hyötyläinen, Tuulia; Rissanen, Aila; Kaprio, Jaakko; Yki-Järvinen, Hannele; Vattulainen, Ilpo; Vidal-Puig, Antonio; Orešič, Matej

2011-01-01

Identification of early mechanisms that may lead from obesity towards complications such as metabolic syndrome is of great interest. Here we performed lipidomic analyses of adipose tissue in twin pairs discordant for obesity but still metabolically compensated. In parallel we studied more evolved states of obesity by investigating a separated set of individuals considered to be morbidly obese. Despite lower dietary polyunsaturated fatty acid intake, the obese twin individuals had increased proportions of palmitoleic and arachidonic acids in their adipose tissue, including increased levels of ethanolamine plasmalogens containing arachidonic acid. Information gathered from these experimental groups was used for molecular dynamics simulations of lipid bilayers combined with dependency network analysis of combined clinical, lipidomics, and gene expression data. The simulations suggested that the observed lipid remodeling maintains the biophysical properties of lipid membranes, at the price, however, of increasing their vulnerability to inflammation. Conversely, in morbidly obese subjects, the proportion of plasmalogens containing arachidonic acid in the adipose tissue was markedly decreased. We also show by in vitro Elovl6 knockdown that the lipid network regulating the observed remodeling may be amenable to genetic modulation. Together, our novel approach suggests a physiological mechanism by which adaptation of adipocyte membranes to adipose tissue expansion associates with positive energy balance, potentially leading to higher vulnerability to inflammation in acquired obesity. Further studies will be needed to determine the cause of this effect. PMID:21666801

[Experimental therapy of cardiac remodeling with quercetin-containing drugs].

PubMed

Kuzmenko, M A; Pavlyuchenko, V B; Tumanovskaya, L V; Dosenko, V E; Moybenko, A A

2013-01-01

It was shown that continuous beta-adrenergic hyperstimulation resulted in cardiac function disturbances and fibrosis of cardiac tissue. Treatment with quercetin-containing drugs, particularly, water-soluble corvitin and tableted quertin exerted favourable effect on cardiac hemodynamics, normalized systolic and diastolic function in cardiac remodeling, induced by sustained beta-adrenergic stimulation. It was estimated that conducted experimental therapy limited cardiac fibrosis area almost three-fold, that could be associated with first and foremost improved cardiac distensibility, characteristics of diastolic and also pump function in cardiac remodeling.

A Matrix Metalloproteinase Mediates Airway Remodeling in Drosophila

PubMed Central

Glasheen, Bernadette M.; Robbins, Renée M.; Piette, Caitlin; Beitel, Greg J.; Page-McCaw, Andrea

2010-01-01

Organ size typically increases dramatically during juvenile growth. This growth presents a fundamental tension, as organs need resiliency to resist stresses while still maintaining plasticity to accommodate growth. Extracellular matrix (ECM) is central to providing resiliency, but how ECM is remodeled to accommodate growth is poorly understood. We investigated remodeling of Drosophila respiratory tubes (tracheae) that elongate continually during larval growth, despite being lined with a rigid cuticular ECM. Cuticle is initially deposited with a characteristic pattern of repeating ridges and valleys known as taenidia. We find that for tubes to elongate, the extracellular protease Mmp1 is required for expansion of ECM between the taenidial ridges during each inter-molt period. Mmp1 protein localizes in periodically-spaced puncta that are in register with the taenidial spacing. Mmp1 also degrades old cuticle at molts, promotes apical membrane expansion in larval tracheae, and promotes tube elongation in embryonic tracheae. Whereas work in other developmental systems has demonstrated that MMPs are required for axial elongation occurring in localized growth zones, this study demonstrates that MMPs can also mediate interstitial matrix remodeling during growth of an organ system. PMID:20513443

REMODELING SENSORY CORTICAL MAPS IMPLANTS SPECIFIC BEHAVIORAL MEMORY

PubMed Central

Bieszczad, Kasia M.; Miasnikov, Alexandre A.; Weinberger, Norman M.

2013-01-01

Neural mechanisms underlying the capacity of memory to be rich with sensory detail are largely unknown. A candidate mechanism is learning-induced plasticity that remodels adult sensory cortex. Here, expansion in the primary auditory cortical (A1) tonotopic map of rats was induced by pairing a 3.66 kHz tone with activation of the nucleus basalis, mimicking the effects of natural associative learning. Remodeling of A1 produced de novo specific behavioral memory, but neither memory nor plasticity were consistently at the frequency of the paired tone, which typically decreased in A1 representation. Rather, there was a specific match between individual subjects’ area of expansion and the tone that was strongest in each animal’s memory, as determined by post-training frequency generalization gradients. These findings provide the first demonstration of a match between the artificial induction of specific neural representational plasticity and artificial induction of behavioral memory. As such, together with prior and present findings for detection, correlation and mimicry of plasticity with the acquisition of memory, they satisfy a key criterion for neural substrates of memory. This demonstrates that directly remodeling sensory cortical maps is sufficient for the specificity of memory formation. PMID:23639876

Grape seed proanthocyanidin extract alleviates ouabain-induced vascular remodeling through regulation of endothelial function.

PubMed

Liu, Xiangju; Qiu, Jie; Zhao, Shaohua; You, Beian; Ji, Xiang; Wang, Yan; Cui, Xiaopei; Wang, Qian; Gao, Haiqing

2012-11-01

Recent studies indicate that chronic ouabain treatment leads to hypertension and hypertensive vascular remodeling. Grape seed proanthocyanidin extract (GSPE) has been reported to be effective in treating arteriosclerosis, while little is known about its effect on systolic blood pressure and vascular remodeling. In this study, the effects of GSPE on systolic blood pressure and vascular remodeling were analyzed by treating ouabain-induced hypertensive rats with GSPE (250 mg/kg·d). The expression of nitric oxide (NO) and endothelin-1 (ET-1) in thoracic aorta was examined by ELISA; the mRNA and protein levels of TGF-β1 were detected using real-time PCR and western blotting, respectively. The results showed that the systolic blood pressure was significantly decreased following treatment with GSPE, with blocked vascular remodeling. The ET-1 content was reduced while NO production was increased in the GSPE group, which showed improved vascular endothelial function. Moreover, GSPE also reduced TGF-β1 expression in the thoracic aorta, which is a determinant in vascular remodeling. In conclusion, GSPE antagonized ouabain-induced hypertension and vascular remodeling and is recommended as a potential anti-hypertensive agent for patients with hypertensive vascular diseases.

Application of Petri Nets in Bone Remodeling

PubMed Central

Li, Lingxi; Yokota, Hiroki

2009-01-01

Understanding a mechanism of bone remodeling is a challenging task for both life scientists and model builders, since this highly interactive and nonlinear process can seldom be grasped by simple intuition. A set of ordinary differential equations (ODEs) have been built for simulating bone formation as well as bone resorption. Although solving ODEs numerically can provide useful predictions for dynamical behaviors in a continuous time frame, an actual bone remodeling process in living tissues is driven by discrete events of molecular and cellular interactions. Thus, an event-driven tool such as Petri nets (PNs), which may dynamically and graphically mimic individual molecular collisions or cellular interactions, seems to augment the existing ODE-based systems analysis. Here, we applied PNs to expand the ODE-based approach and examined discrete, dynamical behaviors of key regulatory molecules and bone cells. PNs have been used in many engineering areas, but their application to biological systems needs to be explored. Our PN model was based on 8 ODEs that described an osteoprotegerin linked molecular pathway consisting of 4 types of bone cells. The models allowed us to conduct both qualitative and quantitative evaluations and evaluate homeostatic equilibrium states. The results support that application of PN models assists understanding of an event-driven bone remodeling mechanism using PN-specific procedures such as places, transitions, and firings. PMID:19838338

Lysyl oxidases regulate fibrillar collagen remodelling in idiopathic pulmonary fibrosis.

PubMed

Tjin, Gavin; White, Eric S; Faiz, Alen; Sicard, Delphine; Tschumperlin, Daniel J; Mahar, Annabelle; Kable, Eleanor P W; Burgess, Janette K

2017-11-01

Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease of the lung with few effective therapeutic options. Structural remodelling of the extracellular matrix [i.e. collagen cross-linking mediated by the lysyl oxidase (LO) family of enzymes (LOX, LOXL1-4)] might contribute to disease pathogenesis and represent a therapeutic target. This study aimed to further our understanding of the mechanisms by which LO inhibitors might improve lung fibrosis. Lung tissues from IPF and non-IPF subjects were examined for collagen structure (second harmonic generation imaging) and LO gene (microarray analysis) and protein (immunohistochemistry and western blotting) levels. Functional effects (collagen structure and tissue stiffness using atomic force microscopy) of LO inhibitors on collagen remodelling were examined in two models, collagen hydrogels and decellularized human lung matrices. LOXL1 / LOXL2 gene expression and protein levels were increased in IPF versus non-IPF. Increased collagen fibril thickness in IPF versus non-IPF lung tissues correlated with increased LOXL1/LOXL2, and decreased LOX, protein expression. β-Aminoproprionitrile (β-APN; pan-LO inhibitor) but not Compound A (LOXL2-specific inhibitor) interfered with transforming growth factor-β-induced collagen remodelling in both models. The β-APN treatment group was tested further, and β-APN was found to interfere with stiffening in the decellularized matrix model. LOXL1 activity might drive collagen remodelling in IPF lungs. The interrelationship between collagen structural remodelling and LOs is disrupted in IPF lungs. Inhibition of LO activity alleviates fibrosis by limiting fibrillar collagen cross-linking, thereby potentially impeding the formation of a pathological microenvironment in IPF. © 2017. Published by The Company of Biologists Ltd.

Delayed Exercise Promotes Remodeling in Sub-Rupture Fatigue Damaged Tendons

PubMed Central

Bell, R.; Boniello, M.R.; Gendron, N.R.; Flatow, E.L.; Andarawis-Puri, N.

2015-01-01

Tendinopathy is a common musculoskeletal injury whose treatment is limited by ineffective therapeutic interventions. Previously we have shown that tendons ineffectively repair early sub-rupture fatigue damage. In contrast, physiological exercise has been shown to promote remodeling of healthy tendons but its utility as a therapeutic to promote repair of fatigue damaged tendons remains unknown. Therefore, the objective of this study was to assess the utility of exercise initiated 1 and 14 days after onset of fatigue damage to promote structural repair in fatigue damaged tendons. We hypothesized that exercise initiated 14 days after fatigue loading would promote remodeling as indicated by a decrease in area of collagen matrix damage, increased procollagen I and decorin, while decreasing proteins indicative of tendinopathy. Rats engaged in 6-week exercise for 30 min/day or 60 min/day starting 1 or 14 days after fatigue loading. Initiating exercise 1-day after onset of fatigue injury led to exacerbation of matrix damage, particularly at the tendon insertion. Initiating exercise 14 days after onset of fatigue injury led to remodeling of damaged regions in the midsubstance and collagen synthesis at the insertion. Physiological exercise applied after the initial biological response to injury has dampened can potentially promote remodeling of damaged tendons. PMID:25732052

Protein kinetic signatures of the remodeling heart following isoproterenol stimulation.

PubMed

Lam, Maggie P Y; Wang, Ding; Lau, Edward; Liem, David A; Kim, Allen K; Ng, Dominic C M; Liang, Xiangbo; Bleakley, Brian J; Liu, Chenguang; Tabaraki, Jason D; Cadeiras, Martin; Wang, Yibin; Deng, Mario C; Ping, Peipei

2014-04-01

Protein temporal dynamics play a critical role in time-dimensional pathophysiological processes, including the gradual cardiac remodeling that occurs in early-stage heart failure. Methods for quantitative assessments of protein kinetics are lacking, and despite knowledge gained from single-protein studies, integrative views of the coordinated behavior of multiple proteins in cardiac remodeling are scarce. Here, we developed a workflow that integrates deuterium oxide (2H2O) labeling, high-resolution mass spectrometry (MS), and custom computational methods to systematically interrogate in vivo protein turnover. Using this workflow, we characterized the in vivo turnover kinetics of 2,964 proteins in a mouse model of β-adrenergic-induced cardiac remodeling. The data provided a quantitative and longitudinal view of cardiac remodeling at the molecular level, revealing widespread kinetic regulations in calcium signaling, metabolism, proteostasis, and mitochondrial dynamics. We translated the workflow to human studies, creating a reference dataset of 496 plasma protein turnover rates from 4 healthy adults. The approach is applicable to short, minimal label enrichment and can be performed on as little as a single biopsy, thereby overcoming critical obstacles to clinical investigations. The protein turnover quantitation experiments and computational workflow described here should be widely applicable to large-scale biomolecular investigations of human disease mechanisms with a temporal perspective.

Protein kinetic signatures of the remodeling heart following isoproterenol stimulation

PubMed Central

Lam, Maggie P.Y.; Wang, Ding; Lau, Edward; Liem, David A.; Kim, Allen K.; Ng, Dominic C.M.; Liang, Xiangbo; Bleakley, Brian J.; Liu, Chenguang; Tabaraki, Jason D.; Cadeiras, Martin; Wang, Yibin; Deng, Mario C.; Ping, Peipei

2014-01-01

Protein temporal dynamics play a critical role in time-dimensional pathophysiological processes, including the gradual cardiac remodeling that occurs in early-stage heart failure. Methods for quantitative assessments of protein kinetics are lacking, and despite knowledge gained from single-protein studies, integrative views of the coordinated behavior of multiple proteins in cardiac remodeling are scarce. Here, we developed a workflow that integrates deuterium oxide (2H2O) labeling, high-resolution mass spectrometry (MS), and custom computational methods to systematically interrogate in vivo protein turnover. Using this workflow, we characterized the in vivo turnover kinetics of 2,964 proteins in a mouse model of β-adrenergic–induced cardiac remodeling. The data provided a quantitative and longitudinal view of cardiac remodeling at the molecular level, revealing widespread kinetic regulations in calcium signaling, metabolism, proteostasis, and mitochondrial dynamics. We translated the workflow to human studies, creating a reference dataset of 496 plasma protein turnover rates from 4 healthy adults. The approach is applicable to short, minimal label enrichment and can be performed on as little as a single biopsy, thereby overcoming critical obstacles to clinical investigations. The protein turnover quantitation experiments and computational workflow described here should be widely applicable to large-scale biomolecular investigations of human disease mechanisms with a temporal perspective. PMID:24614109

Minor Groove Binder Distamycin Remodels Chromatin but Inhibits Transcription

PubMed Central

Majumder, Parijat; Banerjee, Amrita; Shandilya, Jayasha; Senapati, Parijat; Chatterjee, Snehajyoti; Kundu, Tapas K.; Dasgupta, Dipak

2013-01-01

The condensed structure of chromatin limits access of cellular machinery towards template DNA. This in turn represses essential processes like transcription, replication, repair and recombination. The repression is alleviated by a variety of energy dependent processes, collectively known as “chromatin remodeling”. In a eukaryotic cell, a fine balance between condensed and de-condensed states of chromatin helps to maintain an optimum level of gene expression. DNA binding small molecules have the potential to perturb such equilibrium. We present herein the study of an oligopeptide antibiotic distamycin, which binds to the minor groove of B-DNA. Chromatin mobility assays and circular dichroism spectroscopy have been employed to study the effect of distamycin on chromatosomes, isolated from the liver of Sprague-Dawley rats. Our results show that distamycin is capable of remodeling both chromatosomes and reconstituted nucleosomes, and the remodeling takes place in an ATP-independent manner. Binding of distamycin to the linker and nucleosomal DNA culminates in eviction of the linker histone and the formation of a population of off-centered nucleosomes. This hints at a possible corkscrew type motion of the DNA with respect to the histone octamer. Our results indicate that distamycin in spite of remodeling chromatin, inhibits transcription from both DNA and chromatin templates. Therefore, the DNA that is made accessible due to remodeling is either structurally incompetent for transcription, or bound distamycin poses a roadblock for the transcription machinery to advance. PMID:23460895

Prostaglandin F2α receptor silencing attenuates vascular remodeling in rats with type 2 diabetes.

PubMed

Li, Ya; Han, Lu; Ding, Wen-Yuan; Ti, Yun; Li, Yi-Hui; Tang, Meng-Xiong; Wang, Zhi-Hao; Zhang, Yun; Zhang, Wei; Zhong, Ming

2015-12-01

Vascular remodeling is an important feature of diabetic macrovascular complications. The prostaglandin F2α receptor (FP), the expression of which is upregulated by insulin resistance and diabetes, is reportedly involved in myocardial remodeling. In this study, we aimed to investigate whether the FP receptor is implicated in diabetes-induced vascular remodeling. A type 2 diabetic rat model was induced through a high-fat diet and low-dose streptozotocin (STZ). Thirty-two rats were randomized into four groups: control, diabetes, diabetes treated with empty virus and diabetes treated with FP receptor-shRNA. Then, we evaluated the metabolic index, FP receptor expression and vascular remodeling. We used FP receptor gene silencing in vivo to investigate the role that the FP receptor plays in the pathophysiologic features of vascular remodeling. Diabetic rats displayed increased levels of blood glucose, cholesterol, and triglycerides, as well as severe insulin resistance and FP receptor overexpression. In addition, increased medial thickness, excessive collagen deposition and diminished elastic fibers were observed in the diabetic rats, resulting in vascular remodeling. In the FP receptor-shRNA group, the medial thickness, collagen content, elastin/collagen ratio, and collagen I/collagen III content ratio were markedly decreased. Additionally, with FP receptor gene silencing, the JNK phosphorylation level was markedly decreased. Silencing of the FP receptor exerts a protective effect on diabetes-induced vascular remodeling, thereby suggesting a new therapeutic target for vascular remodeling in diabetes. Copyright © 2015 Elsevier Inc. All rights reserved.

Mechanisms of action of sacubitril/valsartan on cardiac remodeling: a systems biology approach.

PubMed

Iborra-Egea, Oriol; Gálvez-Montón, Carolina; Roura, Santiago; Perea-Gil, Isaac; Prat-Vidal, Cristina; Soler-Botija, Carolina; Bayes-Genis, Antoni

2017-01-01

Sacubitril/Valsartan, proved superiority over other conventional heart failure management treatments, but its mechanisms of action remains obscure. In this study, we sought to explore the mechanistic details for Sacubitril/Valsartan in heart failure and post-myocardial infarction remodeling, using an in silico, systems biology approach. Myocardial transcriptome obtained in response to myocardial infarction in swine was analyzed to address post-infarction ventricular remodeling. Swine transcriptome hits were mapped to their human equivalents using Reciprocal Best (blast) Hits, Gene Name Correspondence, and InParanoid database. Heart failure remodeling was studied using public data available in gene expression omnibus (accession GSE57345, subseries GSE57338), processed using the GEO2R tool. Using the Therapeutic Performance Mapping System technology, dedicated mathematical models trained to fit a set of molecular criteria, defining both pathologies and including all the information available on Sacubitril/Valsartan, were generated. All relationships incorporated into the biological network were drawn from public resources (including KEGG, REACTOME, INTACT, BIOGRID, and MINT). An artificial neural network analysis revealed that Sacubitril/Valsartan acts synergistically against cardiomyocyte cell death and left ventricular extracellular matrix remodeling via eight principal synergistic nodes. When studying each pathway independently, Valsartan was found to improve cardiac remodeling by inhibiting members of the guanine nucleotide-binding protein family, while Sacubitril attenuated cardiomyocyte cell death, hypertrophy, and impaired myocyte contractility by inhibiting PTEN. The complex molecular mechanisms of action of Sacubitril/Valsartan upon post-myocardial infarction and heart failure cardiac remodeling were delineated using a systems biology approach. Further, this dataset provides pathophysiological rationale for the use of Sacubitril/Valsartan to prevent post

Osteocyte-Intrinsic TGF-β Signaling Regulates Bone Quality through Perilacunar/Canalicular Remodeling

DOE PAGES

Dole, Neha S.; Mazur, Courtney M.; Acevedo, Claire; ...

2017-11-28

Poor bone quality contributes to bone fragility in diabetes, aging, and osteogenesis imperfecta. However, the mechanisms controlling bone quality are not well understood, contributing to the current lack of strategies to diagnose or treat bone quality deficits. Transforming growth factor beta (TGF-β) signaling is a crucial mechanism known to regulate the material quality of bone, but its cellular target in this regulation is unknown. Studies showing that osteocytes directly remodel their perilacunar/canalicular matrix led us to hypothesize that TGF-β controls bone quality through perilacunar/canalicular remodeling (PLR). Using inhibitors and mice with an osteocyte-intrinsic defect in TGF-β signaling (TβRII ocy-/-), wemore » show that TGF-β regulates PLR in a cell-intrinsic manner to control bone quality. Altogether, this study emphasizes that osteocytes are key in executing the biological control of bone quality through PLR, thereby highlighting the fundamental role of osteocyte-mediated PLR in bone homeostasis and fragility. Resistance to fracture requires healthy bone mass and quality. However, the cellular mechanisms regulating bone quality are unclear. Dole et al. show that osteocyte-intrinsic TGF-β signaling maintains bone quality through perilacunar/canalicular remodeling. Thus, osteocytes mediate perilacunar/canalicular remodeling and osteoclast-directed remodeling to cooperatively maintain bone quality and mass and prevent fragility.« less

Osteocyte-Intrinsic TGF-β Signaling Regulates Bone Quality through Perilacunar/Canalicular Remodeling

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

Dole, Neha S.; Mazur, Courtney M.; Acevedo, Claire

Poor bone quality contributes to bone fragility in diabetes, aging, and osteogenesis imperfecta. However, the mechanisms controlling bone quality are not well understood, contributing to the current lack of strategies to diagnose or treat bone quality deficits. Transforming growth factor beta (TGF-β) signaling is a crucial mechanism known to regulate the material quality of bone, but its cellular target in this regulation is unknown. Studies showing that osteocytes directly remodel their perilacunar/canalicular matrix led us to hypothesize that TGF-β controls bone quality through perilacunar/canalicular remodeling (PLR). Using inhibitors and mice with an osteocyte-intrinsic defect in TGF-β signaling (TβRII ocy-/-), wemore » show that TGF-β regulates PLR in a cell-intrinsic manner to control bone quality. Altogether, this study emphasizes that osteocytes are key in executing the biological control of bone quality through PLR, thereby highlighting the fundamental role of osteocyte-mediated PLR in bone homeostasis and fragility. Resistance to fracture requires healthy bone mass and quality. However, the cellular mechanisms regulating bone quality are unclear. Dole et al. show that osteocyte-intrinsic TGF-β signaling maintains bone quality through perilacunar/canalicular remodeling. Thus, osteocytes mediate perilacunar/canalicular remodeling and osteoclast-directed remodeling to cooperatively maintain bone quality and mass and prevent fragility.« less

Vinpocetine Attenuates Pathological Cardiac Remodeling by Inhibiting Cardiac Hypertrophy and Fibrosis.

PubMed

Wu, Mei-Ping; Zhang, Yi-Shuai; Xu, Xiangbin; Zhou, Qian; Li, Jian-Dong; Yan, Chen

2017-04-01

Pathological cardiac remodeling, characterized by cardiac hypertrophy and fibrosis, is a pathological feature of many cardiac disorders that leads to heart failure and cardiac arrest. Vinpocetine, a derivative of the alkaloid vincamine, has been used for enhancing cerebral blood flow to treat cognitive impairment. However, its role in pathological cardiac remodeling remains unknown. The aim of this study is to examine the effect of vinpocetine on pathological cardiac remodeling induced by chronic stimulation with angiotensin II (Ang II). Mice received Ang II infusion via osmotic pumps in the presence of vehicle or vinpocetine. Cardiac hypertrophy and fibrosis were assessed by morphological, histological, and biochemical analyses. Mechanistic studies were carried out in vitro with isolated mouse adult cardiac myocytes and fibroblasts. We showed that chronic Ang II infusion caused cardiac hypertrophy and fibrosis, which were all significantly attenuated by systemic administration of vinpocetine. In isolated adult mouse cardiomyocytes, vinpocetine suppressed Ang II-stimulated myocyte hypertrophic growth. In cultured cardiac fibroblasts, vinpocetine suppressed TGFβ-induced fibroblast activation and matrix gene expression, consistent with its effect in attenuating cardiac fibrosis. The effects of vinpocetine on cardiac myocyte hypertrophy and fibroblast activation are likely mediated by targeting cyclic nucleotide phosphodiesterase 1 (PDE1). Our results reveal a novel protective effect of vinpocetine in attenuating pathological cardiac remodeling through suppressing cardiac myocyte hypertrophic growth and fibroblast activation and fibrotic gene expression. These studies may also shed light on developing novel therapeutic agents for antagonizing pathological cardiac remodeling.

Lead Poisoning in Remodeling of Old Homes

ERIC Educational Resources Information Center

Barnes, Bart

1973-01-01

An article based on Dr. Muriel D. Wolf's study of elevated blood lead levels in children and adults present during the remodeling of old homes. Lead poisoning examples, symptoms, and precautions are given. (ST)

Simulated bone remodeling around two types of osseointegrated implants for direct fixation of upper-leg prostheses.

PubMed

Tomaszewski, P K; Verdonschot, N; Bulstra, S K; Rietman, J S; Verkerke, G J

2012-11-01

Direct attachment of an upper leg prosthesis to the skeletal system by a percutaneous implant is an alternative solution to the traditional socket fixation. In this study, we investigated long-term periprosthetic bone changes around two types of fixation implants using two different initial conditions, namely immediate post-amputation implantation and the conventional implantation after considerable time of socket prosthesis use. We questioned the difference in bone modeling response the implants provoked and if it could lead to premature bone fracture. Generic CT-based finite element models of an intact femoral bone and amputated bone implanted with models of two existing direct-fixation implants, the OPRA system (Integrum AB) and the ISP Endo/Exo prosthesis (ESKA Implants AG) were created for this study. Adaptive bone-remodeling simulations used the heel-strike and toe-off loads from a normal walking cycle. The bone loss caused by prolonged use of socket prosthesis had more severe effects on the ultimate bone quality than adaptation induced by the direct-fixation implants. Both implants showed considerable bone remodeling; the titanium screw implant (OPRA system) provoked more bone loss than the porous coated CoCrMo stem (ISP implant). The chance of the peri-prosthetic bone fracture remained higher for the post-socket case as compared to the direct amputation cases. In conclusion, both direct-fixation implants lead to considerable bone loss and bone loss is more severe after a prolonged period of post-socket use. Hence, from a biomechanical perspective it is better to limit the post-socket time and to re-design direct fixation devices to reduce bone loss and the probability of peri-prosthetic bone fractures. Copyright © 2012 Elsevier Ltd. All rights reserved.

Intrapulmonary vascular remodeling: MSCT-based evaluation in COPD and alpha-1 antitrypsin deficient subjects

NASA Astrophysics Data System (ADS)

Crosnier, Adeline; Fetita, Catalin; Thabut, Gabriel; Brillet, Pierre-Yves

2016-03-01

Whether COPD is generally known as a small airway disease, recent investigations suggest that vascular remodeling could play a key role in disease progression. This paper develops a specific investigation framework in order to evaluate the remodeling of the intrapulmonary vascular network and its correlation with other image or clinical parameters (emphysema score or FEV1) in patients with smoking- or genetic- (alpha-1 antitrypsin deficiency - AATD) related COPD. The developed approach evaluates the vessel caliber distribution per lung or lung region (upper, lower, 10%- and 20%- periphery) in relation with the severity of the disease and computes a remodeling marker given by the area under the caliber distribution curve for radii less than 1.6mm, AUC16. It exploits a medial axis analysis in relation with local caliber information computed in the segmented vascular network, with values normalized with respect to the lung volume (for which a robust segmentation is developed). The first results obtained on a 34-patient database (13 COPD, 13 AATD and 8 controls) showed significant vascular remodeling for COPD and AATD versus controls, with a negative correlation with the emphysema degree for COPD, but not for AATD. Significant vascular remodeling at 20% lung periphery was found both for the severe COPD and AATD patients, but not for the moderate groups. Also the vascular remodeling in AATD did not correlate with the FEV1, nor with DLCO, which might suggest independent mechanisms for bronchial and vascular remodeling in the lung.

[Remodeling of Cardiovascular System: Causes and Consequences].

PubMed

Lopatina, E V; Kipenko, A V; Penniyaynen, V A; Pasatetckaia, N A; Tsyrline, V A

2016-01-01

Literature and our data suggest the regulatory action of a number of biologically active substances (catecholamines, cardiac glycosides, β-blockers, angiotensin-converting-enzyme inhibitor) on the growth and proliferation of heart cells. By using of organotypic tissue culture has proved that the basis of this regulation is the ability of test substances, receptor- or transducer-mediated signaling to modulate the function of Na⁺, K⁺-ATPase. There is a delay in the development of vascular smooth muscle in the late postnatal period in rats with the blockade of the sympathetic nervous system in the prenatal period. The relationship between vascular remodeling and contractile activity is described. It seems that one of the causes of high blood pressure is a remodeling of the cardiovascular system, which precedes the development of hypertension.

Oxygen drives skeletal muscle remodeling in an amphibious fish out of water.

PubMed

Rossi, Giulia S; Turko, Andy J; Wright, Patricia A

2018-04-24

Skeletal muscle remodeling in response to terrestrial acclimation improves the locomotor performance of some amphibious fishes on land, but the cue for this remodeling is unknown. We tested the hypothesis that muscle remodeling in the amphibious Kryptolebias marmoratus on land is driven by higher O 2 availability in atmospheric air, and the alternative hypothesis that remodeling is induced by a different environmental or physiological condition fish experience on land. Fish were acclimated to 28 days of air, aquatic hyperoxia, hypercapnia, hypoxia, elevated temperature, or fasting conditions. Air, fasting, and hyperoxic conditions increased (>25%) the size of oxidative fibers in K. marmoratus while hypoxia had the reverse effect (23% decrease). Surprisingly, hyperoxia-acclimation also resulted in a transformation of the musculature to include large bands of oxidative-like muscle. Our results show that K. marmoratus is highly responsive to environmental O 2 levels and capitalize on O 2 -rich opportunities to enhance O 2 utilization by skeletal muscle. © 2018. Published by The Company of Biologists Ltd.

NREL Visitors Center Closing Temporarily for Remodeling

Science.gov Websites

Visitors Center Closing Temporarily for Remodeling Media may contact: George Douglas, 303-275-4096 email: George Douglas Golden, Colo., Sept. 6, 2000 - The Visitors Center at the U.S. Department of

Pregnancy-induced remodeling of heart valves.

PubMed

Pierlot, Caitlin M; Moeller, Andrew D; Lee, J Michael; Wells, Sarah M

2015-11-01

Recent studies have demonstrated remodeling of aortic and mitral valves leaflets under the volume loading and cardiac expansion of pregnancy. Those valves' leaflets enlarge with altered collagen fiber architecture, content, and cross-linking and biphasic changes (decreases, then increases) in extensibility during gestation. This study extends our analyses to right-sided valves, with additional compositional measurements for all valves. Valve leaflets were harvested from nonpregnant heifers and pregnant cows. Leaflet structure was characterized by leaflet dimensions, and ECM composition was determined using standard biochemical assays. Histological studies assessed changes in cellular and ECM components. Leaflet mechanical properties were assessed using equibiaxial mechanical testing. Collagen thermal stability and cross-linking were assessed using denaturation and hydrothermal isometric tension tests. Pulmonary and tricuspid leaflet areas increased during pregnancy by 35 and 55%, respectively. Leaflet thickness increased by 20% only in the pulmonary valve and largely in the fibrosa (30% thickening). Collagen crimp length was reduced in both the tricuspid (61%) and pulmonary (42%) valves, with loss of crimped area in the pulmonary valve. Thermomechanics showed decreased collagen thermal stability with surprisingly maintained cross-link maturity. The pulmonary leaflet exhibited the biphasic change in extensibility seen in left side valves, whereas the tricuspid leaflet mechanics remained largely unchanged throughout pregnancy. The tricuspid valve exhibits a remodeling response during pregnancy that is significantly diminished from the other three valves. All valves of the heart remodel in pregnancy in a manner distinct from cardiac pathology, with much similarity valve to valve, but with interesting valve-specific responses in the aortic and tricuspid valves. Copyright © 2015 the American Physiological Society.

Atrioventricular node functional remodeling induced by atrial fibrillation.

PubMed

Zhang, Youhua; Mazgalev, Todor N

2012-09-01

The atrioventricular node (AVN) plays a vital role in determining the ventricular rate during atrial fibrillation (AF). AF results in profound electrophysiological and structural remodeling in the atria as well as the sinus node. However, it is unknown whether AVN undergoes remodeling during AF. To determine whether AVN undergoes functional remodeling during AF. AVN conduction properties were studied in vitro in 9 rabbits with AF and 10 normal controls. A previously validated index of AVN dual-pathway electrophysiology, His-electrogram alternans, was used to monitor fast-pathway or slow-pathway (SP) AVN conduction in these experiments. AVN conduction properties were further studied in vivo in 7 dogs with chronic AF and 8 controls. Compared with the control rabbits, the rabbits with AF had a longer AVN conduction time (83 ± 16 ms vs 68 ± 7 ms; P <.01), longer AVN effective refractory period (141 ± 27 ms vs 100 ± 9 ms; P <.01), an earlier transition from fast-pathway to SP conduction (at a longer prematurity, 249 ± 60 ms vs 171 ± 24 ms; P <.01), and a slower ventricular rate during simulated AF (RR interval 249 ± 42 ms vs 202 ± 12 ms; P <.01). Notably, a larger proportion of conducted beats utilized the SP in AF preparations (92% ± 12% vs 63% ± 32%; P <.05). Long-term AF in dogs resulted in a longer atrioventricular conduction time and AVN effective refractory period and a slower ventricular rate during AF compared with the controls. Pronounced AVN functional electrophysiological remodeling occurs after long-term AF, which could lead to a spontaneous slowing of the ventricular rate. Furthermore, the SP dominance during AF underscores the effectiveness of its modification by ablation for ventricular rate control during AF. Copyright © 2012 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Function of Brg1 Chromatin Remodeling Factor in Sonic Hedgehog-Dependent Medulloblastoma Initiation and Maintenance

DTIC Science & Technology

2014-10-01

Remodeling Factor in Sonic Hedgehog -Dependent Medulloblastoma Initiation and Maintenance PRINCIPAL INVESTIGATOR: Xuanming Shi CONTRACTING...Function of Brg1 Chromatin Remodeling Factor in Sonic Hedgehog -Dependent 5b. GRANT NUMBER W81XWH-12-1-0527 Medulloblastoma Initiation and Maintenance...medulloblastoma. 15. SUBJECT TERMS Medulloblastoma, Sonic Hedgehog , Chromatin remodeling, BAF complex, Brg1, mouse model of shh-subtype medulloblastoma

Preintervention lesion remodelling affects operative mechanisms of balloon optimised directional coronary atherectomy procedures: a volumetric study with three dimensional intravascular ultrasound

PubMed Central

von Birgelen, C; Mintz, G; de Vrey, E A; Serruys, P; Kimura, T; Nobuyoshi, M; Popma, J; Leon, M; Erbel, R; de Feyter, P J

2000-01-01

AIMS—To classify atherosclerotic coronary lesions on the basis of adequate or inadequate compensatory vascular enlargement, and to examine changes in lumen, plaque, and vessel volumes during balloon optimised directional coronary atherectomy procedures in relation to the state of adaptive remodelling before the intervention.
DESIGN—29 lesion segments in 29 patients were examined with intravascular ultrasound before and after successful balloon optimised directional coronary atherectomy procedures, and a validated volumetric intravascular ultrasound analysis was performed off-line to assess the atherosclerotic lesion remodelling and changes in plaque and vessel volumes that occurred during the intervention. Based on the intravascular ultrasound data, lesions were classified according to whether there was inadequate (group I) or adequate (group II) compensatory enlargement.
RESULTS—There was no significant difference in patient and lesion characteristics between groups I and II (n = 10 and 19), including lesion length and details of the intervention. Quantitative coronary angiographic data were similar for both groups. However, plaque and vessel volumes were significantly smaller in group I than in II. In group I, 9 (4)% (mean (SD)) of the plaque volume was ablated, while in group II 16 (11)% was ablated (p = 0.01). This difference was reflected in a lower lumen volume gain in group I than in group II (46 (18) mm3 v 80 (49) mm3 (p < 0.02)).
CONCLUSIONS—Preintervention lesion remodelling has an impact on the operative mechanisms of balloon optimised directional coronary atherectomy procedures. Plaque ablation was found to be particularly low in lesions with inadequate compensatory vascular enlargement.


Keywords: intravascular ultrasound; ultrasonics; remodelling; coronary artery disease; atherectomy PMID:10648496

Qumquad: a UML-based approach for remodeling of legacy systems in health care.

PubMed

Garde, Sebastian; Knaup, Petra; Herold, Ralf

2003-07-01

Health care information systems still comprise legacy systems to a certain extent. For reengineering legacy systems a thorough remodeling is inalienable. Current modeling techniques like the Unified Modeling Language (UML) do not offer a systematic and comprehensive process-oriented method for remodeling activities. We developed a systematic method for remodeling legacy systems in health care called Qumquad. Qumquad consists of three major steps: (i) modeling the actual state of the application system, (ii) systematic identification of weak points in this model and (iii) development of a target concept for the reimplementation considering the identified weak points. We applied Qumquad for remodeling a documentation and therapy planning system for pediatric oncology (DOSPO). As a result of our remodeling activities we regained an abstract model of the system, an analysis of the current weak points of DOSPO and possible (partly alternative) solutions to overcome the weak points. Qumquad proved to be very helpful in the reengineering process of DOSPO since we now have at our disposal a comprehensive model for the reimplementation of DOSPO that current users of the system agree on. Qumquad can easily be applied to other reengineering projects in health care.

Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer

PubMed Central

Cox, Thomas R.; Erler, Janine T.

2011-01-01

Dynamic remodeling of the extracellular matrix (ECM) is essential for development, wound healing and normal organ homeostasis. Life-threatening pathological conditions arise when ECM remodeling becomes excessive or uncontrolled. In this Perspective, we focus on how ECM remodeling contributes to fibrotic diseases and cancer, which both present challenging obstacles with respect to clinical treatment, to illustrate the importance and complexity of cell-ECM interactions in the pathogenesis of these conditions. Fibrotic diseases, which include pulmonary fibrosis, systemic sclerosis, liver cirrhosis and cardiovascular disease, account for over 45% of deaths in the developed world. ECM remodeling is also crucial for tumor malignancy and metastatic progression, which ultimately cause over 90% of deaths from cancer. Here, we discuss current methodologies and models for understanding and quantifying the impact of environmental cues provided by the ECM on disease progression, and how improving our understanding of ECM remodeling in these pathological conditions is crucial for uncovering novel therapeutic targets and treatment strategies. This can only be achieved through the use of appropriate in vitro and in vivo models to mimic disease, and with technologies that enable accurate monitoring, imaging and quantification of the ECM. PMID:21324931

Aging and the cardiac collagen matrix: Novel mediators of fibrotic remodelling.

PubMed

Horn, Margaux A; Trafford, Andrew W

2016-04-01

Cardiovascular disease is a leading cause of death worldwide and there is a pressing need for new therapeutic strategies to treat such conditions. The risk of developing cardiovascular disease increases dramatically with age, yet the majority of experimental research is executed using young animals. The cardiac extracellular matrix (ECM), consisting predominantly of fibrillar collagen, preserves myocardial integrity, provides a means of force transmission and supports myocyte geometry. Disruptions to the finely balanced control of collagen synthesis, post-synthetic deposition, post-translational modification and degradation may have detrimental effects on myocardial functionality. It is now well established that the aged heart is characterized by fibrotic remodelling, but the mechanisms responsible for this are incompletely understood. Furthermore, studies using aged animal models suggest that interstitial remodelling with disease may be age-dependent. Thus with the identification of new therapeutic strategies targeting fibrotic remodelling, it may be necessary to consider age-dependent mechanisms. In this review, we discuss remodelling of the cardiac collagen matrix as a function of age, whilst highlighting potential novel mediators of age-dependent fibrotic pathways. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

On the tidal environment of an outwardly migrating F ring

NASA Astrophysics Data System (ADS)

Sutton, Phil J.

2018-07-01

Saturn's F ring is a unique narrow ring that lies (radially) close to the tidally disruptive Roche limit of water ice for Saturn. Significant work has been done that shows it to be one of the most dynamic places in the Solar system. Aggregates that are fortunate enough to form constantly battle against the strong tidal forces of Saturn and the nearby moons Prometheus and Pandora, which act to gravitationally stir up ring material. Planetary rings are also known to radially spread. Therefore, as the F ring lies at the edge of the main rings, we investigate the effect of an outwardly migrated F ring and its interaction with Prometheus. An increase in the maximum number density of particles at the channel edges is observed with decreasing local tidal environment. Radial velocity dispersions are also observed to fall below the typical escape velocity of a 150 m icy moonlet (<10 cm s^{-1}) where density is enhanced, and are gravitationally unstable with Toomre parameters Q < 2. Additionally, in locations of the ring where Q < 2 is observed, more particles are seen to fall below or close to the critical Toomre parameter as the radial location of the ring increases.

A numerical calculation of outward propagation of solar disturbances. [solar atmospheric model with shock wave propagation

NASA Technical Reports Server (NTRS)

Wu, S. T.

1974-01-01

The responses of the solar atmosphere due to an outward propagation shock are examined by employing the Lax-Wendroff method to solve the set of nonlinear partial differential equations in the model of the solar atmosphere. It is found that this theoretical model can be used to explain the solar phenomena of surge and spray. A criterion to discriminate the surge and spray is established and detailed information concerning the density, velocity, and temperature distribution with respect to the height and time is presented. The complete computer program is also included.

Silent Synapse-Based Circuitry Remodeling in Drug Addiction.

PubMed

Dong, Yan

2016-05-01

Exposure to cocaine, and likely other drugs of abuse, generates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-silent glutamatergic synapses in the nucleus accumbens. These immature synaptic contacts evolve after drug withdrawal to redefine the neurocircuital properties. These results raise at least three critical questions: (1) what are the molecular and cellular mechanisms that mediate drug-induced generation of silent synapses; (2) how are neurocircuits remodeled upon generation and evolution of drug-generated silent synapses; and (3) what behavioral consequences are produced by silent synapse-based circuitry remodeling? This short review analyzes related experimental results, and extends them to some speculations. © The Author 2015. Published by Oxford University Press on behalf of CINP.

Effect of trimetazidine treatment on the transient outward potassium current of the left ventricular myocytes of rats with streptozotocin-induced type 1 diabetes mellitus.

PubMed

Xiang, Yu-luan; He, Li; Xiao, Jun; Xia, Shuang; Deng, Song-bai; Xiu, Yun; She, Qiang

2012-03-01

Cardiovascular complications are a leading cause of mortality in patients with diabetes mellitus (DM). The present study was designed to investigate the effects of trimetazidine (TMZ), an anti-angina drug, on transient outward potassium current (Ito) remodeling in ventricular myocytes and the plasma contents of free fatty acid (FFA) and glucose in DM. Sprague-Dawley rats, 8 weeks old and weighing 200-250 g, were randomly divided into three groups of 20 animals each. The control group was injected with vehicle (1 mM citrate buffer), the DM group was injected with 65 mg/kg streptozotocin (STZ) for induction of type 1 DM, and the DM + TMZ group was injected with the same dose of STZ followed by a 4-week treatment with TMZ (60 mg·kg-1·day-1). All animals were then euthanized and their hearts excised and subjected to electrophysiological measurements or gene expression analyses. TMZ exposure significantly reversed the increased plasma FFA level in diabetic rats, but failed to change the plasma glucose level. The amplitude of Ito was significantly decreased in left ventricular myocytes from diabetic rats relative to control animals (6.25 ± 1.45 vs 20.72 ± 2.93 pA/pF at +40 mV). The DM-associated Ito reduction was attenuated by TMZ. Moreover, TMZ treatment reversed the increased expression of the channel-forming alpha subunit Kv1.4 and the decreased expression of Kv4.2 and Kv4.3 in diabetic rat hearts. These data demonstrate that TMZ can normalize, or partially normalize, the increased plasma FFA content, the reduced Ito of ventricular myocytes, and the altered expression Kv1.4, Kv4.2, and Kv4.3 in type 1 DM.

Epigenetic Mechanisms Regulating Adaptive Responses to Targeted Kinase Inhibitors in Cancer.

PubMed

Angus, Steven P; Zawistowski, Jon S; Johnson, Gary L

2018-01-06

Although targeted inhibition of oncogenic kinase drivers has achieved remarkable patient responses in many cancers, the development of resistance has remained a significant challenge. Numerous mechanisms have been identified, including the acquisition of gatekeeper mutations, activating pathway mutations, and copy number loss or gain of the driver or alternate nodes. These changes have prompted the development of kinase inhibitors with increased selectivity, use of second-line therapeutics to overcome primary resistance, and combination treatment to forestall resistance. In addition to genomic resistance mechanisms, adaptive transcriptional and signaling responses seen in tumors are gaining appreciation as alterations that lead to a phenotypic state change-often observed as an epithelial-to-mesenchymal shift or reversion to a cancer stem cell-like phenotype underpinned by remodeling of the epigenetic landscape. This epigenomic modulation driving cell state change is multifaceted and includes modulation of repressive and activating histone modifications, DNA methylation, enhancer remodeling, and noncoding RNA species. Consequently, the combination of kinase inhibitors with drugs targeting components of the transcriptional machinery and histone-modifying enzymes has shown promise in preclinical and clinical studies. Here, we review mechanisms of resistance to kinase inhibition in cancer, with special emphasis on the rewired kinome and transcriptional signaling networks and the potential vulnerabilities that may be exploited to overcome these adaptive signaling changes.

Remodeling the Vascular Microenvironment of Glioblastoma with α-Particles.

PubMed

Behling, Katja; Maguire, William F; Di Gialleonardo, Valentina; Heeb, Lukas E M; Hassan, Iman F; Veach, Darren R; Keshari, Kayvan R; Gutin, Philip H; Scheinberg, David A; McDevitt, Michael R

2016-11-01

Tumors escape antiangiogenic therapy by activation of proangiogenic signaling pathways. Bevacizumab is approved for the treatment of recurrent glioblastoma, but patients inevitably develop resistance to this angiogenic inhibitor. We previously investigated targeted α-particle therapy with 225 Ac-E4G10 as an antivascular approach and showed increased survival and tumor control in a high-grade transgenic orthotopic glioblastoma model. Here, we investigated changes in tumor vascular morphology and functionality caused by 225 Ac-E4G10. We investigated remodeling of the tumor microenvironment in transgenic Ntva glioblastoma mice using a therapeutic 7.4-kBq dose of 225 Ac-E4G10. Immunofluorescence and immunohistochemical analyses imaged morphologic changes in the tumor blood-brain barrier microenvironment. Multicolor flow cytometry quantified the endothelial progenitor cell population in the bone marrow. Diffusion-weighted MR imaged functional changes in the tumor vascular network. The mechanism of drug action is a combination of remodeling of the glioblastoma vascular microenvironment, relief of edema, and depletion of regulatory T and endothelial progenitor cells. The primary remodeling event is the reduction of both endothelial and perivascular cell populations. Tumor-associated edema and necrosis were lessened, resulting in increased perfusion and reduced diffusion. Pharmacologic uptake of dasatinib into tumor was enhanced after α-particle therapy. Targeted antivascular α-particle radiation remodels the glioblastoma vascular microenvironment via a multimodal mechanism of action and provides insight into the vascular architecture of platelet-derived growth factor-driven glioblastoma. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Vinpocetine Attenuates Pathological Cardiac Remodeling by Inhibiting Cardiac Hypertrophy and Fibrosis

PubMed Central

Wu, Mei-ping; Zhang, Yi-shuai; Xu, Xiangbin; Zhou, Qian

2017-01-01

Purpose Pathological cardiac remodeling, characterized by cardiac hypertrophy and fibrosis, is a pathological feature of many cardiac disorders that leads to heart failure and cardiac arrest. Vinpocetine, a derivative of the alkaloid vincamine, has been used for enhancing cerebral blood flow to treat cognitive impairment. However, its role in pathological cardiac remodeling remains unknown. The aim of this study is to examine the effect of vinpocetine on pathological cardiac remodeling induced by chronic stimulation with angiotensin II (Ang II). Methods Mice received Ang II infusion via osmotic pumps in the presence of vehicle or vinpocetine. Cardiac hypertrophy and fibrosis were assessed by morphological, histological, and biochemical analyses. Mechanistic studies were carried out in vitro with isolated mouse adult cardiac myocytes and fibroblasts. Results We showed that chronic Ang II infusion caused cardiac hypertrophy and fibrosis, which were all significantly attenuated by systemic administration of vinpocetine. In isolated adult mouse cardiomyocytes, vinpocetine suppressed Ang II-stimulated myocyte hypertrophic growth. In cultured cardiac fibroblasts, vinpocetine suppressed TGFβ-induced fibroblast activation and matrix gene expression, consistent with its effect in attenuating cardiac fibrosis. The effects of vinpocetine on cardiac myocyte hypertrophy and fibroblast activation are likely mediated by targeting cyclic nucleotide phosphodiesterase 1 (PDE1). Conclusions Our results reveal a novel protective effect of vinpocetine in attenuating pathological cardiac remodeling through suppressing cardiac myocyte hypertrophic growth and fibroblast activation and fibrotic gene expression. These studies may also shed light on developing novel therapeutic agents for antagonizing pathological cardiac remodeling. PMID:28321644

In vitro chemotaxis and tissue remodeling assays quantitatively characterize foreign body reaction.

PubMed

Jannasch, Maren; Weigel, Tobias; Engelhardt, Lisa; Wiezoreck, Judith; Gaetzner, Sabine; Walles, Heike; Schmitz, Tobias; Hansmann, Jan

2017-01-01

Surgical implantation of a biomaterial triggers foreign-body-induced fibrous encapsulation. Two major mechanisms of this complex physiological process are (I) chemotaxis of fibroblasts from surrounding tissue to the implant region, followed by (II) tissue remodeling. As an alternative to animal studies, we here propose a process-aligned in vitro test platform to investigate the material dependency of fibroblast chemotaxis and tissue remodeling mediated by material-resident macrophages. Embedded in a biomimetic three-dimensional collagen hydrogel, chemotaxis of fibroblasts in the direction of macrophage-material-conditioned cell culture supernatant was analyzed by live cell imaging. A combination of statistical analysis with a complementary parameterized random walk model allowed quantitative and qualitative characterization of the cellular walk process. We thereby identified an increasing macrophage-mediated chemotactic potential ranking of biomaterials from glass over polytetrafluorethylene to titanium. To address long-term effects of bio-material-resident macrophages on fibroblasts in a three-dimensional microenvironment, we further studied tissue remodeling by applying macrophage-material-conditioned medium on fibrous in vitro tissue models. A high correlation of the in vitro tissue model to state of the art in vivo study data was found. Titanium exhibited a significantly lower tissue remodeling capacity compared to polytetrafluorethylene. With this approach, we identified a material dependency of both chemotaxis and tissue remodeling processes, strengthening knowledge on their specific contribution to the foreign body reaction.

Cardiac Remodeling in Response to 1 Year of Intensive Endurance Training

PubMed Central

Arbab-Zadeh, Armin; Perhonen, Merja; Howden, Erin; Peshock, Ronald M.; Zhang, Rong; Adams-Huet, Beverly; Haykowsky, Mark J.; Levine, Benjamin D.

2017-01-01

Background It is unclear whether, and to what extent, the striking cardiac morphological manifestations of endurance athletes are a result of exercise training or a genetically determined characteristic of talented athletes. We hypothesized that prolonged and intensive endurance training in previously sedentary healthy young individuals could induce cardiac remodeling similar to that observed cross-sectionally in elite endurance athletes. Methods and Results Twelve previously sedentary subjects (aged 29±6 years; 7 men and 5 women) trained progressively and intensively for 12 months such that they could compete in a marathon. Magnetic resonance images for assessment of right and left ventricular mass and volumes were obtained at baseline and after 3, 6, 9, and 12 months of training. Maximum oxygen uptake (V̇o2 max) and cardiac output at rest and during exercise (C2H2 rebreathing) were measured at the same time periods. Pulmonary artery catheterization was performed before and after 1 year of training, and pressure-volume and Starling curves were constructed during decreases (lower body negative pressure) and increases (saline infusion) in cardiac volume. Mean V̇o2 max rose from 40.3±1.6 to 48.7±2.5 mL/kg per minute after 1 year (P<0.00001), associated with an increase in both maximal cardiac output and stroke volume. Left and right ventricular mass increased progressively with training duration and intensity and reached levels similar to those observed in elite endurance athletes. In contrast, left ventricular volume did not change significantly until 6 months of training, although right ventricular volume increased progressively from the outset; Starling and pressure-volume curves approached but did not match those of elite athletes. Conclusions One year of prolonged and intensive endurance training leads to cardiac morphological adaptations in previously sedentary young subjects similar to those observed in elite endurance athletes; however, it is not

Outward-dipping ring-fault structure at rabaul caldera as shown by earthquake locations.

PubMed

Mori, J; McKee, C

1987-01-09

The locations of a large number of earthquakes recorded at Rabaul caldera in Papua New Guinea from late 1983 to mid-1985 have produced a picture of this active caldera's structural boundary. The earthquake epicenters form an elliptical annulus about 10 kilometers long by 4 kilometers wide, centered in the southern part of the Rabaul volcanic complex. A set of events with well-constrained depth determinations shows a ring-fault structure that extends from the surface to a depth of about 4 kilometers and slopes steeply outward from the center of the caldera. This is the first geophysical data set that clearly outlines the orientation of an active caldera's bounding faults. This orientation, however, conflicts with the configuration of many other calderas and is not in keeping with currently preferred models of caldera formation.

The Prebiotic Inulin Aggravates Accelerated Atherosclerosis in Hypercholesterolemic APOE*3-Leiden Mice.

PubMed

Hoving, Lisa R; de Vries, Margreet R; de Jong, Rob C M; Katiraei, Saeed; Pronk, Amanda; Quax, Paul H A; van Harmelen, Vanessa; Willems van Dijk, Ko

2018-02-03

The prebiotic inulin has proven effective at lowering inflammation and plasma lipid levels. As atherosclerosis is provoked by both inflammation and hyperlipidemia, we aimed to determine the effect of inulin supplementation on atherosclerosis development in hypercholesterolemic APOE*3-Leiden ( E3L ) mice. Male E3L mice were fed a high-cholesterol (1%) diet, supplemented with or without 10% inulin for 5 weeks. At week 3, a non-constrictive cuff was placed around the right femoral artery to induce accelerated atherosclerosis. At week 5, vascular pathology was determined by lesion thickness, vascular remodeling, and lesion composition. Throughout the study, plasma lipids were measured and in week 5, blood monocyte subtypes were determined using flow cytometry analysis. In contrast to our hypothesis, inulin exacerbated atherosclerosis development, characterized by increased lesion formation and outward vascular remodeling. The lesions showed increased number of macrophages, smooth muscle cells, and collagen content. No effects on blood monocyte composition were found. Inulin significantly increased plasma total cholesterol levels and total cholesterol exposure. In conclusion, inulin aggravated accelerated atherosclerosis development in hypercholesterolemic E3L mice, accompanied by adverse lesion composition and outward remodeling. This process was not accompanied by differences in blood monocyte composition, suggesting that the aggravated atherosclerosis development was driven by increased plasma cholesterol.

The Prebiotic Inulin Aggravates Accelerated Atherosclerosis in Hypercholesterolemic APOE*3-Leiden Mice

PubMed Central

de Jong, Rob C. M.; Katiraei, Saeed; Pronk, Amanda; van Harmelen, Vanessa

2018-01-01

The prebiotic inulin has proven effective at lowering inflammation and plasma lipid levels. As atherosclerosis is provoked by both inflammation and hyperlipidemia, we aimed to determine the effect of inulin supplementation on atherosclerosis development in hypercholesterolemic APOE*3-Leiden (E3L) mice. Male E3L mice were fed a high-cholesterol (1%) diet, supplemented with or without 10% inulin for 5 weeks. At week 3, a non-constrictive cuff was placed around the right femoral artery to induce accelerated atherosclerosis. At week 5, vascular pathology was determined by lesion thickness, vascular remodeling, and lesion composition. Throughout the study, plasma lipids were measured and in week 5, blood monocyte subtypes were determined using flow cytometry analysis. In contrast to our hypothesis, inulin exacerbated atherosclerosis development, characterized by increased lesion formation and outward vascular remodeling. The lesions showed increased number of macrophages, smooth muscle cells, and collagen content. No effects on blood monocyte composition were found. Inulin significantly increased plasma total cholesterol levels and total cholesterol exposure. In conclusion, inulin aggravated accelerated atherosclerosis development in hypercholesterolemic E3L mice, accompanied by adverse lesion composition and outward remodeling. This process was not accompanied by differences in blood monocyte composition, suggesting that the aggravated atherosclerosis development was driven by increased plasma cholesterol. PMID:29401645

Inflammatory Mediators Drive Adverse Right Ventricular Remodeling and Dysfunction and Serve as Potential Biomarkers.

PubMed

Sydykov, Akylbek; Mamazhakypov, Argen; Petrovic, Aleksandar; Kosanovic, Djuro; Sarybaev, Akpay S; Weissmann, Norbert; Ghofrani, Hossein A; Schermuly, Ralph T

2018-01-01

Adverse right ventricular (RV) remodeling leads to ventricular dysfunction and failure that represents an important determinant of outcome in patients with pulmonary hypertension (PH). Recent evidence indicates that inflammatory activation contributes to the pathogenesis of adverse RV remodeling and dysfunction. It has been shown that accumulation of inflammatory cells such as macrophages and mast cells in the right ventricle is associated with maladaptive RV remodeling. In addition, inhibition of inflammation in animal models of RV failure ameliorated RV structural and functional impairment. Furthermore, a number of circulating inflammatory mediators have been demonstrated to be associated with RV performance. This work reviews the role of inflammation in RV remodeling and dysfunction and discusses anti-inflammatory strategies that may attenuate adverse structural alterations while promoting improvement of RV function.

A new method for in vivo visualization of vessel remodeling using a near-infrared dye

PubMed Central

Billaud, Marie; Ross, Jeremy A; Greyson, Mark A; Bruce, Anthony C; Seaman, Scott A; Heberlein, Katherine R; Han, Jenny; Best, Angela K; Peirce, Shayn M; Isakson, Brant E

2011-01-01

Intro Vascular obstructive events can be partially compensated for by remodeling processes that increase vessel diameter and collateral tortuosity. However, methods for visualizing remodeling events in vivo and with temporal comparisons from the same animal remain elusive. Methods Using a novel infrared conjugated polyethylene glycol dye, we investigated the possibility of intravital vascular imaging of the mouse ear before and after ligation of the primary feeder artery. For comparison, we used two different mouse models known to have impaired vascular remodeling post ligation (i.e. aged and PAI-1−/− mice). The results obtained with the infrared dye were confirmed using immunofluorescence labeling of the ear microvasculature with confocal microscopy. Results After ligation, increases in vessel diameter (between 10% and 60%) and tortuosity (approximately 15%) were observed in C57Bl/6 mice using both the infrared dye and the immunofluorescence technique. However, aged C57Bl/6 and PAI-1−/− mice did not show vascular remodeling following ligation. Conclusion Vascular remodeling can be visualized and accurately quantified using a new infrared dye in vivo. This analysis technique could be generally employed for quantitative investigations of changes in vascular remodeling. PMID:21418375

Transforming Growth Factor β1 Function in Airway Remodeling and Hyperresponsiveness. The Missing Link?

PubMed

Ojiaku, Christie A; Yoo, Edwin J; Panettieri, Reynold A

2017-04-01

The pathogenesis of asthma includes a complex interplay among airway inflammation, hyperresponsiveness, and remodeling. Current evidence suggests that airway structural cells, including bronchial smooth muscle cells, myofibroblasts, fibroblasts, and epithelial cells, mediate all three aspects of asthma pathogenesis. Although studies show a connection between airway remodeling and changes in bronchomotor tone, the relationship between the two remains unclear. Transforming growth factor β1 (TGF-β1), a growth factor elevated in the airway of patients with asthma, plays a role in airway remodeling and in the shortening of various airway structural cells. However, the role of TGF-β1 in mediating airway hyperresponsiveness remains unclear. In this review, we summarize the literature addressing the role of TGF-β1 in airway remodeling and shortening. Through our review, we aim to further elucidate the role of TGF-β1 in asthma pathogenesis and the link between airway remodeling and airway hyperresponsiveness in asthma and to define TGF-β1 as a potential therapeutic target for reducing asthma morbidity and mortality.

Bone remodelling of a proximal femur with the thrust plate prosthesis: an in vitro case.

PubMed

Taylor, W R; Ploeg, H; Hertig, D; Warner, M D; Clift, S E

2004-06-01

The key to the development of a successful implant is an understanding of the effect of bone remodelling on its long-term fixation. In this study, clinically observed patterns of bone remodelling have been compared with computer-based predictions for one particular design of prosthesis, the Thrust Plate Prosthesis (Centerpulse Orthopedics, Winterthur, Switzerland). Three-dimensional finite-element models were created using geometrical and bone density data obtained from CT scanning. Results from the bone remodelling simulation indicated that varying the relative rate of bone deposition/resorption and the interfacial conditions between the bone and the implant could produce the trend towards the two clinically observed patterns of remodelling.

Changes in pulmonary arterial wall mechanical properties and lumenal architecture with induced vascular remodeling

NASA Astrophysics Data System (ADS)

Molthen, Robert C.; Heinrich, Amy E.; Haworth, Steven T.; Dawson, Christopher A.

2004-04-01

To explore and quantify pulmonary arterial remodeling we used various methods including micro-CT, high-resolution 3-dimensional x-ray imaging, to examine the structure and function of intact pulmonary vessels in isolated rat lungs. The rat is commonly used as an animal model for studies of pulmonary hypertension (PH) and the accompanying vascular remodeling, where vascular remodeling has been defined primarily by changes in the vessel wall composition in response to hypertension inducing stimuli such as chronic hypoxic exposure (CHE) or monocrotaline (MCT) injection. Little information has been provided as to how such changes affect the vessel wall mechanical properties or the lumenal architecture of the pulmonary arterial system that actually account for the hemodynamic consequences of the remodeling. In addition, although the link between primary forms of pulmonary hypertension and inherited genetics is well established, the role that genetic coding plays in hemodynamics and vascular remodeling is not. Therefore, we are utilizing Fawn-Hooded (FH), Sprague-Dawley (SD) and Brown Norway (BN)rat strains along with unique imaging methods to parameterize both vessel distensibility and lumenal morphometry using a principal pulmonary arterial pathway analysis based on self-consistency. We have found for the hypoxia model, in addition to decreased body weight, increased hematocrit, increased right ventricular hypertrophy, the distensibility of the pulmonary arteries is shown to decrease significantly in the presence of remodeling.

Multigenerational Epigenetic Adaptation of the Hepatic Wound-Healing Response

PubMed Central

Zeybel, Müjdat; Hardy, Timothy; Wong, Yi K.; Mathers, John C.; Fox, Christopher R.; Gackowska, Agata; Oakley, Fiona; Burt, Alastair D.; Wilson, Caroline L.; Anstee, Quentin M.; Barter, Matt J.; Masson, Steven; Elsharkawy, Ahmed M.; Mann, Derek A.; Mann, Jelena

2012-01-01

We asked if ancestral liver damage leads to heritable reprogramming of hepatic wound-healing. We discovered that male rats with a history of liver damage transmit epigenetic suppressive adaptation of the fibrogenic component of wound-healing through male F1 and F2 generations. Underlying this adaptation was reduced generation of liver myofibroblasts, increased hepatic expression of antifibrogenic PPAR-γ and decreased expression of profibrogenic TGF-β1. Remodelling of DNA methylation and histone acetylation underpinned these alterations in gene expression. Sperm from rats with liver fibrosis were enriched for H2A.Z and H3K27me3 at PPAR-γ chromatin. These sperm chromatin modifications were transmittable by adaptive serum transfer from fibrotic rats and were induced in stem cells exposed to myofibroblast-conditioned media. A myofibroblast secreted soluble factor therefore stimulates heritable epigenetic signatures to sperm so as to adapt fibrogenesis in offspring. Humans with mild liver fibrosis display PPAR-γ promoter hypomethylation compared with severe fibrotics, thus lending support for epigenetic regulation of fibrosis. PMID:22941276

Valsartan Reduced Atrial Fibrillation Susceptibility by Inhibiting Atrial Parasympathetic Remodeling through MAPKs/Neurturin Pathway.

PubMed

Liu, Lei; Geng, Jianqiang; Zhao, Hongwei; Yun, Fengxiang; Wang, Xiaoyu; Yan, Sen; Ding, Xue; Li, Wenpeng; Wang, Dingyu; Li, Jianqiang; Pan, Zhenwei; Gong, Yongtai; Tan, Xiangyang; Li, Yue

2015-01-01

Angiotensin II receptor blockers (ARBs) have been proved to be effective in preventing atrial structural and electrical remodelinq in atrial fibrillation (AF). Previous studies have shown that parasympathetic remodeling plays an important role in AF. However, the effects of ARBs on atrial parasympathetic remodeling in AF and the underlying mechanisms are still unknown. Canines were divided into sham-operated, pacing and valsartan + pacing groups. Rats and HL-1 cardiomyocytes were divided into control, angiotensin II (Ang II) and Ang II + valsartan groups, respectively. Atrial parasympathetic remodeling was quantified by immunocytochemical staining with anti-choline acetyltransferase (ChAT) antibody. Western blot was used to analysis the protein expression of neurturin. Both inducibility and duration were increased in chronic atrial rapid-pacing canine model, which was significantly inhibited by the treatment with valsartan. The density of ChAT-positive nerves and the protein level of neurturin in the atria of pacing canines were both increased than those in sham-operated canines. Ang II treatment not only induced atrial parasympathetic remodeling in rats, but also up-regulated the protein expression of neurturin. Valsartan significantly prevented atrial parasympathetic remodeling, and suppressed the protein expression of neurturin. Meanwhile, valsartan inhibited Ang II -induced up-regulation of neurturin and MAPKs in cultured cardiac myocytes. Inhibition of MAPKs dramatically attenuated neurturin up-regulation induced by Ang II. Parasympathetic remodeling was present in animals subjected to rapid pacing or Ang II infusion, which was mediated by MAPKs/neurturin pathway. Valsartan is able to prevent atrial parasympathetic remodeling and the occurrence of AF via inhibiting MAPKs/neurturin pathway. © 2015 S. Karger AG, Basel.

Inflammatory Mediators Drive Adverse Right Ventricular Remodeling and Dysfunction and Serve as Potential Biomarkers

PubMed Central

Sydykov, Akylbek; Mamazhakypov, Argen; Petrovic, Aleksandar; Kosanovic, Djuro; Sarybaev, Akpay S.; Weissmann, Norbert; Ghofrani, Hossein A.; Schermuly, Ralph T.

2018-01-01

Adverse right ventricular (RV) remodeling leads to ventricular dysfunction and failure that represents an important determinant of outcome in patients with pulmonary hypertension (PH). Recent evidence indicates that inflammatory activation contributes to the pathogenesis of adverse RV remodeling and dysfunction. It has been shown that accumulation of inflammatory cells such as macrophages and mast cells in the right ventricle is associated with maladaptive RV remodeling. In addition, inhibition of inflammation in animal models of RV failure ameliorated RV structural and functional impairment. Furthermore, a number of circulating inflammatory mediators have been demonstrated to be associated with RV performance. This work reviews the role of inflammation in RV remodeling and dysfunction and discusses anti-inflammatory strategies that may attenuate adverse structural alterations while promoting improvement of RV function. PMID:29875701

Passive solar design strategies: Remodeling guidelines for conserving energy at home

NASA Astrophysics Data System (ADS)

The idea of passive solar is simple, but applying it effectively does require information and attention to the details of design and construction. Some passive solar techniques are modest and low-cost, and require only small changes in remodeler's typical practice. At the other end of the spectrum, some passive solar systems can almost eliminate a house's need for purchased heating (and in some cases, cooling) energy - but probably at a relatively high first cost. In between are a broad range of energy-conserving passive solar techniques. Whether or not they are cost-effective, practical, and attractive enough to offer a market advantage to any individual remodeler depends on very specific factors such as local costs, climate, and market characteristics. Passive Solar Design Strategies: Remodeling Guidelines For Conserving Energy At Home is written to help give remodelers the information they need to make these decisions. Passive Solar Design Strategies is a package in three basic parts: the guidelines contain information about passive solar techniques and how they work, and provides specific examples of systems which will save various percentages of energy; the worksheets offer a simple, fill-in-the-blank method to pre-evaluate the performance of a specific design; and the worked example demonstrates how to complete the worksheets for a typical residence.

Impact of peri-stent remodeling on restenosis: a volumetric intravascular ultrasound study.

PubMed

Nakamura, M; Yock, P G; Bonneau, H N; Kitamura, K; Aizawa, T; Tamai, H; Fitzgerald, P J; Honda, Y

2001-05-01

Vessel remodeling is an important mechanism of late lumen loss after nonstent coronary interventions. However, its impact on in-stent restenosis has not been systematically investigated. Serial volumetric intravascular ultrasound analyses (poststent and follow-up) were performed in 55 lesions treated with a balloon-expandable stent (ACS MultiLink) using standard stent deployment techniques. The vessel volume (VV), lumen volume (LV), and volume bordered by the stent (SV) were measured using Simpson's method. The volume of plaque and neointima outside the stent (peri-stent volume, PSV) and volume of neointima within the stent (intrastent volume) were also measured. The change of each parameter during the follow-up period (follow-up minus poststent) was calculated and then divided by SV to normalize these values (designated as percent change [%]). As expected, %PSV directly correlated with %VV (P<0.0001, r=0.935), with no significant SV. A highly significant inverse correlation was seen between %PSV and the percent change of intrastent volume (P<0.0001, r=0.517). Consequently, %LV significantly correlated with peri-stent remodeling, as measured by %VV (P<0.0001, r=0.602). Positive remodeling of the vessel exterior to a coronary stent occurs to a variable degree after stent implantation. There is a distinct trade-off between positive remodeling and in-stent hyperplasia: in segments in which the degree of peri-stent remodeling is less, intrastent neointimal proliferation is greater and accompanied by more significant late lumen loss.

Microvascular Remodeling and Wound Healing: A Role for Pericytes

PubMed Central

Dulmovits, Brian M.; Herman, Ira M.

2012-01-01

Physiologic wound healing is highly dependent on the coordinated functions of vascular and non-vascular cells. Resolution of tissue injury involves coagulation, inflammation, formation of granulation tissue, remodeling and scarring. Angiogenesis, the growth of microvessels the size of capillaries, is crucial for these processes, delivering blood-borne cells, nutrients and oxygen to actively remodeling areas. Central to angiogenic induction and regulation is microvascular remodeling, which is dependent upon capillary endothelial cell and pericyte interactions. Despite our growing knowledge of pericyte-endothelial cell crosstalk, it is unclear how the interplay among pericytes, inflammatory cells, glia and connective tissue elements shape microvascular injury response. Here, we consider the relationships that pericytes form with the cellular effectors of healing in normal and diabetic environments, including repair following injury and vascular complications of diabetes, such as diabetic macular edema and proliferative diabetic retinopathy. In addition, pericytes and stem cells possessing “pericyte-like” characteristics are gaining considerable attention in experimental and clinical efforts aimed at promoting healing or eradicating ocular vascular proliferative disorders. As the origin, identification and characterization of microvascular pericyte progenitor populations remains somewhat ambiguous, the molecular markers, structural and functional characteristics of pericytes will be briefly reviewed. PMID:22750474

Nox4 reprograms cardiac substrate metabolism via protein O-GlcNAcylation to enhance stress adaptation

PubMed Central

Nabeebaccus, Adam A.; Zoccarato, Anna; Hafstad, Anne D.; Santos, Celio X.C.; Brewer, Alison C.; Zhang, Min; Beretta, Matteo; West, James A.; Eykyn, Thomas R.; Shah, Ajay M.

2017-01-01

Cardiac hypertrophic remodeling during chronic hemodynamic stress is associated with a switch in preferred energy substrate from fatty acids to glucose, usually considered to be energetically favorable. The mechanistic interrelationship between altered energy metabolism, remodeling, and function remains unclear. The ROS-generating NADPH oxidase-4 (Nox4) is upregulated in the overloaded heart, where it ameliorates adverse remodeling. Here, we show that Nox4 redirects glucose metabolism away from oxidation but increases fatty acid oxidation, thereby maintaining cardiac energetics during acute or chronic stresses. The changes in glucose and fatty acid metabolism are interlinked via a Nox4-ATF4–dependent increase in the hexosamine biosynthetic pathway, which mediates the attachment of O-linked N-acetylglucosamine (O-GlcNAcylation) to the fatty acid transporter CD36 and enhances fatty acid utilization. These data uncover a potentially novel redox pathway that regulates protein O-GlcNAcylation and reprograms cardiac substrate metabolism to favorably modify adaptation to chronic stress. Our results also suggest that increased fatty acid oxidation in the chronically stressed heart may be beneficial. PMID:29263294

Induction of a Radio-Adaptive Response by Low-dose Gamma Irradiation in Mouse Cardiomyocytes

NASA Technical Reports Server (NTRS)

Westby, Christian M.; Seawright, John W.; Wu, Honglu

2011-01-01

One of the most significant occupational hazards to an astronaut is the frequent exposure to radiation. Commonly associated with increased risk for cancer related morbidity and mortality, radiation is also known to increase the risk for cardiovascular related disorders including: pericarditis, hypertension, and heart failure. It is believed that these radiation-induced disorders are a result of abnormal tissue remodeling. It is unknown whether radiation exposure promotes remodeling through fibrotic changes alone or in combination with programmed cell death. Furthermore, it is not known whether it is possible to mitigate the hazardous effects of radiation exposure. As such, we assessed the expression and mechanisms of radiation-induced tissue remodeling and potential radio-adaptive responses of p53-mediated apoptosis and fibrosis pathways along with markers for oxidative stress and inflammation in mice myocardium. 7 week old, male, C57Bl/6 mice were exposed to 6Gy (H) or 5cGy followed 24hr later with 6Gy (LH) 137Cs gamma radiation. Mice were sacrificed and their hearts extirpated 4, 24, or 72hr after final irradiation. Real Time - Polymerase Chain Reaction was used to evaluate target genes. Apoptotic genes Bad and Bax, pro-cell survival genes Bcl2 and Bcl2l2, fibrosis gene Vegfa, and oxidative stress genes Sod2 and GPx4 showed a reduced fold regulation change (Bad,-6.18; Bax,-6.94; Bcl2,-5.09; Bcl2l2,-4.03; Vegfa, -11.84; Sod2,-5.97; GPx4*,-28.72; * = Bonferroni adjusted p-value < or = 0.003) 4hr after H, but not after 4hr LH compared to control. Other p53-mediated apoptosis genes Casp3, Casp9, Trp53, and Myc exhibited down-regulation but did not achieve a notable level of significance 4hr after H. 24hr after H, genetic down-regulation was no longer present compared to 24hr control. These data suggest a general reduction in genetic expression 4hrs after a high dose of gamma radiation. However, pre-exposure to 5cGy gamma radiation appears to facilitate a radio-adaptive

Force-induced bone growth and adaptation: A system theoretical approach to understanding bone mechanotransduction

NASA Astrophysics Data System (ADS)

Maldonado, Solvey; Findeisen, Rolf

2010-06-01

The modeling, analysis, and design of treatment therapies for bone disorders based on the paradigm of force-induced bone growth and adaptation is a challenging task. Mathematical models provide, in comparison to clinical, medical and biological approaches an structured alternative framework to understand the concurrent effects of the multiple factors involved in bone remodeling. By now, there are few mathematical models describing the appearing complex interactions. However, the resulting models are complex and difficult to analyze, due to the strong nonlinearities appearing in the equations, the wide range of variability of the states, and the uncertainties in parameters. In this work, we focus on analyzing the effects of changes in model structure and parameters/inputs variations on the overall steady state behavior using systems theoretical methods. Based on an briefly reviewed existing model that describes force-induced bone adaptation, the main objective of this work is to analyze the stationary behavior and to identify plausible treatment targets for remodeling related bone disorders. Identifying plausible targets can help in the development of optimal treatments combining both physical activity and drug-medication. Such treatments help to improve/maintain/restore bone strength, which deteriorates under bone disorder conditions, such as estrogen deficiency.

Mononuclear Phagocytes Are Dispensable for Cardiac Remodeling in Established Pressure-Overload Heart Failure

PubMed Central

Patel, Bindiya; Ismahil, Mohamed Ameen; Hamid, Tariq; Bansal, Shyam S.; Prabhu, Sumanth D.

2017-01-01

Background Although cardiac and splenic mononuclear phagocytes (MPs), i.e., monocytes, macrophages and dendritic cells (DCs), are key contributors to cardiac remodeling after myocardial infarction, their role in pressure-overload remodeling is unclear. We tested the hypothesis that these immune cells are required for the progression of remodeling in pressure-overload heart failure (HF), and that MP depletion would ameliorate remodeling. Methods and Results C57BL/6 mice were subjected to transverse aortic constriction (TAC) or sham operation, and assessed for alterations in MPs. As compared with sham, TAC mice exhibited expansion of circulating LyC6hi monocytes and pro-inflammatory CD206− cardiac macrophages early (1 w) after pressure-overload, prior to significant hypertrophy and systolic dysfunction, with subsequent resolution during chronic HF. In contrast, classical DCs were expanded in the heart in a biphasic manner, with peaks both early, analogous to macrophages, and late (8 w), during established HF. There was no significant expansion of circulating DCs, or Ly6C+ monocytes and DCs in the spleen. Periodic systemic MP depletion from 2 to 16 w after TAC in macrophage Fas-induced apoptosis (MaFIA) transgenic mice did not alter cardiac remodeling progression, nor did splenectomy in mice with established HF after TAC. Lastly, adoptive transfer of splenocytes from TAC HF mice into naïve recipients did not induce immediate or long-term cardiac dysfunction in recipient mice. Conclusions Mononuclear phagocytes populations expand in a phasic manner in the heart during pressure-overload. However, they are dispensable for the progression of remodeling and failure once significant hypertrophy is evident and blood monocytosis has normalized. PMID:28125666

Retinal arteriolar remodeling evaluated with adaptive optics camera: Relationship with blood pressure levels.

PubMed

Gallo, A; Mattina, A; Rosenbaum, D; Koch, E; Paques, M; Girerd, X

2016-06-01

To research a retinal arterioles wall-to-lumen ratio or lumen diameter cut-off that would discriminate hypertensive from normal subjects using adaptive optics camera. One thousand and five hundred subjects were consecutively recruited and Adaptive Optics Camera rtx1™ (Imagine-Eyes, Orsay, France) was used to measure wall thickness, internal diameter, to calculate wall-to-lumen ratio (WLR) and wall cross-sectional area of retinal arterioles. Sitting office blood pressure was measured once, just before retinal measurements and office blood pressure was defined as systolic blood pressure>=140mmHg and diastolic blood pressure>=90mmHg. ROC curves were constructed to determine cut-off values for retinal parameters to diagnose office hypertension. In another population of 276 subjects office BP, retinal arterioles evaluation and home blood pressure monitoring were obtained. The applicability of retinal WLR or diameter cut-off values were compared in patients with controlled, masked, white-coat and sustained hypertension. In 1500 patients, a WLR>0.31 discriminated office hypertensive subjects with a 0.57 sensitivity and 0.71 specificity. Lumen diameter<78.2μm discriminated office hypertension with a 0.73 sensitivity and a 0.52 specificity. In the other 276 patients, WLR was higher in sustained hypertension vs normotensive patients (0.330±0.06 vs 0.292±0.05; P<0.001) and diameter was narrower in masked hypertensive vs normotensive subjects (73.0±11.2 vs 78.5±11.6μm; P<0.005). A WLR higher than 0.31 is in favour of office arterial hypertension; a diameter under<78μm may indicate a masked hypertension. Retinal arterioles analysis through adaptive optics camera may help the diagnosis of arterial hypertension, in particular in case of masked hypertension. Copyright © 2016. Published by Elsevier SAS.

The angiotensin receptor blocker losartan reduces coronary arteriole remodeling in type 2 diabetic mice

PubMed Central

Husarek, Kathryn E.; Katz, Paige S.; Trask, Aaron J.; Galantowicz, Maarten L.; Cismowski, Mary J.; Lucchesi, Pamela A.

2017-01-01

Cardiovascular complications are a leading cause of morbidity and mortality in type 2 diabetes mellitus (T2DM) and are associated with alterations of blood vessel structure and function. Although endothelial dysfunction and aortic stiffness have been documented, little is known about the effects of T2DM on coronary microvascular structural remodeling. The renin–angiotensin–aldosterone system plays an important role in large artery stiffness and mesenteric vessel remodeling in hypertension and T2DM. The goal of this study was to determine whether the blockade of AT1R signaling dictates vascular smooth muscle growth that partially underlies coronary arteriole remodeling in T2DM. Control and db/db mice were given AT1R blocker losartan via drinking water for 4 weeks. Using pressure myography, we found that coronary arterioles from 16-week db/db mice undergo inward hypertrophic remodeling due to increased wall thickness and wall-to-lumen ratio with a decreased lumen diameter. This remodeling was accompanied by decreased elastic modulus (decreased stiffness). Losartan treatment decreased wall thickness, wall-to-lumen ratio, and coronary arteriole cell number in db/db mice. Losartan treatment did not affect incremental elastic modulus. However, losartan improved coronary flow reserve. Our data suggest that Ang II–AT1R signaling mediates, at least in part, coronary arteriole inward hypertrophic remodeling in T2DM without affecting vascular mechanics, further suggesting that targeting the coronary microvasculature in T2DM may help reduce cardiac ischemic events. PMID:26133668

The chromatin remodeler chd5 is necessary for proper head development during embryogenesis of Danio rerio.

PubMed

Bishop, Brett; Ho, Kwok Ki; Tyler, Kim; Smith, Amanda; Bonilla, Sylvia; Leung, Yuk Fai; Ogas, Joe

2015-08-01

The chromatin remodeler CHD5 plays a critical role in tumor suppression and neurogenesis in mammals. CHD5 contributes to gene expression during neurogenesis, but there is still much to learn regarding how this class of remodelers contributes to differentiation and development. CHD5 remodelers are vertebrate-specific, raising the prospect that CHD5 plays one or more conserved roles in this phylum. Expression of chd5 in adult fish closely mirrors expression of CHD5 in adult mammals. Knockdown of Chd5 during embryogenesis suggests new roles for CHD5 remodelers based on resulting defects in craniofacial development including reduced head and eye size as well as reduced cartilage formation in the head. In addition, knockdown of Chd5 results in altered expression of neural markers in the developing brain and eye as well as a profound defect in differentiation of dopaminergic amacrine cells. Recombinant zebrafish Chd5 protein exhibits nucleosome remodeling activity in vitro, suggesting that it is the loss of this activity that contributes to the observed phenotypes. Our studies indicate that zebrafish is an appropriate model for functional characterization of CHD5 remodelers in vertebrates and highlight the potential of this model for generating novel insights into the role of this vital class of remodelers. Copyright © 2015. Published by Elsevier B.V.

Remodeling characteristics and collagen distribution in synthetic mesh materials explanted from human subjects after abdominal wall reconstruction: an analysis of remodeling characteristics by patient risk factors and surgical site classifications

PubMed Central

Cavallo, Jaime A.; Roma, Andres A.; Jasielec, Mateusz S.; Ousley, Jenny; Creamer, Jennifer; Pichert, Matthew D.; Baalman, Sara; Frisella, Margaret M.; Matthews, Brent D.

2014-01-01

Background The purpose of this study was to evaluate the associations between patient characteristics or surgical site classifications and the histologic remodeling scores of synthetic meshes biopsied from their abdominal wall repair sites in the first attempt to generate a multivariable risk prediction model of non-constructive remodeling. Methods Biopsies of the synthetic meshes were obtained from the abdominal wall repair sites of 51 patients during a subsequent abdominal re-exploration. Biopsies were stained with hematoxylin and eosin, and evaluated according to a semi-quantitative scoring system for remodeling characteristics (cell infiltration, cell types, extracellular matrix deposition, inflammation, fibrous encapsulation, and neovascularization) and a mean composite score (CR). Biopsies were also stained with Sirius Red and Fast Green, and analyzed to determine the collagen I:III ratio. Based on univariate analyses between subject clinical characteristics or surgical site classification and the histologic remodeling scores, cohort variables were selected for multivariable regression models using a threshold p value of ≤0.200. Results The model selection process for the extracellular matrix score yielded two variables: subject age at time of mesh implantation, and mesh classification (c-statistic = 0.842). For CR score, the model selection process yielded two variables: subject age at time of mesh implantation and mesh classification (r2 = 0.464). The model selection process for the collagen III area yielded a model with two variables: subject body mass index at time of mesh explantation and pack-year history (r2 = 0.244). Conclusion Host characteristics and surgical site assessments may predict degree of remodeling for synthetic meshes used to reinforce abdominal wall repair sites. These preliminary results constitute the first steps in generating a risk prediction model that predicts the patients and clinical circumstances for which non

Remodeling by fibroblasts alters the rate-dependent mechanical properties of collagen.

PubMed

Babaei, Behzad; Davarian, Ali; Lee, Sheng-Lin; Pryse, Kenneth M; McConnaughey, William B; Elson, Elliot L; Genin, Guy M

2016-06-01

The ways that fibroblasts remodel their environment are central to wound healing, development of musculoskeletal tissues, and progression of pathologies such as fibrosis. However, the changes that fibroblasts make to the material around them and the mechanical consequences of these changes have proven difficult to quantify, especially in realistic, viscoelastic three-dimensional culture environments, leaving a critical need for quantitative data. Here, we observed the mechanisms and quantified the mechanical effects of fibroblast remodeling in engineered tissue constructs (ETCs) comprised of reconstituted rat tail (type I) collagen and human fibroblast cells. To study the effects of remodeling on tissue mechanics, stress-relaxation tests were performed on ETCs cultured for 24, 48, and 72h. ETCs were treated with deoxycholate and tested again to assess the ECM response. Viscoelastic relaxation spectra were obtained using the generalized Maxwell model. Cells exhibited viscoelastic damping at two finite time constants over which the ECM showed little damping, approximately 0.2s and 10-30s. Different finite time constants in the range of 1-7000s were attributed to ECM relaxation. Cells remodeled the ECM to produce a relaxation time constant on the order of 7000s, and to merge relaxation finite time constants in the 0.5-2s range into a single time content in the 1s range. Results shed light on hierarchical deformation mechanisms in tissues, and on pathologies related to collagen relaxation such as diastolic dysfunction. As fibroblasts proliferate within and remodel a tissue, they change the tissue mechanically. Quantifying these changes is critical for understanding wound healing and the development of pathologies such as cardiac fibrosis. Here, we characterize for the first time the spectrum of viscoelastic (rate-dependent) changes arising from the remodeling of reconstituted collagen by fibroblasts. The method also provides estimates of the viscoelastic spectra of

Mutation of Neuron-Specific Chromatin Remodeling Subunit BAF53b: Rescue of Plasticity and Memory by Manipulating Actin Remodeling

ERIC Educational Resources Information Center

Ciernia, Annie Vogel; Kramár, Enikö A.; Matheos, Dina P.; Havekes, Robbert; Hemstedt, Thekla J.; Magnan, Christophe N.; Sakata, Keith; Tran, Ashley; Azzawi, Soraya; Lopez, Alberto; Dang, Richard; Wang, Weisheng; Trieu, Brian; Tong, Joyce; Barrett, Ruth M.; Post, Rebecca J.; Baldi, Pierre; Abel, Ted; Lynch, Gary; Wood, Marcelo A.

2017-01-01

Recent human exome-sequencing studies have implicated polymorphic Brg1-associated factor (BAF) complexes (mammalian SWI/SNF chromatin remodeling complexes) in several intellectual disabilities and cognitive disorders, including autism. However, it remains unclear how mutations in BAF complexes result in impaired cognitive function. Post-mitotic…

Fat body remodeling and homeostasis control in Drosophila.

PubMed

Zheng, Huimei; Yang, Xiaohang; Xi, Yongmei

2016-12-15

Remarkable advances have been made in recent years in our understanding of the Drosophila fat body and its functions in energy storage, immune response and nutrient sensing. The fat body interplays with other tissues to respond to the physiological needs of the body's growth and coordinates various metabolic processes at different developmental stages and under different environmental conditions. The identification of various conserved genetic functions and signaling pathways relating to the Drosophila fat body may provide clues to lipometabolic disease and other aspects of tissue remodeling in humans. Here, we discuss recent insights into how regulation of fat body remodeling contributes to hemostasis with a special focus on how signaling networks and internal physiological states shape different aspects of the lipid metabolism in Drosophila. Copyright © 2016. Published by Elsevier Inc.

Cardiac-specific overexpression of aldehyde dehydrogenase 2 exacerbates cardiac remodeling in response to pressure overload.

PubMed

Dassanayaka, Sujith; Zheng, Yuting; Gibb, Andrew A; Cummins, Timothy D; McNally, Lindsey A; Brittian, Kenneth R; Jagatheesan, Ganapathy; Audam, Timothy N; Long, Bethany W; Brainard, Robert E; Jones, Steven P; Hill, Bradford G

2018-06-01

Pathological cardiac remodeling during heart failure is associated with higher levels of lipid peroxidation products and lower abundance of several aldehyde detoxification enzymes, including aldehyde dehydrogenase 2 (ALDH2). An emerging idea that could explain these findings concerns the role of electrophilic species in redox signaling, which may be important for adaptive responses to stress or injury. The purpose of this study was to determine whether genetically increasing ALDH2 activity affects pressure overload-induced cardiac dysfunction. Mice subjected to transverse aortic constriction (TAC) for 12 weeks developed myocardial hypertrophy and cardiac dysfunction, which were associated with diminished ALDH2 expression and activity. Cardiac-specific expression of the human ALDH2 gene in mice augmented myocardial ALDH2 activity but did not improve cardiac function in response to pressure overload. After 12 weeks of TAC, ALDH2 transgenic mice had larger hearts than their wild-type littermates and lower capillary density. These findings show that overexpression of ALDH2 augments the hypertrophic response to pressure overload and imply that downregulation of ALDH2 may be an adaptive response to certain forms of cardiac pathology. Copyright © 2018. Published by Elsevier B.V.

Interdependency between mechanical parameters and afferent nerve discharge in remodeled diabetic Goto-Kakizaki rat intestine.

PubMed

Zhao, Jingbo; Yang, Jian; Liao, Donghua; Gregersen, Hans

2017-01-01

Gastrointestinal disorders are very common in diabetic patients, but the pathogenesis is still not well understood. Peripheral afferent nerves may be involved due to the complex regulation of gastrointestinal function by the enteric nervous system. We aimed to characterize the stimulus-response function of afferent fibers innervating the jejunum in the Goto-Kakizaki (GK) type 2 diabetic rat model. A key question is whether changes in afferent firing arise from remodeled tissue or from adaptive afferent processes. Seven 32-week-old male GK rats and seven age-matched normal Wistar rats were studied. Firing from mesenteric afferent nerves was recorded in excised jejunal segments of seven GK rats and seven normal Wistar rats during ramp test, stress relaxation test, and creep test. The circumferential stress-strain, spike rate increase ratio (SRIR), and single unit firing rates were calculated for evaluation of interdependency of the mechanical stimulations and the afferent nerve discharge. Elevated sensitivity to mechanical stimuli was found for diabetic nerve bundles and single unit activity ( P <0.05). The stress relaxed less in the diabetic intestinal segment ( P <0.05). Linear association between SRIR and the thickness of circumferential muscle layer was found at high stress levels as well as for SRIR and the glucose level. Altered viscoelastic properties and elevated mechanosensitivity were found in the GK rat intestine. The altered nerve signaling is related to muscle layer remodeling and glucose levels and may contribute to gastrointestinal symptoms experienced by diabetic patients.

Reverse left ventricular remodeling after acute myocardial infarction: the prognostic impact of left ventricular global torsion.

PubMed

Spinelli, Letizia; Morisco, Carmine; Assante di Panzillo, Emiliano; Izzo, Raffaele; Trimarco, Bruno

2013-04-01

Reverse left ventricular (LV) remodeling (>10 % reduction in LV end-systolic volume) may occur in patients recovering for acute ST-elevation myocardial infarction (STEMI), undergoing percutaneous revascularization of infarct-related coronary artery (PCI). To detect whether LV global torsion obtained by two-dimensional speckle-tracking echocardiography was predictive of reverse LV remodeling, 75 patients with first anterior wall STEMI were studied before (T1) and after PCI (T2) and at 6-month follow-up. Two-year clinical follow-up was also accomplished. LV volumes and both LV sphericity index and conic index were obtained by three-dimensional echocardiography. Reverse remodeling was observed in 25 patients (33 %). By multivariate analysis, independent predictors of reverse LV remodeling were: LV conic index, T2 LV torsion and Δ torsion (difference between T2 and T1 LV torsion expressed as percentage of this latter). According to receiver operating characteristic analysis, 1.34°/cm for T2 LV torsion (sensitivity 88 % and specificity 80 %) and 54 % for Δ torsion (sensitivity 92 % and specificity 82 %) were the optimal cutoff values in predicting reverse LV remodeling. In up to 24 month follow-up, 4 non-fatal re-infarction, 7 hospitalization for heart failure and 4 cardiac deaths occurred. By multivariate Cox analysis, the best variable significantly associated with event-free survival rate was reverse LV remodeling with a hazard ratio = 9.9 (95 % confidence interval, 7.9-31.4, p < 0.01). In conclusion, reverse LV remodeling occurring after anterior wall STEMI is associated with favorable long-term outcome. The improvement of global LV torsion following coronary artery revascularization is the major predictor of reverse LV remodeling.

Endocrine remodelling of the adult intestine sustains reproduction in Drosophila

PubMed Central

Reiff, Tobias; Jacobson, Jake; Cognigni, Paola; Antonello, Zeus; Ballesta, Esther; Tan, Kah Junn; Yew, Joanne Y; Dominguez, Maria; Miguel-Aliaga, Irene

2015-01-01

The production of offspring is energetically costly and relies on incompletely understood mechanisms that generate a positive energy balance. In mothers of many species, changes in key energy-associated internal organs are common yet poorly characterised functionally and mechanistically. In this study, we show that, in adult Drosophila females, the midgut is dramatically remodelled to enhance reproductive output. In contrast to extant models, organ remodelling does not occur in response to increased nutrient intake and/or offspring demands, but rather precedes them. With spatially and temporally directed manipulations, we identify juvenile hormone (JH) as an anticipatory endocrine signal released after mating. Acting through intestinal bHLH-PAS domain proteins Methoprene-tolerant (Met) and Germ cell-expressed (Gce), JH signals directly to intestinal progenitors to yield a larger organ, and adjusts gene expression and sterol regulatory element-binding protein (SREBP) activity in enterocytes to support increased lipid metabolism. Our findings identify a metabolically significant paradigm of adult somatic organ remodelling linking hormonal signals, epithelial plasticity, and reproductive output. DOI: http://dx.doi.org/10.7554/eLife.06930.001 PMID:26216039

Bone remodelling around HA-coated acetabular cups

PubMed Central

Nielsen, P. T.; Søballe, K.

2006-01-01

This study was designed to investigate bone remodelling around the cup in cementless THA. Previous studies indicate an advantage of better sealing of the bone-prosthesis interface by HA/TCP coating of implants, inhibiting polyethylene-induced osteolysis. One hundred patients gave informed consent to participate in a controlled randomized study between porous coated Trilogy versus Trilogy Calcicoat (HA/TCP coated). The cup was inserted in press-fit fixation. The femoral component was a cementless porous coated titanium alloy stem (Bi-Metric), with a modular 28-mm CrCo head. The Harris Hip Score (HHS) and bone mineral density (BMD) determined by DEXA scanning were used to study the effect. Measurements revealed no difference between the two groups after 3 years either in the clinical outcome or in terms of periprosthetic bone density. Patients with a body mass index above normal regained more bone mineral than patients with normal weight. This finding supports the assumption that load is beneficial to bone remodelling. PMID:16761153

Sphingosine-1-phosphate induces pro-remodelling response in airway smooth muscle cells

PubMed Central

Fuerst, E; Foster, H R; Ward, J P T; Corrigan, C J; Cousins, D J; Woszczek, G

2014-01-01

Background Increased proliferation of airway smooth muscle (ASM) cells leading to hyperplasia and increased ASM mass is one of the most characteristic features of airway remodelling in asthma. A bioactive lipid, sphingosine-1-phosphate (S1P), has been suggested to affect airway remodelling by stimulation of human ASM cell proliferation. Objective To investigate the effect of S1P on signalling and regulation of gene expression in ASM cells from healthy and asthmatic individuals. Methods Airway smooth muscle cells grown from bronchial biopsies of healthy and asthmatic individuals were exposed to S1P. Gene expression was analysed using microarray, real-time PCR and Western blotting. Receptor signalling and function were determined by mRNA knockdown and intracellular calcium mobilization experiments. Results S1P potently regulated the expression of more than 80 genes in human ASM cells, including several genes known to be involved in the regulation of cell proliferation and airway remodelling (HBEGF, TGFB3, TXNIP, PLAUR, SERPINE1, RGS4). S1P acting through S1P2 and S1P3 receptors activated intracellular calcium mobilization and extracellular signal-regulated and Rho-associated kinases to regulate gene expression. S1P-induced responses were not inhibited by corticosteroids and did not differ significantly between ASM cells from healthy and asthmatic individuals. Conclusion S1P induces a steroid-resistant, pro-remodelling pathway in ASM cells. Targeting S1P or its receptors could be a novel treatment strategy for inhibiting airway remodelling in asthma. PMID:25041788

New aspects of vascular remodelling: the involvement of all vascular cell types.

PubMed

McGrath, John C; Deighan, Clare; Briones, Ana M; Shafaroudi, Majid Malekzadeh; McBride, Melissa; Adler, Jeremy; Arribas, Silvia M; Vila, Elisabet; Daly, Craig J

2005-07-01

Conventionally, the architecture of arteries is based around the close-packed smooth muscle cells and extracellular matrix. However, the adventitia and endothelium are now viewed as key players in vascular growth and repair. A new dynamic picture has emerged of blood vessels in a constant state of self-maintenance. Recent work raises fundamental questions about the cellular heterogeneity of arteries and the time course and triggering of normal and pathological remodelling. A common denominator emerging in hypertensive remodelling is an early increase in adventitial cell density suggesting that adventitial cells drive remodelling and may initiate subsequent changes such as re-arrangement of smooth muscle cells and extracellular matrix. The organization of vascular smooth muscle cells follows regular arrangements that can be modelled mathematically. In hypertension, new patterns can be quantified in these terms and give insights to how structure affects function. As with smooth muscle, little is known about the organization of the vascular endothelium, or its role in vascular remodelling. Current observations suggest that there may be a close relationship between the helical organization of smooth muscle cells and the underlying pattern of endothelial cells. The function of myoendothelial connections is a topic of great current interest and may relate to the structure of the internal elastic lamina through which the connections must pass. In hypertensive remodelling this must present an organizational challenge. The objective of this paper is to show how the functions of blood vessels depend on their architecture and a continuous interaction of different cell types and extracellular proteins.

Aortic root remodeling: ten-year experience with 274 patients.

PubMed

Aicher, Diana; Langer, Frank; Lausberg, Henning; Bierbach, Benjamin; Schäfers, Hans-Joachim

2007-10-01

Dilatation of the aortic root with concomitant aortic regurgitation can be treated by valve-preserving surgery. We have consistently chosen root remodeling rather than reimplantation whenever the aortoventricular junction was not dilated. We have analyzed our 11-year experience with root remodeling. Between October 1995 and October 2006, 274 patients (201 male; 73 female, aged 59 +/- 15 years) were treated by root remodeling in the presence of a preserved aortoventricular diameter (<30 mm). Acute aortic dissection was present in 46 patients. The valve anatomy was tricuspid in 193 and bicuspid in 81 patients. Cusp disease was additionally corrected in 173 (63%) patients. Follow-up was complete in 99%. Cumulative follow-up was 1045 patient-years (mean of 4.0 +/- 2.7 years). Hospital mortality was 3.6% (elective 3.1%; emergency 6.5%). One patient had endocarditis 2 months postoperatively and subsequently underwent valve replacement. Freedom from aortic regurgitation of grade II or more was 91% and 87% at 10 years for bicuspid and tricuspid aortic valves. Nine patients required reoperation: in 6 patients the valve was replaced and in 3 patients rerepaired. Freedom from reoperation was 96% at 5 and 10 years, and freedom from valve replacement was 98% at 5 and 10 years. A comparison of 3 operative periods (1995-1998, 1999-2002, and 2003-2006) showed that with increasing experience cusp prolapse was diagnosed and corrected more frequently (8/49 = 17%; 62/105 = 59%; 103/108 = 82%; P < .0001), and repair stability significantly improved over time (P = .007). Root remodeling leads to durable restoration of aortic valve function in both tricuspid and bicuspid valve anatomy. Aggressive correction of cusp prolapse seems to have a beneficial effect on aortic valve competence.

Quantification of three-dimensional cell-mediated collagen remodeling using graph theory.

PubMed

Bilgin, Cemal Cagatay; Lund, Amanda W; Can, Ali; Plopper, George E; Yener, Bülent

2010-09-30

Cell cooperation is a critical event during tissue development. We present the first precise metrics to quantify the interaction between mesenchymal stem cells (MSCs) and extra cellular matrix (ECM). In particular, we describe cooperative collagen alignment process with respect to the spatio-temporal organization and function of mesenchymal stem cells in three dimensions. We defined two precise metrics: Collagen Alignment Index and Cell Dissatisfaction Level, for quantitatively tracking type I collagen and fibrillogenesis remodeling by mesenchymal stem cells over time. Computation of these metrics was based on graph theory and vector calculus. The cells and their three dimensional type I collagen microenvironment were modeled by three dimensional cell-graphs and collagen fiber organization was calculated from gradient vectors. With the enhancement of mesenchymal stem cell differentiation, acceleration through different phases was quantitatively demonstrated. The phases were clustered in a statistically significant manner based on collagen organization, with late phases of remodeling by untreated cells clustering strongly with early phases of remodeling by differentiating cells. The experiments were repeated three times to conclude that the metrics could successfully identify critical phases of collagen remodeling that were dependent upon cooperativity within the cell population. Definition of early metrics that are able to predict long-term functionality by linking engineered tissue structure to function is an important step toward optimizing biomaterials for the purposes of regenerative medicine.

Drosophila Transcription Factor Tramtrack69 Binds MEP1 To Recruit the Chromatin Remodeler NuRD ▿ †

PubMed Central

Reddy, B. Ashok; Bajpe, Prashanth Kumar; Bassett, Andrew; Moshkin, Yuri M.; Kozhevnikova, Elena; Bezstarosti, Karel; Demmers, Jeroen A. A.; Travers, Andrew A.; Verrijzer, C. Peter

2010-01-01

ATP-dependent chromatin-remodeling complexes (remodelers) are essential regulators of chromatin structure and gene transcription. How remodelers can act in a gene-selective manner has remained enigmatic. A yeast two-hybrid screen for proteins binding the Drosophila transcription factor Tramtrack69 (TTK69) identified MEP1. Proteomic characterization revealed that MEP1 is a tightly associated subunit of the NuRD remodeler, harboring the Mi2 enzymatic core ATPase. In addition, we identified the fly homolog of human Deleted in oral cancer 1 (DOC1), also known as CDK2-associated protein 1 (CDK2AP1), as a bona fide NuRD subunit. Biochemical and genetic assays supported the functional association between MEP1, Mi2, and TTK69. Genomewide expression analysis established that TTK69, MEP1, and Mi2 cooperate closely to control transcription. The TTK69 transcriptome profile correlates poorly with remodelers other than NuRD, emphasizing the selectivity of remodeler action. On the genes examined, TTK69 is able to bind chromatin in the absence of NuRD, but targeting of NuRD is dependent on TTK69. Thus, there appears to be a hierarchical relationship in which transcription factor binding precedes remodeler recruitment. PMID:20733004

Transferrin Receptor 1 in Chronic Hypoxia-Induced Pulmonary Vascular Remodeling.

PubMed

Naito, Yoshiro; Hosokawa, Manami; Sawada, Hisashi; Oboshi, Makiko; Hirotani, Shinichi; Iwasaku, Toshihiro; Okuhara, Yoshitaka; Morisawa, Daisuke; Eguchi, Akiyo; Nishimura, Koichi; Soyama, Yuko; Fujii, Kenichi; Mano, Toshiaki; Ishihara, Masaharu; Tsujino, Takeshi; Masuyama, Tohru

2016-06-01

Iron is associated with the pathophysiology of several cardiovascular diseases, including pulmonary hypertension (PH). In addition, disrupted pulmonary iron homeostasis has been reported in several chronic lung diseases. Transferrin receptor 1 (TfR1) plays a key role in cellular iron transport. However, the role of TfR1 in the pathophysiology of PH has not been well characterized. In this study, we investigate the role of TfR1 in the development of hypoxia-induced pulmonary vascular remodeling. PH was induced by exposing wild-type (WT) mice and TfR1 hetero knockout mice to hypoxia for 4 weeks and evaluated via assessment of pulmonary vascular remodeling, right ventricular (RV) systolic pressure, and RV hypertrophy. In addition, we assessed the functional role of TfR1 in pulmonary artery smooth muscle cells in vitro. The morphology of pulmonary arteries did not differ between WT mice and TfR1 hetero knockout mice under normoxic conditions. In contrast, TfR1 hetero knockout mice exposed to 4 weeks hypoxia showed attenuated pulmonary vascular remodeling, RV systolic pressure, and RV hypertrophy compared with WT mice. In addition, the depletion of TfR1 by RNA interference attenuated human pulmonary artery smooth muscle cells proliferation induced by platelet-derived growth factor-BB (PDGF-BB) in vitro. These results suggest that TfR1 plays an important role in the development of hypoxia-induced pulmonary vascular remodeling. © American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Vascular remodeling and mineralocorticoids.

PubMed

Weber, K T; Sun, Y; Campbell, S E; Slight, S H; Ganjam, V K

1995-01-01

Circulating mineralocorticoid hormones are so named because of their important homeostatic properties that regulate salt and water balance via their action on epithelial cells. A broader range of functions in nonclassic target cellular sites has been proposed for these steroids and includes their contribution to wound healing following injury. A chronic, inappropriate (relative to intravascular volume and dietary sodium intake) elevation of these circulating hormones evokes a wound healing response in the absence of tissue injury--a wound healing response gone awry. The adverse remodeling of vascularized tissues seen in association with chronic mineralocorticoid excess is the focus of this review.

On the pivotal role of PPARα in adaptation of the heart to hypoxia and why fat in the diet increases hypoxic injury

PubMed Central

Cole, Mark A.; Abd Jamil, Amira H.; Heather, Lisa C.; Murray, Andrew J.; Sutton, Elizabeth R.; Slingo, Mary; Sebag-Montefiore, Liam; Tan, Suat Cheng; Aksentijević, Dunja; Gildea, Ottilie S.; Stuckey, Daniel J.; Yeoh, Kar Kheng; Carr, Carolyn A.; Evans, Rhys D.; Aasum, Ellen; Schofield, Christopher J.; Ratcliffe, Peter J.; Neubauer, Stefan; Robbins, Peter A.; Clarke, Kieran

2016-01-01

The role of peroxisome proliferator-activated receptor α (PPARα)-mediated metabolic remodeling in cardiac adaptation to hypoxia has yet to be defined. Here, mice were housed in hypoxia for 3 wk before in vivo contractile function was measured using cine MRI. In isolated, perfused hearts, energetics were measured using 31P magnetic resonance spectroscopy (MRS), and glycolysis and fatty acid oxidation were measured using [3H] labeling. Compared with a normoxic, chow-fed control mouse heart, hypoxia decreased PPARα expression, fatty acid oxidation, and mitochondrial uncoupling protein 3 (UCP3) levels, while increasing glycolysis, all of which served to maintain normal ATP concentrations ([ATP]) and thereby, ejection fractions. A high-fat diet increased cardiac PPARα expression, fatty acid oxidation, and UCP3 levels with decreased glycolysis. Hypoxia was unable to alter the high PPARα expression or reverse the metabolic changes caused by the high-fat diet, with the result that [ATP] and contractile function decreased significantly. The adaptive metabolic changes caused by hypoxia in control mouse hearts were found to have occurred already in PPARα-deficient (PPARα−/−) mouse hearts and sustained function in hypoxia despite an inability for further metabolic remodeling. We conclude that decreased cardiac PPARα expression is essential for adaptive metabolic remodeling in hypoxia, but is prevented by dietary fat.—Cole, M. A., Abd Jamil, A. H., Heather, L. C., Murray, A. J., Sutton, E. R., Slingo, M., Sebag-Montefiore, L., Tan, S. C., Aksentijević, D., Gildea, O. S., Stuckey, D. J., Yeoh, K. K., Carr, C. A., Evans, R. D., Aasum, E., Schofield, C. J., Ratcliffe, P. J., Neubauer, S., Robbins, P. A., Clarke, K. On the pivotal role of PPARα in adaptation of the heart to hypoxia and why fat in the diet increases hypoxic injury. PMID:27103577

Coronary Collateral Growth—Back to the Future

PubMed Central

Chilian, William M.; Penn, Marc S.; Pung, Yuh Fen; Dong, Feng; Mayorga, Maritza; Ohanyan, Vahagn; Logan, Suzanna; Yin, Liya

2012-01-01

The coronary collateral circulation is critically important as an adaptation of the heart to prevent the damage from ischemic insults. In their native state, collaterals in the heart would be classified as part of the microcirculation, existing as arterial-arterial anastomotic connections in the range of 30 to 100 μM in diameter. However, these vessels also show a propensity to remodel into components of the macrocirculation and can become arteries larger than a 1000 μM in diameter. This process of outward remodelling is critically important in the adaptation of the heart to ischemia because the resistance to blood flow is inversely related to the fourth power of the diameter of the vessel. Thus, an expansion of a vessel from 100 to 1000 μM would reduce resistance (in this part of the circuit) to a negligible amount and enable delivery of flow to the region at risk. Our goal in this review is to highlight the voids in understanding this adaptation to ischemia—the growth of the coronary collateral circulation. In doing so we discuss the controversies and unknown aspects of the causal factors that stimulate growth of the collateral circulation, the role of genetics, and the role of endogenous stem and progenitor cells in the context of the normal, physiological situation and under more pathological conditions of ischemic heart disease or with some of the underlying risk factors, e.g., diabetes. The major conclusion of this review is that there are many gaps in our knowledge of coronary collateral growth and this knowledge is critical before the potential of stimulating collateralization in the hearts of patients can be realized. PMID:22210280

A Bioreactor to Identify the Driving Mechanical Stimuli of Tissue Growth and Remodeling.

PubMed

van Kelle, Mathieu A J; Oomen, Pim J A; Bulsink, Jurgen A; Janssen-van den Broek, Marloes W J T; Lopata, Richard G P; Rutten, Marcel C M; Loerakker, Sandra; Bouten, Carlijn V C

2017-06-01

Tissue growth and remodeling are essential processes that should ensure long-term functionality of tissue-engineered (TE) constructs. Even though it is widely recognized that these processes strongly depend on mechanical stimuli, the underlying mechanisms of mechanically induced growth and remodeling are only partially understood. It is generally accepted that cells sense mechanical changes and respond by altering their surroundings, by means of extracellular matrix growth and remodeling, in an attempt to return to a certain preferred mechanical homeostatic state. However, the exact mechanical cues that trigger cells to synthesize and remodel their environment remain unclear. To identify the driving mechanical stimuli of these processes, it is critical to be able to temporarily follow the mechanical state of developing tissues under physiological loading conditions. Therefore, a novel "versatile tissue growth and remodeling" (Vertigro) bioreactor was developed that is capable of tissue culture and mechanical stimulation for a prolonged time period, while simultaneously performing mechanical testing. The Vertigro's unique two-chamber design allows easy, sterile handling of circular 3D TE constructs in a dedicated culture chamber, while a separate pressure chamber facilitates a pressure-driven dynamic loading regime during culture. As a proof-of-concept, temporal changes in the mechanical state of cultured tissues were quantified using nondestructive mechanical testing by means of a classical bulge test, in which the tissue displacement was tracked using ultrasound imaging. To demonstrate the successful development of the bioreactor system, compositional, structural, and geometrical changes were qualitatively and quantitatively assessed using a series of standard analysis techniques. With this bioreactor and associated mechanical analysis technique, a powerful toolbox has been developed to quantitatively study and identify the driving mechanical stimuli of engineered

The PDE4 inhibitor CHF-6001 and LAMAs inhibit bronchoconstriction-induced remodeling in lung slices.

PubMed

Kistemaker, Loes E M; Oenema, Tjitske A; Baarsma, Hoeke A; Bos, I Sophie T; Schmidt, Martina; Facchinetti, Fabrizio; Civelli, Maurizio; Villetti, Gino; Gosens, Reinoud

2017-09-01

Combination therapy of PDE4 inhibitors and anticholinergics induces bronchoprotection in COPD. Mechanical forces that arise during bronchoconstriction may contribute to airway remodeling. Therefore, we investigated the impact of PDE4 inhibitors and anticholinergics on bronchoconstriction-induced remodeling. Because of the different mechanism of action of PDE4 inhibitors and anticholinergics, we hypothesized functional interactions of these two drug classes. Guinea pig precision-cut lung slices were preincubated with the PDE4 inhibitors CHF-6001 or roflumilast and/or the anticholinergics tiotropium or glycopyorrolate, followed by stimulation with methacholine (10 μM) or TGF-β 1 (2 ng/ml) for 48 h. The inhibitory effects on airway smooth muscle remodeling, airway contraction, and TGF-β release were investigated. Methacholine-induced protein expression of smooth muscle-myosin was fully inhibited by CHF-6001 (0.3-100 nM), whereas roflumilast (1 µM) had smaller effects. Tiotropium and glycopyrrolate fully inhibited methacholine-induced airway remodeling (0.1-30 nM). The combination of CHF-6001 and tiotropium or glycopyrrolate, in concentrations partially effective by themselves, fully inhibited methacholine-induced remodeling in combination. CHF-6001 did not affect airway closure and had limited effects on TGF-β 1 -induced remodeling, but rather, it inhibited methacholine-induced TGF-β release. The PDE4 inhibitor CHF-6001, and to a lesser extent roflumilast, and the LAMAs tiotropium and glycopyrrolate inhibit bronchoconstriction-induced remodeling. The combination of CHF-6001 and anticholinergics was more effective than the individual compounds. This cooperativity might be explained by the distinct mechanisms of action inhibiting TGF-β release and bronchoconstriction. Copyright © 2017 the American Physiological Society.

The angiotensin receptor blocker losartan reduces coronary arteriole remodeling in type 2 diabetic mice.

PubMed

Husarek, Kathryn E; Katz, Paige S; Trask, Aaron J; Galantowicz, Maarten L; Cismowski, Mary J; Lucchesi, Pamela A

2016-01-01

Cardiovascular complications are a leading cause of morbidity and mortality in type 2 diabetes mellitus (T2DM) and are associated with alterations of blood vessel structure and function. Although endothelial dysfunction and aortic stiffness have been documented, little is known about the effects of T2DM on coronary microvascular structural remodeling. The renin-angiotensin-aldosterone system plays an important role in large artery stiffness and mesenteric vessel remodeling in hypertension and T2DM. The goal of this study was to determine whether the blockade of AT1R signaling dictates vascular smooth muscle growth that partially underlies coronary arteriole remodeling in T2DM. Control and db/db mice were given AT1R blocker losartan via drinking water for 4 weeks. Using pressure myography, we found that coronary arterioles from 16-week db/db mice undergo inward hypertrophic remodeling due to increased wall thickness and wall-to-lumen ratio with a decreased lumen diameter. This remodeling was accompanied by decreased elastic modulus (decreased stiffness). Losartan treatment decreased wall thickness, wall-to-lumen ratio, and coronary arteriole cell number in db/db mice. Losartan treatment did not affect incremental elastic modulus. However, losartan improved coronary flow reserve. Our data suggest that Ang II-AT1R signaling mediates, at least in part, coronary arteriole inward hypertrophic remodeling in T2DM without affecting vascular mechanics, further suggesting that targeting the coronary microvasculature in T2DM may help reduce cardiac ischemic events. Copyright © 2015 Elsevier Inc. All rights reserved.

[Characteristics of electrophysiology and effects of ouabain on transient outward potassium current and L-type calcium current of left atrium posterior wall in rabbits].

PubMed

Wang, Teng; Huang, Cong-xin; Jiang, Hong; Tang, Qi-zhu; Yang, Bo; Li, Geng-shan

2009-12-01

To investigate the properties of electrophysiology and effects of ouabain upon transient outward potassium current (I(to)) and L-type calcium current (I(Ca-L)) of left atrium posterior wall (LAPW) and left atrium appendage tissue (LAA)in rabbit so as to provide the scientific explanations that LAPW and ouabain can enhance atrial fibrillation (AF) vulnerability through increasing electrophysiological heterogeneity and electrical remodeling of different regions of left atrium in rabbits. Atrial myocytes from LAPWs and LAAs of rabbits on an in vitro heart perfusion system were obtained by enzymatic dissociation. The whole-cell patch-clamp technique was used to assess the effects of ouabain upon I(to) and I(Ca-L). The current-voltage (I-V) curves of I(to) and I(Ca-L) in LAPW and LAA myocytes were fitted before and after ouabain administration. (1) With holding potential +50 mV and commanding potential +50 mV, the current densities of LAPW I(to) decreased slightly less than that of LAA I(to) in control groups (P > 0.05). After ouabain administration, the current densities of LAPW I(to) were significantly larger than that of LAA I(to) [(10.97 +/- 0.58) pA/pF vs (9.39 +/- 0.83) pA/pF, P < 0.05]. The I-V curve of LAPW I(to) was slightly lowered to I-V curve of LAA I(to) in control groups. But with perfusion of ouabain, the I-V curve of LAPW I(to) opposed to I-V curve of LAA I(to) significantly changed from the bottom to the top with the same upward direction. (2) With the voltage clamp protocol of I(Ca-L), the current densities of LAPW I(Ca-L) markedly decreased compared with that of LAA I(Ca-L) in control groups (P < 0.05). With the addition of ouabain, the peak of amplitude of LAPW I(Ca-L) at +20 mV obviously increased to that of LAA I(Ca-L) [(-11.13 +/- 0.99) pA/pF vs (-8.86 +/- 0.51) pA/pF, P < 0.01]. In the control groups, the I-V curve of LAPW I(Ca-L) was shifted to the bottom of all I-V curves of I(Ca-L). Through the effects of ouabain, the I-V curve of LAPW I

Long Noncoding RNA-GAS5: A Novel Regulator of Hypertension-Induced Vascular Remodeling.

PubMed

Wang, Yang-Ning-Zhi; Shan, Kun; Yao, Mu-Di; Yao, Jin; Wang, Jia-Jian; Li, Xiang; Liu, Ban; Zhang, Yang-Yang; Ji, Yong; Jiang, Qin; Yan, Biao

2016-09-01

Vascular remodeling is an important pathological feature of hypertension, leading to increased vascular resistance and reduced compliance. Endothelial cell (EC) and vascular smooth muscle cell (VSMC) dysfunction is involved in vascular remodeling. Long noncoding RNAs are potential regulators of EC and VSMC function. Herein, we determined whether long noncoding RNA-growth arrest-specific 5 (GAS5) is involved in hypertension-related vascular remodeling. We revealed that GAS5 knockdown aggravated hypertension-induced microvascular dysfunction as shown by increased retinal neovascularization and capillary leakage. GAS5 regulated the remodeling of arteries, including caudal arteries, carotid arteries, renal arteries, and thoracic arteries. GAS5 was mainly expressed in ECs and VSMCs, and its expression was significantly downregulated in hypertension. GAS5 knockdown affected endothelial activation, endothelial proliferation, VSMC phenotypic conversion, and EC-VSMC communication in vivo and in vitro. Mechanistically, GAS5 regulated EC and VSMC function through β-catenin signaling. This study identified GAS5 as a critical regulator in hypertension and demonstrated the potential of gene therapy and drug development for treating hypertension. © 2016 American Heart Association, Inc.

Remodeling of muscle fibers approaching the human myotendinous junction.

PubMed

Jakobsen, J R; Jakobsen, N R; Mackey, A L; Koch, M; Kjaer, M; Krogsgaard, M R

2018-04-19

The myotendinous junction (MTJ) is at high risk of strain injuries, due to high amounts of energy that is transferred through this structure. The risk of strain injury is significantly reduced by heavy resistance training (HRT), indicating a remodeling capacity of MTJ. We investigated the degree of remodeling of muscle fibers near the human MTJ. In 8 individuals, samples were taken from the semitendinosus and gracilis MTJ and they were stained immunohistochemically for myonuclei (DAPI), fibroblasts (TCF7L2), and satellite cells (CD56). A high portion of the muscle fibers adjacent to the MTJ contained a centrally located myonucleus (47 ± 8%, mean ± SD) and half of the muscle fibers were CD56 positive. The number of satellite cells and fibroblasts were not higher than what has previously been reported from muscle bellies. The immunohistochemical findings suggest that the rate of remodeling of muscle fibers near the MTJ is very high. The finding that there was no increased number of satellite cells and fibroblasts could be explained as a dynamic phenomenon. The effect of HRT should be evaluated in a randomized setting. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

PDGFRα plays a crucial role in connective tissue remodeling.

PubMed

Horikawa, Shinjiro; Ishii, Yoko; Hamashima, Takeru; Yamamoto, Seiji; Mori, Hisashi; Fujimori, Toshihiko; Shen, Jie; Inoue, Ran; Nishizono, Hirofumi; Itoh, Hiroshi; Majima, Masataka; Abraham, David; Miyawaki, Toshio; Sasahara, Masakiyo

2015-12-07

Platelet derived growth factor (PDGF) plays a pivotal role in the remodeling of connective tissues. Emerging data indicate the distinctive role of PDGF receptor-α (PDGFRα) in this process. In the present study, the Pdgfra gene was systemically inactivated in adult mouse (α-KO mouse), and the role of PDGFRα was examined in the subcutaneously implanted sponge matrices. PDGFRα expressed in the fibroblasts of Pdgfra-preserving control mice (Flox mice), was significantly reduced in the sponges in α-KO mice. Neovascularized areas were largely suppressed in the α-KO mice than in the Flox mice, whereas the other parameters related to the blood vessels and endothelial cells were similar. The deposition of collagen and fibronectin and the expression of collagen 1a1 and 3a1 genes were significantly reduced in α-KO mice. There was a significantly decrease in the number and dividing fibroblasts in the α-KO mice, and those of macrophages were similar between the two genotypes. Hepatocyte growth factor (Hgf) gene expression was suppressed in Pdgfra-inactivated fibroblasts and connective tissue. The findings implicate the role of PDGFRα-dependent ECM and HGF production in fibroblasts that promotes the remodeling of connective tissue and suggest that PDGFRα may be a relevant target to regulate connective tissue remodeling.

PDGFRα plays a crucial role in connective tissue remodeling

PubMed Central

Horikawa, Shinjiro; Ishii, Yoko; Hamashima, Takeru; Yamamoto, Seiji; Mori, Hisashi; Fujimori, Toshihiko; Shen, Jie; Inoue, Ran; Nishizono, Hirofumi; Itoh, Hiroshi; Majima, Masataka; Abraham, David; Miyawaki, Toshio; Sasahara, Masakiyo

2015-01-01

Platelet derived growth factor (PDGF) plays a pivotal role in the remodeling of connective tissues. Emerging data indicate the distinctive role of PDGF receptor-α (PDGFRα) in this process. In the present study, the Pdgfra gene was systemically inactivated in adult mouse (α-KO mouse), and the role of PDGFRα was examined in the subcutaneously implanted sponge matrices. PDGFRα expressed in the fibroblasts of Pdgfra-preserving control mice (Flox mice), was significantly reduced in the sponges in α-KO mice. Neovascularized areas were largely suppressed in the α-KO mice than in the Flox mice, whereas the other parameters related to the blood vessels and endothelial cells were similar. The deposition of collagen and fibronectin and the expression of collagen 1a1 and 3a1 genes were significantly reduced in α-KO mice. There was a significantly decrease in the number and dividing fibroblasts in the α-KO mice, and those of macrophages were similar between the two genotypes. Hepatocyte growth factor (Hgf) gene expression was suppressed in Pdgfra-inactivated fibroblasts and connective tissue. The findings implicate the role of PDGFRα-dependent ECM and HGF production in fibroblasts that promotes the remodeling of connective tissue and suggest that PDGFRα may be a relevant target to regulate connective tissue remodeling. PMID:26639755

Measurement of retinal wall-to-lumen ratio by adaptive optics retinal camera: a clinical research.

PubMed

Meixner, Eva; Michelson, Georg

2015-11-01

To measure the wall-to-lumen ratio (WLR) and the cross-sectional area of the vascular wall (WCSA) of retinal arterioles by an Adaptive Optics (AO) retinal camera. Forty-seven human subjects were examined and their medical history was explored. WLR and WCSA were measured on the basis of retinal arteriolar wall thickness (VW), lumen diameter (LD) and vessel diameter (VD) assessed by rtx1 Adaptive Optics retinal camera. WLR was calculated by the formula [Formula: see text]. Arterio-venous ratio (AVR) and microvascular abnormalities were attained by quantitative and qualitative assessment of fundus photographs. Influence of age, arterial hypertension, body mass index (BMI) and retinal microvascular abnormalities on the WLR was examined. An age-adjusted WLR was created to test influences on WLR independently of age. Considering WLR and WCSA, a distinction between eutrophic and hypertrophic retinal remodeling processes was possible. The intra-observer variability (IOV) was 6 % ± 0.9 for arteriolar wall thickness and 2 % ± 0.2 for arteriolar wall thickness plus vessel lumen. WLR depended significantly on the wall thickness (r = 0.715; p < 0.01) of retinal arterioles, but was independent of the total vessel diameter (r = 0.052; p = 0.728). WLR correlated significantly with age (r = 0.769; p < 0.01). Arterial hypertension and a higher BMI were significantly associated with an increased age-adjusted WLR. WLR correlated significantly with the stage of microvascular abnormalities. 55 % of the hypertensive subjects and 11 % of the normotensive subjects showed eutrophic remodeling, while hypertrophic remodeling was not detectable. WLR correlated inversely with AVR. AVR was independent of the arteriolar wall thickness, age and arterial hypertension. The technique of AO retinal imaging allows a direct measurement of the retinal vessel wall and lumen diameter with good intra-observer variability. Age, arterial hypertension and an elevated BMI level

MicroRNAs in right ventricular remodelling.

PubMed

Batkai, Sandor; Bär, Christian; Thum, Thomas

2017-10-01

Right ventricular (RV) remodelling is a lesser understood process of the chronic, progressive transformation of the RV structure leading to reduced functional capacity and subsequent failure. Besides conditions concerning whole hearts, some pathology selectively affects the RV, leading to a distinct RV-specific clinical phenotype. MicroRNAs have been identified as key regulators of biological processes that drive the progression of chronic diseases. The role of microRNAs in diseases affecting the left ventricle has been studied for many years, however there is still limited information on microRNAs specific to diseases in the right ventricle. Here, we review recently described details on the expression, regulation, and function of microRNAs in the pathological remodelling of the right heart. Recently identified strategies using microRNAs as pharmacological targets or biomarkers will be highlighted. Increasing knowledge of pathogenic microRNAs will finally help improve our understanding of underlying distinct mechanisms and help utilize novel targets or biomarkers to develop treatments for patients suffering from right heart diseases. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.

Application of an anisotropic bone-remodelling model based on a damage-repair theory to the analysis of the proximal femur before and after total hip replacement.

PubMed

Doblaré, M; García, J M

2001-09-01

In this work, a new model for internal anisotropic bone remodelling is applied to the study of the remodelling behaviour of the proximal femur before and after total hip replacement (THR). This model considers bone remodelling under the scope of a general damage-repair theory following the principles of continuum damage mechanics. A "damage-repair" tensor is defined in terms of the apparent density and Cowin's "fabric tensor", respectively, associated with porosity and directionality of the trabeculae. The different elements of a thermodynamically consistent damage theory are established, including resorption and apposition criteria, evolution law and rate of remodelling. All of these elements were introduced and discussed in detail in a previous paper (García, J. M., Martinez, M. A., Doblaré, M., 2001. An anisotrophic internal-external bone adaptation model based on a combination of CAO and continuum damage mechanics technologies. Computer Methods in Biomechanics and Biomedical Engineering 4(4), 355-378.), including the definition of the proposed mechanical stimulus and the qualitative properties of the model. In this paper, the fundamentals of the proposed model are briefly reviewed and the computational aspects of its implementation are discussed. This model is then applied to the analysis of the remodelling behaviour of the intact femur obtaining densities and mass principal values and directions very close to the experimental data. The second application involved the proximal femoral extremity after THR and the inclusion of an Exeter prosthesis. As a result of the simulation process, some well-known features previously detected in medical clinics were recovered, such as the stress yielding effect in the proximal part of the implant or the enlargement of the cortical layer at the distal part of the implant. With respect to the anisotropic properties, bone microstructure and local stiffness are known to tend to align with the stress principal directions. This

[Epithelial mesenchymal transition in airway remodeling of asthma and its molecular regulation].

PubMed

Zhu, Xiaohua; Li, Qiugen

2018-05-28

Asthma is a chronic inflammatory disease of the airway. Repeated inflammatory injury and tissue repair can lead to airway remodeling. The airway epithelial mesenchymal transformation (EMT) plays an important role in airway remodeling of asthma. Various cytokines and signaling pathways, such as transforming growth factor β (TGF-β), nuclear factor-kappa B (NF-κB) and bromodomain-containing protein 4 (BRD4), are involved in the molecular regulation of EMT.

Perspectives on biological growth and remodeling

PubMed Central

Ambrosi, D.; Ateshian, G. A.; Arruda, E. M.; Cowin, S. C.; Dumais, J.; Goriely, A.; Holzapfel, G. A.; Humphrey, J. D.; Kemkemer, R.; Kuhl, E.; Olberding, J. E.; Taber, L. A.; Garikipati, K.

2011-01-01

The continuum mechanical treatment of biological growth and remodeling has attracted considerable attention over the past fifteen years. Many aspects of these problems are now well-understood, yet there remain areas in need of significant development from the standpoint of experiments, theory, and computation. In this perspective paper we review the state of the field and highlight open questions, challenges, and avenues for further development. PMID:21532929

The importance of capillary density-stroke work mismatch for right ventricular adaptation to chronic pressure overload.

PubMed

Noly, Pierre-Emmanuel; Haddad, François; Arthur-Ataam, Jennifer; Langer, Nathaniel; Dorfmüller, Peter; Loisel, Fanny; Guihaire, Julien; Decante, Benoit; Lamrani, Lilia; Fadel, Elie; Mercier, Olaf

2017-12-01

Mechanisms of right ventricular (RV) adaptation to chronic pressure overload are not well understood. We hypothesized that a lower capillary density (CD) to stroke work ratio would be associated with more fibrosis and RV maladaptive remodeling. We induced RV chronic pressure overload over a 20-week period in 2 piglet models of pulmonary hypertension; that is, a shunt model (n = 5) and a chronic thromboembolic pulmonary hypertension model (n = 5). We assessed hemodynamic parameters and RV remodeling as well as RV CD, fibrosis, and angiogenic factors expression. Although RV was similarly hypertrophied in both models, maladapted RV remodeling with impaired systolic function was only seen in chronic thromboembolic pulmonary hypertension group members who had lower CD (484 ± 99 vs 1213 ± 74 cap/mm 2 ; P < .01), lower CD to stroke work ratio (0.29 ± 0.07 vs 0.82 ± 0.16; P = .02), higher myocardial fibrosis (15.4% ± 3.8% vs 8.0% ± 2.5%; P < .01), as well as a higher angiogenic and fibrosis factors expression. The RV adaptive response to chronic pressure overload differs between 2 different piglet models of PH. Mismatch between angiogenesis and workload (CD to stroke work ratio) was associated with greater degree of myocardial fibrosis and RV dysfunction and could be a promising index of RV maladaptation. Further studies are needed to understand the underlying mechanisms. Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Molecular Mechanisms Underlying Cardiac Adaptation to Exercise

PubMed Central

Vega, Rick B.; Konhilas, John P.; Kelly, Daniel P.; Leinwand, Leslie A.

2017-01-01

Exercise elicits coordinated multi-organ responses including skeletal muscle, vasculature, heart and lung. In the short term, the output of the heart increases to meet the demand of strenuous exercise. Long term exercise instigates remodeling of the heart including growth and adaptive molecular and cellular re-programming. Signaling pathways such as the insulin-like growth factor 1/PI3K/Akt pathway mediate many of these responses. Exercise-induced, or physiologic, cardiac growth contrasts with growth elicited by pathological stimuli such as hypertension. Comparing the molecular and cellular underpinnings of physiologic and pathologic cardiac growth has unveiled phenotype-specific signaling pathways and transcriptional regulatory programs. Studies suggest that exercise pathways likely antagonize pathological pathways, and exercise training is often recommended for patients with chronic stable heart failure or following myocardial infarction. Herein, we summarize the current understanding of the structural and functional cardiac responses to exercise as well as signaling pathways and downstream effector molecules responsible for these adaptations. PMID:28467921

Patterns of left ventricular remodeling among patients with essential and secondary hypertension.

PubMed

Radulescu, Dan; Stoicescu, Laurentiu; Buzdugan, Elena; Donca, Valer

2013-12-01

High blood pressure causes left ventricular hypertrophy, which is a negative prognostic factor among hypertensive patients. To assess left ventricular geometric remodeling patterns in patients with essential hypertension or with hypertension secondary to parenchymal renal disease. We analyzed data from echocardiograms performed in 250 patients with essential hypertension (150 females) and 100 patients with secondary hypertension (60 females). The interventricular septum and the left ventricular posterior wall thickness were measured in the parasternal long-axis. Left ventricular mass was calculated using the Devereaux formula. The most common remodeling type in females and males with essential hypertension were eccentric and concentric left ventricular hypertrophy (cLVH), respectively. Among patients with secondary arterial hypertension, cLVH was most commonly observed in both genders. The prevalence of left ventricular hypertrophy was higher among patients with secondary hypertension. The left ventricular mass index and the relative left ventricular wall thickness were higher in males and also in the secondary hypertension group. Age, blood pressure values and the duration of hypertension, influenced remodeling patterns. We documented a higher prevalence of LVH among patients with secondary hypertension. The type of ventricular remodeling depends on gender, age, type of hypertension, blood pressure values and the duration of hypertension.

Reverse right ventricular structural and extracellular matrix remodeling by estrogen in severe pulmonary hypertension

PubMed Central

Nadadur, Rangarajan D.; Umar, Soban; Wong, Gabriel; Eghbali, Mansour; Iorga, Andrea; Matori, Humann; Partow-Navid, Rod

2012-01-01

Chronic pulmonary hypertension (PH) leads to right-ventricular failure (RVF) characterized by RV remodeling. Ventricular remodeling is emerging as an important process during heart failure and recovery. Remodeling in RVF induced by PH is not fully understood. Recently we discovered that estrogen (E2) therapy can rescue severe preexisting PH. Here, we focused on whether E2 (42.5 μg·kg−1·day−1, 10 days) can reverse adverse RV structural and extracellular matrix (ECM) remodeling induced by PH using monocrotaline (MCT, 60 mg/kg). RV fibrosis was evident in RVF males. Intact females developed less severe RV remodeling compared with males and ovariectomized (OVX) females. Novel ECM-degrading disintegrin-metalloproteinases ADAM15 and ADAM17 transcripts were elevated ∼2-fold in all RVF animals. E2 therapy reversed RV remodeling in all groups. In vitro, E2 directly inhibited ANG II-induced expression of fibrosis markers as well as the metalloproteinases in cultured cardiac fibroblasts. Estrogen receptor-β agonist diarylpropionitrile (DPN) but not estrogen receptor-α agonist 4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) was as effective as E2 in inhibiting expression of these genes. Expression of ECM-interacting cardiac fetal-gene osteopontin (OPN) also increased ∼9-fold in RVF males. Intact females were partially protected from OPN upregulation (∼2-fold) but OVX females were not. E2 reversed OPN upregulation in all groups. Upregulation of OPN was also reversed in vitro by E2. Plasma OPN was elevated in RVF (∼1.5-fold) and decreased to control levels in the E2 group. RVF resulted in elevated Akt phosphorylation, but not ERK, in the RV, and E2 therapy restored Akt phosphorylation. In conclusion, E2 therapy reverses adverse RV remodeling associated with PH by reversing fibrosis and upregulation of novel ECM enzymes ADAM15, ADAM17, and OPN. These effects are likely mediated through estrogen receptor-β. PMID:22628376

Quantification of fibronectin as a method to assess ex vivo extracellular matrix remodeling

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

Bager, C.L., E-mail: cba@nordicbioscience.com; Technical University of Denmark; Gudmann, N.

Altered architecture, composition and quality of the extracellular matrix (ECM) are pathological hallmarks of several inflammatory and fibro-proliferative pathological processes such as osteoarthritis (OA), rheumatoid arthritis (RA), fibrosis and cancer. One of the most important components of the ECM is fibronectin. Fibronectin serves as an adhesion molecule anchoring cells to the underlying basement membrane through direct interaction with integrin receptors. Fibronectin hereby modulates the properties of the ECM and affects cellular processes. Quantification of fibronectin remodeling could therefore be used to assess the changes in the ECM that occur during progression of fibro-proliferative pathologies. Ex vivo models are becoming state-of-the-art toolsmore » to study ECM remodeling as the cellular composition and the organization of the ECM are preserved. Ex vivo models may therefore be a valuable tool to study the ECM remodeling that occurs during progression of fibro-proliferative pathologies. The aim of this study was to quantify fibronectin remodeling in ex vivo models of cartilage and cancer. A competitive The enzyme-linked immunosorbent assay (ELISA) against the C-terminus of fibronectin was developed (FBN-C). The assay was evaluated in relation to specificity, technical performance and as a marker for quantification of fibronectin in cartilage and cancer ex vivo models. The ELISA was specific and technically stable. Cleavage of tumor tissue with MMP-2 released significantly higher levels of FBN-C compared to tissue with buffer only and western blot analysis revealed that FBN-C recognizes both full length and degraded fibronectin. When ex vivo cartilage cultures were stimulated with the anabolic factor TGFβ and catabolic factors TNF-α and OSM, significantly higher levels of FBN-C were found in the conditioned media. Lastly, FBN-C was released from a cancer ex vivo model. In conclusion, we were able to quantify fibronectin remodeling in ex

Left ventricular remodelling in chronic primary mitral regurgitation: implications for medical therapy.

PubMed

McCutcheon, Keir; Manga, Pravin

Surgical repair or replacement of the mitral valve is currently the only recommended therapy for severe primary mitral regurgitation. The chronic elevation of wall stress caused by the resulting volume overload leads to structural remodelling of the muscular, vascular and extracellular matrix components of the myocardium. These changes are initially compensatory but in the long term have detrimental effects, which ultimately result in heart failure. Understanding the changes that occur in the myocardium due to volume overload at the molecular and cellular level may lead to medical interventions, which potentially could delay or prevent the adverse left ventricular remodelling associated with primary mitral regurgitation. The pathophysiological changes involved in left ventricular remodelling in response to chronic primary mitral regurgitation and the evidence for potential medical therapy, in particular beta-adrenergic blockers, are the focus of this review.

JNK Controls the Onset of Mitosis in Planarian Stem Cells and Triggers Apoptotic Cell Death Required for Regeneration and Remodeling

PubMed Central

Almuedo-Castillo, María; Crespo, Xenia; Seebeck, Florian; Bartscherer, Kerstin; Salò, Emili; Adell, Teresa

2014-01-01

Regeneration of lost tissues depends on the precise interpretation of molecular signals that control and coordinate the onset of proliferation, cellular differentiation and cell death. However, the nature of those molecular signals and the mechanisms that integrate the cellular responses remain largely unknown. The planarian flatworm is a unique model in which regeneration and tissue renewal can be comprehensively studied in vivo. The presence of a population of adult pluripotent stem cells combined with the ability to decode signaling after wounding enable planarians to regenerate a complete, correctly proportioned animal within a few days after any kind of amputation, and to adapt their size to nutritional changes without compromising functionality. Here, we demonstrate that the stress-activated c-jun–NH2–kinase (JNK) links wound-induced apoptosis to the stem cell response during planarian regeneration. We show that JNK modulates the expression of wound-related genes, triggers apoptosis and attenuates the onset of mitosis in stem cells specifically after tissue loss. Furthermore, in pre-existing body regions, JNK activity is required to establish a positive balance between cell death and stem cell proliferation to enable tissue renewal, remodeling and the maintenance of proportionality. During homeostatic degrowth, JNK RNAi blocks apoptosis, resulting in impaired organ remodeling and rescaling. Our findings indicate that JNK-dependent apoptotic cell death is crucial to coordinate tissue renewal and remodeling required to regenerate and to maintain a correctly proportioned animal. Hence, JNK might act as a hub, translating wound signals into apoptotic cell death, controlled stem cell proliferation and differentiation, all of which are required to coordinate regeneration and tissue renewal. PMID:24922054

Compartmental and temporal dynamics of chronic inflammation and airway remodelling in a chronic asthma mouse model.

PubMed

Alrifai, Mohammed; Marsh, Leigh M; Dicke, Tanja; Kılıç, Ayse; Conrad, Melanie L; Renz, Harald; Garn, Holger

2014-01-01

Allergic asthma is associated with chronic airway inflammation and progressive airway remodelling. However, the dynamics of the development of these features and their spontaneous and pharmacological reversibility are still poorly understood. We have therefore investigated the dynamics of airway remodelling and repair in an experimental asthma model and studied how pharmacological intervention affects these processes. Using BALB/c mice, the kinetics of chronic asthma progression and resolution were characterised in absence and presence of inhaled corticosteroid (ICS) treatment. Airway inflammation and remodelling was assessed by the analysis of bronchoalveolar and peribronichal inflammatory cell infiltrate, goblet cell hyperplasia, collagen deposition and smooth muscle thickening. Chronic allergen exposure resulted in early (goblet cell hyperplasia) and late remodelling (collagen deposition and smooth muscle thickening). After four weeks of allergen cessation eosinophilic inflammation, goblet cell hyperplasia and collagen deposition were resolved, full resolution of lymphocyte inflammation and smooth muscle thickening was only observed after eight weeks. ICS therapy when started before the full establishment of chronic asthma reduced the development of lung inflammation, decreased goblet cell hyperplasia and collagen deposition, but did not affect smooth muscle thickening. These effects of ICS on airway remodelling were maintained for a further four weeks even when therapy was discontinued. Utilising a chronic model of experimental asthma we have shown that repeated allergen exposure induces reversible airway remodelling and inflammation in mice. Therapeutic intervention with ICS was partially effective in inhibiting the transition from acute to chronic asthma by reducing airway inflammation and remodelling but was ineffective in preventing smooth muscle hypertrophy.

CorMatrix valved conduit in a porcine model: long-term remodelling and biomechanical characterization.

PubMed

Mosala Nezhad, Zahra; Poncelet, Alain; de Kerchove, Laurent; Fervaille, Caroline; Banse, Xavier; Bollen, Xavier; Dehoux, Jean-Paul; El Khoury, Gebrine; Gianello, Pierre

2017-01-01

Porcine small intestinal submucosa extracellular matrix (CorMatrix; CorMatrix Cardiovascular, Rosewell, GA) is a relatively novel tissue substitute used in cardiovascular applications. We investigated the biological reaction and remodelling of CorMatrix as a tri-leaflet valved conduit in a pig model. We hypothesized that CorMatrix maintains a durable architecture as a valved conduit and remodels to resemble surrounding tissues. We fashioned the valved conduit using a 7 × 10 cm 4-ply CorMatrix sheet and placed it in the thoracic aorta of seven landrace pigs for 3, 4, 5 and 6 months. Biodegradation, replacement by native tissue, strength and durability were examined by histology, immunohistochemistry and mechanical testing. Four pigs, one per time frame, completed the study. The conduit lost its original architecture as a tri-leaflet valve due to cusp immobility, subsequent attachment to the wall segment and consequent maintenance of a thick arterial wall-like structure. Scaffold resorption was incomplete, with disorganized inconsistent spatial and temporal degradation even at 6 months. Fibrosis, scarring and calcification started at 4 months and chronic inflammation persisted. The partially remodelled scaffold did not resemble the aortic wall, suggesting impaired remodelling. Mechanical testing showed progressive weakening of the tissues over time, which were liable to breakage. CorMatrix is biodegradable; however, it failed to remodel in a structured and anatomical fashion in an arterial environment. Progressive mechanical and remodelling failure in this scenario might be explained by the complexity of the conduit design and the host's chronic inflammatory response, leading to early fibrosis and calcification. © The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Some aspects of the cosmogonic outward migration of Neptune. Co-planar migration

NASA Astrophysics Data System (ADS)

Neslušan, L.; Jakubík, M.

2013-10-01

Considering a simple model of the cosmogonic outward migration of Neptune, we investigate if the assumption of an extremely low orbital inclination of small bodies in a once-existing proto-planetary disk could influence the structure of reservoirs of the objects in the trans-Neptunian region. We found no significant influence. Our models predict only the existence of the mean-motion resonances (MMRs) with Neptune 2:3, 3:5, 1:2, and an anemic scattered disk (MMRs 3:4, 5:7, and 9:11 are also indicated). To explain the classical Edgeworth-Kuiper belt, relatively abundant 4:7 and 2:5 MMRs, and the more numerous scattered disk, we need to assume that, e.g., the outer boundary of the original proto-planetary disk considerably exceeded the distance of the current Neptune's orbit (Neptune probably ended its migration at the distance, where the disk's density started to be sub-critical), or that some Pluto-sized objects resided inside the MMRs and in the distant parts of the original proto-planetary disk.

Matrix remodeling maintains ESC self-renewal by activating Stat3

PubMed Central

Przybyla, Laralynne M.; Theunissen, Thorold W.; Jaenisch, Rudolf; Voldman, Joel

2013-01-01

While a variety of natural and synthetic matrices have been used to influence embryonic stem cell (ESC) self-renewal or differentiation, and ESCs also deposit a rich matrix of their own, the mechanisms behind how extracellular matrix affects cell fate are largely unexplored. The ESC matrix is continuously remodeled by matrix metalloproteinases (MMPs), a process that we find is enhanced by the presence of mouse embryonic fibroblast feeders in a paracrine manner. Matrix remodeling by MMPs aids in the self-renewal of ESCs, as inhibition of MMPs inhibits the ability of ESCs to self-renew. We also find that addition of the interstitial collagenase MMP1 is sufficient to maintain long-term LIF-independent mESC self-renewal in a dose-dependent manner. This remarkable ability is due to the presence of endogenously produced self-renewal-inducing signals, including the LIF-family ligand CNTF, that are normally trapped within the ECM and become exposed upon MMP-induced matrix remodeling to signal through JAK and Stat3. These results uncover a new role for feeder cells in maintaining self-renewal and show that mESCs normally produce sufficient levels of autocrine-acting pro-self-renewal ligands. PMID:23404867

Bone remodelling in Neanderthal mandibles from the El Sidrón site (Asturias, Spain)

PubMed Central

Martinez-Maza, Cayetana; Rosas, Antonio; García-Vargas, Samuel; Estalrrich, Almudena; de la Rasilla, Marco

2011-01-01

Skull morphology results from the bone remodelling mechanism that underlies the specific bone growth dynamics. Histological study of the bone surface from Neanderthal mandible specimens of El Sidrón (Spain) provides information about the distribution of the remodelling fields (bone remodelling patterns or BRP) indicative of the bone growth directions. In comparison with other primate species, BRP shows that Neanderthal mandibles from the El Sidrón (Spain) sample present a specific BRP. The interpretation of this map allows inferences concerning the growth directions that explain specific morphological traits of the Neanderthal mandible, such as its quadrangular shape and the posterior location of the mental foramen. PMID:21307043

Force and pressure-recovery characteristics at supersonic speeds of a conical nose inlet with bypasses discharging outward from the body axis

NASA Technical Reports Server (NTRS)

Beke, Andrew; Allen, J L

1953-01-01

Aerodynamic and performance characteristics of a conical spike nacelle-type inlet with two bypasses are presented at Mach numbers of 1.6, 1.8, and 2.0 for angles of attach up to 90 degrees. The bypasses were located 6 inlet diameters downstream of the inlet and were designed to discharge the bypass mass flow outward from the body axis. The inlet was designed to attain a mass-flow ratio of unity at a Mach number of 2.0. It is shown that discharging the bypass mass flow outward from the body nearly doubles the critical drag of a similar configuration but with bypass discharge in an axial direction. As a result of this greater drag, the net force on the model in the flight direction is reduced when comparison is made with the axial discharge case. The lift and pitching-moment coefficients are slightly higher than those for a configuration without bypasses. Approximately 25 % of the maximum inlet mass flow was discharged through the bypasses, and the pressure-recovery and mass-flow characteristics were in qualitative and quantitative agreement with the results of an investigation of a similar configuration with axial discharge.

Predictors of Left Ventricular Remodeling After Myocardial Infarction in Patients With a Patent Infarct Related Coronary Artery After Percutaneous Coronary Intervention (from the Post-Myocardial Infarction Remodeling Prevention Therapy [PRomPT] Trial).

PubMed

Garber, Leonid; McAndrew, Thomas C; Chung, Eugene S; Stancak, Branislav; Svendsen, Jesper H; Monteiro, Joao; Fischer, Trent M; Kueffer, Fred; Ryan, Thomas; Bax, Jeroen; Leon, Angel R; Stone, Gregg W

2018-06-01

Left ventricular (LV) remodeling after myocardial infarction (MI) is a strong predictor of heart failure and mortality. The predictors of long-term remodeling after MI have been incompletely studied. We therefore examined the correlates of LV remodeling in patients with large ST-segment elevation myocardial infarction and a patent infarct artery after percutaneous 2coronary intervention (PCI) from the randomized Post-Myocardial Infarction Remodeling Prevention Therapy trial. Peri-infarct pacing had a neutral effect on long-term remodeling in patients with large first MI. The present analysis includes 109 patients in whom an open artery was restored after PCI, and in whom LV end-diastolic volume (LVEDV) at baseline and 18 months was assessed by transthoracic echocardiography. Multivariable models were fit to identify the independent predictors of LVEDV at baseline and 18 months. By multivariable analysis, male sex (p = 0.004) and anterior MI location (p = 0.03) were independently associated with baseline LVEDV. The following variables were independent predictors of increased LVEDV at 18 months: younger age (p = 0.01), male sex (p = 0.03), peak creatine phosphokinase (p = 0.03), shorter time from MI to baseline transthoracic echocardiography (p = 0.04), baseline LVEDV (p < 0.0001), and lack of statin use (p = 0.03). In conclusion, patients with large MI and an open infarct artery after PCI, anterior MI location, and male sex were associated with greater baseline LVEDV, but MI location was not associated with 18-month LVEDV. In contrast, younger age, peak creatine phosphokinase, male sex, baseline LVEDV, and lack of statin use were associated with long-term LV remodeling. Copyright © 2018 Elsevier Inc. All rights reserved.

A Comparison of Recidivism Rates for Operation Outward Reach (OOR) Participants and Control Groups of Non-Participants for the Years 1990 through 1994.

ERIC Educational Resources Information Center

Ryan, Thomas P.; Desuta, Joesph F.

2000-01-01

A 5-year study of Operation Outward Reach, a nonprofit program providing community-based vocational training in carpentry and masonry for Pennsylvania inmates, compared completers and control groups. Results showed average differences in recidivism between the groups of 16% per year. Fiscal and social cost savings were also identified. (JOW)

High wall shear stress and spatial gradients in vascular pathology: a review.

PubMed

Dolan, Jennifer M; Kolega, John; Meng, Hui

2013-07-01

Cardiovascular pathologies such as intracranial aneurysms (IAs) and atherosclerosis preferentially localize to bifurcations and curvatures where hemodynamics are complex. While extensive knowledge about low wall shear stress (WSS) has been generated in the past, due to its strong relevance to atherogenesis, high WSS (typically >3 Pa) has emerged as a key regulator of vascular biology and pathology as well, receiving renewed interests. As reviewed here, chronic high WSS not only stimulates adaptive outward remodeling, but also contributes to saccular IA formation (at bifurcation apices or outer curves) and atherosclerotic plaque destabilization (in stenosed vessels). Recent advances in understanding IA pathogenesis have shed new light on the role of high WSS in pathological vascular remodeling. In complex geometries, high WSS can couple with significant spatial WSS gradient (WSSG). A combination of high WSS and positive WSSG has been shown to trigger aneurysm initiation. Since endothelial cells (ECs) are sensors of WSS, we have begun to elucidate EC responses to high WSS alone and in combination with WSSG. Understanding such responses will provide insight into not only aneurysm formation, but also plaque destabilization and other vascular pathologies and potentially lead to improved strategies for disease management and novel targets for pharmacological intervention.

Quantitative proteomic changes during post myocardial infarction remodeling reveals altered cardiac metabolism and Desmin aggregation in the infarct region.

PubMed

Datta, Kaberi; Basak, Trayambak; Varshney, Swati; Sengupta, Shantanu; Sarkar, Sagartirtha

2017-01-30

Myocardial infarction is one of the leading causes of cardiac dysfunction, failure and sudden death. Post infarction cardiac remodeling presents a poor prognosis, with 30%-45% of patients developing heart failure, in a period of 5-25years. Oxidative stress has been labelled as the primary causative factor for cardiac damage during infarction, however, the impact it may have during the process of post infarction remodeling has not been well probed. In this study, we have implemented iTRAQ proteomics to catalogue proteins and functional processes, participating both temporally (early and late phases) and spatially (infarct and remote zones), during post myocardial infarction remodeling of the heart as functions of the differential oxidative stress manifest during the remodeling process. Cardiac metabolism was the dominant network to be affected during infarction and the remodeling time points considered in this study. A distinctive expression pattern of cytoskeletal proteins was also observed with increased remodeling time points. Further, it was found that the cytoskeletal protein Desmin, aggregated in the infarct zone during the remodeling process, mediated by the protease Calpain1. Taken together, all of these data in conjunction may lay the foundation to understand the effects of oxidative stress on the remodeling process and elaborate the mechanism behind the compromised cardiac function observed during post myocardial infarction remodeling. Oxidative stress is the major driving force for cardiac damage during myocardial infarction. However, the impact of oxidative stress on the process of post MI remodeling in conducting the heart towards functional failure has not been well explored. In this study, a spatial and temporal approach was taken to elaborate the major proteins and cellular processes involved in post MI remodeling. Based on level/ intensity of ROS, spatially, infarct and noninfarct zones were chosen for analysis while on the temporal scale, early (30

A collagen-based scaffold delivering exogenous microrna-29B to modulate extracellular matrix remodeling.

PubMed

Monaghan, Michael; Browne, Shane; Schenke-Layland, Katja; Pandit, Abhay

2014-04-01

Directing appropriate extracellular matrix remodeling is a key aim of regenerative medicine strategies. Thus, antifibrotic interfering RNA (RNAi) therapy with exogenous microRNA (miR)-29B was proposed as a method to modulate extracellular matrix remodeling following cutaneous injury. It was hypothesized that delivery of miR-29B from a collagen scaffold will efficiently modulate the extracellular matrix remodeling response and reduce maladaptive remodeling such as aggressive deposition of collagen type I after injury. The release of RNA from the scaffold was assessed and its ability to silence collagen type I and collagen type III expression was evaluated in vitro. When primary fibroblasts were cultured with scaffolds doped with miR-29B, reduced levels of collagen type I and collagen type III mRNA expression were observed for up to 2 weeks of culture. When the scaffolds were applied to full thickness wounds in vivo, reduced wound contraction, improved collagen type III/I ratios and a significantly higher matrix metalloproteinase (MMP)-8: tissue inhibitor of metalloproteinase (TIMP)-1 ratio were detected when the scaffolds were functionalized with miR-29B. Furthermore, these effects were significantly influenced by the dose of miR-29B in the collagen scaffold (0.5 versus 5 μg). This study shows a potential of combining exogenous miRs with collagen scaffolds to improve extracellular matrix remodeling following injury.

mTOR and vascular remodeling in lung diseases: current challenges and therapeutic prospects.

PubMed

Goncharova, Elena A

2013-05-01

Mammalian target of rapamycin (mTOR) is a major regulator of cellular metabolism, proliferation, and survival that is implicated in various proliferative and metabolic diseases, including obesity, type 2 diabetes, hamartoma syndromes, and cancer. Emerging evidence suggests a potential critical role of mTOR signaling in pulmonary vascular remodeling. Remodeling of small pulmonary arteries due to increased proliferation, resistance to apoptosis, and altered metabolism of cells forming the pulmonary vascular wall is a key currently irreversible pathological feature of pulmonary hypertension, a progressive pulmonary vascular disorder with high morbidity and mortality. In addition to rare familial and idiopathic forms, pulmonary hypertension is also a life-threatening complication of several lung diseases associated with hypoxia. This review aims to summarize our current knowledge and recent advances in understanding the role of the mTOR pathway in pulmonary vascular remodeling, with a specific focus on the hypoxia component, a confirmed shared trigger of pulmonary hypertension in lung diseases. We also discuss the emerging role of mTOR as a promising therapeutic target and mTOR inhibitors as potential pharmacological approaches to treat pulmonary vascular remodeling in pulmonary hypertension.

Membrane remodeling by amyloidogenic and non-amyloidogenic proteins studied by EPR.

PubMed

Varkey, Jobin; Langen, Ralf

2017-07-01

The advancement in site-directed spin labeling of proteins has enabled EPR studies to expand into newer research areas within the umbrella of protein-membrane interactions. Recently, membrane remodeling by amyloidogenic and non-amyloidogenic proteins has gained a substantial interest in relation to driving and controlling vital cellular processes such as endocytosis, exocytosis, shaping of organelles like endoplasmic reticulum, Golgi and mitochondria, intracellular vesicular trafficking, formation of filopedia and multivesicular bodies, mitochondrial fusion and fission, and synaptic vesicle fusion and recycling in neurotransmission. Misregulation in any of these processes due to an aberrant protein (mutation or misfolding) or alteration of lipid metabolism can be detrimental to the cell and cause disease. Dissection of the structural basis of membrane remodeling by proteins is thus quite necessary for an understanding of the underlying mechanisms, but it remains a formidable task due to the difficulties of various common biophysical tools in monitoring the dynamic process of membrane binding and bending by proteins. This is largely since membranes generally complicate protein structure analysis and this problem is amplified for structural analysis in the presence of different types of membrane curvatures. Recent EPR studies on membrane remodeling by proteins show that a significant structural information can be generated to delineate the role of different protein modules, domains and individual amino acids in the generation of membrane curvature. These studies also show how EPR can complement the data obtained by high resolution techniques such as X-ray and NMR. This perspective covers the application of EPR in recent studies for understanding membrane remodeling by amyloidogenic and non-amyloidogenic proteins that is useful for researchers interested in using or complimenting EPR to gain better understanding of membrane remodeling. We also discuss how a single

Membrane remodeling by amyloidogenic and non-amyloidogenic proteins studied by EPR

NASA Astrophysics Data System (ADS)

Varkey, Jobin; Langen, Ralf

2017-07-01

The advancement in site-directed spin labeling of proteins has enabled EPR studies to expand into newer research areas within the umbrella of protein-membrane interactions. Recently, membrane remodeling by amyloidogenic and non-amyloidogenic proteins has gained a substantial interest in relation to driving and controlling vital cellular processes such as endocytosis, exocytosis, shaping of organelles like endoplasmic reticulum, Golgi and mitochondria, intracellular vesicular trafficking, formation of filopedia and multivesicular bodies, mitochondrial fusion and fission, and synaptic vesicle fusion and recycling in neurotransmission. Misregulation in any of these processes due to an aberrant protein (mutation or misfolding) or alteration of lipid metabolism can be detrimental to the cell and cause disease. Dissection of the structural basis of membrane remodeling by proteins is thus quite necessary for an understanding of the underlying mechanisms, but it remains a formidable task due to the difficulties of various common biophysical tools in monitoring the dynamic process of membrane binding and bending by proteins. This is largely since membranes generally complicate protein structure analysis and this problem is amplified for structural analysis in the presence of different types of membrane curvatures. Recent EPR studies on membrane remodeling by proteins show that a significant structural information can be generated to delineate the role of different protein modules, domains and individual amino acids in the generation of membrane curvature. These studies also show how EPR can complement the data obtained by high resolution techniques such as X-ray and NMR. This perspective covers the application of EPR in recent studies for understanding membrane remodeling by amyloidogenic and non-amyloidogenic proteins that is useful for researchers interested in using or complimenting EPR to gain better understanding of membrane remodeling. We also discuss how a single

Metabolic remodeling of substrate utilization during heart failure progression.

PubMed

Chen, Liang; Song, Jiangping; Hu, Shengshou

2018-05-23

Heart failure (HF) is a clinical syndrome caused by a decline in cardiac systolic or diastolic function, which leaves the heart unable to pump enough blood to meet the normal physiological requirements of the human body. It is a serious disease burden worldwide affecting nearly 23 million patients. The concept that heart failure is "an engine out of fuel" has been generally accepted and metabolic remodeling has been recognized as an important aspect of this condition; it is characterized by defects in energy production and changes in metabolic pathways involved in the regulation of essential cellular functions such as the process of substrate utilization, the tricarboxylic acid cycle, oxidative phosphorylation, and high-energy phosphate metabolism. Advances in second-generation sequencing, proteomics, and metabolomics have made it possible to perform comprehensive tests on genes and metabolites that are crucial in the process of HF, thereby providing a clearer and comprehensive understanding of metabolic remodeling during HF. In recent years, new metabolic changes such as ketone bodies and branched-chain amino acids were demonstrated as alternative substrates in end-stage HF. This systematic review focuses on changes in metabolic substrate utilization during the progression of HF and the underlying regulatory mechanisms. Accordingly, the conventional concepts of metabolic remodeling characteristics are reviewed, and the latest developments, particularly multi-omics studies, are compiled.

Tribbles 3: A potential player in diabetic aortic remodelling.

PubMed

Ti, Yun; Xie, Guo-lu; Wang, Zhi-hao; Ding, Wen-yuan; Zhang, Yun; Zhong, Ming; Zhang, Wei

2016-01-01

Tribbles 3, whose expression is up-regulated by insulin resistance, was confirmed to be involved in diabetic cardiomyopathy in our previous study. However, it is not known whether Tribbles 3 has a role on conduit arteries such as the aorta in diabetes. Type 2 diabetic rat model was induced by high-fat diet and low-dose streptozotocin. We evaluated the characteristics of diabetic rats by serial ultrasonography and histopathologic analyses of aortic wall architecture. Diabetic rats displayed increased aortic medial thickness, excessive collagen deposition, diminished elastic fibres and reduced vascular compliance together with Tribbles 3 overexpression. To further investigate the role of Tribbles 3 in aortic remodelling, we used Tribbles 3 gene silencing in vivo 12 weeks after onset of diabetes. Silence of Tribbles 3 significantly reversed pathological aortic remodelling without blood pressure modification. In Tribbles 3-small interfering RNA group, medial thickness and perivascular fibrosis were markedly decreased; moreover, there were prominent reductions in collagen content and collagen/elastin ratio, resulting in an improved arterial compliance. Additionally, with Tribbles 3 silencing, the diminished phosphorylation of PI3K/Akt was restored, and increased activation of MKK4/JNK was decreased. Silence of Tribbles 3 is potent in mediating reversal of aortic remodelling, implicating that Tribbles 3 is proposed to be a potential therapeutic target for vascular complication in diabetes. © The Author(s) 2015.

A Computational Model for Simulating Spaceflight Induced Bone Remodeling

NASA Technical Reports Server (NTRS)

Pennline, James A.; Mulugeta, Lealem

2014-01-01

An overview of an initial development of a model of bone loss due to skeletal unloading in weight bearing sites is presented. The skeletal site chosen for the initial application of the model is the femoral neck region because hip fractures can be debilitating to the overall performance health of astronauts. The paper begins with the motivation for developing such a model of the time course of change in bone in order to understand the mechanism of bone demineralization experienced by astronauts in microgravity, to quantify the health risk, and to establish countermeasures. Following this, a general description of a mathematical formulation of the process of bone remodeling is discussed. Equations governing the rate of change of mineralized bone volume fraction and active osteoclast and osteoblast are illustrated. Some of the physiology of bone remodeling, the theory of how imbalance in remodeling can cause bone loss, and how the model attempts to capture this is discussed. The results of a preliminary validation analysis that was carried out are presented. The analysis compares a set of simulation results against bone loss data from control subjects who participated in two different bed rest studies. Finally, the paper concludes with outlining the current limitations and caveats of the model, and planned future work to enhance the state of the model.

Cardiac remodeling in response to chronic iron deficiency: role of the erythropoietin receptor.

PubMed

Naito, Yoshiro; Sawada, Hisashi; Oboshi, Makiko; Iwasaku, Toshihiro; Okuhara, Yoshitaka; Morisawa, Daisuke; Eguchi, Akiyo; Hirotani, Shinichi; Mano, Toshiaki; Tsujino, Takeshi; Masuyama, Tohru

2015-06-01

Anemia is a common comorbidity of patients with heart failure, and iron deficiency is known as one of the causes of anemia in heart failure. Recent studies have shown that iron deficiency alone, without overt anemia, is associated with poor outcomes in patients with heart failure. Thus, to minimize the mortality in patients with heart failure, it is important to understand the link between iron deficiency and cardiac function. Chronic untreated iron deficiency results in cardiac remodeling, and we have previously reported that erythropoietin (Epo) and cardiac Epo receptor (EpoR) signaling may be associated with its remodeling. However, the link between EpoR signaling and its remodeling remains to be elucidated. Herein, we investigated the role of EpoR signaling on cardiac remodeling in response to chronic iron deficiency. Wild-type mice and transgene-rescued EpoR-null mutant mice, which express EpoR only in the hematopoietic lineage (EpoR-restricted mice), were fed with either a normal or an iron-restricted diet, and the molecular mechanisms were investigated. Dietary iron restriction gradually induced anemia, Epo secretion, and cardiac hypertrophy in wild-type mice. In contrast, EpoR-restricted mice fed with an iron-restricted diet exhibited anemia, left ventricular dilatation, and cardiac dysfunction compared with wild-type mice. Interestingly, altered cardiac mitochondrial biogenesis was observed in EpoR-restricted mice following iron deficiency. Moreover, cardiac p53 expression was increased in EpoR-restricted mice compared with wild-type mice following iron deficiency. These data indicate that EpoR signaling is associated with cardiac remodeling following chronic iron deficiency.

Novel Mechanistic Link between Focal Adhesion Remodeling and Glucose-stimulated Insulin Secretion*

PubMed Central

Rondas, Dieter; Tomas, Alejandra; Soto-Ribeiro, Martinho; Wehrle-Haller, Bernhard; Halban, Philippe A.

2012-01-01

Actin cytoskeleton remodeling is well known to be positively involved in glucose-stimulated pancreatic β cell insulin secretion. We have observed glucose-stimulated focal adhesion remodeling at the β cell surface and have shown this to be crucial for glucose-stimulated insulin secretion. However, the mechanistic link between such remodeling and the insulin secretory machinery remained unknown and was the major aim of this study. MIN6B1 cells, a previously validated model of primary β cell function, were used for all experiments. Total internal reflection fluorescence microscopy revealed the glucose-responsive co-localization of focal adhesion kinase (FAK) and paxillin with integrin β1 at the basal cell surface after short term stimulation. In addition, blockade of the interaction between β1 integrins and the extracellular matrix with an anti-β1 integrin antibody (Ha2/5) inhibited short term glucose-induced phosphorylation of FAK (Tyr-397), paxillin (Tyr-118), and ERK1/2 (Thr-202/Tyr-204). Pharmacological inhibition of FAK activity blocked glucose-induced actin cytoskeleton remodeling and glucose-induced disruption of the F-actin/SNAP-25 association at the plasma membrane as well as the distribution of insulin granules to regions in close proximity to the plasma membrane. Furthermore, FAK inhibition also completely blocked short term glucose-induced activation of the Akt/AS160 signaling pathway. In conclusion, these results indicate 1) that glucose-induced activation of FAK, paxillin, and ERK1/2 is mediated by β1 integrin intracellular signaling, 2) a mechanism whereby FAK mediates glucose-induced actin cytoskeleton remodeling, hence allowing docking and fusion of insulin granules to the plasma membrane, and 3) a possible functional role for the Akt/AS160 signaling pathway in the FAK-mediated regulation of glucose-stimulated insulin secretion. PMID:22139838

Fibroblast Electrical Remodeling in Heart Failure and Potential Effects on Atrial Fibrillation

PubMed Central

Aguilar, Martin; Qi, Xiao Yan; Huang, Hai; Nattel, Stanley

2014-01-01

Fibroblasts are activated in heart failure (HF) and produce fibrosis, which plays a role in maintaining atrial fibrillation (AF). The effect of HF on fibroblast ion currents and its potential role in AF are unknown. Here, we used a patch-clamp technique to investigate the effects of HF on atrial fibroblast ion currents, and mathematical computation to assess the potential impact of this remodeling on atrial electrophysiology and arrhythmogenesis. Atrial fibroblasts were isolated from control and tachypacing-induced HF dogs. Tetraethylammonium-sensitive voltage-gated fibroblast current (IKv,fb) was significantly downregulated (by ∼44%), whereas the Ba2+-sensitive inward rectifier current (IKir,fb) was upregulated by 79%, in HF animals versus controls. The fibroblast resting membrane potential was hyperpolarized (−53 ± 2 mV vs. −42 ± 2 mV in controls) and the capacitance was increased (29.7 ± 2.2 pF vs. 17.8 ± 1.4 pF in controls) in HF. These experimental findings were implemented in a mathematical model that included cardiomyocyte-fibroblast electrical coupling. IKir,fb upregulation had a profibrillatory effect through shortening of the action potential duration and hyperpolarization of the cardiomyocyte resting membrane potential. IKv,fb downregulation had the opposite electrophysiological effects and was antifibrillatory. Simulated pharmacological blockade of IKv,fb successfully terminated reentry under otherwise profibrillatory conditions. We conclude that HF induces fibroblast ion-current remodeling with IKv,fb downregulation and IKir,fb upregulation, and that, assuming cardiomyocyte-fibroblast electrical coupling, this remodeling has a potentially important effect on atrial electrophysiology and arrhythmogenesis, with the overall response depending on the balance of pro- and antifibrillatory contributions. These findings suggest that fibroblast K+-current remodeling is a novel component of AF-related remodeling that might contribute to arrhythmia

FGF2 modulates cardiac remodeling in an isoform- and sex-specific manner

PubMed Central

Nusayr, Eyad; Sadideen, Doraid Tarek; Doetschman, Tom

2013-01-01

Pathological cardiac hypertrophy and cardiac fibrosis are remodeling events that result in mechanical stiffness and pathophysiological changes in the myocardium. Both humans and animal models display a sexual dimorphism where females are more protected from pathological remodeling. Fibroblast growth factor 2 (FGF2) mediates cardiac hypertrophy, cardiac fibrosis, and protection against cardiac injury, and is made in high molecular weight and low molecular weight isoforms (Hi FGF2 and Lo FGF2, respectively). Although some light has been shed on isoform-specific functions in cardiac pathophysiology, their roles in pathologic cardiac remodeling have yet to be determined. We tested the hypothesis that Lo FGF2 and Hi FGF2 modulate pathological cardiac remodeling in an isoform-specific manner. Young adult male and female mice between 8 and 12 weeks of age of mixed background that were deficient in either Hi FGF2 or Lo FGF2 (Hi KO or Lo KO, respectively) were subjected to daily injections of isoproterenol (Iso) for 4 days after which their hearts were compared to wild-type cohorts. Post-Iso treatment, female Lo KO hearts do not exhibit significant differences in their hypertrophic and fibrotic response, whereas female Hi KO hearts present with a blunted hypertrophic response. In male animals, Lo KO hearts present with an exacerbated fibrotic response and increased α-smooth muscle actin protein expression, whereas Hi KO hearts present with a blunted fibrotic response and increased atrial natriuretic factor protein expression Thus, in female hearts Hi FGF2 mediates cardiac hypertrophy, whereas in male hearts Lo FGF2 and Hi FGF2 display an antithetical role in cardiac fibrosis where Lo FGF2 is protective while Hi FGF2 is damaging. In conclusion, cardiac remodeling following catecholamine overactivation is modulated by FGF2 in isoform- and sex-specific manners. PMID:24244869

Interdependency between mechanical parameters and afferent nerve discharge in remodeled diabetic Goto-Kakizaki rat intestine

PubMed Central

Zhao, Jingbo; Yang, Jian; Liao, Donghua; Gregersen, Hans

2017-01-01

Background Gastrointestinal disorders are very common in diabetic patients, but the pathogenesis is still not well understood. Peripheral afferent nerves may be involved due to the complex regulation of gastrointestinal function by the enteric nervous system. Objective We aimed to characterize the stimulus–response function of afferent fibers innervating the jejunum in the Goto-Kakizaki (GK) type 2 diabetic rat model. A key question is whether changes in afferent firing arise from remodeled tissue or from adaptive afferent processes. Design Seven 32-week-old male GK rats and seven age-matched normal Wistar rats were studied. Firing from mesenteric afferent nerves was recorded in excised jejunal segments of seven GK rats and seven normal Wistar rats during ramp test, stress relaxation test, and creep test. The circumferential stress–strain, spike rate increase ratio (SRIR), and single unit firing rates were calculated for evaluation of interdependency of the mechanical stimulations and the afferent nerve discharge. Results Elevated sensitivity to mechanical stimuli was found for diabetic nerve bundles and single unit activity (P<0.05). The stress relaxed less in the diabetic intestinal segment (P<0.05). Linear association between SRIR and the thickness of circumferential muscle layer was found at high stress levels as well as for SRIR and the glucose level. Conclusion Altered viscoelastic properties and elevated mechanosensitivity were found in the GK rat intestine. The altered nerve signaling is related to muscle layer remodeling and glucose levels and may contribute to gastrointestinal symptoms experienced by diabetic patients. PMID:29238211

Altered thermogenesis and impaired bone remodeling in Misty mice.

PubMed

Motyl, Katherine J; Bishop, Kathleen A; DeMambro, Victoria E; Bornstein, Sheila A; Le, Phuong; Kawai, Masanobu; Lotinun, Sutada; Horowitz, Mark C; Baron, Roland; Bouxsein, Mary L; Rosen, Clifford J

2013-09-01

Fat mass may be modulated by the number of brown-like adipocytes in white adipose tissue (WAT) in humans and rodents. Bone remodeling is dependent on systemic energy metabolism and, with age, bone remodeling becomes uncoupled and brown adipose tissue (BAT) function declines. To test the interaction between BAT and bone, we employed Misty (m/m) mice, which were reported be deficient in BAT. We found that Misty mice have accelerated age-related trabecular bone loss and impaired brown fat function (including reduced temperature, lower expression of Pgc1a, and less sympathetic innervation compared to wild-type (+/ +)). Despite reduced BAT function, Misty mice had normal core body temperature, suggesting heat is produced from other sources. Indeed, upon acute cold exposure (4°C for 6 hours), inguinal WAT from Misty mice compensated for BAT dysfunction by increasing expression of Acadl, Pgc1a, Dio2, and other thermogenic genes. Interestingly, acute cold exposure also decreased Runx2 and increased Rankl expression in Misty bone, but only Runx2 was decreased in wild-type. Browning of WAT is under the control of the sympathetic nervous system (SNS) and, if present at room temperature, could impact bone metabolism. To test whether SNS activity could be responsible for accelerated trabecular bone loss, we treated wild-type and Misty mice with the β-blocker, propranolol. As predicted, propranolol slowed trabecular bone volume/total volume (BV/TV) loss in the distal femur of Misty mice without affecting wild-type. Finally, the Misty mutation (a truncation of DOCK7) also has a significant cell-autonomous role. We found DOCK7 expression in whole bone and osteoblasts. Primary osteoblast differentiation from Misty calvaria was impaired, demonstrating a novel role for DOCK7 in bone remodeling. Despite the multifaceted effects of the Misty mutation, we have shown that impaired brown fat function leads to altered SNS activity and bone loss, and for the first time that cold

Altered thermogenesis and impaired bone remodeling in Misty mice

PubMed Central

Motyl, Katherine J; Bishop, Kathleen A; DeMambro, Victoria E; Bornstein, Sheila A; Le, Phuong; Kawai, Masanobu; Lotinun, Sutada; Horowitz, Mark C; Baron, Roland; Bouxsein, Mary L; Rosen, Clifford J

2013-01-01

Fat mass may be modulated by the number of brown-like adipocytes in white adipose tissue (WAT) in humans and rodents. Bone remodeling is dependent on systemic energy metabolism and, with age, bone remodeling becomes uncoupled and brown adipose tissue (BAT) function declines. To test the interaction between BAT and bone, we employed Misty (m/m) mice, which were reported be deficient in BAT. We found that Misty mice have accelerated age-related trabecular bone loss and impaired brown fat function (including reduced temperature, lower expression of Pgc1a and less sympathetic innervation compared to wildtype (+/+)). Despite reduced BAT function, Misty mice had normal core body temperature, suggesting heat is produced from other sources. Indeed, upon acute cold exposure (4°C for 6 hr), inguinal WAT from Misty mice compensated for BAT dysfunction by increasing expression of Acadl, Pgc1a, Dio2 and other thermogenic genes. Interestingly, acute cold exposure also decreased Runx2 and increased Rankl expression in Misty bone, but only Runx2 was decreased in wildtype. Browning of WAT is under the control of the sympathetic nervous system (SNS) and, if present at room temperature, could impact bone metabolism. To test whether SNS activity could be responsible for accelerated trabecular bone loss, we treated wildtype and Misty mice with the β-blocker, propranolol. As predicted, propranolol slowed trabecular BV/TV loss in the distal femur of Misty mice without affecting wildtype. Finally, the Misty mutation (a truncation of DOCK7) also has a significant cell-autonomous role. We found DOCK7 expression in whole bone and osteoblasts. Primary osteoblast differentiation from Misty calvaria was impaired, demonstrating a novel role for DOCK7 in bone remodeling. Despite the multifaceted effects of the Misty mutation, we have shown that impaired brown fat function leads to altered SNS activity and bone loss, and for the first time that cold exposure negatively affects bone remodeling

TNF-alpha drives remodeling of blood vessels and lymphatics in sustained airway inflammation in mice.

PubMed

Baluk, Peter; Yao, Li-Chin; Feng, Jennifer; Romano, Talia; Jung, Sonia S; Schreiter, Jessica L; Yan, Li; Shealy, David J; McDonald, Donald M

2009-10-01

Inflammation is associated with blood vessel and lymphatic vessel proliferation and remodeling. The microvasculature of the mouse trachea provides an ideal opportunity to study this process, as Mycoplasma pulmonis infection of mouse airways induces widespread and sustained vessel remodeling, including enlargement of capillaries into venules and lymphangiogenesis. Although the mediators responsible for these vascular changes in mice have not been identified, VEGF-A is known not to be involved. Here, we sought to determine whether TNF-alpha drives the changes in blood vessels and lymphatics in M. pulmonis-infected mice. The endothelial cells, but not pericytes, of blood vessels, but not lymphatics, were immunoreactive for TNF receptor 1 (TNF-R1) and lymphotoxin B receptors. Most TNF-R2 immunoreactivity was on leukocytes. Infection resulted in a large and sustained increase in TNF-alpha expression, as measured by real-time quantitative RT-PCR, and smaller increases in lymphotoxins and TNF receptors that preceded vessel remodeling. Substantially less vessel remodeling and lymphangiogenesis occurred when TNF-alpha signaling was inhibited by a blocking antibody or was silenced in Tnfr1-/- mice. When administered after infection was established, the TNF-alpha-specific antibody slowed but did not reverse blood vessel remodeling and lymphangiogenesis. The action of TNF-alpha on blood vessels is probably mediated through direct effects on endothelial cells, but its effects on lymphangiogenesis may require inflammatory mediators from recruited leukocytes. We conclude that TNF-alpha is a strong candidate for a mediator that drives blood vessel remodeling and lymphangiogenesis in inflammation.

Communication of Energy Efficiency Information to Remodelers: Lessons From Current Practice

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

Liaukus, C.

2012-10-01

The effective communication of energy efficiency and building science information to remodeling contractors is achieved through varying formats, timelines, and modes depending on who is delivering the information, who is intended to receive it, and what technical, intellectual,and time resources the recipients have at their disposal. Determining what type of communication is effective does not lend itself to a clearly quantifiable test but rather a qualitative one. That qualitative judgment can be supported by the research of current practices deemed effective for one or more of the following reasons: it has led to the successful completion of a certifying testmore » or other evaluation, it has been widely used for the remodeling industry, it has been considered effective by a sampling of remodeling contractors, and/or it has proven effective in the field for the BARA team. These criteria were used to create a select list of communications to be further analyzed to determine why they are effective and how less successful formats or strategies can be revised for greater effectiveness.« less

Multiple roles of the Rho GEF ephexin1 in synapse remodeling

PubMed Central

Shi, Lei; Fu, Amy KY

2010-01-01

Synapse remodeling, which involves changes in the synaptic structure and their molecular composition, is required for the maturation and refinement of neural circuits. Although synapse remodeling is known to be tightly dependent on the assembly of local actin cytoskeleton, how actin directs the structural changes of synapse and targeting of synaptic proteins are not fully understood. Recently, we identified ephexin1, a Rho guanine nucleotide exchange factor (GEF) that regulates actin dynamics, to play an essential role in the maturation and functioning of the mammalian neuromuscular junction (NMJ). We showed that ephexin1 regulates the synaptic organization of the neurotransmitter receptor acetylcholine receptor (AChR) clusters through RhoA-dependent actin reorganization. Interestingly, ephexin1 has been implicated in the regulation of postsynaptic structure as well as the presynaptic vesicle release at various types of synapses. Our findings thus establish a novel function of ephexin1 in synapse remodeling through regulating the synaptic targeting of neurotransmitter receptors, revealing a versatile role of ephexin1 at synapses. PMID:21331259

Oxido-reductive regulation of vascular remodeling by receptor tyrosine kinase ROS1

PubMed Central

Ali, Ziad A.; de Jesus Perez, Vinicio; Yuan, Ke; Orcholski, Mark; Pan, Stephen; Qi, Wei; Chopra, Gaurav; Adams, Christopher; Kojima, Yoko; Leeper, Nicholas J.; Qu, Xiumei; Zaleta-Rivera, Kathia; Kato, Kimihiko; Yamada, Yoshiji; Oguri, Mitsutoshi; Kuchinsky, Allan; Hazen, Stanley L.; Jukema, J. Wouter; Ganesh, Santhi K.; Nabel, Elizabeth G.; Channon, Keith; Leon, Martin B.; Charest, Alain; Quertermous, Thomas; Ashley, Euan A.

2014-01-01

Angioplasty and stenting is the primary treatment for flow-limiting atherosclerosis; however, this strategy is limited by pathological vascular remodeling. Using a systems approach, we identified a role for the network hub gene glutathione peroxidase-1 (GPX1) in pathological remodeling following human blood vessel stenting. Constitutive deletion of Gpx1 in atherosclerotic mice recapitulated this phenotype of increased vascular smooth muscle cell (VSMC) proliferation and plaque formation. In an independent patient cohort, gene variant pair analysis identified an interaction of GPX1 with the orphan protooncogene receptor tyrosine kinase ROS1. A meta-analysis of the only genome-wide association studies of human neointima-induced in-stent stenosis confirmed the association of the ROS1 variant with pathological remodeling. Decreased GPX1 expression in atherosclerotic mice led to reductive stress via a time-dependent increase in glutathione, corresponding to phosphorylation of the ROS1 kinase activation site Y2274. Loss of GPX1 function was associated with both oxidative and reductive stress, the latter driving ROS1 activity via s-glutathiolation of critical residues of the ROS1 tyrosine phosphatase SHP-2. ROS1 inhibition with crizotinib and deglutathiolation of SHP-2 abolished GPX1-mediated increases in VSMC proliferation while leaving endothelialization intact. Our results indicate that GPX1-dependent alterations in oxido-reductive stress promote ROS1 activation and mediate vascular remodeling. PMID:25401476

Pro-arrhythmogenic effects of atrial fibrillation-induced electrical remodelling: insights from the three-dimensional virtual human atria

PubMed Central

Colman, Michael A; Aslanidi, Oleg V; Kharche, Sanjay; Boyett, Mark R; Garratt, Clifford; Hancox, Jules C; Zhang, Henggui

2013-01-01

Chronic atrial fibrillation (AF) is associated with structural and electrical remodelling in the atria, which are associated with a high recurrence of AF. Through biophysically detailed computer modelling, this study investigated mechanisms by which AF-induced electrical remodelling promotes and perpetuates AF. A family of Courtemanche–Ramirez–Nattel variant models of human atrial cell action potentials (APs), taking into account of intrinsic atrial electrophysiological properties, was modified to incorporate various experimental data sets on AF-induced changes of major ionic channel currents (ICaL, IKur, Ito, IK1, IKs, INaCa) and on intracellular Ca2+ handling. The single cell models for control and AF-remodelled conditions were incorporated into multicellular three-dimensional (3D) atrial tissue models. Effects of the AF-induced electrical remodelling were quantified as the changes of AP profile, AP duration (APD) and its dispersion across the atria, and the vulnerability of atrial tissue to the initiation of re-entry. The dynamic behaviour of re-entrant excitation waves in the 3D models was characterised. In our simulations, AF-induced electrical remodelling abbreviated atrial APD non-uniformly across the atria; this resulted in relatively short APDs co-existing with marked regional differences in the APD at junctions of the crista terminalis/pectinate muscle, pulmonary veins/left atrium. As a result, the measured tissue vulnerability to re-entry initiation at these tissue junctions was increased. The AF-induced electrical remodelling also stabilized and accelerated re-entrant excitation waves, leading to rapid and sustained re-entry. Under the AF-remodelled condition, re-entrant scroll waves in the 3D model degenerated into persistent and erratic wavelets, leading to fibrillation. In conclusion, realistic 3D atrial tissue models indicate that AF-induced electrical remodelling produces regionally heterogeneous and shortened APD; these respectively facilitate

Pro-arrhythmogenic effects of atrial fibrillation-induced electrical remodelling: insights from the three-dimensional virtual human atria.

PubMed

Colman, Michael A; Aslanidi, Oleg V; Kharche, Sanjay; Boyett, Mark R; Garratt, Clifford; Hancox, Jules C; Zhang, Henggui

2013-09-01

Chronic atrial fibrillation (AF) is associated with structural and electrical remodelling in the atria, which are associated with a high recurrence of AF. Through biophysically detailed computer modelling, this study investigated mechanisms by which AF-induced electrical remodelling promotes and perpetuates AF. A family of Courtemanche-Ramirez-Nattel variant models of human atrial cell action potentials (APs), taking into account of intrinsic atrial electrophysiological properties, was modified to incorporate various experimental data sets on AF-induced changes of major ionic channel currents (ICaL, IKur, Ito, IK1, IKs, INaCa) and on intracellular Ca(2+) handling. The single cell models for control and AF-remodelled conditions were incorporated into multicellular three-dimensional (3D) atrial tissue models. Effects of the AF-induced electrical remodelling were quantified as the changes of AP profile, AP duration (APD) and its dispersion across the atria, and the vulnerability of atrial tissue to the initiation of re-entry. The dynamic behaviour of re-entrant excitation waves in the 3D models was characterised. In our simulations, AF-induced electrical remodelling abbreviated atrial APD non-uniformly across the atria; this resulted in relatively short APDs co-existing with marked regional differences in the APD at junctions of the crista terminalis/pectinate muscle, pulmonary veins/left atrium. As a result, the measured tissue vulnerability to re-entry initiation at these tissue junctions was increased. The AF-induced electrical remodelling also stabilized and accelerated re-entrant excitation waves, leading to rapid and sustained re-entry. Under the AF-remodelled condition, re-entrant scroll waves in the 3D model degenerated into persistent and erratic wavelets, leading to fibrillation. In conclusion, realistic 3D atrial tissue models indicate that AF-induced electrical remodelling produces regionally heterogeneous and shortened APD; these respectively facilitate

Barriers to adaptive reasoning in community ecology.

PubMed

McLachlan, Athol J; Ladle, Richard J

2011-08-01

Recent high-profile calls for a more trait-focused approach to community ecology have the potential to open up novel research areas, generate new insights and to transform community ecology into a more predictive science. However, a renewed emphasis on function and phenotype also requires a fundamental shift in approach and research philosophy within community ecology to more fully embrace evolutionary reasoning. Such a subject-wise transformation will be difficult due to at least four factors: (1) the historical development of the academic discipline of ecology and its roots as a descriptive science; (2) the dominating role of the ecosystem concept in the driving of contemporary ecological thought; (3) the practical difficulties associated with defining and identifying (phenotypic) adaptations, and; (4) scaling effects in ecology; the difficulty of teasing apart the overlapping and shifting hierarchical processes that generate the observed environment-trait correlations in nature. We argue that the ability to predict future ecological conditions through a sufficient understanding of ecological processes will not be achieved without the placement of the concept of adaptation at the centre of ecology, with influence radiating outwards through all the related (and rapidly specializing) sub-disciplines. © 2010 The Authors. Biological Reviews © 2010 Cambridge Philosophical Society.

The nucleosomal acidic patch relieves auto-inhibition by the ISWI remodeler SNF2h

PubMed Central

Gamarra, Nathan; Johnson, Stephanie L; Trnka, Michael J; Burlingame, Alma L

2018-01-01

ISWI family chromatin remodeling motors use sophisticated autoinhibition mechanisms to control nucleosome sliding. Yet how the different autoinhibitory domains are regulated is not well understood. Here we show that an acidic patch formed by histones H2A and H2B of the nucleosome relieves the autoinhibition imposed by the AutoN and the NegC regions of the human ISWI remodeler SNF2h. Further, by single molecule FRET we show that the acidic patch helps control the distance travelled per translocation event. We propose a model in which the acidic patch activates SNF2h by providing a landing pad for the NegC and AutoN auto-inhibitory domains. Interestingly, the INO80 complex is also strongly dependent on the acidic patch for nucleosome sliding, indicating that this substrate feature can regulate remodeling enzymes with substantially different mechanisms. We therefore hypothesize that regulating access to the acidic patch of the nucleosome plays a key role in coordinating the activities of different remodelers in the cell. PMID:29664398

The extracellular matrix in myocardial injury, repair, and remodeling

PubMed Central

2017-01-01

The cardiac extracellular matrix (ECM) not only provides mechanical support, but also transduces essential molecular signals in health and disease. Following myocardial infarction, dynamic ECM changes drive inflammation and repair. Early generation of bioactive matrix fragments activates proinflammatory signaling. The formation of a highly plastic provisional matrix facilitates leukocyte infiltration and activates infarct myofibroblasts. Deposition of matricellular proteins modulates growth factor signaling and contributes to the spatial and temporal regulation of the reparative response. Mechanical stress due to pressure and volume overload and metabolic dysfunction also induce profound changes in ECM composition that contribute to the pathogenesis of heart failure. This manuscript reviews the role of the ECM in cardiac repair and remodeling and discusses matrix-based therapies that may attenuate remodeling while promoting repair and regeneration. PMID:28459429

Interleukin-6 Contributes to Inflammation and Remodeling in a Model of Adenosine Mediated Lung Injury

PubMed Central

Pedroza, Mesias; Schneider, Daniel J.; Karmouty-Quintana, Harry; Coote, Julie; Shaw, Stevan; Corrigan, Rebecca; Molina, Jose G.; Alcorn, Joseph L.; Galas, David; Gelinas, Richard; Blackburn, Michael R.

2011-01-01

Background Chronic lung diseases are the third leading cause of death in the United States due in part to an incomplete understanding of pathways that govern the progressive tissue remodeling that occurs in these disorders. Adenosine is elevated in the lungs of animal models and humans with chronic lung disease where it promotes air-space destruction and fibrosis. Adenosine signaling increases the production of the pro-fibrotic cytokine interleukin-6 (IL-6). Based on these observations, we hypothesized that IL-6 signaling contributes to tissue destruction and remodeling in a model of chronic lung disease where adenosine levels are elevated. Methodology/Principal Findings We tested this hypothesis by neutralizing or genetically removing IL-6 in adenosine deaminase (ADA)-deficient mice that develop adenosine dependent pulmonary inflammation and remodeling. Results demonstrated that both pharmacologic blockade and genetic removal of IL-6 attenuated pulmonary inflammation, remodeling and fibrosis in this model. The pursuit of mechanisms involved revealed adenosine and IL-6 dependent activation of STAT-3 in airway epithelial cells. Conclusions/Significance These findings demonstrate that adenosine enhances IL-6 signaling pathways to promote aspects of chronic lung disease. This suggests that blocking IL-6 signaling during chronic stages of disease may provide benefit in halting remodeling processes such as fibrosis and air-space destruction. PMID:21799929

Contributions of adaptation currents to dynamic spike threshold on slow timescales: Biophysical insights from conductance-based models

NASA Astrophysics Data System (ADS)

Yi, Guosheng; Wang, Jiang; Wei, Xile; Deng, Bin; Li, Huiyan; Che, Yanqiu

2017-06-01

Spike-frequency adaptation (SFA) mediated by various adaptation currents, such as voltage-gated K+ current (IM), Ca2+-gated K+ current (IAHP), or Na+-activated K+ current (IKNa), exists in many types of neurons, which has been shown to effectively shape their information transmission properties on slow timescales. Here we use conductance-based models to investigate how the activation of three adaptation currents regulates the threshold voltage for action potential (AP) initiation during the course of SFA. It is observed that the spike threshold gets depolarized and the rate of membrane depolarization (dV/dt) preceding AP is reduced as adaptation currents reduce firing rate. It is indicated that the presence of inhibitory adaptation currents enables the neuron to generate a dynamic threshold inversely correlated with preceding dV/dt on slower timescales than fast dynamics of AP generation. By analyzing the interactions of ionic currents at subthreshold potentials, we find that the activation of adaptation currents increase the outward level of net membrane current prior to AP initiation, which antagonizes inward Na+ to result in a depolarized threshold and lower dV/dt from one AP to the next. Our simulations demonstrate that the threshold dynamics on slow timescales is a secondary effect caused by the activation of adaptation currents. These findings have provided a biophysical interpretation of the relationship between adaptation currents and spike threshold.

Synaptic remodeling generates synchronous oscillations in the degenerated outer mouse retina

PubMed Central

Haq, Wadood; Arango-Gonzalez, Blanca; Zrenner, Eberhart; Euler, Thomas; Schubert, Timm

2014-01-01

During neuronal degenerative diseases, neuronal microcircuits undergo severe structural alterations, leading to remodeling of synaptic connectivity. The functional consequences of such remodeling are mostly unknown. For instance, in mutant rd1 mouse retina, a common model for Retinitis Pigmentosa, rod bipolar cells (RBCs) establish contacts with remnant cone photoreceptors (cones) as a consequence of rod photoreceptor cell death and the resulting lack of presynaptic input. To assess the functional connectivity in the remodeled, light-insensitive outer rd1 retina, we recorded spontaneous population activity in retinal wholemounts using Ca2+ imaging and identified the participating cell types. Focusing on cones, RBCs and horizontal cells (HCs), we found that these cell types display spontaneous oscillatory activity and form synchronously active clusters. Overall activity was modulated by GABAergic inhibition from interneurons such as HCs and/or possibly interplexiform cells. Many of the activity clusters comprised both cones and RBCs. Opposite to what is expected from the intact (wild-type) cone-ON bipolar cell pathway, cone and RBC activity was positively correlated and, at least partially, mediated by glutamate transporters expressed on RBCs. Deletion of gap junctional coupling between cones reduced the number of clusters, indicating that electrical cone coupling plays a crucial role for generating the observed synchronized oscillations. In conclusion, degeneration-induced synaptic remodeling of the rd1 retina results in a complex self-sustained outer retinal oscillatory network, that complements (and potentially modulates) the recently described inner retinal oscillatory network consisting of amacrine, bipolar and ganglion cells. PMID:25249942

Stem cell-based growth, regeneration, and remodeling of the planarian intestine

PubMed Central

Forsthoefel, David J.; Park, Amanda E.; Newmark, Phillip A.

2011-01-01

Although some animals are capable of regenerating organs, the mechanisms by which this is achieved are poorly understood. In planarians, pluripotent somatic stem cells called neoblasts supply new cells for growth, replenish tissues in response to cellular turnover, and regenerate tissues after injury. For most tissues and organs, however, the spatiotemporal dynamics of stem cell differentiation and the fate of tissue that existed prior to injury have not been characterized systematically. Utilizing in vivo imaging and bromodeoxyuridine pulse-chase experiments, we have analyzed growth and regeneration of the planarian intestine, the organ responsible for digestion and nutrient distribution. During growth, we observe that new gut branches are added along the entire anteroposterior axis. We find that new enterocytes differentiate throughout the intestine rather than in specific growth zones, suggesting that branching morphogenesis is achieved primarily by remodeling of differentiated intestinal tissues. During regeneration, we also demonstrate a previously unappreciated degree of intestinal remodeling, in which pre-existing posterior gut tissue contributes extensively to the newly formed anterior gut, and vice versa. By contrast to growing animals, differentiation of new intestinal cells occurs at preferential locations, including within newly generated tissue (the blastema), and along pre-existing intestinal branches undergoing remodeling. Our results indicate that growth and regeneration of the planarian intestine are achieved by coordinated differentiation of stem cells and the remodeling of pre-existing tissues. Elucidation of the mechanisms by which these processes are integrated will be critical for understanding organogenesis in a post-embryonic context. PMID:21664348

IMD-4690, a novel specific inhibitor for plasminogen activator inhibitor-1, reduces allergic airway remodeling in a mouse model of chronic asthma via regulating angiogenesis and remodeling-related mediators.

PubMed

Tezuka, Toshifumi; Ogawa, Hirohisa; Azuma, Masahiko; Goto, Hisatsugu; Uehara, Hisanori; Aono, Yoshinori; Hanibuchi, Masaki; Yamaguchi, Yoichi; Fujikawa, Tomoyuki; Itai, Akiko; Nishioka, Yasuhiko

2015-01-01

Plasminogen activator inhibitor (PAI)-1 is the principal inhibitor of plasminogen activators, and is responsible for the degradation of fibrin and extracellular matrix. IMD-4690 is a newly synthesized inhibitor for PAI-1, whereas the effect on allergic airway inflammation and remodeling is still unclear. We examined the in vivo effects by using a chronic allergen exposure model of bronchial asthma in mice. The model was generated by an immune challenge for 8 weeks with house dust mite antigen, Dermatophagoides pteronyssinus (Dp). IMD-4690 was intraperitoneally administered during the challenge. Lung histopathology, hyperresponsiveness and the concentrations of mediators in lung homogenates were analyzed. The amount of active PAI-1 in the lungs was increased in mice treated with Dp. Administration with IMD-4690 reduced an active/total PAI-1 ratio. IMD-4690 also reduced the number of bronchial eosinophils in accordance with the decreased expressions of Th2 cytokines in the lung homogenates. Airway remodeling was inhibited by reducing subepithelial collagen deposition, smooth muscle hypertrophy, and angiogenesis. The effects of IMD-4690 were partly mediated by the regulation of TGF-β, HGF and matrix metalloproteinase. These results suggest that PAI-1 plays crucial roles in airway inflammation and remodeling, and IMD-4690, a specific PAI-1 inhibitor, may have therapeutic potential for patients with refractory asthma due to airway remodeling.

Pregnancy-induced remodelling and enhanced endothelium-derived hyperpolarization-type vasodilator activity in rat uterine radial artery: transient receptor potential vanilloid type 4 channels, caveolae and myoendothelial gap junctions

PubMed Central

Senadheera, Sevvandi; Bertrand, Paul P; Grayson, T Hilton; Leader, Leo; Murphy, Timothy V; Sandow, Shaun L

2013-01-01

In pregnancy, the vasculature of the uterus undergoes rapid remodelling to increase blood flow and maintain perfusion to the fetus. The present study determines the distribution and density of caveolae, transient receptor potential vanilloid type 4 channels (TRPV4) and myoendothelial gap junctions, and the relative contribution of related endothelium-dependent vasodilator components in uterine radial arteries of control virgin non-pregnant and 20-day late-pregnant rats. The hypothesis examined is that specific components of endothelium-dependent vasodilator mechanisms are altered in pregnancy-related uterine radial artery remodelling. Conventional and serial section electron microscopy were used to determine the morphological characteristics of uterine radial arteries from control and pregnant rats. TRPV4 distribution and expression was examined using conventional confocal immunohistochemistry, and the contribution of endothelial TRPV4, nitric oxide (NO) and endothelium-derived hyperpolarization (EDH)-type activity determined using pressure myography with pharmacological intervention. Data show outward hypertrophic remodelling occurs in uterine radial arteries in pregnancy. Further, caveolae density in radial artery endothelium and smooth muscle from pregnant rats was significantly increased by ∼94% and ∼31%, respectively, compared with control, whereas caveolae density did not differ in endothelium compared with smooth muscle from control. Caveolae density was significantly higher by ∼59% on the abluminal compared with the luminal surface of the endothelium in uterine radial artery of pregnant rats but did not differ at those surfaces in control. TRPV4 was present in endothelium and smooth muscle, but not associated with internal elastic lamina hole sites in radial arteries. TRPV4 fluorescence intensity was significantly increased in the endothelium and smooth muscle of radial artery of pregnant compared with control rats by ∼2.6- and 5.5-fold

Understanding How Space Travel Affects Blood Vessels: Arterial Remodeling and Functional Adaptations Induced by Microgravity

NASA Technical Reports Server (NTRS)

Delp, Michael; Vasques, Marilyn; Aquilina, Rudy (Technical Monitor)

2002-01-01

Ever rise quickly from the couch to get something from the kitchen and suddenly feel dizzy? With a low heart rate and relaxed muscles, the cardiovascular system does not immediately provide the resistance necessary to keep enough blood going to your head. Gravity wins, at least for a short time, before your heart and blood vessels can respond to the sudden change in position and correct the situation. Actually, the human cardiovascular system is quite well adapted to the constant gravitational force of the Earth. When standing, vessels in the legs constrict to prevent blood from collecting in the lower extremities. In the space environment, the usual head-to-foot blood pressure and tissue fluid gradients that exist during the upright posture on Earth are removed. The subsequent shift in fluids from the lower to the upper portions of the body triggers adaptations within the cardiovascular system to accommodate the new pressure and fluid gradients. In animal models that simulate microgravity, the vessels in the head become more robust while those in the lower limbs become thin and lax. Similar changes may also occur in humans during spaceflight and while these adaptations are appropriate for a microgravity environment, they can cause problems when the astronauts return to Earth or perhaps another planet. Astronauts often develop orthostatic intolerance which means they become dizzy or faint when standing upright. This dizziness can persist for a number of days making routine activities difficult. In an effort to understand the physiological details of these cardiovascular adaptations, Dr. Michael Delp at Texas A&M University, uses the rat as a model for his studies. For the experiment flown on STS-107, he will test the hypothesis that blood vessels in the rats' hindlimbs become thinner, weaker, and constrict less in response to pressure changes and to chemical signals when exposed to microgravity. In addition, he will test the hypothesis that arteries in the brain

Structural and molecular remodeling of dendritic spine substructures during long-term potentiation

PubMed Central

Bosch, Miquel; Castro, Jorge; Saneyoshi, Takeo; Matsuno, Hitomi; Sur, Mriganka; Hayashi, Yasunori

2014-01-01

SUMMARY Synapses store information by long-lasting modifications of their structure and molecular composition, but the precise chronology of these changes has not been studied at single synapse resolution in real time. Here we describe the spatiotemporal reorganization of postsynaptic substructures during long-term potentiation (LTP) at individual dendritic spines. Proteins translocated to the spine in four distinct patterns through three sequential phases. In the initial phase, the actin cytoskeleton was rapidly remodeled while active cofilin was massively transported to the spine. In the stabilization phase, cofilin formed a stable complex with F-actin, was persistently retained at the spine, and consolidated spine expansion. In contrast, the postsynaptic density (PSD) was independently remodeled, as PSD scaffolding proteins did not change their amount and localization until a late protein synthesis-dependent third phase. Our findings show how and when spine substructures are remodeled during LTP and explain why synaptic plasticity rules change over time. PMID:24742465

TRPV1 Blocking Alleviates Airway Inflammation and Remodeling in a Chronic Asthma Murine Model.

PubMed

Choi, Joon Young; Lee, Hwa Young; Hur, Jung; Kim, Kyung Hoon; Kang, Ji Young; Rhee, Chin Kook; Lee, Sook Young

2018-05-01

Asthma is a chronic inflammatory airway disease characterized by airway hyperresponsiveness (AHR), inflammation, and remodeling. There is emerging interest in the involvement of the transient receptor potential vanilloid 1 (TRPV1) channel in the pathophysiology of asthma. This study examined whether TRPV1 antagonism alleviates asthma features in a murine model of chronic asthma. BALB/c mice were sensitized to and challenged by ovalbumin to develop chronic asthma. Capsazepine (TRPV1 antagonist) or TRPV1 small interfering RNA (siRNA) was administered in the treatment group to evaluate the effect of TPV1 antagonism on AHR, airway inflammation, and remodeling. The mice displayed increased AHR, airway inflammation, and remodeling. Treatment with capsazepine or TRPV1 siRNA reduced AHR to methacholine and airway inflammation. Type 2 T helper (Th2) cytokines (interleukin [IL]-4, IL-5, and IL-13) were reduced and epithelial cell-derived cytokines (thymic stromal lymphopoietin [TSLP], IL-33, and IL-25), which regulate Th2 cytokine-associated inflammation, were also reduced. Airway remodeling characterized by goblet cell hyperplasia, increased α-smooth muscle action, and collagen deposition was also alleviated by both treatments. Treatment directed at TRPV1 significantly alleviated AHR, airway inflammation, and remodeling in a chronic asthma murine model. The TRPV1 receptor can be a potential drug target for chronic bronchial asthma. Copyright © 2018 The Korean Academy of Asthma, Allergy and Clinical Immunology · The Korean Academy of Pediatric Allergy and Respiratory Disease.

Effects of aging and Parkinson's disease on motor unit remodeling: influence of resistance exercise training.

PubMed

Kelly, Neil A; Hammond, Kelley G; Bickel, C Scott; Windham, Samuel T; Tuggle, S Craig; Bamman, Marcas M

2018-04-01

Aging muscle atrophy is in part a neurodegenerative process revealed by denervation/reinnervation events leading to motor unit remodeling (i.e., myofiber type grouping). However, this process and its physiological relevance are poorly understood, as is the wide-ranging heterogeneity among aging humans. Here, we attempted to address 1) the relation between myofiber type grouping and molecular regulators of neuromuscular junction (NMJ) stability; 2) the impact of motor unit remodeling on recruitment during submaximal contractions; 3) the prevalence and impact of motor unit remodeling in Parkinson's disease (PD), an age-related neurodegenerative disease; and 4) the influence of resistance exercise training (RT) on regulators of motor unit remodeling. We compared type I myofiber grouping, molecular regulators of NMJ stability, and the relative motor unit activation (MUA) requirement during a submaximal sit-to-stand task among untrained but otherwise healthy young (YA; 26 yr, n = 27) and older (OA; 66 yr, n = 91) adults and OA with PD (PD; 67 yr, n = 19). We tested the effects of RT on these outcomes in OA and PD. PD displayed more motor unit remodeling, alterations in NMJ stability regulation, and a higher relative MUA requirement than OA, suggesting PD-specific effects. The molecular and physiological outcomes tracked with the severity of type I myofiber grouping. Together these findings suggest that age-related motor unit remodeling, manifested by type I myofiber grouping, 1) reduces MUA efficiency to meet submaximal contraction demand, 2) is associated with disruptions in NMJ stability, 3) is further impacted by PD, and 4) may be improved by RT in severe cases. NEW & NOTEWORTHY Because the physiological consequences of varying amounts of myofiber type grouping are unknown, the current study aims to characterize the molecular and physiological correlates of motor unit remodeling. Furthermore, because exercise training has demonstrated neuromuscular benefits in aged

Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium.

PubMed

Decker, Keith F; Heijman, Jordi; Silva, Jonathan R; Hund, Thomas J; Rudy, Yoram

2009-04-01

Computational models of cardiac myocytes are important tools for understanding ionic mechanisms of arrhythmia. This work presents a new model of the canine epicardial myocyte that reproduces a wide range of experimentally observed rate-dependent behaviors in cardiac cell and tissue, including action potential (AP) duration (APD) adaptation, restitution, and accommodation. Model behavior depends on updated formulations for the 4-aminopyridine-sensitive transient outward current (I(to1)), the slow component of the delayed rectifier K(+) current (I(Ks)), the L-type Ca(2+) channel current (I(Ca,L)), and the Na(+)-K(+) pump current (I(NaK)) fit to data from canine ventricular myocytes. We found that I(to1) plays a limited role in potentiating peak I(Ca,L) and sarcoplasmic reticulum Ca(2+) release for propagated APs but modulates the time course of APD restitution. I(Ks) plays an important role in APD shortening at short diastolic intervals, despite a limited role in AP repolarization at longer cycle lengths. In addition, we found that I(Ca,L) plays a critical role in APD accommodation and rate dependence of APD restitution. Ca(2+) entry via I(Ca,L) at fast rate drives increased Na(+)-Ca(2+) exchanger Ca(2+) extrusion and Na(+) entry, which in turn increases Na(+) extrusion via outward I(NaK). APD accommodation results from this increased outward I(NaK). Our simulation results provide valuable insight into the mechanistic basis of rate-dependent phenomena important for determining the heart's response to rapid and irregular pacing rates (e.g., arrhythmia). Accurate simulation of rate-dependent phenomena and increased understanding of their mechanistic basis will lead to more realistic multicellular simulations of arrhythmia and identification of molecular therapeutic targets.

Mechanism of block by tedisamil of transient outward current in human ventricular subepicardial myocytes

PubMed Central

Wettwer, Erich; Himmel, Herbert M; Amos, Gregory J; Li, Qi; Metzger, Franz; Ravens, Ursula

1998-01-01

Tedisamil is a new antiarrhythmic drug with predominant class III action. The aim of the present study was to investigate the blocking pattern of the compound on the transient outward current (Ito) in human subepicardial myocytes isolated from explanted left ventricles. Using the single electrode whole cell voltage clamp technique, Ito was analysed after appropriate voltage inactivation of sodium current and block of calcium current.Tedisamil reduced the amplitude of peak Ito, but did not affect the amplitude of non-inactivating outward current. The drug accelerated the apparent rate of Ito inactivation. The reduction in time constant of Ito inactivation depended on drug concentration, the apparent IC50 value was 4.4 μM.Tedisamil affected Ito amplitude in a use-dependent manner. After 2 min at −80 mV, maximum block of Ito was reached after 4–5 clamp steps either at the frequency of 0.2 or 2 Hz, indicating that the block was not frequency-dependent in an experimentally relevant range. Recovery from block was very slow and proceeded with a time constant of 12.1±1.8 s. Also in the presence of drug, a fraction of channels recovered from inactivation with a similar time constant as in control myocytes (i.e. 81±40 ms and 51±8 ms, respectively, n.s.).From the onset of fractional block of Ito by tedisamil during the initial 60 ms of a clamp step, we calculated k1=9×106 mol−1 s−1 for the association rate constant, and k2=23 s−1 for the dissociation rate constant. The resulting apparent KD was 2.6 μM and is similar to the IC50 value.The effects of tedisamil on Ito could be simulated by assuming a four state channel model where the drug binds to the channel in an open (activated) conformation. It is concluded that in human subepicardial myocytes tedisamil is an open channel blocker of Ito and that this effect probably contributes to the antiarrhythmic potential of this drug. PMID:9831899

HDAC2 Suppresses IL17A-Mediated Airway Remodeling in Human and Experimental Modeling of COPD.

PubMed

Lai, Tianwen; Tian, Baoping; Cao, Chao; Hu, Yue; Zhou, Jiesen; Wang, Yong; Wu, Yanping; Li, Zhouyang; Xu, Xuchen; Zhang, Min; Xu, Feng; Cao, Yuan; Chen, Min; Wu, Dong; Wu, Bin; Dong, Chen; Li, Wen; Ying, Songmin; Chen, Zhihua; Shen, Huahao

2018-04-01

Although airway remodeling is a central feature of COPD, the mechanisms underlying its development have not been fully elucidated. The goal of this study was to determine whether histone deacetylase (HDAC) 2 protects against cigarette smoke (CS)-induced airway remodeling through IL-17A-dependent mechanisms. Sputum samples and lung tissue specimens were obtained from control subjects and patients with COPD. The relationships between HDAC2, IL-17A, and airway remodeling were investigated. The effect of HDAC2 on IL-17A-mediated airway remodeling was assessed by using in vivo models of COPD induced by CS and in vitro culture of human bronchial epithelial cells and primary human fibroblasts exposed to CS extract, IL-17A, or both. HDAC2 and IL-17A expression in the sputum cells and lung tissue samples of patients with COPD were associated with bronchial wall thickening and collagen deposition. Il-17a deficiency (Il-17a -/- ) resulted in attenuation of, whereas Hdac2 deficiency (Hdac2 +/- ) exacerbated, CS-induced airway remodeling in mice. IL-17A deletion also attenuated airway remodeling in CS-exposed Hdac2 +/- mice. HDAC2 regulated IL-17A production partially through modulation of CD4 + T cells during T helper 17 cell differentiation and retinoid-related orphan nuclear receptor γt in airway epithelial cells. In vitro, IL-17A deficiency attenuated CS-induced mouse fibroblast activation from Hdac2 +/- mice. IL-17A-induced primary human fibroblast activation was at least partially mediated by autocrine production of transforming growth factor beta 1. These findings suggest that activation of HDAC2 and/or inhibition of IL-17A production could prevent the development of airway remodeling by suppressing airway inflammation and modulating fibroblast activation in COPD. Copyright © 2017. Published by Elsevier Inc.

In Situ Imaging of Tissue Remodeling with Collagen Hybridizing Peptides

PubMed Central

2017-01-01

Collagen, the major structural component of nearly all mammalian tissues, undergoes extensive proteolytic remodeling during developmental states and a variety of life-threatening diseases such as cancer, myocardial infarction, and fibrosis. While degraded collagen could be an important marker of tissue damage, it is difficult to detect and target using conventional tools. Here, we show that a designed peptide (collagen hybridizing peptide: CHP), which specifically hybridizes to the degraded, unfolded collagen chains, can be used to image degraded collagen and inform tissue remodeling activity in various tissues: labeled with 5-carboxyfluorescein and biotin, CHPs enabled direct localization and quantification of collagen degradation in isolated tissues within pathologic states ranging from osteoarthritis and myocardial infarction to glomerulonephritis and pulmonary fibrosis, as well as in normal tissues during developmental programs associated with embryonic bone formation and skin aging. The results indicate the general correlation between the level of collagen remodeling and the amount of denatured collagen in tissue and show that the CHP probes can be used across species and collagen types, providing a versatile tool for not only pathology and developmental biology research but also histology-based disease diagnosis, staging, and therapeutic screening. This study lays the foundation for further testing CHP as a targeting moiety for theranostic delivery in various animal models. PMID:28877431

Electrophysiological and Structural Remodeling in Heart Failure Modulate Arrhythmogenesis. 2D Simulation Study

PubMed Central

Gomez, Juan F.; Cardona, Karen; Martinez, Laura; Saiz, Javier; Trenor, Beatriz

2014-01-01

Background Heart failure is operationally defined as the inability of the heart to maintain blood flow to meet the needs of the body and it is the final common pathway of various cardiac pathologies. Electrophysiological remodeling, intercellular uncoupling and a pro-fibrotic response have been identified as major arrhythmogenic factors in heart failure. Objective In this study we investigate vulnerability to reentry under heart failure conditions by incorporating established electrophysiological and anatomical remodeling using computer simulations. Methods The electrical activity of human transmural ventricular tissue (5 cm×5 cm) was simulated using the human ventricular action potential model Grandi et al. under control and heart failure conditions. The MacCannell et al. model was used to model fibroblast electrical activity, and their electrotonic interactions with myocytes. Selected degrees of diffuse fibrosis and variations in intercellular coupling were considered and the vulnerable window (VW) for reentry was evaluated following cross-field stimulation. Results No reentry was observed in normal conditions or in the presence of HF ionic remodeling. However, defined amount of fibrosis and/or cellular uncoupling were sufficient to elicit reentrant activity. Under conditions where reentry was generated, HF electrophysiological remodeling did not alter the width of the VW. However, intermediate fibrosis and cellular uncoupling significantly widened the VW. In addition, biphasic behavior was observed, as very high fibrotic content or very low tissue conductivity hampered the development of reentry. Detailed phase analysis of reentry dynamics revealed an increase of phase singularities with progressive fibrotic components. Conclusion Structural remodeling is a key factor in the genesis of vulnerability to reentry. A range of intermediate levels of fibrosis and intercellular uncoupling can combine to favor reentrant activity. PMID:25054335

Weighted gene co‑expression network analysis in identification of key genes and networks for ischemic‑reperfusion remodeling myocardium.

PubMed

Guo, Nan; Zhang, Nan; Yan, Liqiu; Lian, Zheng; Wang, Jiawang; Lv, Fengfeng; Wang, Yunfei; Cao, Xufen

2018-06-14

Acute myocardial infarction induces ventricular remodeling, which is implicated in dilated heart and heart failure. The pathogenical mechanism of myocardium remodeling remains to be elucidated. The aim of the present study was to identify key genes and networks for myocardium remodeling following ischemia‑reperfusion (IR). First, the mRNA expression data from the National Center for Biotechnology Information database were downloaded to identify differences in mRNA expression of the IR heart at days 2 and 7. Then, weighted gene co‑expression network analysis, hierarchical clustering, protein‑protein interaction (PPI) network, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were used to identify key genes and networks for the heart remodeling process following IR. A total of 3,321 differentially expressed genes were identified during the heart remodeling process. A total of 6 modules were identified through gene co‑expression network analysis. GO and KEGG analysis results suggested that each module represented a different biological function and was associated with different pathways. Finally, hub genes of each module were identified by PPI network construction. The present study revealed that heart remodeling following IR is a complicated process, involving extracellular matrix organization, neural development, apoptosis and energy metabolism. The dysregulated genes, including SRC proto‑oncogene, non‑receptor tyrosine kinase, discs large MAGUK scaffold protein 1, ATP citrate lyase, RAN, member RAS oncogene family, tumor protein p53, and polo like kinase 2, may be essential for heart remodeling following IR and may be used as potential targets for the inhibition of heart remodeling following acute myocardial infarction.

Quantification of Protein-Induced Membrane Remodeling Kinetics In Vitro with Lipid Multilayer Gratings

PubMed Central

Lowry, Troy W.; Hariri, Hanaa; Prommapan, Plengchart; Kusi-Appiah, Aubrey; Vafai, Nicholas; Bienkiewicz, Ewa A.; Van Winkle, David H.; Stagg, Scott M.

2016-01-01

The dynamic self-organization of lipids in biological systems is a highly regulated process that enables the compartmentalization of living systems at micro- and nanoscopic scales. Consequently, quantitative methods for assaying the kinetics of supramolecular remodeling such as vesicle formation from planar lipid bilayers or multilayers are needed to understand cellular self-organization. Here, a new nanotechnology-based method for quantitative measurements of lipid–protein interactions is presented and its suitability for quantifying the membrane binding, inflation, and budding activity of the membrane-remodeling protein Sar1 is demonstrated. Lipid multilayer gratings are printed onto surfaces using nanointaglio and exposed to Sar1, resulting in the inflation of lipid multilayers into unilamellar structures, which can be observed in a label-free manner by monitoring the diffracted light. Local variations in lipid multilayer volume on the surface is used to vary substrate availability in a microarray format. A quantitative model is developed that allows quantification of binding affinity (KD) and kinetics (kon and koff). Importantly, this assay is uniquely capable of quantifying membrane remodeling. Upon Sar1-induced inflation of single bilayers from surface supported multilayers, the semicylindrical grating lines are observed to remodel into semispherical buds when a critical radius of curvature is reached. PMID:26649649

Chronic alcoholism and bone remodeling processes: Caveats and considerations for the forensic anthropologist.

PubMed

Michael, Amy R; Bengtson, Jennifer D

2016-02-01

Clinical literature provides substantial information on the effects of chronic alcohol abuse on bone remodeling and related skeletal disease processes. This biomedical information is seldom considered in detail by forensic anthropologists, who often rely on normative macroscopic models of bone remodeling and traditional macroscopic age estimation methods in the creation of biological profiles. The case study presented here considers the ways that alcoholism disrupts normal bone remodeling processes, thus skewing estimations of age-at-death. Alcoholism affects bone macroscopically, resulting in a porous appearance and an older estimation of age, while simultaneously inhibiting osteoblastic activity and resulting in a younger microscopic appearance. Forensic anthropologists must also be cognizant of pathological remodeling stemming from alcoholism in cases where trauma analysis is critical to the reconstruction of events leading up to death, as fracture healing rates can be affected. Beyond the case study, we also consider how forensic anthropologists and practitioners can recognize and account for osteological signatures of alcoholism in medico-legal contexts. In order to best estimate age at death, a combined macroscopic and microscopic approach should be employed whenever possible alcohol and drug abuse is known or suspected. Copyright © 2015 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

Nandrolone decanoate and load increase remodeling and strength in human supraspinatus bioartificial tendons.

PubMed

Triantafillopoulos, Ioannis K; Banes, Albert J; Bowman, Karl F; Maloney, Melissa; Garrett, William E; Karas, Spero G

2004-06-01

To date, no studies document the effect of anabolic steroids on rotator cuff tendons. Controlled laboratory study. Anabolic steroids enhance remodeling and improve the biomechanical properties of bioartificially engineered human supraspinatus tendons. Bioartificial tendons were treated with either nandrolone decanoate (nonload, steroid, n = 18), loading (load, nonsteroid, n = 18), or both (load, steroid, n = 18). A control group received no treatment (nonload, nonsteroid [NLNS], n = 18). Bioartificial tendons' remodeling was assessed by daily scanning, cytoskeletal organization by staining, matrix metalloproteinase-3 levels by ELISA assay, and biomechanical properties by load-to-failure testing. The load, steroid group showed the greatest remodeling and the best organized actin cytoskeleton. Matrix metallo-proteinase-3 levels in the load, steroid group were greater than those of the nonload, nonsteroid group (P <.05). Ultimate stress and ultimate strain in the load, steroid group were greater than those of the nonload, nonsteroid and nonload, steroid groups (P <.05). The strain energy density in the load, steroid group was greater when compared to other groups (P <.05). Nandrolone decanoate and load acted synergistically to increase matrix remodeling and biomechanical properties of bioartificial tendons. Data suggest anabolic steroids may enhance production of bioartificial tendons and rotator cuff tendon healing in vitro. More research is necessary before such clinical use is recommended.

Remodelling of cellular excitation (reaction) and intercellular coupling (diffusion) by chronic atrial fibrillation represented by a reaction-diffusion system

NASA Astrophysics Data System (ADS)

Zhang, Henggui; Garratt, Clifford J.; Kharche, Sanjay; Holden, Arun V.

2009-06-01

Human atrial tissue is an excitable system, in which myocytes are excitable elements, and cell-to-cell electrotonic interactions are via diffusive interactions of cell membrane potentials. We developed a family of excitable system models for human atrium at cellular, tissue and anatomical levels for both normal and chronic atrial fibrillation (AF) conditions. The effects of AF-induced remodelling of cell membrane ionic channels (reaction kinetics) and intercellular gap junctional coupling (diffusion) on atrial excitability, conduction of excitation waves and dynamics of re-entrant excitation waves are quantified. Both ionic channel and gap junctional coupling remodelling have rate dependent effects on atrial propagation. Membrane channel conductance remodelling allows the propagation of activity at higher rates than those sustained in normal tissue or in tissue with gap junctional remodelling alone. Membrane channel conductance remodelling is essential for the propagation of activity at rates higher than 300/min as seen in AF. Spatially heterogeneous gap junction coupling remodelling increased the risk of conduction block, an essential factor for the genesis of re-entry. In 2D and 3D anatomical models, the dynamical behaviours of re-entrant excitation waves are also altered by membrane channel modelling. This study provides insights to understand the pro-arrhythmic effects of AF-induced reaction and diffusion remodelling in atrial tissue.

DNA repair goes hip-hop: SMARCA and CHD chromatin remodellers join the break dance.

PubMed

Rother, Magdalena B; van Attikum, Haico

2017-10-05

Proper signalling and repair of DNA double-strand breaks (DSB) is critical to prevent genome instability and diseases such as cancer. The packaging of DNA into chromatin, however, has evolved as a mere obstacle to these DSB responses. Posttranslational modifications and ATP-dependent chromatin remodelling help to overcome this barrier by modulating nucleosome structures and allow signalling and repair machineries access to DSBs in chromatin. Here we recap our current knowledge on how ATP-dependent SMARCA- and CHD-type chromatin remodellers alter chromatin structure during the signalling and repair of DSBs and discuss how their dysfunction impacts genome stability and human disease.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'. © 2017 The Authors.

Right ventricular relative wall thickness as a predictor of outcomes and of right ventricular reverse remodeling for patients with pulmonary hypertension.

PubMed

Sano, Hiroyuki; Tanaka, Hidekazu; Motoji, Yoshiki; Fukuda, Yuko; Mochizuki, Yasuhide; Hatani, Yutaka; Matsuzoe, Hiroki; Hatazawa, Keiko; Shimoura, Hiroyuki; Ooka, Junichi; Ryo-Koriyama, Keiko; Nakayama, Kazuhiko; Matsumoto, Kensuke; Emoto, Noriaki; Hirata, Ken-Ichi

2017-03-01

Mid-term right ventricular (RV) reverse remodeling after treatment in patients with pulmonary hypertension (PH) is associated with long-term outcome as well as baseline RV remodeling. However, baseline factors influencing mid-term RV reverse remodeling after treatment and its prognostic capability remain unclear. We studied 54 PH patients. Mid-term RV remodeling was assessed in terms of the RV area, which was traced planimetrically at the end-systole (RVESA). RV reverse remodeling was defined as a relative decrease in the RVESA of at least 15% at 10.2 ± 9.4 months after treatment. Long-term follow-up was 5 years. Adverse events occurred in ten patients (19%) and mid-term RV reverse remodeling after treatment was observed in 37 (69%). Patients with mid-term RV reverse remodeling had more favorable long-term outcomes than those without (log-rank: p = 0.01). Multivariate logistic regression analysis showed that RV relative wall thickness (RV-RWT), as calculated as RV free-wall thickness/RV basal linear dimension at end-diastole, was an independent predictor of mid-term RV reverse remodeling (OR 1.334; 95% CI, 1.039-1.713; p = 0.03). Moreover, patients with RV-RWT ≥0.21 showed better long-term outcomes than did those without (log-rank p = 0.03), while those with RV-RWT ≥0.21 and mid-term RV reverse remodeling had the best long-term outcomes. Patients with RV-RWT <0.21 and without mid-term RV reverse remodeling, on the other hand, had worse long-term outcomes than other sub-groups. In conclusions, RV-RWT could predict mid-term RV reverse remodeling after treatment in PH patients, and was associated with long-term outcomes. Our finding may have clinical implications for better management of PH patients.

Multigenerational epigenetic adaptation of the hepatic wound-healing response.

PubMed

Zeybel, Müjdat; Hardy, Timothy; Wong, Yi K; Mathers, John C; Fox, Christopher R; Gackowska, Agata; Oakley, Fiona; Burt, Alastair D; Wilson, Caroline L; Anstee, Quentin M; Barter, Matt J; Masson, Steven; Elsharkawy, Ahmed M; Mann, Derek A; Mann, Jelena

2012-09-01

We investigated whether ancestral liver damage leads to heritable reprogramming of hepatic wound healing in male rats. We found that a history of liver damage corresponds with transmission of an epigenetic suppressive adaptation of the fibrogenic component of wound healing to the male F1 and F2 generations. Underlying this adaptation was less generation of liver myofibroblasts, higher hepatic expression of the antifibrogenic factor peroxisome proliferator-activated receptor γ (PPAR-γ) and lower expression of the profibrogenic factor transforming growth factor β1 (TGF-β1) compared to rats without this adaptation. Remodeling of DNA methylation and histone acetylation underpinned these alterations in gene expression. Sperm from rats with liver fibrosis were enriched for the histone variant H2A.Z and trimethylation of histone H3 at Lys27 (H3K27me3) at PPAR-γ chromatin. These modifications to the sperm chromatin were transmittable by adaptive serum transfer from fibrotic rats to naive rats and similar modifications were induced in mesenchymal stem cells exposed to conditioned media from cultured rat or human myofibroblasts. Thus, it is probable that a myofibroblast-secreted soluble factor stimulates heritable epigenetic signatures in sperm so that the resulting offspring better adapt to future fibrogenic hepatic insults. Adding possible relevance to humans, we found that people with mild liver fibrosis have hypomethylation of the PPARG promoter compared to others with severe fibrosis.

VEGF attenuated increase of outward delayed-rectifier potassium currents in hippocampal neurons induced by focal ischemia via PI3-K pathway.

PubMed

Wu, K W; Yang, P; Li, S S; Liu, C W; Sun, F Y

2015-07-09

We recently indicated that the vascular endothelial growth factor (VEGF) protects neurons against hypoxic death via enhancement of tyrosine phosphorylation of Kv1.2, an isoform of the delayed-rectifier potassium channels through activation of the phosphatidylinositol 3-kinase (PI3-K) signaling pathway. The present study investigated whether VEGF could attenuate ischemia-induced increase of the potassium currents in the hippocampal pyramidal neurons of rats after ischemic injury. Adult male Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion (MCAO) to induce brain ischemia. The whole-cell patch-clamp technique was used to record the potassium currents of hippocampal neurons in brain slices from the ischemically injured brains of the rats 24h after MCAO. We detected that transient MCAO caused a significant increase of voltage-gated potassium currents (Kv) and outward delayed-rectifier potassium currents (IK), but not outward transient potassium currents (IA), in the ipsilateral hippocampus compared with the sham. Moreover, we found that VEGF could acutely, reversibly and voltage-dependently inhibit the ischemia-induced IK increase. This inhibitory effect of VEGF could be completely abolished by wortmannin, an inhibitor of PI3-K. Our data indicate that VEGF attenuates the ischemia-induced increase of IK via activation of the PI3-K signaling pathway. Published by Elsevier Ltd.

Mechanical force-induced midpalatal suture remodeling in mice

PubMed Central

Hou, Bo; Fukai, Naomi; Olsen, Bjorn R.

2007-01-01

Mechanical stress is an important epigenetic factor for regulating skeletal remodeling, and application of force can lead to remodeling of both bone and cartilage. Chondrocytes, osteoblasts and osteoclasts all participate and interact with each other in this remodeling process. To study cellular responses to mechanical stimuli in a system that can be genetically manipulated, we used mouse midpalatal suture expansion in vivo. 6-weeks-old male C57BL/6 mice were subjected to palatal suture expansion by opening loops with an initial force of 0.56N for periods of 1, 3, 7, 14 or 28 days. Periosteal cells in expanding sutures showed increased proliferation, with Ki67 positive cells representing 1.8±0.1% to 4.5±0.4% of total suture cells in control groups and 12.0±2.6% to 19.9±1.2% in experimental/expansion groups (p<0.05). Starting at day 1, cells expressing alkaline phosphatase and type I collagen were seen. New cartilage and bone formation was observed at the oral edges of the palatal bones at day 7; at the nasal edges only bone formation without cartilage appeared to occur. An increase in osteoclast numbers suggested increased bone remodeling, ranging from 60 to 160% throughout the experimental period. Decreased Saffranin O staining after day 3 suggested decreased proteoglycan content in the secondary cartilage. MicroCT showed a significant increase in maxillary width at days 14 and 28 (from 2334±4μm to 2485±3μm at day 14 and from 2383±5μm to 2574±7μm at day 28, p<0.001). The suture width was increased at days 14 and 28, except in the oral third region at day 28 (from 48±5μm to 36±4μm, p<0.05). Bone volume/total volume was significantly reduced at days 14 and 28 (50.2±0.7% vs. 68.0±3.7% and 56.5±1.0%vs. 60.9±1.3%, respectively, p<0.05), indicative of increased bone marrow space. These findings demonstrate that expansion forces across the midpalatal suture promote bone resorption through activation of osteoclasts and bone and cartilage formation via

Mechanical force-induced midpalatal suture remodeling in mice.

PubMed

Hou, Bo; Fukai, Naomi; Olsen, Bjorn R

2007-06-01

Mechanical stress is an important epigenetic factor for regulating skeletal remodeling, and application of force can lead to remodeling of both bone and cartilage. Chondrocytes, osteoblasts and osteoclasts all participate and interact with each other in this remodeling process. To study cellular responses to mechanical stimuli in a system that can be genetically manipulated, we used mouse midpalatal suture expansion in vivo. Six-week-old male C57BL/6 mice were subjected to palatal suture expansion by opening loops with an initial force of 0.56 N for the periods of 1, 3, 5, 7, 14 or 28 days. Periosteal cells in expanding sutures showed increased proliferation, with Ki67-positive cells representing 1.8+/-0.1% to 4.5+/-0.4% of total suture cells in control groups and 12.0+/-2.6% to 19.9+/-1.2% in experimental/expansion groups (p<0.05). Starting at day 1, cells expressing alkaline phosphatase and type I collagen were seen. New cartilage and bone formation was observed at the oral edges of the palatal bones at day 7; at the nasal edges only bone formation without cartilage appeared to occur. An increase in osteoclast numbers suggested increased bone remodeling, ranging from 60 to 160% throughout the experimental period. Decreased Saffranin O staining after day 3 suggested decreased proteoglycan content in the secondary cartilage. Micro-CT showed a significant increase in maxillary width at days 14 and 28 (from 2334+/-4 microm to 2485+/-3 microm at day 14 and from 2383+/-5 microm to 2574+/-7 microm at day 28, p<0.001). The suture width was increased at days 14 and 28, except in the oral third region at day 28 (from 48+/-5 microm to 36+/-4 microm, p<0.05). Bone volume/total volume was significantly reduced at days 14 and 28 (50.2+/-0.7% vs. 68.0+/-3.7% and 56.5+/-1.0% vs. 60.9+/-1.3%, respectively, p<0.05), indicative of increased bone marrow space. These findings demonstrate that expansion forces across the midpalatal suture promote bone resorption through activation of

Filamin A regulates the organization and remodeling of the pericellular collagen matrix.

PubMed

Mezawa, Masaru; Pinto, Vanessa I; Kazembe, Mwayi P; Lee, Wilson S; McCulloch, Christopher A

2016-10-01

Extracellular matrix remodeling by cell adhesion-related processes is critical for proliferation and tissue homeostasis, but how adhesions and the cytoskeleton interact to organize the pericellular matrix (PCM) is not understood. We examined the role of the actin-binding protein, filamin A (FLNa), in pericellular collagen remodeling. Compared with wild-type (WT), mice with fibroblast-specific deletion of FLNa exhibited higher density but reduced organization of collagen fibers after increased loading of the periodontal ligament for 2 wk. In cultured fibroblasts, FLNa knockdown (KD) did not affect collagen mRNA, but after 24 h of culture, FLNa WT cells exhibited ∼2-fold higher cell-surface collagen KD cells and 13-fold higher levels of activated β1 integrins. In FLNa WT cells, there was 3-fold more colocalization of talin with pericellular cleaved collagen than in FLNa KD cells. MMP-9 mRNA and protein expression were >2-fold higher in FLNa KD cells than in WT cells. Cathepsin B, which is necessary for intracellular collagen digestion, was >3-fold higher in FLNa WT cells than in KD cells. FLNa WT cells exhibited 2-fold more collagen phagocytosis than KD cells, which involved the FLNa actin-binding domain. Evidently, FLNa regulates PCM remodeling through its effects on degradation pathways that affect the abundance and organization of collagen.-Mezawa, M., Pinto, V. I., Kazembe, M. P., Lee, W. S., McCulloch, C. A. Filamin A regulates the organization and remodeling of the pericellular collagen matrix. © FASEB.

Targeted deletion of apoptosis signal-regulating kinase 1 attenuates left ventricular remodeling

PubMed Central

Yamaguchi, Osamu; Higuchi, Yoshiharu; Hirotani, Shinichi; Kashiwase, Kazunori; Nakayama, Hiroyuki; Hikoso, Shungo; Takeda, Toshihiro; Watanabe, Tetsuya; Asahi, Michio; Taniike, Masayuki; Matsumura, Yasushi; Tsujimoto, Ikuko; Hongo, Kenichi; Kusakari, Yoichiro; Kurihara, Satoshi; Nishida, Kazuhiko; Ichijo, Hidenori; Hori, Masatsugu; Otsu, Kinya

2003-01-01

Left ventricular remodeling that occurs after myocardial infarction (MI) and pressure overload is generally accepted as a determinant of the clinical course of heart failure. The molecular mechanism of this process, however, remains to be elucidated. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays an important role in stress-induced apoptosis. We used ASK1 knockout mice (ASK-/-) to test the hypothesis that ASK1 is involved in development of left ventricular remodeling. ASK-/- hearts showed no morphological or histological defects. Echocardiography and cardiac catheterization revealed normal global structure and function. Left ventricular structural and functional remodeling were determined 4 weeks after coronary artery ligation or thoracic transverse aortic constriction (TAC). ASK-/- had significantly smaller increases in left ventricular end-diastolic and end-systolic ventricular dimensions and smaller decreases in fractional shortening in both experimental models compared with WT mice. The number of terminal deoxynucleotidyl transferase biotin-dUDP nick end-labeling-positive myocytes after MI or TAC was decreased in ASK-/- compared with that in WT mice. Overexpression of a constitutively active mutant of ASK1 induced apoptosis in isolated rat neonatal cardiomyocytes, whereas neonatal ASK-/- cardiomyocytes were resistant to H2O2-induced apoptosis. An in vitro kinase assay showed increased ASK1 activity in heart after MI or TAC in WT mice. Thus, ASK1 plays an important role in regulating left ventricular remodeling by promoting apoptosis. PMID:14665690

Inhibition of TRPC3 downregulates airway hyperresponsiveness, remodeling of OVA-sensitized mouse

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

Wang, Lingwei; Li, Jie; Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou

Airway hyperresponsiveness (AHR), airway remodeling and inflammation are the fundamental pathological alterations that occur in asthma. Transient receptor potential canonical 3 (TRPC3) has been implicated in diverse functions of airway smooth muscle cells (ASMCs) in asthma. However, the underlying mechanisms remain incompletely understood. We investigated the mRNA and protein expression of TRPC3 in ASMCs from normal and OVA-sensitized mouse. And the effects of inhibition or knockdown of TRPC3 with Ethyl-1- (4- (2,3,3-trichloroacrylamide) phenyl) −5 - (trifluoromethyl) -1H -pyrazole -4-carboxylate (Pyr3) and lentiviral shRNA on OVA-sensitized mouse AHR, airway remodeling, circulating inflammatory cytokines, cell proliferation and migration. We found that TRPC3 mRNAmore » and protein expression levels were significantly increased in ASMCs from OVA-sensitized mouse. Inhibiting TRPC3 with continuous subcutaneous administration of Pyr3 decreased enhanced pause (Penh) of OVA-sensitized mouse. Meanwhile, both Pyr3 and lentiviral shRNA treatment of ASMCs in OVA-sensitized mouse significantly decreased their proliferation and migration. These results suggest that TRPC3 plays a critical role in asthma and represents a promising new target for asthma treatment. - Highlights: • Penh, airway remodeling and the gene expression and protein of TRPC3 are increased in OVA-sensitized mice. • Inhibition of TRPC3 suppresses the OVA-sensitized mice Penh and airway remodeling. • Inhibition of TRPC3 decreases OVA-sensitized mice ASMC proliferation and migration.« less

Adaptation of Candida albicans to environmental pH induces cell wall remodelling and enhances innate immune recognition

PubMed Central

Sorsby, Eleanor; Mahtey, Nabeel; Brown, Ian

2017-01-01

Candida albicans is able to proliferate in environments that vary dramatically in ambient pH, a trait required for colonising niches such as the stomach, vaginal mucosal and the GI tract. Here we show that growth in acidic environments involves cell wall remodelling which results in enhanced chitin and β-glucan exposure at the cell wall periphery. Unmasking of the underlying immuno-stimulatory β-glucan in acidic environments enhanced innate immune recognition of C. albicans by macrophages and neutrophils, and induced a stronger proinflammatory cytokine response, driven through the C-type lectin-like receptor, Dectin-1. This enhanced inflammatory response resulted in significant recruitment of neutrophils in an intraperitoneal model of infection, a hallmark of symptomatic vaginal colonisation. Enhanced chitin exposure resulted from reduced expression of the cell wall chitinase Cht2, via a Bcr1-Rim101 dependent signalling cascade, while increased β-glucan exposure was regulated via a non-canonical signalling pathway. We propose that this “unmasking” of the cell wall may induce non-protective hyper activation of the immune system during growth in acidic niches, and may attribute to symptomatic vaginal infection. PMID:28542528

Prioritizing Popular Proteins in Liver Cancer: Remodelling One-Carbon Metabolism.

PubMed

Mora, María Isabel; Molina, Manuela; Odriozola, Leticia; Elortza, Félix; Mato, José María; Sitek, Barbara; Zhang, Pumin; He, Fuchu; Latasa, María Uxue; Ávila, Matías Antonio; Corrales, Fernando José

2017-12-01

Primary liver cancer (HCC) is recognized as the fifth most common neoplasm and the second leading cause of cancer death worldwide. Most risk factors are known, and the molecular pathogenesis has been widely studied in the past decade; however, the underlying molecular mechanisms remain to be unveiled, as they will facilitate the definition of novel biomarkers and clinical targets for more effective patient management. We utilize the B/D-HPP popular protein strategy. We report a list of popular proteins that have been highly cocited with the expression "liver cancer". Several enzymes highlight the known metabolic remodeling of liver cancer cells, four of which participate in one-carbon metabolism. This pathway is central to the maintenance of differentiated hepatocytes, as it is considered the connection between intermediate metabolism and epigenetic regulation. We designed a targeted selective reaction monitoring (SRM) method to follow up one-carbon metabolism adaptation in mouse HCC and in regenerating liver following exposure to CCl 4 . This method allows systematic monitoring of one-carbon metabolism and could prove useful in the follow-up of HCC and of chronically liver-diseased patients (cirrhosis) at risk of HCC. The SRM data are available via ProteomeXchange in PASSEL (PASS01060).

Longitudinal changes in airway remodeling and air trapping in severe asthma

PubMed Central

Witt, Chad A.; Sheshadri, Ajay; Carlstrom, Luke; Tarsi, Jaime; Kozlowski, James; Wilson, Brad; Gierada, David; Hoffman, Eric; Fain, Sean; Cook-Granroth, Janice; Sajol, Geneline; Sierra, Oscar; Giri, Tusar; O'Neil, Michael; Zheng, Jie; Schechtman, Kenneth B.; Bacharier, Leonard B.; Jarjour, Nizar; Busse, William; Castro, Mario

2014-01-01

Rationale and Objectives Previous cross-sectional studies have demonstrated that airway wall thickness and air trapping are greater in subjects with severe asthma than in those with mild-to-moderate asthma. However, a better understanding of how airway remodeling and lung density change over time is needed. This study aims to evaluate predictors of airway wall remodeling and change in lung function and lung density over time in severe asthma. Materials and Methods Phenotypic characterization and quantitative multidetector computed tomography (MDCT) of the chest was performed at baseline and ∼2.6 years later in 38 participants with asthma (severe n=24, mild-moderate n=14) and 9 normal controls from the Severe Asthma Research Program. Results Subjects with severe asthma had a significant decline in post-bronchodilator FEV1% predicted over time (p = <0.001). Airway wall thickness measured by MDCT was increased at multiple airway generations in severe asthma compared to mild-to-moderate asthma (wall area percent (WA%): p <0.05) and normals (p <0.05) at baseline and year 2. Over time, there was an increase in WA% and wall thickness (WT%) in all subjects (p = 0.030 and 0.009 respectively) with no change in emphysema-like lung or air trapping. Baseline pre-bronchodilator FEV1% inversely correlated with WA% and WT% (both p = <0.05). In a multivariable regression model, baseline WA%, race and healthcare utilization were predictors of subsequent airway remodeling. Conclusions Severe asthma subjects have a greater decline in lung function over time than normal subjects or those with mild-to-moderate asthma. MDCT provides a noninvasive measure of airway wall thickness that may predict subsequent airway remodeling. PMID:25018070

Mi2, an auto-antigen for dermatomyositis, is an ATP-dependent nucleosome remodeling factor.

PubMed

Wang, H B; Zhang, Y

2001-06-15

Dynamic changes in chromatin structure play an important role in transcription regulation. Recent studies have revealed two mechanisms that alter chromatin structure. One involves ATP-dependent chromatin remodeling, and the other involves acetylation of the core histone tails. We have previously purified and characterized a multi-subunit protein complex, NuRD, which possesses both nucleosome remodeling and histone deacetylase activities. Despite extensive biochemical characterization of the complex, little is known about the functions of its individual components. In this study, we focused on Mi2, a component of the NuRD complex. We found that, similar to the native NuRD complex, recombinant Mi2 is a DNA-dependent, nucleosome-stimulated ATPase. Kinetic analysis of the ATP hydrolysis reaction indicated that the differential stimulation of the Mi2 ATPase by DNA and nucleosomes were primarily due to their differential effects on the turnover number of the reaction. Furthermore, we demonstrated that recombinant Mi2 is an efficient nucleosome remodeling factor when compared to that of the native NuRD complex. Our results define the biochemical function of Mi2 and set the stage for understanding the mechanism of nucleosome remodeling in a defined reconstituted system.

Mi2, an auto-antigen for dermatomyositis, is an ATP-dependent nucleosome remodeling factor

PubMed Central

Wang, Heng-Bin; Zhang, Yi

2001-01-01

Dynamic changes in chromatin structure play an important role in transcription regulation. Recent studies have revealed two mechanisms that alter chromatin structure. One involves ATP-dependent chromatin remodeling, and the other involves acetylation of the core histone tails. We have previously purified and characterized a multi-subunit protein complex, NuRD, which possesses both nucleosome remodeling and histone deacetylase activities. Despite extensive biochemical characterization of the complex, little is known about the functions of its individual components. In this study, we focused on Mi2, a component of the NuRD complex. We found that, similar to the native NuRD complex, recombinant Mi2 is a DNA-dependent, nucleosome-stimulated ATPase. Kinetic analysis of the ATP hydrolysis reaction indicated that the differential stimulation of the Mi2 ATPase by DNA and nucleosomes were primarily due to their differential effects on the turnover number of the reaction. Furthermore, we demonstrated that recombinant Mi2 is an efficient nucleosome remodeling factor when compared to that of the native NuRD complex. Our results define the biochemical function of Mi2 and set the stage for understanding the mechanism of nucleosome remodeling in a defined reconstituted system. PMID:11410659

65. (Credit JTL) Filter room looking WSW across remodelled New ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

65. (Credit JTL) Filter room looking WSW across remodelled New York horizontal pressure filters (in foreground). - McNeil Street Pumping Station, McNeil Street & Cross Bayou, Shreveport, Caddo Parish, LA

Characterization of human cervical remodeling throughout pregnancy using in vivo Raman spectroscopy

NASA Astrophysics Data System (ADS)

O'Brien, Christine M.; Vargis, Elizabeth; Slaughter, Chris; Rudin, Amy P.; Herington, Jennifer L.; Bennett, Kelly A.; Reese, Jeff; Mahadevan-Jansen, Anita

2015-02-01

Globally, fifteen million babies are born preterm each year, affecting 1 in 8 pregnancies in the US alone. Cervical remodeling includes a biochemical cascade of changes that ultimately result in the thinning and dilation of the cervix for passage of a fetus. This process is poorly understood and is the focus of this study. Our group is utilizing Raman spectroscopy to evaluate biochemical changes occurring in the human cervix throughout pregnancy. This technique has high molecular specificity and can be performed in vivo, with the potential to unveil new molecular dynamics essential for cervical remodeling.

Simulating Bone Loss in Microgravity Using Mathematical Formulations of Bone Remodeling

NASA Technical Reports Server (NTRS)

Pennline, James A.

2009-01-01

Most mathematical models of bone remodeling are used to simulate a specific bone disease, by disrupting the steady state or balance in the normal remodeling process, and to simulate a therapeutic strategy. In this work, the ability of a mathematical model of bone remodeling to simulate bone loss as a function of time under the conditions of microgravity is investigated. The model is formed by combining a previously developed set of biochemical, cellular dynamics, and mechanical stimulus equations in the literature with two newly proposed equations; one governing the rate of change of the area of cortical bone tissue in a cross section of a cylindrical section of bone and one governing the rate of change of calcium in the bone fluid. The mechanical stimulus comes from a simple model of stress due to a compressive force on a cylindrical section of bone which can be reduced to zero to mimic the effects of skeletal unloading in microgravity. The complete set of equations formed is a system of first order ordinary differential equations. The results of selected simulations are displayed and discussed. Limitations and deficiencies of the model are also discussed as well as suggestions for further research.

Roles of PDE1 in Pathological Cardiac Remodeling and Dysfunction.

PubMed

Chen, Si; Knight, Walter E; Yan, Chen

2018-04-23

Pathological cardiac hypertrophy and dysfunction is a response to various stress stimuli and can result in reduced cardiac output and heart failure. Cyclic nucleotide signaling regulates several cardiac functions including contractility, remodeling, and fibrosis. Cyclic nucleotide phosphodiesterases (PDEs), by catalyzing the hydrolysis of cyclic nucleotides, are critical in the homeostasis of intracellular cyclic nucleotide signaling and hold great therapeutic potential as drug targets. Recent studies have revealed that the inhibition of the PDE family member PDE1 plays a protective role in pathological cardiac remodeling and dysfunction by the modulation of distinct cyclic nucleotide signaling pathways. This review summarizes recent key findings regarding the roles of PDE1 in the cardiac system that can lead to a better understanding of its therapeutic potential.

Centriole Remodeling during Spermiogenesis in Drosophila.

PubMed

Khire, Atul; Jo, Kyoung H; Kong, Dong; Akhshi, Tara; Blachon, Stephanie; Cekic, Anthony R; Hynek, Sarah; Ha, Andrew; Loncarek, Jadranka; Mennella, Vito; Avidor-Reiss, Tomer

2016-12-05

The first cell of an animal (zygote) requires centrosomes that are assembled from paternally inherited centrioles and maternally inherited pericentriolar material (PCM) [1]. In some animals, sperm centrioles with typical ultrastructure are the origin of the first centrosomes in the zygote [2-4]. In other animals, however, sperm centrioles lose their proteins and are thought to be degenerated and non-functional during spermiogenesis [5, 6]. Here, we show that the two sperm centrioles (the giant centriole [GC] and the proximal centriole-like structure [PCL]) in Drosophila melanogaster are remodeled during spermiogenesis through protein enrichment and ultrastructure modification in parallel to previously described centrosomal reduction [7]. We found that the ultrastructure of the matured sperm (spermatozoa) centrioles is modified dramatically and that the PCL does not resemble a typical centriole. We also describe a new phenomenon of Poc1 enrichment of the atypical centrioles in the spermatozoa. Using various mutants, protein expression during spermiogenesis, and RNAi knockdown of paternal Poc1, we found that paternal Poc1 enrichment is essential for the formation of centrioles during spermiogenesis and for the formation of centrosomes after fertilization in the zygote. Altogether, these findings demonstrate that the sperm centrioles are remodeled both in their protein composition and in ultrastructure, yet they are functional and are essential for normal embryogenesis in Drosophila. Copyright © 2016 Elsevier Ltd. All rights reserved.

Airway remodelling in the transplanted lung.

PubMed

Kuehnel, Mark; Maegel, Lavinia; Vogel-Claussen, Jens; Robertus, Jan Lukas; Jonigk, Danny

2017-03-01

Following lung transplantation, fibrotic remodelling of the small airways has been recognized for almost 5 decades as the main correlate of chronic graft failure and a major obstacle to long-term survival. Mainly due to airway fibrosis, pulmonary allografts currently show the highest attrition rate of all solid organ transplants, with a 5-year survival rate of 58 % on a worldwide scale. The observation that these morphological changes are not just the hallmark of chronic rejection but rather represent a manifestation of a multitude of alloimmune-dependent and -independent injuries was made more recently, as was the discovery that chronic lung allograft dysfunction manifests in different clinical phenotypes of respiratory impairment and corresponding morphological subentities. Although recent years have seen considerable advances in identifying and categorizing these subgroups on the basis of clinical, functional and histomorphological changes, as well as susceptibility to medicinal treatment, this process is far from over. Since the actual pathophysiological mechanisms governing airway remodelling are still only poorly understood, diagnosis and therapy of chronic lung allograft dysfunction presents a major challenge to clinicians, radiologists and pathologists alike. Here, we review and discuss the current state of the literature on chronic lung allograft dysfunction and shed light on classification systems, corresponding clinical and morphological changes, key cellular players and underlying molecular pathways, as well as on emerging diagnostic and therapeutic approaches.

Extensive Gene Remodeling in the Viral World: New Evidence for Nongradual Evolution in the Mobilome Network

PubMed Central

Jachiet, Pierre-Alain; Colson, Philippe; Lopez, Philippe; Bapteste, Eric

2014-01-01

Complex nongradual evolutionary processes such as gene remodeling are difficult to model, to visualize, and to investigate systematically. Despite these challenges, the creation of composite (or mosaic) genes by combination of genetic segments from unrelated gene families was established as an important adaptive phenomena in eukaryotic genomes. In contrast, almost no general studies have been conducted to quantify composite genes in viruses. Although viral genome mosaicism has been well-described, the extent of gene mosaicism and its rules of emergence remain largely unexplored. Applying methods from graph theory to inclusive similarity networks, and using data from more than 3,000 complete viral genomes, we provide the first demonstration that composite genes in viruses are 1) functionally biased, 2) involved in key aspects of the arm race between cells and viruses, and 3) can be classified into two distinct types of composite genes in all viral classes. Beyond the quantification of the widespread recombination of genes among different viruses of the same class, we also report a striking sharing of genetic information between viruses of different classes and with different nucleic acid types. This latter discovery provides novel evidence for the existence of a large and complex mobilome network, which appears partly bound by the sharing of genetic information and by the formation of composite genes between mobile entities with different genetic material. Considering that there are around 10E31 viruses on the planet, gene remodeling appears as a hugely significant way of generating and moving novel sequences between different kinds of organisms on Earth. PMID:25104113

[The cancer paradigm in pulmonary arterial hypertension: towards anti-remodeling therapies targeting metabolic dysfunction?

PubMed

Dumas, Sébastien J; Humbert, Marc; Cohen-Kaminsky, Sylvia

2016-01-01

Pulmonary arterial hypertension (PAH) is a rare, complex and multifactorial disease in which pulmonary vascular remodeling plays a major role ending in right heart failure and death. Current specific therapies of PAH that mainly target the vasoconstriction/vasodilatation imbalance are not curative. Bi-pulmonary transplantation remains the only option in patients resistant to current therapies. It is thus crucial to identify novel vascular anti-remodeling therapeutic targets. This remodeling displays several properties of cancer cells, especially overproliferation and apoptosis resistance of pulmonary vascular cells, hallmarks of cancer related to the metabolic shift known as the "Warburg effect". The latter is characterized by a shift of ATP production, from oxidative phosphorylation to low rate aerobic glycolysis. In compensation, the cancer cells exhibit exacerbated glutaminolysis thus resulting in glutamine addiction, necessary to their overproliferation. Glutamine intake results in glutamate production, a molecule at the crossroads of energy metabolism and cancer cell communication, thus contributing to cell proliferation. Accordingly, therapeutic strategies targeting glutamate production, its release into the extracellular space and its membrane receptors have been suggested to treat different types of cancers, not only in the central nervous system but also in the periphery. We propose that similar strategies targeting glutamatergic signaling may be considered in PAH, especially as they could affect not only the vascular remodeling but also the right heart hypertrophy known to involve the glutaminolysis pathway. Ongoing studies aim to characterize the involvement of the glutamate pathway and its receptors in vascular remodeling, and the therapeutic potential of specific molecules targeting this pathway. © Société de Biologie, 2017.

[The biological role of exosomes in bone remodeling and bone diseases.

PubMed

Urabe, Fumihiko; Yoshioka, Yusuke; Ochiya, Takahiro

Exosomes are about 100nm membrane vesicles, and released from almost all cell types. They carry and transfer a wide variety of molecules, such as mRNAs, microRNAs, proteins, and lipids, as modulators of intercellular communication. Various studies have shown that this exosome-mediated intercellular communication lead to proliferation, invasion and metastasis of cancer cells. In addition to that, emerging data suggest that exosomes are also involved in physiological processes of bone remodeling and bone diseases. Increasing understanding of the working mechanism of exosomes will provide us with new therapeutic and diagnostic opportunities. Here we summarize the current research on exosomes in bone remodeling and bone diseases.

Endothelial Mineralocorticoid Receptor Mediates Parenchymal Arteriole and Posterior Cerebral Artery Remodeling During Angiotensin II-Induced Hypertension.

PubMed

Diaz-Otero, Janice M; Fisher, Courtney; Downs, Kelsey; Moss, M Elizabeth; Jaffe, Iris Z; Jackson, William F; Dorrance, Anne M

2017-12-01

The brain is highly susceptible to injury caused by hypertension because the increased blood pressure causes artery remodeling that can limit cerebral perfusion. Mineralocorticoid receptor (MR) antagonism prevents hypertensive cerebral artery remodeling, but the vascular cell types involved have not been defined. In the periphery, the endothelial MR mediates hypertension-induced vascular injury, but cerebral and peripheral arteries are anatomically distinct; thus, these findings cannot be extrapolated to the brain. The parenchymal arterioles determine cerebrovascular resistance. Determining the effects of hypertension and MR signaling on these arterioles could lead to a better understanding of cerebral small vessel disease. We hypothesized that endothelial MR signaling mediates inward cerebral artery remodeling and reduced cerebral perfusion during angiotensin II (AngII) hypertension. The biomechanics of the parenchymal arterioles and posterior cerebral arteries were studied in male C57Bl/6 and endothelial cell-specific MR knockout mice and their appropriate controls using pressure myography. AngII increased plasma aldosterone and decreased cerebral perfusion in C57Bl/6 and MR-intact littermates. Endothelial cell MR deletion improved cerebral perfusion in AngII-treated mice. AngII hypertension resulted in inward hypotrophic remodeling; this was prevented by MR antagonism and endothelial MR deletion. Our studies suggest that endothelial cell MR mediates hypertensive remodeling in the cerebral microcirculation and large pial arteries. AngII-induced inward remodeling of cerebral arteries and arterioles was associated with a reduction in cerebral perfusion that could worsen the outcome of stroke or contribute to vascular dementia. © 2017 American Heart Association, Inc.

Suppression of Eosinophil Integrins Prevents Remodeling of Airway Smooth Muscle in Asthma

PubMed Central

Januskevicius, Andrius; Gosens, Reinoud; Sakalauskas, Raimundas; Vaitkiene, Simona; Janulaityte, Ieva; Halayko, Andrew J.; Hoppenot, Deimante; Malakauskas, Kestutis

2017-01-01

Background: Airway smooth muscle (ASM) remodeling is an important component of the structural changes to airways seen in asthma. Eosinophils are the prominent inflammatory cells in asthma, and there is some evidence that they contribute to ASM remodeling via released mediators and direct contact through integrin–ligand interactions. Eosinophils express several types of outer membrane integrin, which are responsible for cell–cell and cell–extracellular matrix interactions. In our previous study we demonstrated that asthmatic eosinophils show increased adhesion to ASM cells and it may be important factor contributing to ASM remodeling in asthma. According to these findings, in the present study we investigated the effects of suppression of eosinophil integrin on eosinophil-induced ASM remodeling in asthma. Materials and Methods: Individual combined cell cultures of immortalized human ASM cells and eosinophils from peripheral blood of 22 asthmatic patients and 17 healthy controls were prepared. Eosinophil adhesion was evaluated using eosinophil peroxidase activity assay. Genes expression levels in ASM cells and eosinophils were measured using quantitative real-time PCR. ASM cell proliferation was measured using alamarBlue® solution. Eosinophil integrins were blocked by incubating with Arg-Gly-Asp-Ser peptide. Results: Eosinophils from the asthma group showed increased outer membrane α4β1 and αMβ2 integrin expression, increased adhesion to ASM cells, and overexpression of TGF-β1 compared with eosinophils from the healthy control group. Blockade of eosinophil RGD-binding integrins by Arg-Gly-Asp-Ser peptide significantly reduced adhesion of eosinophils to ASM cells in both groups. Integrin-blocking decreased the effects of eosinophils on TGF-β1, WNT-5a, and extracellular matrix protein gene expression in ASM cells and ASM cell proliferation in both groups. These effects were more pronounced in the asthma group compared with the control group. Conclusion

Pulmonary arterial stiffening in COPD and its implications for right ventricular remodelling.

PubMed

Weir-McCall, Jonathan R; Liu-Shiu-Cheong, Patrick Sk; Struthers, Allan D; Lipworth, Brian J; Houston, J Graeme

2018-02-27

Pulmonary pulse wave velocity (PWV) allows the non-invasive measurement of pulmonary arterial stiffening, but has not previously been assessed in COPD. The aim of the current study was to assess PWV in COPD and its association with right ventricular (RV) remodelling. Fifty-eight participants with COPD underwent pulmonary function tests, 6-min walk test and cardiac MRI, while 21 healthy controls (HCs) underwent cardiac MRI. Thirty-two COPD patients underwent a follow-up MRI to assess for longitudinal changes in RV metrics. Cardiac MRI was used to quantify RV mass, volumes and PWV. Differences in continuous variables between the COPD and HC groups was tested using an independent t-test, and associations between PWV and right ventricular parameters was examined using Pearson's correlation coefficient. Those with COPD had reduced pulsatility (COPD (mean±SD):24.88±8.84% vs. HC:30.55±11.28%, p=0.021), pulmonary acceleration time (COPD:104.0±22.9ms vs. HC: 128.1±32.2ms, p<0.001), higher PWV (COPD:2.62±1.29ms -1 vs. HC:1.78±0.72ms -1 , p=0.001), lower RV end diastolic volume (COPD:53.6±11.1ml vs. HC:59.9±13.0ml, p=0.037) and RV stroke volume (COPD:31.9±6.9ml/m 2 vs. HC:37.1±6.2ml/m 2 , p=0.003) with no difference in mass (p=0.53). PWV was not associated with right ventricular parameters. While pulmonary vascular remodelling is present in COPD, cardiac remodelling favours reduced filling rather than increased afterload. Treatment of obstructive lung disease may have greater effect on cardiac function than treatment of pulmonary vascular disease in most COPD patients KEY POINTS: • Pulmonary pulse wave velocity (PWV) is elevated in COPD. • Pulmonary PWV is not associated with right ventricular remodelling. • Right ventricular remodelling is more in keeping with that of reduced filling.

Out of Africa: modern human origins special feature: explaining worldwide patterns of human genetic variation using a coalescent-based serial founder model of migration outward from Africa.

PubMed

DeGiorgio, Michael; Jakobsson, Mattias; Rosenberg, Noah A

2009-09-22

Studies of worldwide human variation have discovered three trends in summary statistics as a function of increasing geographic distance from East Africa: a decrease in heterozygosity, an increase in linkage disequilibrium (LD), and a decrease in the slope of the ancestral allele frequency spectrum. Forward simulations of unlinked loci have shown that the decline in heterozygosity can be described by a serial founder model, in which populations migrate outward from Africa through a process where each of a series of populations is formed from a subset of the previous population in the outward expansion. Here, we extend this approach by developing a retrospective coalescent-based serial founder model that incorporates linked loci. Our model both recovers the observed decline in heterozygosity with increasing distance from Africa and produces the patterns observed in LD and the ancestral allele frequency spectrum. Surprisingly, although migration between neighboring populations and limited admixture between modern and archaic humans can be accommodated in the model while continuing to explain the three trends, a competing model in which a wave of outward modern human migration expands into a series of preexisting archaic populations produces nearly opposite patterns to those observed in the data. We conclude by developing a simpler model to illustrate that the feature that permits the serial founder model but not the archaic persistence model to explain the three trends observed with increasing distance from Africa is its incorporation of a cumulative effect of genetic drift as humans colonized the world.

Beneficial effects of grape seed proanthocyanidin extract on arterial remodeling in spontaneously hypertensive rats via protecting against oxidative stress.

PubMed

Liang, Ying; Wang, Jian; Gao, Haiqing; Wang, Quanzhen; Zhang, Jun; Qiu, Jie

2016-10-01

Arterial remodeling is a pathogenic occurrence during hypertension and, in turn, is closely associated with the development and complications of hypertension. Grape seed proanthocyanidin extract (GSPE) has been reported to exhibit a protective effect on cardiovascular disease, however its effect on arterial remodeling remains to be fully elucidated. In the present study, the effects of GSPE on arterial remodeling were analyzed by treating spontaneously hypertensive rats (SHRs) with GSPE (250 mg/kg·day). Arterial remodeling was quantified through morphological methods; thoracic aortas were stained with hematoxylin-eosin or sirius red‑victoria blue. The arterial ultrastructure was imaged using transmission electron microscopy. The content of nitric oxide (NO) and endothelin‑1 (ET‑1) were examined to determine endothelial function. Oxidative stress was assessed by malondialdehyde (MDA) levels and the activities of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT). Administration of GSPE markedly alleviated hypertension‑induced arterial remodeling, which was not associated with blood pressure control. ET‑1 production was reduced, while NO production was increased in the GSPE group, which exhibited improved endothelial function. In addition, treatment with GSPE significantly ameliorated oxidative stress by improving SOD and CAT activities and reducing MDA formation. In conclusion, GSPE may attenuate hypertension‑induced arterial remodeling by repressing oxidative stress and is recommended as a potential anti‑arterial remodeling agent for patients with hypertensive vascular diseases.

A model of muscle atrophy based on live microscopy of muscle remodelling in Drosophila metamorphosis.

PubMed

Kuleesha, Yadav; Puah, Wee Choo; Wasser, Martin

2016-02-01

Genes controlling muscle size and survival play important roles in muscle wasting diseases. In Drosophila melanogaster metamorphosis, larval abdominal muscles undergo two developmental fates. While a doomed population is eliminated by cell death, another persistent group is remodelled and survives into adulthood. To identify and characterize genes involved in the development of remodelled muscles, we devised a workflow consisting of in vivo imaging, targeted gene perturbation and quantitative image analysis. We show that inhibition of TOR signalling and activation of autophagy promote developmental muscle atrophy in early, while TOR and yorkie activation are required for muscle growth in late pupation. We discovered changes in the localization of myonuclei during remodelling that involve anti-polar migration leading to central clustering followed by polar migration resulting in localization along the midline. We demonstrate that the Cathepsin L orthologue Cp1 is required for myonuclear clustering in mid, while autophagy contributes to central positioning of nuclei in late metamorphosis. In conclusion, studying muscle remodelling in metamorphosis can provide new insights into the cell biology of muscle wasting.

A model of muscle atrophy based on live microscopy of muscle remodelling in Drosophila metamorphosis

PubMed Central

Kuleesha, Yadav; Puah, Wee Choo; Wasser, Martin

2016-01-01

Genes controlling muscle size and survival play important roles in muscle wasting diseases. In Drosophila melanogaster metamorphosis, larval abdominal muscles undergo two developmental fates. While a doomed population is eliminated by cell death, another persistent group is remodelled and survives into adulthood. To identify and characterize genes involved in the development of remodelled muscles, we devised a workflow consisting of in vivo imaging, targeted gene perturbation and quantitative image analysis. We show that inhibition of TOR signalling and activation of autophagy promote developmental muscle atrophy in early, while TOR and yorkie activation are required for muscle growth in late pupation. We discovered changes in the localization of myonuclei during remodelling that involve anti-polar migration leading to central clustering followed by polar migration resulting in localization along the midline. We demonstrate that the Cathepsin L orthologue Cp1 is required for myonuclear clustering in mid, while autophagy contributes to central positioning of nuclei in late metamorphosis. In conclusion, studying muscle remodelling in metamorphosis can provide new insights into the cell biology of muscle wasting. PMID:26998322

Trypanosoma brucei gambiense adaptation to different mammalian sera is associated with VSG expression site plasticity.

PubMed

Cordon-Obras, Carlos; Cano, Jorge; González-Pacanowska, Dolores; Benito, Agustin; Navarro, Miguel; Bart, Jean-Mathieu

2013-01-01

Trypanosoma brucei gambiense infection is widely considered an anthroponosis, although it has also been found in wild and domestic animals. Thus, fauna could act as reservoir, constraining the elimination of the parasite in hypo-endemic foci. To better understand the possible maintenance of T. b. gambiense in local fauna and investigate the molecular mechanisms underlying adaptation, we generated adapted cells lines (ACLs) by in vitro culture of the parasites in different mammalian sera. Using specific antibodies against the Variant Surface Glycoproteins (VSGs) we found that serum ACLs exhibited different VSG variants when maintained in pig, goat or human sera. Although newly detected VSGs were independent of the sera used, the consistent appearance of different VSGs suggested remodelling of the co-transcribed genes at the telomeric Expression Site (VSG-ES). Thus, Expression Site Associated Genes (ESAGs) sequences were analysed to investigate possible polymorphism selection. ESAGs 6 and 7 genotypes, encoding the transferrin receptor (TfR), expressed in different ACLs were characterised. In addition, we quantified the ESAG6/7 mRNA levels and analysed transferrin (Tf) uptake. Interestingly, the best growth occurred in pig and human serum ACLs, which consistently exhibited a predominant ESAG7 genotype and higher Tf uptake than those obtained in calf and goat sera. We also detected an apparent selection of specific ESAG3 genotypes in the pig and human serum ACLs, suggesting that other ESAGs could be involved in the host adaptation processes. Altogether, these results suggest a model whereby VSG-ES remodelling allows the parasite to express a specific set of ESAGs to provide selective advantages in different hosts. Finally, pig serum ACLs display phenotypic adaptation parameters closely related to human serum ACLs but distinct to parasites grown in calf and goat sera. These results suggest a better suitability of swine to maintain T. b. gambiense infection supporting

Excessive interatrial adiposity is associated with left atrial remodeling, augmented contractile performance in asymptomatic population.

PubMed

Lai, Yau-Huei; Yun, Chun-Ho; Su, Cheng-Huang; Yang, Fei-Shih; Yeh, Hung-I; Hou, Charles Jia-Yin; Wu, Tung-Hsin; Cury, Ricardo C; Bezerra, Hiram G; Hung, Chung-Lieh

2016-03-01

Pericardial adipose tissue had been shown to exert local effects on adjacent cardiac structures. Data regarding the mechanistic link between such measures and left atrial (LA) structural/functional remodeling, a clinical hallmark of early stage heart failure (HF) and atrial fibrillation (AF) incidence, in asymptomatic population remain largely unexplored. This retrospective analysis includes 356 subjects free from significant valvular disorders, atrial fibrillation, or clinical HF. Regional adipose tissue including pericardial and periaortic fat volumes, interatrial septal (IAS), and left atrioventricular groove (AVG) fat thickness were all measured by multidetector computed tomography (MDCT) (Aquarius 3D Workstation, TeraRecon, San Mateo, CA, USA). We measured LA volumes, booster performance, reservoir capacity as well as conduit function, and analyzed their association with adiposity measures. All four adiposity measures were positively associated with greater LA volumes (all P < 0.05), while IAS and AVG fat were also related to larger LA kinetic energy and worse reservoir capacity (both P < 0.01). In multivariate models, IAS fat thickness remained independently associated with larger LA volumes, increased LA kinetic energy and ejection force (β-coef: 0.17 & 0.15, both P < 0.05), and impaired LA reservoir and conduit function (β-coef: -0.20 & -0.12, both P < 0.05) after adjusting for clinical variables. Accumulated visceral adiposity, especially interatrial fat depots, was associated with certain LA structural/functional remodeling characterized by impaired LA reservoir and conduit function though augmented kinetic energy and ejection performance. Our data suggested that interatrial fat burden may be associated with certain detrimental LA functions with compensatory LA adaptation in an asymptomatic population. © 2016 The authors.

Endothelial and Smooth Muscle Cell Ion Channels in Pulmonary Vasoconstriction and Vascular Remodeling

PubMed Central

Makino, Ayako; Firth, Amy L.; Yuan, Jason X.-J.

2017-01-01

The pulmonary circulation is a low resistance and low pressure system. Sustained pulmonary vasoconstriction and excessive vascular remodeling often occur under pathophysiological conditions such as in patients with pulmonary hypertension. Pulmonary vasoconstriction is a consequence of smooth muscle contraction. Many factors released from the endothelium contribute to regulating pulmonary vascular tone, while the extracellular matrix in the adventitia is the major determinant of vascular wall compliance. Pulmonary vascular remodeling is characterized by adventitial and medial hypertrophy due to fibroblast and smooth muscle cell proliferation, neointimal proliferation, intimal, and plexiform lesions that obliterate the lumen, muscularization of precapillary arterioles, and in situ thrombosis. A rise in cytosolic free Ca2+ concentration ([Ca2+]cyt) in pulmonary artery smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction, while increased release of mitogenic factors, upregulation (or downregulation) of ion channels and transporters, and abnormalities in intracellular signaling cascades are key to the remodeling of the pulmonary vasculature. Changes in the expression, function, and regulation of ion channels in PASMC and pulmonary arterial endothelial cells play an important role in the regulation of vascular tone and development of vascular remodeling. This article will focus on describing the ion channels and transporters that are involved in the regulation of pulmonary vascular function and structure and illustrating the potential pathogenic role of ion channels and transporters in the development of pulmonary vascular disease. PMID:23733654

The Moderating Role of Dysfunctional Parent-Child Relationships on the Association Between Outward Anger Expression and Physical Health in Youth From Low-Income Families.

PubMed

Guenther, Kassie D; Van Dyk, Tori R; Kidwell, Katherine M; Nelson, Timothy D

2016-01-01

The purpose of this study is to examine the role of outward anger expression on physical health outcomes (number of illnesses in the past year, 2-year medical service utilization, and health-related quality of life) while also expanding on previous research by assessing the moderating effect of parent-child dysfunction. An ethnically diverse sample of 125 children, ages 8 to 11 years, was recruited from a family medicine practice serving a low-income population. High levels of outward anger expression were related to a greater number of illnesses, greater medical service utilization, and lower health-related quality of life. Additionally, worse parent-child dysfunction exacerbated this relationship for a number of illnesses and medical service utilization. Results suggest that health care providers should consider the influence of environmental and familial factors on the physical health of children with anger. Recommendations for identifying at-risk youth and improving anger expression as well as parent-child relationships are provided. Copyright © 2016 National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved.

A viscoelastic-stochastic model of the effects of cytoskeleton remodelling on cell adhesion.

PubMed

Li, Long; Zhang, Wenyan; Wang, Jizeng

2016-10-01

Cells can adapt their mechanical properties through cytoskeleton remodelling in response to external stimuli when the cells adhere to the extracellular matrix (ECM). Many studies have investigated the effects of cell and ECM elasticity on cell adhesion. However, experiments determined that cells are viscoelastic and exhibiting stress relaxation, and the mechanism behind the effect of cellular viscoelasticity on the cell adhesion behaviour remains unclear. Therefore, we propose a theoretical model of a cluster of ligand-receptor bonds between two dissimilar viscoelastic media subjected to an applied tensile load. In this model, the distribution of interfacial traction is assumed to follow classical continuum viscoelastic equations, whereas the rupture and rebinding of individual molecular bonds are governed by stochastic equations. On the basis of this model, we determined that viscosity can significantly increase the lifetime, stability and dynamic strength of the adhesion cluster of molecular bonds, because deformation relaxation attributed to the viscoelastic property can increase the rebinding probability of each open bond and reduce the stress concentration in the adhesion area.

A viscoelastic–stochastic model of the effects of cytoskeleton remodelling on cell adhesion

PubMed Central

Li, Long; Zhang, Wenyan

2016-01-01

Cells can adapt their mechanical properties through cytoskeleton remodelling in response to external stimuli when the cells adhere to the extracellular matrix (ECM). Many studies have investigated the effects of cell and ECM elasticity on cell adhesion. However, experiments determined that cells are viscoelastic and exhibiting stress relaxation, and the mechanism behind the effect of cellular viscoelasticity on the cell adhesion behaviour remains unclear. Therefore, we propose a theoretical model of a cluster of ligand–receptor bonds between two dissimilar viscoelastic media subjected to an applied tensile load. In this model, the distribution of interfacial traction is assumed to follow classical continuum viscoelastic equations, whereas the rupture and rebinding of individual molecular bonds are governed by stochastic equations. On the basis of this model, we determined that viscosity can significantly increase the lifetime, stability and dynamic strength of the adhesion cluster of molecular bonds, because deformation relaxation attributed to the viscoelastic property can increase the rebinding probability of each open bond and reduce the stress concentration in the adhesion area. PMID:27853571

Myocardial adaptations to recreational marathon training among middle-aged men.

PubMed

Zilinski, Jodi L; Contursi, Miranda E; Isaacs, Stephanie K; Deluca, James R; Lewis, Gregory D; Weiner, Rory B; Hutter, Adolph M; d'Hemecourt, Pierre A; Troyanos, Christopher; Dyer, K Sophia; Baggish, Aaron L

2015-02-01

Myocardial adaptations to exercise have been well documented among competitive athletes. To what degree cardiac remodeling occurs among recreational exercisers is unknown. We sought to evaluate the effect of recreational marathon training on myocardial structure and function comprehensively. Male runners (n=45; age, 48±7 years; 64% with ≥1 cardiovascular risk factor) participated in a structured marathon-training program. Echocardiography, cardiopulmonary exercise testing, and laboratory evaluation were performed pre and post training to quantify changes in myocardial structure and function, cardiorespiratory fitness, and traditional cardiac risk parameters. Completion of an 18-week running program (25±9 miles/wk) led to increased cardiorespiratory fitness (peak oxygen consumption, 44.6±5.2 versus 46.3±5.4 mL/kg per minute; P<0.001). In this setting, there was a significant structural cardiac remodeling characterized by dilation of the left ventricle (end-diastolic volume, 156±26 versus 172±28 mL, P<0.001), right ventricle (end-diastolic area=27.0±4.8 versus 28.6±4.3 cm(2); P=0.02), and left atrium (end-diastolic volume, 65±19 versus 72±19; P=0.02). Functional adaptations included increases in both early (E'=12.4±2.5 versus 13.2±2.0 cm/s; P=0.007) and late (A'=11.5±1.9 versus 12.2±2.1 cm/s; P=0.02) left ventricular diastolic velocities. Myocardial remodeling was accompanied by beneficial changes in cardiovascular risk factors, including body mass index (27.0±2.7 versus 26.7±2.6 kg/m(2); P<0.001), total cholesterol (199±33 versus 192±29 mg/dL; P=0.01), low-density lipoprotein (120±29 versus 114±26 mg/dL; P=0.01), and triglycerides (100±52 versus 85±36 mg/dL; P=0.02). Among middle-aged men, recreational marathon training is associated with biventricular dilation, enhanced left ventricular diastolic function, and favorable changes in nonmyocardial determinants of cardiovascular risk. Recreational marathon training may, therefore, serve as an

Localized tissue mineralization regulated by bone remodelling: A computational approach

PubMed Central

Decco, Oscar; Adams, George; Cook, Richard B.; García Aznar, José Manuel

2017-01-01

Bone is a living tissue whose main mechanical function is to provide stiffness, strength and protection to the body. Both stiffness and strength depend on the mineralization of the organic matrix, which is constantly being remodelled by the coordinated action of the bone multicellular units (BMUs). Due to the dynamics of both remodelling and mineralization, each sample of bone is composed of structural units (osteons in cortical and packets in cancellous bone) created at different times, therefore presenting different levels of mineral content. In this work, a computational model is used to understand the feedback between the remodelling and the mineralization processes under different load conditions and bone porosities. This model considers that osteoclasts primarily resorb those parts of bone closer to the surface, which are younger and less mineralized than older inner ones. Under equilibrium loads, results show that bone volumes with both the highest and the lowest levels of porosity (cancellous and cortical respectively) tend to develop higher levels of mineral content compared to volumes with intermediate porosity, thus presenting higher material densities. In good agreement with recent experimental measurements, a boomerang-like pattern emerges when plotting apparent density at the tissue level versus material density at the bone material level. Overload and disuse states are studied too, resulting in a translation of the apparent–material density curve. Numerical results are discussed pointing to potential clinical applications. PMID:28306746

Direct measurement of conformational strain energy in protofilaments curling outward from disassembling microtubule tips.

PubMed

Driver, Jonathan W; Geyer, Elisabeth A; Bailey, Megan E; Rice, Luke M; Asbury, Charles L

2017-06-19

Disassembling microtubules can generate movement independently of motor enzymes, especially at kinetochores where they drive chromosome motility. A popular explanation is the 'conformational wave' model, in which protofilaments pull on the kinetochore as they curl outward from a disassembling tip. But whether protofilaments can work efficiently via this spring-like mechanism has been unclear. By modifying a previous assay to use recombinant tubulin and feedback-controlled laser trapping, we directly demonstrate the spring-like elasticity of curling protofilaments. Measuring their mechanical work output suggests they carry ~25% of the energy of GTP hydrolysis as bending strain, enabling them to drive movement with efficiency similar to conventional motors. Surprisingly, a β-tubulin mutant that dramatically slows disassembly has no effect on work output, indicating an uncoupling of disassembly speed from protofilament strain. These results show the wave mechanism can make a major contribution to kinetochore motility and establish a direct approach for measuring tubulin mechano-chemistry.

The adaptation of the cerebral circulation to pregnancy: mechanisms and consequences

PubMed Central

Cipolla, Marilyn J

2013-01-01

The adaptation of the cerebral circulation to pregnancy is unique from other vascular beds. Most notably, the growth and vasodilatory response to high levels of circulating growth factors and cytokines that promote substantial hemodynamic changes in other vascular beds is limited in the cerebral circulation. This is accomplished through several mechanisms, including downregulation of key receptors and transcription factors, and production of circulating factors that counteract the vasodilatory effects of vascular endothelial growth factor (VEGF) and placental growth factor. Pregnancy both prevents and reverses hypertensive inward remodeling of cerebral arteries, possibly through downregulation of the angiotensin type 1 receptor. The blood–brain barrier (BBB) importantly adapts to pregnancy by preventing the passage of seizure provoking serum into the brain and limiting the permeability effects of VEGF that is more highly expressed in cerebral vasculature during pregnancy. While the adaptation of the cerebral circulation to pregnancy provides for relatively normal cerebral blood flow and BBB properties in the face of substantial cardiovascular changes and high levels of circulating factors, under pathologic conditions, these adaptations appear to promote greater brain injury, including edema formation during acute hypertension, and greater sensitivity to bacterial endotoxin. PMID:23321787

Hypothyroidism and its rapid correction alter cardiac remodeling.

PubMed

Hajje, Georges; Saliba, Youakim; Itani, Tarek; Moubarak, Majed; Aftimos, Georges; Farès, Nassim

2014-01-01

The cardiovascular effects of mild and overt thyroid disease include a vast array of pathological changes. As well, thyroid replacement therapy has been suggested for preserving cardiac function. However, the influence of thyroid hormones on cardiac remodeling has not been thoroughly investigated at the molecular and cellular levels. The purpose of this paper is to study the effect of hypothyroidism and thyroid replacement therapy on cardiac alterations. Thirty Wistar rats were divided into 2 groups: a control (n = 10) group and a group treated with 6-propyl-2-thiouracil (PTU) (n = 20) to induce hypothyroidism. Ten of the 20 rats in the PTU group were then treated with L-thyroxine to quickly re-establish euthyroidism. The serum levels of inflammatory markers, such as C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL6) and pro-fibrotic transforming growth factor beta 1 (TGF-β1), were significantly increased in hypothyroid rats; elevations in cardiac stress markers, brain natriuretic peptide (BNP) and cardiac troponin T (cTnT) were also noted. The expressions of cardiac remodeling genes were induced in hypothyroid rats in parallel with the development of fibrosis, and a decline in cardiac function with chamber dilation was measured by echocardiography. Rapidly reversing the hypothyroidism and restoring the euthyroid state improved cardiac function with a decrease in the levels of cardiac remodeling markers. However, this change further increased the levels of inflammatory and fibrotic markers in the plasma and heart and led to myocardial cellular infiltration. In conclusion, we showed that hypothyroidism is related to cardiac function decline, fibrosis and inflammation; most importantly, the rapid correction of hypothyroidism led to cardiac injuries. Our results might offer new insights for the management of hypothyroidism-induced heart disease.

Hypothyroidism and Its Rapid Correction Alter Cardiac Remodeling

PubMed Central

Itani, Tarek; Moubarak, Majed; Aftimos, Georges; Farès, Nassim

2014-01-01

The cardiovascular effects of mild and overt thyroid disease include a vast array of pathological changes. As well, thyroid replacement therapy has been suggested for preserving cardiac function. However, the influence of thyroid hormones on cardiac remodeling has not been thoroughly investigated at the molecular and cellular levels. The purpose of this paper is to study the effect of hypothyroidism and thyroid replacement therapy on cardiac alterations. Thirty Wistar rats were divided into 2 groups: a control (n = 10) group and a group treated with 6-propyl-2-thiouracil (PTU) (n = 20) to induce hypothyroidism. Ten of the 20 rats in the PTU group were then treated with L-thyroxine to quickly re-establish euthyroidism. The serum levels of inflammatory markers, such as C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL6) and pro-fibrotic transforming growth factor beta 1 (TGF-β1), were significantly increased in hypothyroid rats; elevations in cardiac stress markers, brain natriuretic peptide (BNP) and cardiac troponin T (cTnT) were also noted. The expressions of cardiac remodeling genes were induced in hypothyroid rats in parallel with the development of fibrosis, and a decline in cardiac function with chamber dilation was measured by echocardiography. Rapidly reversing the hypothyroidism and restoring the euthyroid state improved cardiac function with a decrease in the levels of cardiac remodeling markers. However, this change further increased the levels of inflammatory and fibrotic markers in the plasma and heart and led to myocardial cellular infiltration. In conclusion, we showed that hypothyroidism is related to cardiac function decline, fibrosis and inflammation; most importantly, the rapid correction of hypothyroidism led to cardiac injuries. Our results might offer new insights for the management of hypothyroidism-induced heart disease. PMID:25333636

Chromatin Remodeling Function of BRCA1 and Its Implication in Regulation of DNA Replication

DTIC Science & Technology

2001-09-01

Remodeling Function of BRCAI and its Implication in Regulation of DNA Replication PRINCIPAL INVESTIGATOR: Rong Li, Ph.D. CONTRACTING ORGANIZATION: University...of BRCAI and its Implication DAMD17-99-1-9572 in Regulation of DNA Replication 6. AUTHOR(S) Rong Li, Ph.D. 7. PERFORMING ORGANIZATION NAME(S) AND...1-mediated nuclear functions. 14. SUBJECT TERMS 15. NUMBER OF PAGES Breast Cancer, DNA replication , chromatin remodeling, transcription, 19 cell cycle

Remodeling of the postsynaptic plasma membrane during neural development.

PubMed

Tulodziecka, Karolina; Diaz-Rohrer, Barbara B; Farley, Madeline M; Chan, Robin B; Di Paolo, Gilbert; Levental, Kandice R; Waxham, M Neal; Levental, Ilya

2016-11-07

Neuronal synapses are the fundamental units of neural signal transduction and must maintain exquisite signal fidelity while also accommodating the plasticity that underlies learning and development. To achieve these goals, the molecular composition and spatial organization of synaptic terminals must be tightly regulated; however, little is known about the regulation of lipid composition and organization in synaptic membranes. Here we quantify the comprehensive lipidome of rat synaptic membranes during postnatal development and observe dramatic developmental lipidomic remodeling during the first 60 postnatal days, including progressive accumulation of cholesterol, plasmalogens, and sphingolipids. Further analysis of membranes associated with isolated postsynaptic densities (PSDs) suggests the PSD-associated postsynaptic plasma membrane (PSD-PM) as one specific location of synaptic remodeling. We analyze the biophysical consequences of developmental remodeling in reconstituted synaptic membranes and observe remarkably stable microdomains, with the stability of domains increasing with developmental age. We rationalize the developmental accumulation of microdomain-forming lipids in synapses by proposing a mechanism by which palmitoylation of the immobilized scaffold protein PSD-95 nucleates domains at the postsynaptic plasma membrane. These results reveal developmental changes in lipid composition and palmitoylation that facilitate the formation of postsynaptic membrane microdomains, which may serve key roles in the function of the neuronal synapse. © 2016 Tulodziecka et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

Permian-Triassic Tethyan realm reorganization: Implications for the outward Pangea margin

NASA Astrophysics Data System (ADS)

Riel, Nicolas; Jaillard, Etienne; Martelat, Jean-Emmanuel; Guillot, Stéphane; Braun, Jean

2018-01-01

We present a new conceptual model to explain the first order Permian-Triassic evolution of the whole > 30 000 km long Pangea margin facing the Panthalassa ocean. Compilation of available geological, geochemical, geochronogical and paleomagnetic data all along this system allowed us to distinguish three part of the margin: western Laurentia, western Gondwana and eastern Gondwana. These segments record distinct tectonic and magmatic events, which all occur synchronously along the whole margin and correlate well with the main geodynamic events of this period, i.e. subduction of the Paleotethys mid-ocean ridge at 310-280 Ma, opening of the Neotethys at 280-260 Ma, counterclockwise rotation of Pangea at 260-230 Ma and closure of the Paleotethys at 230-220 Ma. Between 260 and 230 Ma, the reorganization of the Tethyan realm triggered the up to 35° rotation of Pangea around an Euler pole located in northernmost South America. This implied both an increase and a decrease of the convergence rate between the margin and the Panthalassa ocean, north and south of the Euler pole, respectively. Thus, the Permian-Triassic Pangean margin was marked: in western Laurentia by marginal sea closure, in western Gondwana by widespread bimodal magmatic and volcanic activity, in eastern Gondwana by transpressive orogenic phase. Therefore, we propose that the Permian-Triassic evolution of the outward margin of Pangea was controlled by the Tethyan realm reorganization.

Remodeling of angulation deformities in diaphyseal femoral fracture in children.

PubMed

Kamegaya, Makoto; Saisu, Takashi; Segawa, Yuko; Kakizaki, Jun; Sakamoto, Yuko; Hagiwara, Shigeo

2012-11-01

The purpose of this study was to reconsider the factors influencing the remodeling effects in diaphyseal femoral fractures in children based on radiological results. We reviewed 39 patients with more than a 5° residual angulation deformity at the fracture site on anteroposterior and/or lateral views at the primary healing stage. The average follow-up period was 30.4 months. Angulation deformity was measured on plain radiographs both at the primary healing stage and the final follow-up. The correction rate (A - B/A × 100, A angulation deformities at the primary healing, B the angulation at the final follow-up) between at the primary healing stage and final follow-up was analyzed in terms of age at injury (0-5, 6-9, and ≥10 years), fracture site (proximal one third, middle one third, and distal one third) and direction of the deformities (coronal and sagittal planes). The remodeling effect significantly appeared on the coronal plane (correction rate 66.7 %) rather than on the sagittal plane (correction rate 31.6 %) in the 0- to 5-year age group (P < 0.05). There was a statistically significant difference in the correction rate between the 0- to 5-year age group (66.7 %) and the 6- to 9-year group (30.6 %) on the coronal plane (P < 0.05), with no significance between any other two groups on both planes. No statistical difference of remodeling effect appeared among the three fracture sites. The average leg-length discrepancy was 4.7 mm longer. We suggest that a patient ≤5 years at injury could expect more sufficient remodeling on the coronal plane compared with the other age groups on both planes. However, a patient >5 years at injury should be encouraged to undergo the maximum possible correction of the angulation deformity at the initial treatment. Surgical intervention might be considered for that purpose.

Pressure-overload-induced angiotensin-mediated early remodeling in mouse heart

PubMed Central

Kim, Jeremy H.; Jiang, Ya-Ping; Cohen, Ira S.; Lin, Richard Z.; Mathias, Richard T.

2017-01-01

Our previous work on angiotensin II-mediated electrical-remodeling in canine left ventricle, in connection with a long history of other studies, suggested the hypothesis: increases in mechanical load induce autocrine secretion of angiotensin II (A2), which coherently regulates a coterie of membrane ion transporters in a manner that increases contractility. However, the relation between load and A2 secretion was correlative. We subsequently showed a similar or identical system was present in murine heart. To investigate whether the relation between mechanical load and A2-mediated electrical remodeling was causal, we employed transverse aortic constriction in mice to subject the left ventricle to pressure overload for short-term (1 to 2 days) or long-term (1 to 2 weeks) periods. Heart-to-body weight ratios and cell capacitance measurements were used to determine hypertrophy. Whole-cell patch clamp recordings of the predominant repolarization currents Ito,fast and IK,slow were used to assess electrical remodeling. Hearts or myocytes subjected to long-term load displayed significant hypertrophy, which was not evident in short-term load. However, short-term load induced significant reductions in Ito,fast and IK,slow. Incubation of these myocytes with the angiotensin II type 1 receptor inhibitor saralasin for 2 hours restored Ito,fast and IK,slow to control levels. The number of Ito.fast or IK,slow channels did not change with A2 or long-term load, however the hypertrophic increase in membrane area reduced the current densities for both channels. For Ito,fast but not IK,slow there was an additional reduction that was reversed by inhibition of angiotensin receptors. These results suggest increased load activates an endogenous renin angiotensin system that initially reduces Ito,fast and IK,slow prior to the onset of hypertrophic growth. However, there are functional interactions between electrical and anatomical remodeling. First, hypertrophy tends to reduce all current

Critical role of actin-associated proteins in smooth muscle contraction, cell proliferation, airway hyperresponsiveness and airway remodeling.

PubMed

Tang, Dale D

2015-10-30

Asthma is characterized by airway hyperresponsiveness and airway remodeling, which are largely attributed to increased airway smooth muscle contractility and cell proliferation. It is known that both chemical and mechanical stimulation regulates smooth muscle contraction. Recent studies suggest that contractile activation and mechanical stretch induce actin cytoskeletal remodeling in smooth muscle. However, the mechanisms that control actin cytoskeletal reorganization are not completely elucidated. This review summarizes our current understanding regarding how actin-associated proteins may regulate remodeling of the actin cytoskeleton in airway smooth muscle. In particular, there is accumulating evidence to suggest that Abelson tyrosine kinase (Abl) plays a critical role in regulating airway smooth muscle contraction and cell proliferation in vitro, and airway hyperresponsiveness and remodeling in vivo. These studies indicate that Abl may be a novel target for the development of new therapy to treat asthma.

Modalities for Visualization of Cortical Bone Remodeling: The Past, Present, and Future

PubMed Central

Harrison, Kimberly D.; Cooper, David M. L.

2015-01-01

Bone’s ability to respond to load-related phenomena and repair microdamage is achieved through the remodeling process, which renews bone by activating groups of cells known as basic multicellular units (BMUs). The products of BMUs, secondary osteons, have been extensively studied via classic two-dimensional techniques, which have provided a wealth of information on how histomorphology relates to skeletal structure and function. Remodeling is critical in maintaining healthy bone tissue; however, in osteoporotic bone, imbalanced resorption results in increased bone fragility and fracture. With increasing life expectancy, such degenerative bone diseases are a growing concern. The three-dimensional (3D) morphology of BMUs and their correlation to function, however, are not well-characterized and little is known about the specific mechanisms that initiate and regulate their activity within cortical bone. We believe a key limitation has been the lack of 3D information about BMU morphology and activity. Thus, this paper reviews methodologies for 3D investigation of cortical bone remodeling and, specifically, structures associated with BMU activity (resorption spaces) and the structures they create (secondary osteons), spanning from histology to modern ex vivo imaging modalities, culminating with the growing potential of in vivo imaging. This collection of papers focuses on the theme of “putting the ‘why’ back into bone architecture.” Remodeling is one of two mechanisms “how” bone structure is dynamically modified and thus an improved 3D understanding of this fundamental process is crucial to ultimately understanding the “why.” PMID:26322017

Novel therapeutic strategies for lung disorders associated with airway remodelling and fibrosis.

PubMed

Royce, Simon G; Moodley, Yuben; Samuel, Chrishan S

2014-03-01

Inflammatory cell infiltration, cytokine release, epithelial damage, airway/lung remodelling and fibrosis are central features of inflammatory lung disorders, which include asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome and idiopathic pulmonary fibrosis. Although the lung has some ability to repair itself from acute injury, in the presence of ongoing pathological stimuli and/or insults that lead to chronic disease, it no longer retains the capacity to heal, resulting in fibrosis, the final common pathway that causes an irreversible loss of lung function. Despite inflammation, genetic predisposition/factors, epithelial-mesenchymal transition and mechanotransduction being able to independently contribute to airway remodelling and fibrosis, current therapies for inflammatory lung diseases are limited by their ability to only target the inflammatory component of the disease without having any marked effects on remodelling (epithelial damage and fibrosis) that can cause lung dysfunction independently of inflammation. Furthermore, as subsets of patients suffering from these diseases are resistant to currently available therapies (such as corticosteroids), novel therapeutic approaches are required to combat all aspects of disease pathology. This review discusses emerging therapeutic approaches, such as trefoil factors, relaxin, histone deacetylase inhibitors and stem cells, amongst others that have been able to target airway inflammation and airway remodelling while improving related lung dysfunction. A better understanding of the mode of action of these therapies and their possible combined effects may lead to the identification of their clinical potential in the setting of lung disease, either as adjunct or alternative therapies to currently available treatments. © 2013.

Simulation of multi-stage nonlinear bone remodeling induced by fixed partial dentures of different configurations: a comparative clinical and numerical study.

PubMed

Liao, Zhipeng; Yoda, Nobuhiro; Chen, Junning; Zheng, Keke; Sasaki, Keiichi; Swain, Michael V; Li, Qing

2017-04-01

This paper aimed to develop a clinically validated bone remodeling algorithm by integrating bone's dynamic properties in a multi-stage fashion based on a four-year clinical follow-up of implant treatment. The configurational effects of fixed partial dentures (FPDs) were explored using a multi-stage remodeling rule. Three-dimensional real-time occlusal loads during maximum voluntary clenching were measured with a piezoelectric force transducer and were incorporated into a computerized tomography-based finite element mandibular model. Virtual X-ray images were generated based on simulation and statistically correlated with clinical data using linear regressions. The strain energy density-driven remodeling parameters were regulated over the time frame considered. A linear single-stage bone remodeling algorithm, with a single set of constant remodeling parameters, was found to poorly fit with clinical data through linear regression (low [Formula: see text] and R), whereas a time-dependent multi-stage algorithm better simulated the remodeling process (high [Formula: see text] and R) against the clinical results. The three-implant-supported and distally cantilevered FPDs presented noticeable and continuous bone apposition, mainly adjacent to the cervical and apical regions. The bridged and mesially cantilevered FPDs showed bone resorption or no visible bone formation in some areas. Time-dependent variation of bone remodeling parameters is recommended to better correlate remodeling simulation with clinical follow-up. The position of FPD pontics plays a critical role in mechanobiological functionality and bone remodeling. Caution should be exercised when selecting the cantilever FPD due to the risk of overloading bone resorption.

Remodeling Air Force Cyber Command and Control

DTIC Science & Technology

2017-10-10

AIR FORCE CYBERWORX REPORT: REMODELING AIR FORCE CYBER COMMAND & CONTROL COURSE DESIGN PROJECT CONDUCTED 5 Jan – 5 May 17 Produced...For the Air Force Cyber Command and Control (C2) Design Project, CyberWorx brought together 25 cadets from the United States Air Force Academy...warfighting based upon the findings of the design teams. Participants The design course was attended by a diverse group of civilians from industry

Stepwise Loop Insertion Strategy for Active Site Remodeling to Generate Novel Enzyme Functions.

PubMed

Hoque, Md Anarul; Zhang, Yong; Chen, Liuqing; Yang, Guangyu; Khatun, Mst Afroza; Chen, Haifeng; Hao, Liu; Feng, Yan

2017-05-19

The remodeling of active sites to generate novel biocatalysts is an attractive and challenging task. We developed a stepwise loop insertion strategy (StLois), in which randomized residue pairs are inserted into active site loops. The phosphotriesterase-like lactonase from Geobacillus kaustophilus (GkaP-PLL) was used to investigate StLois's potential for changing enzyme function. By inserting six residues into active site loop 7, the best variant ML7-B6 demonstrated a 16-fold further increase in catalytic efficiency toward ethyl-paraoxon compared with its initial template, that is a 609-fold higher, >10 7 fold substrate specificity shift relative to that of wild-type lactonase. The remodeled variants displayed 760-fold greater organophosphate hydrolysis activity toward the organophosphates parathion, diazinon, and chlorpyrifos. Structure and docking computations support the source of notably inverted enzyme specificity. Considering the fundamental importance of active site loops, the strategy has potential for the rapid generation of novel enzyme functions by loop remodeling.

Mechanisms of epoxyeicosatrienoic acids to improve cardiac remodeling in chronic renal failure disease.

PubMed

Zhang, Kun; Wang, Ju; Zhang, Huanji; Chen, Jie; Zuo, Zhiyi; Wang, Jingfeng; Huang, Hui

2013-02-15

Both clinical and basic science studies have demonstrated that cardiac remodeling in patients with chronic renal failure (CRF) is very common. It is a key feature during the course of heart failure and an important risk factor for subsequent cardiac mortality. Traditional drugs or therapies rarely have effects on cardiac regression of CRF and cardiovascular events are still the first cause of death. Epoxyeicosatrienoic acids (EETs) are the products of arachidonic acids metabolized by cytochrome P450 epoxygenases. It has been found that EETs have important biological effects including anti-hypertension and anti-inflammation. Recent data suggest that EETs are involved in regulating cardiomyocyte injury, renal dysfunction, chronic kidney disease (CKD)-related risk factors and signaling pathways, all of which play key roles in cardiac remodeling induced by CRF. This review analyzes the literature to identify the possible mechanisms for EETs to improve cardiac remodeling induced by CRF and indicates the therapeutic potential of EETs in it. Copyright © 2012 Elsevier B.V. All rights reserved.

The solid state environment orchestrates embryonic development and tissue remodeling

NASA Technical Reports Server (NTRS)

Damsky, C. H.; Moursi, A.; Zhou, Y.; Fisher, S. J.; Globus, R. K.

1997-01-01

Cell interactions with extracellular matrix and with other cells play critical roles in morphogenesis during development and in tissue homeostasis and remodeling throughout life. Extracellular matrix is information-rich, not only because it is comprised of multifunctional structural ligands for cell surface adhesion receptors, but also because it contains peptide signaling factors, and proteinases and their inhibitors. The functions of these groups of molecules are extensively interrelated. In this review, three primary cell culture models are described that focus on adhesion receptors and their roles in complex aspects of morphogenesis and remodeling: the regulation of proteinase expression by fibronectin and integrins in synovial fibroblasts; the regulation of osteoblast differentiation and survival by fibronectin, and the regulation of trophoblast differentiation and invasion by integrins, cadherins and immunoglobulin family adhesion receptors.

Exercise-induced adaptations to white and brown adipose tissue.

PubMed

Lehnig, Adam C; Stanford, Kristin I

2018-03-07

The beneficial effects of exercise on skeletal muscle and the cardiovascular system have long been known. Recent studies have focused on investigating the effects of exercise on adipose tissue and the effects that these exercise-induced adaptations have on overall metabolic health. Examination of exercise-induced adaptations in both white adipose tissue (WAT) and brown adipose tissue (BAT) has revealed marked differences in each tissue with exercise. In WAT, there are changes to both subcutaneous WAT (scWAT) and visceral WAT (vWAT), including decreased adipocyte size and lipid content, increased expression of metabolic genes, altered secretion of adipokines and increased mitochondrial activity. Adaptations specific to scWAT include lipidomic remodeling of phospholipids and, in rodents, the beiging of scWAT. The changes to BAT are less clear: studies evaluating the effect of exercise on the BAT of humans and rodents have revealed contradictory data, making this an important area of current investigation. In this Review, we discuss the exercise-induced changes to WAT and BAT that have been reported by different studies and highlight the current questions in this field. © 2018. Published by The Company of Biologists Ltd.

The Nucleosome Remodeling and Deacetylase (NuRD) Complex in Development and Disease

PubMed Central

Basta, Jeannine; Rauchman, Michael

2014-01-01

The Nucleosome Remodeling and Deacetylase (NuRD) complex is one of the major chromatin remodeling complexes found in cells. It plays an important role in regulating gene transcription, genome integrity and cell cycle progression. Through its impact on these basic cellular processes, increasing evidence indicates that alterations in the activity of this macromolecular complex can lead to developmental defects, oncogenesis and accelerated ageing. Recent genetic and biochemical studies have elucidated the mechanisms of NuRD action in modifying the chromatin landscape. These advances have the potential to lead to new therapeutic approaches to birth defects and cancer. PMID:24880148

Effect of Brain-Derived Neurotrophic Factor Haploinsufficiency on Stress-Induced Remodeling of Hippocampal Neurons

PubMed Central

Magariños, A.M.; Li, C.J.; Toth, J. Gal; Bath, K.G.; Jing, D.; Lee, F.S.; McEwen, B.S.

2010-01-01

Chronic restraint stress (CRS) induces the remodeling (i.e., retraction and simplification) of the apical dendrites of hippocampal CA3 pyramidal neurons in rats, suggesting that intrahippocampal connectivity can be affected by a prolonged stressful challenge. Since the structural maintenance of neuronal dendritic arborizations and synaptic connectivity requires neurotrophic support, we investigated the potential role of brain derived neurotrophic factor (BDNF), a neurotrophin enriched in the hippocampus and released from neurons in an activity-dependent manner, as a mediator of the stress-induced dendritic remodeling. The analysis of Golgi-impregnated hippocampal sections revealed that wild type (WT) C57BL/6 male mice showed a similar CA3 apical dendritic remodeling in response to three weeks of CRS to that previously described for rats. Haploinsufficient BDNF mice (BDNF±) did not show such remodeling, but, even without CRS, they presented shorter and simplified CA3 apical dendritic arbors, like those observed in stressed WT mice. Furthermore, unstressed BDNF± mice showed a significant decrease in total hippocampal volume. The dendritic arborization of CA1 pyramidal neurons was not affected by CRS or genotype. However, only in WT mice, CRS induced changes in the density of dendritic spine shape subtypes in both CA1 and CA3 apical dendrites. These results suggest a complex role of BDNF in maintaining the dendritic and spine morphology of hippocampal neurons and the associated volume of the hippocampal formation. The inability of CRS to modify the dendritic structure of CA3 pyramidal neurons in BDNF± mice suggests an indirect, perhaps permissive, role of BDNF in mediating hippocampal dendritic remodeling. PMID:20095008

Cell Wall Remodeling Enzymes Modulate Fungal Cell Wall Elasticity and Osmotic Stress Resistance.

PubMed

Ene, Iuliana V; Walker, Louise A; Schiavone, Marion; Lee, Keunsook K; Martin-Yken, Hélène; Dague, Etienne; Gow, Neil A R; Munro, Carol A; Brown, Alistair J P

2015-07-28

a network of cell wall polysaccharides, which are remodeled in response to growth conditions and environmental stress. However, little is known about how cell wall elasticity is regulated and how it affects adaptation to stresses such as sudden changes in osmolarity. We show that elasticity is critical for survival under conditions of osmotic shock, before stress signaling pathways have time to induce gene expression and drive glycerol accumulation. Critical cell wall remodeling enzymes control cell wall flexibility, and its regulation is strongly dependent on host nutritional inputs. We also demonstrate an entirely new level of cell wall dynamism, where significant architectural changes and structural realignment occur within seconds of an osmotic shock. Copyright © 2015 Ene et al.

Toxic effects of environmental rare earth elements on delayed outward potassium channels and their mechanisms from a microscopic perspective.

PubMed

Wang, Lihong; He, Jingfang; Xia, Ao; Cheng, Mengzhu; Yang, Qing; Du, Chunlei; Wei, Haiyan; Huang, Xiaohua; Zhou, Qing

2017-08-01

The wide applications cause a large amount of rare earth elements (REEs) to be released into the environment, and ultimately into the human body through food chain. Toxic effects of REEs on humans have been extensively studied, but their toxic effects and binding targets in cells are not understood. Delayed outward potassium channels (K + channels) are good targets for exogenous substances or clinical drugs. To evaluate cellular toxicities of REEs and clarify toxic mechanisms, the toxicities of REEs on the K + channel and their structural basis were investigated. The results showed that delayed outward potassium channels on the plasma membrane are the targets of REEs acting on living organisms, and the changes in the thermodynamic and kinetic characteristics of the K + channel are the reasons of diseases induced by REEs. Two types of REEs, a light REE La 3+ and a heavy REE Tb 3+ , displayed different intensity of toxicities on the K + channel, in which the toxicity of Tb 3+ was stronger than that of La 3+ . More interestingly, in comparison with that of heavy metal Cd 2+ , the cytotoxicities of the light and heavy REEs showed discriminative differences, and the cytotoxicity of Tb 3+ was higher than that of Cd 2+ , while the cytotoxicity of La 3+ was lower than that of Cd 2+ . These different cytotoxicities of La 3+ , Tb 3+ and Cd 2+ on human resulted from the varying binding abilities of the metals to this channel protein. Copyright © 2017 Elsevier Ltd. All rights reserved.

Lung parenchyma remodeling in a murine model of chronic allergic inflammation.

PubMed

Xisto, Debora G; Farias, Luciana L; Ferreira, Halina C; Picanço, Miguel R; Amitrano, Daniel; Lapa E Silva, Jose R; Negri, Elnara M; Mauad, Thais; Carnielli, Denise; Silva, Luiz Fernando F; Capelozzi, Vera L; Faffe, Debora S; Zin, Walter A; Rocco, Patricia R M

2005-04-15

This study tested the hypotheses that chronic allergic inflammation induces not only bronchial but also lung parenchyma remodeling, and that these histologic changes are associated with concurrent changes in respiratory mechanics. For this purpose, airway and lung parenchyma remodeling were evaluated by quantitative analysis of collagen and elastin, immunohistochemistry (smooth-muscle actin expression, eosinophil, and dendritic cell densities), and electron microscopy. In vivo (airway resistance, viscoelastic pressure, and static elastance) and in vitro (tissue elastance, resistance, and hysteresivity) respiratory mechanics were also analyzed. BALB/c mice were sensitized with ovalbumin and exposed to repeated ovalbumin challenges. A marked eosinophilic infiltration was seen in lung parenchyma and in large and distal airways. Neutrophils, lymphocytes, and dendritic cells also infiltrated the lungs. There was subepithelial fibrosis, myocyte hypertrophy and hyperplasia, elastic fiber fragmentation, and increased numbers of myofibroblasts in airways and lung parenchyma. Collagen fiber content was increased in the alveolar walls. The volume proportion of smooth muscle-specific actin was augmented in distal airways and alveolar duct walls. Airway resistance, viscoelastic pressure, static elastance, and tissue elastance and resistance were significantly increased. In conclusion, prolonged allergen exposure induced remodeling not only of the airway wall but also of the lung parenchyma, leading to in vivo and in vitro mechanical changes.

Trabecular meshwork ECM remodeling in glaucoma: could RAS be a target?

PubMed

Agarwal, Puneet; Agarwal, Renu

2018-06-14

Disturbances of extracellular matrix (ECM) homeostasis in trabecular meshwork (TM) cause increased aqueous outflow resistance leading to elevated intraocular pressure (IOP) in glaucomatous eyes. Therefore, restoration of ECM homeostasis is a rational approach to prevent disease progression. Since renin-angiotensin system (RAS) inhibition positively alters ECM homeostasis in cardiovascular pathologies involving pressure and volume overload, it is likely that RAS inhibitors reduce IOP primarily by restoring ECM homeostasis. Areas covered: Current evidence showing the presence of RAS components in ocular tissue and its role in regulating aqueous humor dynamics is briefly summarized. The role of RAS in ECM remodeling is discussed both in terms of its effects on ECM synthesis and its breakdown. The mechanisms of ECM remodeling involving interactions of RAS with transforming growth factor-β, Wnt/β-catenin signaling, bone morphogenic proteins, connective tissue growth factor, and matrix metalloproteinases in ocular tissue are discussed. Expert opinion: Current literature strongly indicates a significant role of RAS in ECM remodeling in TM of hypertensive eyes. Hence, IOP-lowering effect of RAS inhibitors may primarily be attributed to restoration of ECM homeostasis in aqueous outflow pathways rather than its vascular effects. However, the mechanistic targets for RAS inhibitors have much wider distribution and consequences, which remain relatively unexplored in TM.

Spatiotemporal dynamics of membrane remodeling and fusion proteins during endocytic transport

PubMed Central

Arlt, Henning; Auffarth, Kathrin; Kurre, Rainer; Lisse, Dominik; Piehler, Jacob; Ungermann, Christian

2015-01-01

Organelles of the endolysosomal system undergo multiple fission and fusion events to combine sorting of selected proteins to the vacuole with endosomal recycling. This sorting requires a consecutive remodeling of the organelle surface in the course of endosomal maturation. Here we dissect the remodeling and fusion machinery on endosomes during the process of endocytosis. We traced selected GFP-tagged endosomal proteins relative to exogenously added fluorescently labeled α-factor on its way from the plasma membrane to the vacuole. Our data reveal that the machinery of endosomal fusion and ESCRT proteins has similar temporal localization on endosomes, whereas they precede the retromer cargo recognition complex. Neither deletion of retromer nor the fusion machinery with the vacuole affects this maturation process, although the kinetics seems to be delayed due to ESCRT deletion. Of importance, in strains lacking the active Rab7-like Ypt7 or the vacuolar SNARE fusion machinery, α-factor still proceeds to late endosomes with the same kinetics. This indicates that endosomal maturation is mainly controlled by the early endosomal fusion and remodeling machinery but not the downstream Rab Ypt7 or the SNARE machinery. Our data thus provide important further understanding of endosomal biogenesis in the context of cargo sorting. PMID:25657322

Enhanced alveolar growth and remodeling in Guinea pigs raised at high altitude.

PubMed

Hsia, Connie C W; Carbayo, Juan J Polo; Yan, Xiao; Bellotto, Dennis J

2005-05-12

To examine the effects of chronic high altitude (HA) exposure on lung structure during somatic maturation, we raised male weanling guinea pigs at HA (3800m) for 1, 3, or 6 months, while their respective male littermates were simultaneously raised at low altitude (LA, 1200m). Under anaesthesia, airway pressure was measured at different lung volumes. The right lung was fixed at a constant airway pressure for morphometric analysis under light and electron microscopy. In animals raised at HA for 1 month, lung volume, alveolar surface area and alveolar-capillary blood volume (V(c)) were elevated above LA control values. Following 3-6 months of HA exposure, increases in lung volume and alveolar surface area persisted while the initial increase in V(c) normalized. Additional adaptation occurred, including a higher epithelial cell volume, septal tissue volume and capillary surface area, a lower alveolar duct volume and lower harmonic mean diffusion barrier resulting in higher membrane and lung diffusing capacities. These data demonstrate enhanced alveolar septal growth and progressive acinar remodeling during chronic HA exposure with long-term augmentation of alveolar dimensions as well as functional compensation in lung compliance and diffusive gas transport.

Nucleosome breathing and remodeling constrain CRISPR-Cas9 function

PubMed Central

Isaac, R Stefan; Jiang, Fuguo; Doudna, Jennifer A; Lim, Wendell A; Narlikar, Geeta J; Almeida, Ricardo

2016-01-01

The CRISPR-Cas9 bacterial surveillance system has become a versatile tool for genome editing and gene regulation in eukaryotic cells, yet how CRISPR-Cas9 contends with the barriers presented by eukaryotic chromatin is poorly understood. Here we investigate how the smallest unit of chromatin, a nucleosome, constrains the activity of the CRISPR-Cas9 system. We find that nucleosomes assembled on native DNA sequences are permissive to Cas9 action. However, the accessibility of nucleosomal DNA to Cas9 is variable over several orders of magnitude depending on dynamic properties of the DNA sequence and the distance of the PAM site from the nucleosome dyad. We further find that chromatin remodeling enzymes stimulate Cas9 activity on nucleosomal templates. Our findings imply that the spontaneous breathing of nucleosomal DNA together with the action of chromatin remodelers allow Cas9 to effectively act on chromatin in vivo. DOI: http://dx.doi.org/10.7554/eLife.13450.001 PMID:27130520

p53 regulates cytoskeleton remodeling to suppress tumor progression.

PubMed

Araki, Keigo; Ebata, Takahiro; Guo, Alvin Kunyao; Tobiume, Kei; Wolf, Steven John; Kawauchi, Keiko

2015-11-01

Cancer cells possess unique characteristics such as invasiveness, the ability to undergo epithelial-mesenchymal transition, and an inherent stemness. Cell morphology is altered during these processes and this is highly dependent on actin cytoskeleton remodeling. Regulation of the actin cytoskeleton is, therefore, important for determination of cell fate. Mutations within the TP53 (tumor suppressor p53) gene leading to loss or gain of function (GOF) of the protein are often observed in aggressive cancer cells. Here, we highlight the roles of p53 and its GOF mutants in cancer cell invasion from the perspective of the actin cytoskeleton; in particular its reorganization and regulation by cell adhesion molecules such as integrins and cadherins. We emphasize the multiple functions of p53 in the regulation of actin cytoskeleton remodeling in response to the extracellular microenvironment, and oncogene activation. Such an approach provides a new perspective in the consideration of novel targets for anti-cancer therapy.

Effects of atorvastatin and losartan on monocrotaline-induced pulmonary artery remodeling in rats.

PubMed

Xie, Liangdi; Lin, Peisen; Xie, Hong; Xu, Changsheng

2010-01-01

Structural remodeling of pulmonary artery plays an important role in maintaining sustained pulmonary arterial hypertension (PAH). The anti-remodeling effects of statins have been reported in systemic hypertension. In this study, we studied the effects of atovastatin (Ato) or losartan (Los) in monocrotaline (MCL)-induced pulmonary artery remodeling using a rat model. Forty Sprague-Dawley (SD) rats were randomly assigned into four groups (n = 10): normal control (Ctr), PAH, PAH treated with Los, and PAH treated with Ato. We found that in the Los- or Ato-treated group, the mean pulmonary arterial pressure, right heart hypertrophy index, ratio of wall/lumen thickness (WT%), as well as the wall/lumen area (WA%) were significantly reduced compared to the PAH group. Also in pulmonary arteries dissected from rats in the Ato- or Los-treated group, in both mRNA and protein levels, the expression of α1C subunit of voltage-gated calcium channel (Ca(v)α1c) was downregulated, while sarcoplasmic/endoplasmic reticulum calcium-ATPase (SERCA-2a) and inositol 1,4,5 triphosphate receptor 1 (IP3R-1) upregulated. However, the mRNA level of RyR-3 subunit of calcium regulating channel was increased, whereas its protein level was reduced in the treated groups. Our results suggest that atorvastatin or losartan may regress the remodeling of the pulmonary artery in pulmonary hypertensive rats, with differential expression of calcium regulating channels.

Evaluation of bone remodeling in regard to the age of scaphoid non-unions.

PubMed

Rein, Susanne; Hanisch, Uwe; Schaller, Hans-Eberhard; Zwipp, Hans; Rammelt, Stefan; Weindel, Stefan

2016-07-18

To analyse bone remodeling in regard to the age of scaphoid non-unions (SNU) with immunohistochemistry. Thirty-six patients with symptomatic SNU underwent surgery with resection of the pseudarthrosis. The resected material was evaluated histologically after staining with hematoxylin-eosin (HE), tartrate resistant acid phosphatase (TRAP), CD 68, osteocalcin (OC) and osteopontin (OP). Histological examination was performed in a blinded fashion. The number of multinuclear osteoclasts in the TRAP-staining correlated with the age of the SNU and was significantly higher in younger SNU (P = 0.034; r = 0.75). A higher number of OP-immunoreactive osteoblasts significantly correlated with a higher number of OC-immunoreactive osteoblasts (P = 0.001; r = 0.55). Furthermore, a greater number of OP-immunoreactive osteoblasts correlated significantly with a higher number of OP-immunoreactive multinuclear osteoclasts (P = 0.008; r = 0.43). SNU older than 6 mo showed a significant decrease of the number of fibroblasts (P = 0.04). Smoking and the age of the patients had no influence on bone remodeling in SNU. Multinuclear osteoclasts showed a significant decrease in relation to the age of SNU. However, most of the immunhistochemical findings of bone remodeling do not correlate with the age of the SNU. This indicates a permanent imbalance of bone formation and resorption as indicated by a concurrent increase in both osteoblast and osteoclast numbers. A clear histological differentiation into phases of bone remodeling in SNU is not possible.

Evaluation of bone remodeling in regard to the age of scaphoid non-unions

PubMed Central

Rein, Susanne; Hanisch, Uwe; Schaller, Hans-Eberhard; Zwipp, Hans; Rammelt, Stefan; Weindel, Stefan

2016-01-01

AIM: To analyse bone remodeling in regard to the age of scaphoid non-unions (SNU) with immunohistochemistry. METHODS: Thirty-six patients with symptomatic SNU underwent surgery with resection of the pseudarthrosis. The resected material was evaluated histologically after staining with hematoxylin-eosin (HE), tartrate resistant acid phosphatase (TRAP), CD 68, osteocalcin (OC) and osteopontin (OP). Histological examination was performed in a blinded fashion. RESULTS: The number of multinuclear osteoclasts in the TRAP-staining correlated with the age of the SNU and was significantly higher in younger SNU (P = 0.034; r = 0.75). A higher number of OP-immunoreactive osteoblasts significantly correlated with a higher number of OC-immunoreactive osteoblasts (P = 0.001; r = 0.55). Furthermore, a greater number of OP-immunoreactive osteoblasts correlated significantly with a higher number of OP-immunoreactive multinuclear osteoclasts (P = 0.008; r = 0.43). SNU older than 6 mo showed a significant decrease of the number of fibroblasts (P = 0.04). Smoking and the age of the patients had no influence on bone remodeling in SNU. CONCLUSION: Multinuclear osteoclasts showed a significant decrease in relation to the age of SNU. However, most of the immunhistochemical findings of bone remodeling do not correlate with the age of the SNU. This indicates a permanent imbalance of bone formation and resorption as indicated by a concurrent increase in both osteoblast and osteoclast numbers. A clear histological differentiation into phases of bone remodeling in SNU is not possible. PMID:27458552

A fetal cardiovascular score to predict infant hypertension and arterial remodeling in intrauterine growth restriction.

PubMed

Cruz-Lemini, Mónica; Crispi, Fátima; Valenzuela-Alcaraz, Brenda; Figueras, Francesc; Gómez, Olga; Sitges, Marta; Bijnens, Bart; Gratacós, Eduard

2014-06-01

Intrauterine growth restricted (IUGR) fetuses experience cardiovascular remodeling that persists into infancy and has been related to cardiovascular outcomes in adulthood. Hypertension in infancy has been demonstrated to be a strong risk factor for later cardiovascular disease. Close monitoring together with dietary interventions have shown to improve cardiovascular health in hypertensive children; however, not all IUGR infants show increased blood pressure. We evaluated the potential of fetal echocardiography for predicting hypertension and arterial remodeling in 6-month-old IUGR infants. One hundred consecutive IUGR and 100 control fetuses were observed into infancy. Fetal assessment included perinatal Doppler imaging, cardiac morphometry, ejection fraction, cardiac output, isovolumic relaxation time (IVRT), tricuspid annular-plane systolic excursion (TAPSE), and tissue Doppler imaging. Infant hypertension and arterial remodeling were defined as mean blood pressure of >95th percentile together with aortic intima-media thickness of >75th percentile at 6 months of age. Odds ratio were obtained for fetal parameters that were associated with infant outcomes. Fetal TAPSE, right sphericity index, IVRT, and cerebroplacental ratio were the strongest predictors for postnatal vascular remodeling. A cardiovascular risk score that was based on fetal TAPSE, cerebroplacental ratio, right sphericity index, and IVRT was highly predictive of infant hypertension and arterial remodeling (area under the curve, 0.87; 95% confidence interval, 0.79-0.93; P < .001). Fetal echocardiographic parameters identify a high-risk group within the IUGR fetuses who could be targeted for early screening of blood pressure and other cardiovascular risk factors and for promoting healthy diet and physical exercise. Copyright © 2014 Mosby, Inc. All rights reserved.

Venous Grafts Procured During the Learning Curve for Endoscopic Veins Harvesting Show Compromised Vascular Remodeling

PubMed Central

Kiani, Soroosh; Desai, Pranjal H.; Thirumvalavan, Nannan; Kurian, Dinesh John; Flynn, Mary Margaret; Zhao, XiaoQing

2011-01-01

BACKGROUND Endoscopic vein harvest (EVH) is the US standard of care for CABG but recent comparisons to open harvest suggest that conduit quality and outcomes may be compromised. To test the hypothesis that problems with EVH may relate to its learning curve and conduit quality, we analyzed the quality and early function of conduits procured by technicians with varying EVH experience. METHODS EVH was performed during CABG by “experienced” (>900 cases, n=55 patients) vs. “novice” (<100 cases, n=30 patients) technicians. Afterwards, conduits were and examined for vascular injury using optical coherence tomography (OCT), with segments identified as injured further examined for gene expression using a tissue injury array. Conduit diameter was measured intra- and postoperatively (day 5 and 6 months) using OCT and Computed-Tomography angiography. RESULTS EVH performed by novice harvesters resulted in increased number of discrete graft injuries and higher expression of tissue injury genes. Regression analysis revealed an association between shear stress and early dilation (positive remodeling) (R2 =0.48, p <0.01). Injured veins showed blunted positive remodeling at 5 days and a greater degree of late lumen loss at 6 months. CONCLUSION Under normal conditions, intraluminal shear stress leads vein grafts to develop positive remodeling over the first postoperative week. Injury to conduits, a frequent sequela of the learning curve for EVH, was a predictor of early graft failure, blunted positive remodeling and greater negative remodeling. Given the ongoing annual volume of EVH cases, rigorous monitoring of the learning curve represents an important and unrecognized public health issue. PMID:21996436

PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

PubMed Central

Knight, Walter E.; Chen, Si; Zhang, Yishuai; Oikawa, Masayoshi; Wu, Meiping; Zhou, Qian; Miller, Clint L.; Cai, Yujun; Mickelsen, Deanne M.; Moravec, Christine; Small, Eric M.; Abe, Junichi; Yan, Chen

2016-01-01

Cyclic nucleotide phosphodiesterase 1C (PDE1C) represents a major phosphodiesterase activity in human myocardium, but its function in the heart remains unknown. Using genetic and pharmacological approaches, we studied the expression, regulation, function, and underlying mechanisms of PDE1C in the pathogenesis of cardiac remodeling and dysfunction. PDE1C expression is up-regulated in mouse and human failing hearts and is highly expressed in cardiac myocytes but not in fibroblasts. In adult mouse cardiac myocytes, PDE1C deficiency or inhibition attenuated myocyte death and apoptosis, which was largely dependent on cyclic AMP/PKA and PI3K/AKT signaling. PDE1C deficiency also attenuated cardiac myocyte hypertrophy in a PKA-dependent manner. Conditioned medium taken from PDE1C-deficient cardiac myocytes attenuated TGF-β–stimulated cardiac fibroblast activation through a mechanism involving the crosstalk between cardiac myocytes and fibroblasts. In vivo, cardiac remodeling and dysfunction induced by transverse aortic constriction, including myocardial hypertrophy, apoptosis, cardiac fibrosis, and loss of contractile function, were significantly attenuated in PDE1C-knockout mice relative to wild-type mice. These results indicate that PDE1C activation plays a causative role in pathological cardiac remodeling and dysfunction. Given the continued development of highly specific PDE1 inhibitors and the high expression level of PDE1C in the human heart, our findings could have considerable therapeutic significance. PMID:27791092

Effects of aging and resistance training in rat tendon remodeling.

PubMed

Marqueti, Rita C; Durigan, João L Q; Oliveira, Anderson José S; Mekaro, Marcelo Shinyu; Guzzoni, Vinicius; Aro, Andrea A; Pimentel, Edson Rosa; Selistre-de-Araujo, Heloisa S

2018-01-01

In elderly persons, weak tendons contribute to functional limitations, injuries, and disability, but resistance training can attenuate this age-related decline. We evaluated the effects of resistance training on the extracellular matrix (ECM) of the calcaneal tendon (CT) in young and old rats and its effect on tendon remodeling. Wistar rats aged 3 mo (young, n = 30) and 20 mo (old, n = 30) were divided into 4 groups: young sedentary, young trained, old sedentary (OS), and old trained (OT). The training sessions were conducted over a 12-wk period. Aging in sedentary rats showed down-regulation in key genes that regulated ECM remodeling. Moreover, the OS group showed a calcification focus in the distal region of the CT, with reduced blood vessel volume density. In contrast, resistance training was effective in up-regulating connective tissue growth factor, VEGF, and decorin gene expression in old rats. Resistance training also increased proteoglycan content in young and old rats in special small leucine-rich proteoglycans and blood vessels and prevented calcification in OT rats. These findings confirm that resistance training is a potential mechanism in the prevention of aging-related loss in ECM and that it attenuates the detrimental effects of aging in tendons, such as ruptures and tendinopathies.-Marqueti, R. C., Durigan, J. L. Q., Oliveira, A. J. S., Mekaro, M. S., Guzzoni, V., Aro, A. A., Pimentel, E. R., Selistre-de-Araujo, H. S. Effects of aging and resistance training in rat tendon remodeling. © FASEB.

Function of Brg1 Chromatin Remodeling Factor in Sonic Hedgehog-Dependent Medulloblastoma Initiation and Maintenance

DTIC Science & Technology

2013-10-01

Remodeling Factor in Sonic Hedgehog -Dependent Medulloblastoma Initiation and Maintenance PRINCIPAL INVESTIGATOR: Xuanming Shi CONTRACTING...5a. CONTRACT NUMBER W81XWH-12-1-0527 Function of Brg1 Chromatin Remodeling Factor in Sonic Hedgehog -Dependent 5b. GRANT NUMBER W81XWH-12-1...drug development and therapy of pediatric brain tumor and other Shh- dependent tumors. 15. SUBJECT TERMS Medulloblastoma, Sonic Hedgehog , Chromatin

Left ventricular remodeling in the post-infarction heart: a review of cellular, molecular mechanisms, and therapeutic modalities.

PubMed

Gajarsa, Jason J; Kloner, Robert A

2011-01-01

As more patients survive myocardial infarctions, the incidence of heart failure increases. After an infarction, the human heart undergoes a series of structural changes, which are governed by cellular and molecular mechanisms in a pathological metamorphosis termed "remodeling." This review will discuss the current developments in our understanding of these molecular and cellular events in remodeling and the various pharmacological, cellular and device therapies used to treat, and potentially retard, this condition. Specifically, this paper will examine the neurohormonal activity of the renin-angiotensin-aldosterone axis and its molecular effects on the heart. The emerging understanding of the extra-cellular matrix and the various active molecules within it, such as the matrix metalloproteinases, elicits new appreciation for their role in cardiac remodeling and as possible future therapeutic targets. Cell therapy with stem cells is another recent therapy with great potential in improving post-infarcted hearts. Lastly, the cellular and molecular effects of left ventricular assist devices on remodeling will be reviewed. Our increasing knowledge of the cellular and molecular mechanisms underlying cardiac remodeling enables us not only to better understand how our more successful therapies, like angiotensin-converting enzyme inhibitors, work, but also to explore new therapies of the future.

Minimizing Surface Exposure to Climate Extremity in Coastal Megacities by Structure Remodelling using Integral Geographic Information System: Lessons from Greater Mumbai Metropolitan

NASA Astrophysics Data System (ADS)

Tiwari, A.

2016-12-01

Coastal metropolitans in South Asia represent the most densely populated and congested urban spaces ranking among the largest urban settlements of the planet. These megacities are characterized by inadequate infrastructure, lack of mitigation tools, and weak resilience of urban ecosystems. Additionally, climate change has increased vulnerability of poor and marginalized population living in rapidly growing coastal megacities to increased frequency, severity and intensity of extreme weather events. This has adversely affected local counter strategies and adaptation tools, transforming such events into hazards with the inability to respond and mitigate. Study aimed to develop a participatory framework for risk reduction in Greater Mumbai Metropolitan by Structure Remodeling (SR) in integral GIS. Research utilized terrain analysis tools and vulnerability mapping, and identified risk susceptible fabric and checked its scope for SR without: 1.adding to its (often) complex fragmentation, and 2.without interference with the ecosystem services accommodated by it. Surfaces available included paved ground, streetscapes commercial facades, rooftops,public spaces, open as well as dark spaces. Remodeling altered certain characteristics in the intrinsic or extrinsic cross-section profile or in both (if suitable) with infrastructure measures (grey, green, blue) that collectively involved ecosystem services and maintained natural hydrological connection. This method fairly reduced exposure of vulnerable surface and minimized risk to achieve extremity-neutral state. Harmonizing with public perception and incorporating priorities of local authorities, the method is significant as it rises above the fundamental challenges arising during management of (often) conflicting perspectives and interests of multiplicity of stakeholders involved at various levels in urban climate governance while ensuring inclusive solutions with reduced vulnerability and increased resilience. Additionally

Spatial pattern analysis of nuclear migration in remodelled muscles during Drosophila metamorphosis.

PubMed

Kuleesha; Feng, Lin; Wasser, Martin

2017-07-10

Many human muscle wasting diseases are associated with abnormal nuclear localization. During metamorphosis in Drosophila melanogaster, multi-nucleated larval dorsal abdominal muscles either undergo cell death or are remodeled to temporary adult muscles. Muscle remodeling is associated with anti-polar nuclear migration and atrophy during early pupation followed by polar migration and muscle growth during late pupation. Muscle remodeling is a useful model to study genes involved in myonuclear migration. Previously, we showed that loss of Cathepsin-L inhibited anti-polar movements, while knockdown of autophagy-related genes affected nuclear positioning along the medial axis in late metamorphosis. To compare the phenotypic effects of gene perturbations on nuclear migration more objectively, we developed new descriptors of myonuclear distribution. To obtain nuclear pattern features, we designed an algorithm to detect and track nuclear regions inside live muscles. Nuclear tracks were used to distinguish between fast moving nuclei associated with fragments of dead muscles (sarcolytes) and slow-moving nuclei inside remodelled muscles. Nuclear spatial pattern features, such as longitudinal (lonNS) and lateral nuclear spread (latNS), allowed us to compare nuclear migration during muscle remodelling in different genetic backgrounds. Anti-polar migration leads to a lonNS decrease. As expected, lack of myonuclear migration caused by the loss of Cp1 was correlated with a significantly lower lonNS decrease. Unexpectedly, the decrease in lonNS was significantly enhanced by Atg9, Atg5 and Atg18 silencing, indicating that the loss of autophagy promotes the migration and clustering of nuclei. Loss of autophagy also caused a scattering of nuclei along the lateral axis, leading to a two-row as opposed to single row distribution in control muscles. Increased latNS resulting from knockdown of Atg9 and Atg18 was correlated with increased muscle diameter, suggesting that the wider muscle

Arteriolar and Venular Remodeling Are Differentially Regulated by Bone Marrow-Derived Cell-Specific CX3CR1 and CCR2 Expression

PubMed Central

Meisner, Joshua K.; Song, Ji; Price, Richard J.

2012-01-01

The chemokine receptors CCR2 and CX3CR1 are critical for the recruitment of “inflammatory” and “resident” monocytes, respectively, subpopulations that differentially affect vascular remodeling in atherosclerosis. Here, we tested the hypothesis that bone marrow-derived cell (BMC)-specific CCR2 and CX3CR1 differentially control venular and arteriolar remodeling. Venular and arteriolar lumenal remodeling were observed by intravital microscopy in mice with either CCR2 or CX3CR1 deficient BMCs after implantation of a dorsal skinfold window chamber, a model in which arterioles and venules lumenally enlarge in wild-type (WT) mice. Arteriolar remodeling was abolished in mice with either CCR2 or CX3CR1-deficient BMCs. In contrast, the loss of CX3CR1 from BMCs, but not CCR2, significantly reduced small venule remodeling compared to WT controls. We conclude that microvascular remodeling is differentially regulated by BMC-expressed chemokine receptors. Both CCR2 and CX3CR1 regulate arteriole growth; however, only BMC-expressed CX3CR1 impacts small venule growth. These findings may provide a basis for additional investigations aimed at determining how patterns of monocyte subpopulation recruitment spatially influence microvascular remodeling. PMID:23029475

Morphological remodeling of C. elegans neurons during aging is modified by compromised protein homeostasis

PubMed Central

Vayndorf, Elena M; Scerbak, Courtney; Hunter, Skyler; Neuswanger, Jason R; Toth, Marton; Parker, J Alex; Neri, Christian; Driscoll, Monica; Taylor, Barbara E

2016-01-01

Understanding cellular outcomes, such as neuronal remodeling, that are common to both healthy and diseased aging brains is essential to the development of successful brain aging strategies. Here, we used Caenorhabdits elegans to investigate how the expression of proteotoxic triggers, such as polyglutamine (polyQ)-expanded huntingtin and silencing of proteostasis regulators, such as the ubiquitin–proteasome system (UPS) and protein clearance components, may impact the morphological remodeling of individual neurons as animals age. We examined the effects of disrupted proteostasis on the integrity of neuronal cytoarchitecture by imaging a transgenic C. elegans strain in which touch receptor neurons express the first 57 amino acids of the human huntingtin (Htt) gene with expanded polyQs (128Q) and by using neuron-targeted RNA interference in adult wild-type neurons to knockdown genes encoding proteins involved in proteostasis. We found that proteostatic challenges conferred by polyQ-expanded Htt and knockdown of specific genes involved in protein homeostasis can lead to morphological changes that are restricted to specific domains of specific neurons. The age-associated branching of PLM neurons is suppressed by N-ter polyQ-expanded Htt expression, whereas ALM neurons with polyQ-expanded Htt accumulate extended outgrowths and other soma abnormalities. Furthermore, knockdown of genes important for ubiquitin-mediated degradation, lysosomal function, and autophagy modulated these age-related morphological changes in otherwise normal neurons. Our results show that the expression of misfolded proteins in neurodegenerative disease such as Huntington’s disease modifies the morphological remodeling that is normally associated with neuronal aging. Our results also show that morphological remodeling of healthy neurons during aging can be regulated by the UPS and other proteostasis pathways. Collectively, our data highlight a model in which morphological remodeling during

Extensive gene remodeling in the viral world: new evidence for nongradual evolution in the mobilome network.

PubMed

Jachiet, Pierre-Alain; Colson, Philippe; Lopez, Philippe; Bapteste, Eric

2014-08-07

Complex nongradual evolutionary processes such as gene remodeling are difficult to model, to visualize, and to investigate systematically. Despite these challenges, the creation of composite (or mosaic) genes by combination of genetic segments from unrelated gene families was established as an important adaptive phenomena in eukaryotic genomes. In contrast, almost no general studies have been conducted to quantify composite genes in viruses. Although viral genome mosaicism has been well-described, the extent of gene mosaicism and its rules of emergence remain largely unexplored. Applying methods from graph theory to inclusive similarity networks, and using data from more than 3,000 complete viral genomes, we provide the first demonstration that composite genes in viruses are 1) functionally biased, 2) involved in key aspects of the arm race between cells and viruses, and 3) can be classified into two distinct types of composite genes in all viral classes. Beyond the quantification of the widespread recombination of genes among different viruses of the same class, we also report a striking sharing of genetic information between viruses of different classes and with different nucleic acid types. This latter discovery provides novel evidence for the existence of a large and complex mobilome network, which appears partly bound by the sharing of genetic information and by the formation of composite genes between mobile entities with different genetic material. Considering that there are around 10E31 viruses on the planet, gene remodeling appears as a hugely significant way of generating and moving novel sequences between different kinds of organisms on Earth. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Organization and dynamics of the actin cytoskeleton during dendritic spine morphological remodeling.

PubMed

Chazeau, Anaël; Giannone, Grégory

2016-08-01

In the central nervous system, most excitatory post-synapses are small subcellular structures called dendritic spines. Their structure and morphological remodeling are tightly coupled to changes in synaptic transmission. The F-actin cytoskeleton is the main driving force of dendritic spine remodeling and sustains synaptic plasticity. It is therefore essential to understand how changes in synaptic transmission can regulate the organization and dynamics of actin binding proteins (ABPs). In this review, we will provide a detailed description of the organization and dynamics of F-actin and ABPs in dendritic spines and will discuss the current models explaining how the actin cytoskeleton sustains both structural and functional synaptic plasticity.

Design and testing of botanical thermotropic actuator mechanisms in thermally adaptive building coverings

NASA Astrophysics Data System (ADS)

Barrett, Ronald M.; Barrett, Ronald P.; Barrett, Cassandra M.

2017-09-01

This paper lays out the inspiration, operational principles, analytical modeling and coupon testing of a new class of thermally adaptive building coverings. The fundamental driving concepts for these coverings are derived from various families of thermotropic plant structures. Certain plant cellular structures like those in Mimosa pudica (Sensitive Plant), Rhododendron leaves or Albizia julibrissin (Mimosa Tree), exhibit actuation physiology which depends on changes in cellular turgor pressures to generate motion. This form of cellular action via turgor pressure manipulation is an inspiration for a new field of thermally adaptive building coverings which use various forms of cellular foam to aid or enable actuation much like plant cells are used to move leaves. When exposed to high solar loading, the structures use the inherent actuation capability of pockets of air trapped in closed cell foam as actuators to curve plates upwards and outwards. When cold, these same structures curve back towards the building forming large convex pockets of dead air to insulate the building. This paper describes basic classical laminated plate theory models comparing theory and experiment of such coupons containing closed-cell foam actuators. The study concludes with a global description of the effectiveness of this class of thermally adaptive building coverings.

CREB Selectively Controls Learning-Induced Structural Remodeling of Neurons

ERIC Educational Resources Information Center

Middei, Silvia; Spalloni, Alida; Longone, Patrizia; Pittenger, Christopher; O'Mara, Shane M.; Marie, Helene; Ammassari-Teule, Martine

2012-01-01

The modulation of synaptic strength associated with learning is post-synaptically regulated by changes in density and shape of dendritic spines. The transcription factor CREB (cAMP response element binding protein) is required for memory formation and in vitro dendritic spine rearrangements, but its role in learning-induced remodeling of neurons…

New angiotensin II type 1 receptor blocker, azilsartan, attenuates cardiac remodeling after myocardial infarction.

PubMed

Nakamura, Yuichi; Suzuki, Satoshi; Saitoh, Shu-ichi; Takeishi, Yasuchika

2013-01-01

After an acute myocardial infarction (MI), neurohumoral systems including renin-angiotensin-aldosterone system (RAAS) are activated which in turn aggravate cardiac remodeling. Angiotensin receptor blockers (ARBs) are useful drugs for suppression of RAAS. The purpose of this study was to evaluate a new ARB, azilsartan, for suppressing cardiac remodeling and progression to heart failure after MI. We created MI by left anterior descending coronary artery ligation in male mice, and these mice were orally administered saline (0.2 mL) in the control group (Group C), 0.1 mg/kg/d of azilsartan in the low dose group (Group L), and 1.0 mg/kg/d in the high dose group (Group H) everyday. Blood pressure was decreased in Group H, but not in Group L, compared to Group C. At 2 weeks after MI creation, infarct size and fibrotic change at the site remote to the myocardial infarcted area were attenuated in Group L and Group H compared to Group C. Echocardiography revealed that cardiac remodeling was suppressed in Group L and Group H compared to Group C. Increases of mRNA expression levels related to fibrotic change were attenuated in Group L and Group H compared to Group C. The new ARB, azilsartan, had a cardiac remodeling suppression effect after MI, and this effect was observed without blood pressure lowering.

Antenatal Hypoxia and Pulmonary Vascular Function and Remodeling

PubMed Central

Papamatheakis, Demosthenes G.; Blood, Arlin B.; Kim, Joon H.; Wilson, Sean M.

2015-01-01

This review provides evidence that antenatal hypoxia, which represents a significant and worldwide problem, causes prenatal programming of the lung. A general overview of lung development is provided along with some background regarding transcriptional and signaling systems of the lung. The review illustrates that antenatal hypoxic stress can induce a continuum of responses depending on the species examined. Fetuses and newborns of certain species and specific human populations are well acclimated to antenatal hypoxia. However, antenatal hypoxia causes pulmonary vascular disease in fetuses and newborns of most mammalian species and humans. Disease can range from mild pulmonary hypertension, to severe vascular remodeling and dangerous elevations in pressure. The timing, length, and magnitude of the intrauterine hypoxic stress are important to disease development, however there is also a genetic-environmental relationship that is not yet completely understood. Determining the origins of pulmonary vascular remodeling and pulmonary hypertension and their associated effects is a challenging task, but is necessary in order to develop targeted therapies for pulmonary hypertension in the newborn due to antenatal hypoxia that can both treat the symptoms and curtail or reverse disease progression. PMID:24063380

Mechanisms of bone remodeling: implications for clinical practice.

PubMed

Kenny, Anne M; Raisz, Lawrence G

2002-01-01

The adult skeleton undergoes continuous remodeling. The remodeling cycle involves the interaction of cells of osteoblastic and osteoclastic lineage and is regulated by both systemic hormones and local factors. In addition to the systemic calcium-regulating hormones, parathyroid hormone, 1,25-dihydroxy vitamin D and calcitonin, sex hormones play an important role. Estrogen has been identified as the major inhibitor of bone resorption in both men and women. Androgen is important not only as a source of estrogen, through the action of aromatase, but also for its direct effect in stimulating bone formation. The effects of sex hormones may be mediated by their ability to alter the secretion of local cytokines, prostaglandins and growth factors. Sex hormone action is also modulated by the level of sex hormone-binding globulin in the circulation. A more precise analysis of these effects has been made possible by the development of new methods of measuring not only bone mineral density, but also relative rates of bone formation and resorption using biochemical markers. These new approaches have allowed us to define more precisely the specific roles of androgens, estrogens and other regulatory hormones in human skeletal physiology and pathophysiology.

TDP-43 Promotes Neurodegeneration by Impairing Chromatin Remodeling.

PubMed

Berson, Amit; Sartoris, Ashley; Nativio, Raffaella; Van Deerlin, Vivianna; Toledo, Jon B; Porta, Sílvia; Liu, Shichong; Chung, Chia-Yu; Garcia, Benjamin A; Lee, Virginia M-Y; Trojanowski, John Q; Johnson, F Brad; Berger, Shelley L; Bonini, Nancy M

2017-12-04

Regulation of chromatin structure is critical for brain development and function. However, the involvement of chromatin dynamics in neurodegeneration is less well understood. Here we find, launching from Drosophila models of amyotrophic lateral sclerosis and frontotemporal dementia, that TDP-43 impairs the induction of multiple key stress genes required to protect from disease by reducing the recruitment of the chromatin remodeler Chd1 to chromatin. Chd1 depletion robustly enhances TDP-43-mediated neurodegeneration and promotes the formation of stress granules. Conversely, upregulation of Chd1 restores nucleosomal dynamics, promotes normal induction of protective stress genes, and rescues stress sensitivity of TDP-43-expressing animals. TDP-43-mediated impairments are conserved in mammalian cells, and, importantly, the human ortholog CHD2 physically interacts with TDP-43 and is strikingly reduced in level in temporal cortex of human patient tissue. These findings indicate that TDP-43-mediated neurodegeneration causes impaired chromatin dynamics that prevents appropriate expression of protective genes through compromised function of the chromatin remodeler Chd1/CHD2. Enhancing chromatin dynamics may be a treatment approach to amyotrophic lateral scleorosis (ALS)/frontotemporal dementia (FTD). Copyright © 2017 Elsevier Ltd. All rights reserved.

Vascular Remodelling and Mesenchymal Transition in Systemic Sclerosis

PubMed Central

Nicolosi, Pier Andrea; Tombetti, Enrico; Maugeri, Norma; Rovere-Querini, Patrizia; Brunelli, Silvia; Manfredi, Angelo A.

2016-01-01

Fibrosis of the skin and of internal organs, autoimmunity, and vascular inflammation are hallmarks of Systemic Sclerosis (SSc). The injury and activation of endothelial cells, with hyperplasia of the intima and eventual obliteration of the vascular lumen, are early features of SSc. Reduced capillary blood flow coupled with deficient angiogenesis leads to chronic hypoxia and tissue ischemia, enforcing a positive feed-forward loop sustaining vascular remodelling, further exacerbated by extracellular matrix accumulation due to fibrosis. Despite numerous developments and a growing number of controlled clinical trials no treatment has been shown so far to alter SSc natural history, outlining the need of further investigation in the molecular pathways involved in the pathogenesis of the disease. We review some processes potentially involved in SSc vasculopathy, with attention to the possible effect of sustained vascular inflammation on the plasticity of vascular cells. Specifically we focus on mesenchymal transition, a key phenomenon in the cardiac and vascular development as well as in the remodelling of injured vessels. Recent work supports the role of transforming growth factor-beta, Wnt, and Notch signaling in these processes. Importantly, endothelial-mesenchymal transition may be reversible, possibly offering novel cues for treatment. PMID:27069480

Integrative models of vascular remodeling during tumor growth

PubMed Central

Rieger, Heiko; Welter, Michael

2015-01-01

Malignant solid tumors recruit the blood vessel network of the host tissue for nutrient supply, continuous growth, and gain of metastatic potential. Angiogenesis (the formation of new blood vessels), vessel cooption (the integration of existing blood vessels into the tumor vasculature), and vessel regression remodel the healthy vascular network into a tumor-specific vasculature that is in many respects different from the hierarchically organized arterio-venous blood vessel network of the host tissues. Integrative models based on detailed experimental data and physical laws implement in silico the complex interplay of molecular pathways, cell proliferation, migration, and death, tissue microenvironment, mechanical and hydrodynamic forces, and the fine structure of the host tissue vasculature. With the help of computer simulations high-precision information about blood flow patterns, interstitial fluid flow, drug distribution, oxygen and nutrient distribution can be obtained and a plethora of therapeutic protocols can be tested before clinical trials. In this review, we give an overview over the current status of integrative models describing tumor growth, vascular remodeling, blood and interstitial fluid flow, drug delivery, and concomitant transformations of the microenvironment. © 2015 The Authors. WIREs Systems Biology and Medicine published by Wiley Periodicals, Inc. PMID:25808551

Lab-on-a-chip platforms for quantification of multicellular interactions in bone remodeling.

PubMed

George, Estee L; Truesdell, Sharon L; York, Spencer L; Saunders, Marnie M

2018-04-01

Researchers have been using lab-on-a-chip systems to isolate factors for study, simulate laboratory analysis and model cellular, tissue and organ level processes. The technology is increasing rapidly, but the bone field has been slow to keep pace. Novel models are needed that have the power and flexibility to investigate the elegant and synchronous multicellular interactions that occur in normal bone turnover and in disease states in which remodeling is implicated. By removing temporal and spatial limitations and enabling quantification of functional outcomes, the platforms should provide unique environments that are more biomimetic than single cell type systems while minimizing complex systemic effects of in vivo models. This manuscript details the development and characterization of lab-on-a-chip platforms for stimulating osteocytes and quantifying bone remodeling. Our platforms provide the foundation for a model that can be used to investigate remodeling interactions as a whole or as a standard mechanotransduction tool by which isolated activity can be quantified as a function of load. Copyright © 2018 Elsevier Inc. All rights reserved.

Maintenance of neural progenitor cell stemness in 3D hydrogels requires matrix remodelling

NASA Astrophysics Data System (ADS)

Madl, Christopher M.; Lesavage, Bauer L.; Dewi, Ruby E.; Dinh, Cong B.; Stowers, Ryan S.; Khariton, Margarita; Lampe, Kyle J.; Nguyen, Duong; Chaudhuri, Ovijit; Enejder, Annika; Heilshorn, Sarah C.

2017-12-01

Neural progenitor cell (NPC) culture within three-dimensional (3D) hydrogels is an attractive strategy for expanding a therapeutically relevant number of stem cells. However, relatively little is known about how 3D material properties such as stiffness and degradability affect the maintenance of NPC stemness in the absence of differentiation factors. Over a physiologically relevant range of stiffness from ~0.5 to 50 kPa, stemness maintenance did not correlate with initial hydrogel stiffness. In contrast, hydrogel degradation was both correlated with, and necessary for, maintenance of NPC stemness. This requirement for degradation was independent of cytoskeletal tension generation and presentation of engineered adhesive ligands, instead relying on matrix remodelling to facilitate cadherin-mediated cell-cell contact and promote β-catenin signalling. In two additional hydrogel systems, permitting NPC-mediated matrix remodelling proved to be a generalizable strategy for stemness maintenance in 3D. Our findings have identified matrix remodelling, in the absence of cytoskeletal tension generation, as a previously unknown strategy to maintain stemness in 3D.

Maintenance of Neural Progenitor Cell Stemness in 3D Hydrogels Requires Matrix Remodeling

PubMed Central

Madl, Christopher M.; LeSavage, Bauer L.; Dewi, Ruby E.; Dinh, Cong B.; Stowers, Ryan S.; Khariton, Margarita; Lampe, Kyle J.; Nguyen, Duong; Chaudhuri, Ovijit; Enejder, Annika; Heilshorn, Sarah C.

2017-01-01

Neural progenitor cell (NPC) culture within 3D hydrogels is an attractive strategy for expanding a therapeutically-relevant number of stem cells. However, relatively little is known about how 3D material properties such as stiffness and degradability affect the maintenance of NPC stemness in the absence of differentiation factors. Over a physiologically-relevant range of stiffness from ~0.5–50 kPa, stemness maintenance did not correlate with initial hydrogel stiffness. In contrast, hydrogel degradation was both correlated with, and necessary for, maintenance of NPC stemness. This requirement for degradation was independent of cytoskeletal tension generation and presentation of engineered adhesive ligands, instead relying on matrix remodeling to facilitate cadherin-mediated cell-cell contact and promote β-catenin signaling. In two additional hydrogel systems, permitting NPC-mediated matrix remodeling proved to be a generalizable strategy for stemness maintenance in 3D. Our findings have identified matrix remodeling, in the absence of cytoskeletal tension generation, as a previously unknown strategy to maintain stemness in 3D. PMID:29115291

Piezo1 in Smooth Muscle Cells Is Involved in Hypertension-Dependent Arterial Remodeling.

PubMed

Retailleau, Kevin; Duprat, Fabrice; Arhatte, Malika; Ranade, Sanjeev Sumant; Peyronnet, Rémi; Martins, Joana Raquel; Jodar, Martine; Moro, Céline; Offermanns, Stefan; Feng, Yuanyi; Demolombe, Sophie; Patel, Amanda; Honoré, Eric

2015-11-10

The mechanically activated non-selective cation channel Piezo1 is a determinant of vascular architecture during early development. Piezo1-deficient embryos die at midgestation with disorganized blood vessels. However, the role of stretch-activated ion channels (SACs) in arterial smooth muscle cells in the adult remains unknown. Here, we show that Piezo1 is highly expressed in myocytes of small-diameter arteries and that smooth-muscle-specific Piezo1 deletion fully impairs SAC activity. While Piezo1 is dispensable for the arterial myogenic tone, it is involved in the structural remodeling of small arteries. Increased Piezo1 opening has a trophic effect on resistance arteries, influencing both diameter and wall thickness in hypertension. Piezo1 mediates a rise in cytosolic calcium and stimulates activity of transglutaminases, cross-linking enzymes required for the remodeling of small arteries. In conclusion, we have established the connection between an early mechanosensitive process, involving Piezo1 in smooth muscle cells, and a clinically relevant arterial remodeling. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Quantitation of maxillary remodeling. 2. Masking of remodeling effects when an "anatomical" method of superimposition is used in the absence of metallic implants.

PubMed

Baumrind, S; Korn, E L; Ben-Bassat, Y; West, E E

1987-06-01

We report the results of a study aimed at quantifying the differences in the perceived pattern of maxillary remodeling that are observed when different methods are used to superimpose maxillary images in roentgenographic cephalometrics. In a previous article, we reported cumulative changes in the positions of anterior nasal spine (ANS), posterior nasal spine (PNS), and Point A for a sample of 31 subjects with maxillary metallic implants. Measurements had been made on lateral cephalograms taken at annual intervals relative to superimposition on the implants. In the present article, we quantify the differences in the perceived displacement of the same landmarks in the same sample when a standard "anatomical best bit" rule was used in lieu of superimposition on the implants. The anatomical best fit superimposition as herein defined was found in this sample to lose important information on the downward remodeling of the superior surface of the maxilla that had been detected when the implant superimposition was used. In fact, we observed a small artifactual upward displacement of the ANS-PNS line. In the anteroposterior direction, the tendency toward backward displacement of skeletal landmarks through time that had been detected with the implant superimposition was replaced by a small forward displacement of ANS and Point A together with reduced backward displacement of PNS. To the extent that the implant superimposition is to be considered the true and correct one, the anatomical best fit superimposition appears to understate the true downward remodeling of the palate by an average of about 0.3 and 0.4 mm per year, although this value differs at different ages and timepoints. The anatomical best fit superimposition also misses entirely the small mean tendency toward backward remodeling that was observed when the implant superimposition was used. In situations in which there are no implants, clinicians and research workers must necessarily continue to use anatomically

JAFCO d/b/a Paul Davis Restoration and Remodeling Information Sheet

EPA Pesticide Factsheets

JAFCO d/b/a Paul Davis Restoration and Remodeling (the Company) is located in Memphis, Tennessee. The settlement involves renovation activities conducted at property constructed prior to 1978, located in Memphis, Tennessee.

Nutritional strategies to modulate the adaptive response to endurance training.

PubMed

Hawley, John A

2013-01-01

In recent years, advances in molecular biology have allowed scientists to elucidate how endurance exercise training stimulates skeletal muscle remodeling (i.e. promotes mitochondrial biogenesis). A growing field of interest directly arising from our understanding of the molecular bases of training adaptation is how nutrient availability can alter the regulation of many contraction-induced events in muscle in response to endurance exercise. Acutely manipulating substrate availability can exert profound effects on muscle energy stores and patterns of fuel metabolism during exercise, as well as many processes activating gene expression and cell signaling. Accordingly, such interventions when repeated over weeks and months have the potential to modulate numerous adaptive processes in skeletal muscle that ultimately drive the phenotype-specific characteristics observed in highly trained athletes. In this review, the molecular and cellular events that occur in skeletal muscle during and after endurance exercise are discussed and evidence provided to demonstrate that nutrient availability plays an important role in modulating many of the adaptive responses to training. Emphasis is on human studies that have determined the regulatory role of muscle glycogen availability on cell metabolism, endurance training capacity and performance. Copyright © 2013 Nestec Ltd., Vevey/S. Karger AG, Basel.

Bio-Adaption between Magnesium Alloy Stent and the Blood Vessel: A Review.

PubMed

Ma, Jun; Zhao, Nan; Betts, Lexxus; Zhu, Donghui

2016-09-01

Biodegradable magnesium (Mg) alloy stents are the most promising next generation of bio-absorbable stents. In this article, we summarized the progresses on the in vitro studies, animal testing and clinical trials of biodegradable Mg alloy stents in the past decades. These exciting findings led us to propose the importance of the concept "bio-adaption" between the Mg alloy stent and the local tissue microenvironment after implantation. The healing responses of stented blood vessel can be generally described in three overlapping phases: inflammation, granulation and remodeling. The ideal bio-adaption of the Mg alloy stent, once implanted into the blood vessel, needs to be a reasonable function of the time and the space/dimension. First, a very slow degeneration of mechanical support is expected in the initial four months in order to provide sufficient mechanical support to the injured vessels. Although it is still arguable whether full mechanical support in stented lesions is mandatory during the first four months after implantation, it would certainly be a safety design parameter and a benchmark for regulatory evaluations based on the fact that there is insufficient human in vivo data available, especially the vessel wall mechanical properties during the healing/remodeling phase. Second, once the Mg alloy stent being degraded, the void space will be filled by the regenerated blood vessel tissues. The degradation of the Mg alloy stent should be 100% completed with no residues, and the degradation products (e.g., ions and hydrogen) will be helpful for the tissue reconstruction of the blood vessel. Toward this target, some future research perspectives are also discussed.

Cardiolipin Fatty Acid Remodeling Regulates Mitochondrial Function by Modifying the Electron Entry Point in the Respiratory Chain

PubMed Central

Vergeade, Aurelia; Bertram, Clinton C.; Bikineyeva, Alfiya T.; Zackert, William E.; Zinkel, Sandra S.; May, James M.; Dikalov, Sergey I.; Roberts, L. Jackson; Boutaud, Olivier

2016-01-01

Modifications of cardiolipin (CL) levels or compositions are associated with changes in mitochondrial function in a wide range of pathologies. We have made the discovery that acetaminophen remodels CL fatty acids composition from tetralinoleoyl to linoleoyltrioleoyl-CL, a remodeling that is associated with decreased mitochondrial respiration. Our data show that CL remodeling causes a shift in electron entry from complex II to the β-oxidation electron transfer flavoprotein quinone oxidoreductase (ETF/QOR) pathway. These data demonstrate that electron entry in the respiratory chain is regulated by CL fatty acid composition and provide proof-of-concept that pharmacological intervention can be used to modify CL composition. PMID:27085476

Membrane remodeling, an early event in benzo[alpha]pyrene-induced apoptosis

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

Tekpli, Xavier; Rissel, Mary; Huc, Laurence

2010-02-15

Benzo[alpha]pyrene (B[alpha]P) often serves as a model for mutagenic and carcinogenic polycyclic aromatic hydrocarbons (PAHs). Our previous work suggested a role of membrane fluidity in B[alpha]P-induced apoptotic process. In this study, we report that B[alpha]P modifies the composition of cholesterol-rich microdomains (lipid rafts) in rat liver F258 epithelial cells. The cellular distribution of the ganglioside-GM1 was markedly changed following B[alpha]P exposure. B[alpha]P also modified fatty acid composition and decreased the cholesterol content of cholesterol-rich microdomains. B[alpha]P-induced depletion of cholesterol in lipid rafts was linked to a reduced expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase). Aryl hydrocarbon receptor (AhR) and B[alpha]P-related H{submore » 2}O{sub 2} formation were involved in the reduced expression of HMG-CoA reductase and in the remodeling of membrane microdomains. The B[alpha]P-induced membrane remodeling resulted in an intracellular alkalinization observed during the early phase of apoptosis. In conclusion, B[alpha]P altered the composition of plasma membrane microstructures through AhR and H{sub 2}O{sub 2} dependent-regulation of lipid biosynthesis. In F258 cells, the B[alpha]P-induced membrane remodeling was identified as an early apoptotic event leading to an intracellular alkalinization.« less

∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis.

PubMed

Pankow, Sandra; Bamberger, Casimir; Calzolari, Diego; Martínez-Bartolomé, Salvador; Lavallée-Adam, Mathieu; Balch, William E; Yates, John R

2015-12-24

Deletion of phenylalanine 508 of the cystic fibrosis transmembrane conductance regulator (∆F508 CFTR) is the major cause of cystic fibrosis, one of the most common inherited childhood diseases. The mutated CFTR anion channel is not fully glycosylated and shows minimal activity in bronchial epithelial cells of patients with cystic fibrosis. Low temperature or inhibition of histone deacetylases can partly rescue ∆F508 CFTR cellular processing defects and function. A favourable change of ∆F508 CFTR protein-protein interactions was proposed as a mechanism of rescue; however, CFTR interactome dynamics during temperature shift and inhibition of histone deacetylases are unknown. Here we report the first comprehensive analysis of the CFTR and ∆F508 CFTR interactome and its dynamics during temperature shift and inhibition of histone deacetylases. By using a novel deep proteomic analysis method, we identify 638 individual high-confidence CFTR interactors and discover a ∆F508 deletion-specific interactome, which is extensively remodelled upon rescue. Detailed analysis of the interactome remodelling identifies key novel interactors, whose loss promote ∆F508 CFTR channel function in primary cystic fibrosis epithelia or which are critical for CFTR biogenesis. Our results demonstrate that global remodelling of ∆F508 CFTR interactions is crucial for rescue, and provide comprehensive insight into the molecular disease mechanisms of cystic fibrosis caused by deletion of F508.

Suppressed bone remodeling in black bears conserves energy and bone mass during hibernation

PubMed Central

McGee-Lawrence, Meghan; Buckendahl, Patricia; Carpenter, Caren; Henriksen, Kim; Vaughan, Michael; Donahue, Seth

2015-01-01

ABSTRACT Decreased physical activity in mammals increases bone turnover and uncouples bone formation from bone resorption, leading to hypercalcemia, hypercalcuria, bone loss and increased fracture risk. Black bears, however, are physically inactive for up to 6 months annually during hibernation without losing cortical or trabecular bone mass. Bears have been shown to preserve trabecular bone volume and architectural parameters and cortical bone strength, porosity and geometrical properties during hibernation. The mechanisms that prevent disuse osteoporosis in bears are unclear as previous studies using histological and serum markers of bone remodeling show conflicting results. However, previous studies used serum markers of bone remodeling that are known to accumulate with decreased renal function, which bears have during hibernation. Therefore, we measured serum bone remodeling markers (BSALP and TRACP) that do not accumulate with decreased renal function, in addition to the concentrations of serum calcium and hormones involved in regulating bone remodeling in hibernating and active bears. Bone resorption and formation markers were decreased during hibernation compared with when bears were physically active, and these findings were supported by histomorphometric analyses of bone biopsies. The serum concentration of cocaine and amphetamine regulated transcript (CART), a hormone known to reduce bone resorption, was 15-fold higher during hibernation. Serum calcium concentration was unchanged between hibernation and non-hibernation seasons. Suppressed and balanced bone resorption and formation in hibernating bears contributes to energy conservation, eucalcemia and the preservation of bone mass and strength, allowing bears to survive prolonged periods of extreme environmental conditions, nutritional deprivation and anuria. PMID:26157160

Multiscale molecular dynamics simulations of membrane remodeling by Bin/Amphiphysin/Rvs family proteins

NASA Astrophysics Data System (ADS)

Chun, Chan; Haohua, Wen; Lanyuan, Lu; Jun, Fan

2016-01-01

Membrane curvature is no longer thought of as a passive property of the membrane; rather, it is considered as an active, regulated state that serves various purposes in the cell such as between cells and organelle definition. While transport is usually mediated by tiny membrane bubbles known as vesicles or membrane tubules, such communication requires complex interplay between the lipid bilayers and cytosolic proteins such as members of the Bin/Amphiphysin/Rvs (BAR) superfamily of proteins. With rapid developments in novel experimental techniques, membrane remodeling has become a rapidly emerging new field in recent years. Molecular dynamics (MD) simulations are important tools for obtaining atomistic information regarding the structural and dynamic aspects of biological systems and for understanding the physics-related aspects. The availability of more sophisticated experimental data poses challenges to the theoretical community for developing novel theoretical and computational techniques that can be used to better interpret the experimental results to obtain further functional insights. In this review, we summarize the general mechanisms underlying membrane remodeling controlled or mediated by proteins. While studies combining experiments and molecular dynamics simulations recall existing mechanistic models, concurrently, they extend the role of different BAR domain proteins during membrane remodeling processes. We review these recent findings, focusing on how multiscale molecular dynamics simulations aid in understanding the physical basis of BAR domain proteins, as a representative of membrane-remodeling proteins. Project supported by the National Natural Science Foundation of China (Grant No. 21403182) and the Research Grants Council of Hong Kong, China (Grant No. CityU 21300014).