bluuebunny/crossref_metadata_2025_split huggingface dataset:
N‐cadherin Signaling via RhoGEF Trio Stabilizes VE‐cadherin Junctions and Regulates Vascular Permeability
Authors: Kruse Kevin Jonathan , Lee Quinn , Sun Ying , Yang Xiaoyan , Klomp Jeff , Huang Fei , Vogel Stephen , Tai Leon M. , Malik Asrar B. , Shin Jae Won , Komarova Yulia A. 
Published: June 2021

Capillary endothelial cells express Vascular Endothelial (VE)‐ and Neural (N)‐cadherin, with overlapping functions. VE‐cadherin forms homotypic adhesion between endothelial cells whereas N‐cadherin forms heterotypic adhesion with the surrounding pericytes in capillary endothelia. Endothelial specific deletions of Cdh2 (N‐cadherin) or Cdh5 (VE‐cadherin) in mice demonstrated poorly formed leaky capillaries and in utero death at E9.5 due to defective angiogenesis. These findings raise the question of whether N‐ and VE‐cadherin function independently or whether N‐cadherin activated signaling regulates the assembly of VE‐cadherin and thereby the formation of adherens junctions. We investigated the role of N‐cadherin in the formation of VE‐cadherin junctions using mouse genetic models and identifying N‐cadherin signaling pathways in endothelial monolayers. We show that N‐cadherin functions by interacting with the RhoGEF Trio to activate the RhoGTPases Rac1 and RhoA in nascent adherens junctions, inducing the recruitment of VE‐cadherin. This N‐cadherin activated signaling pathway is essential for maximal VE‐cadherin assembly and the formation of the endothelial junctional barrier.Support or Funding InformationSupported by NIH grant R01 HL103922 to Y.A.K.; AHA AWARD 16PRE27260230 to K.K.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Validation of Evans Blue inhibits Compound 48/80 induced inflammation in hypertension rat models
Authors: Lue Sheng‐I , Lu Tzongshi , Fu Yaw‐Syan 
Published: June 2021

BackgroundHypertension (HT) is a multifactorial cardiovascular disorder involves in variety genetic and environmental factors, and it is a major risk factor for cardiovascular disease. In order to study the pathophysiology of HT, the proper robust and reproducible experimental animal models are required. Phase‐1 hypertension (P1‐HT) is the beginning stage of high blood pressure (BP). The ideal P1‐HT animal model should have human‐like cardiovascular anatomy, hemodynamics, and physiology that includes genetic and non‐genetic models. Moreover, inflammation responses may cause plasma leakage and affect BT readings in experimental animals. Among current HT rat models, Spontaneously Hypertensive Rats (SHR) with both neural and vascular alterations is the most commonly used genetic HT animal model. In this study, we investigated inflammatory mediators' effects and responses in correlation with BP readings among current commercial available SD/SHR rats and our new breeding P1‐HT rat to further calibrating BP readings in variety rat HT models.MethodsHistamine, Capsaicin, Compound 48/80 or Substance P were administered into the femoral vein of rats individually to induce inflammation and vascular dysfunction. Then we analyzed mean arterial pressure (MAP) and analyze plasma extravasation using Evans Blue dye. One Way ANOVA with Bonferroni correction and linear regression were used for statistics. Statistical significances were set at a P< 0.05.ResultsOur data showed significant negative linear regression on the degree of plasma extravasation with BP changes in substance P induced neurogenic inflammation but positive linear regression in compound 48/80 induced immunogenic inflammation. In addition, pretreated with Evans blue dye could inhibit compound 48/80 induced extensive plasma extravasation, mast cell degranulation, and edema significantly. In addition, our data show significant variation BP readings among neurogenic and immunogenic inflammation induced BP changes in different rat HT models.ConclusionOur data shows for the first time that methodical variations observed among normal and hypertensive animals, can potentially translate into differential BP patterns, which can be falsely taken to generate significant biological bias. Our study therefore highlights the pivotal need in interpretation of BP data using different HT rat models in the study.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Single nephron proteomes connect morphology and function in proteinuric kidney disease
Authors: Rinschen Markus 
Published: June 2021

In diseases of many parenchymatous organs, heterogeneous deterioration of individual functional units determines the clinical prognosis. However, the molecular characterization at the level of such individual subunits remains a technological challenge that needs to be addressed in order to better understand pathological mechanisms. Proteinuric glomerular kidney disease is a frequent and heterogeneous disease which affects a fraction of glomeruli and their draining tubules to variable extents, and for which no specific treatment exists.Here, we developed and applied a mass spectrometry‐based methodology to investigate heterogeneity of proteomes from individually isolated nephron segments from mice and patients with proteinuric kidney disease. In single glomeruli from two different mouse models of sclerotic glomerular disease, we identified a coherent protein expression module consisting of extracellular matrix protein deposition (reflecting glomerular sclerosis), glomerular albumin (reflecting proteinuria) and LAMP1, a lysosomal protein. This module was associated with a loss of podocyte marker proteins while genetic ablation of LAMP1‐correlated lysosomal proteases could ameliorate glomerular damage in vivo. Furthermore, MS analyses of individual glomeruli from patients with genetic sclerotic and non‐sclerotic proteinuric diseases revealed increased abundance of lysosomal proteins, in combination with a decreased abundance of the mutated gene product, nephrin. Up to 2000 proteins were quantified in an individual glomerulus.In conclusion we show that altered protein homeostasis (proteostasis) is a conserved key mechanism in proteinuric kidney diseases. Moreover, the “one‐nephron‐one‐proteome” technology developed here can capture intraindividual variability in diseases of the kidney and other tissues at a sub‐biopsy scale.Support or Funding InformationMMR was supported by the DFG.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Obese Mice Are Protected From Increased Energy Intake in Response to Voluntary Wheel Running
Authors: Kwan Jamie R. , Lark Daniel Stephen , Lantier Louise , Wasserman David H. 
Published: June 2021

Diseases of metabolism pose an increasing threat to public health that has led to greater demand for effective treatments. Obesity is a highly prevalent metabolic disease that afflicts over 100 million Americans and increases the risk of developing diabetes and cardiovascular disease. Lifestyle modifications that incorporate exercise are a standard prescription for obesity, but its effectiveness is limited due to variability in compliance and physiological adaptations (e.g. compensatory increases in energy intake). Previous studies have shown that voluntary exercise fails to induce weight loss in high fat fed mice, but little is known regarding the onset of exercise. Here, we tested the hypothesis that chronic overnutrition from high fat feeding will mitigate the compensatory increase in food intake that commonly accompanies increased energy expenditure from voluntary exercise.Starting at 12 weeks of age, male C57BL/6J mice were weight matched, singly housed and fed a chow (n=8) or high fat diet (HFD; 60% calories from fat; n=6) for 4 weeks. At 18 weeks of age, mice were housed in a Promethion Metabolic Analyzer to measure energy expenditure, food intake and physical activity. Experiments were performed at 21°C with running wheels locked for four days then unlocked for the subsequent nine days. Body composition was assessed both prior to and immediately following indirect calorimetry experiments. Ethoscan (Sable Systems) analysis was performed to examine voluntary wheel running (VWR) distance, duration and speed and measured the time and distance for off‐wheel activities (i.e. roaming and feeding).HF‐fed mice were heavier (WT: 26.9 ± 1.1 vs. HF: 36.8 ± 4.2 g; p < 0.05) and had greater fat mass (WT: 3.5 ± 0.6 vs. HF: 11.1 ± 3.1 g; p < 0.05) than chow‐fed mice prior to energy balance studies. VWR caused a decrease in whole body (WT: −0.3 ± 0.8 vs. HF: −4.0 ± 1.3 g; p > 0.05) and fat mass (WT: 0.3 ± 0.6 vs. HF: −3.0 ± 0.9 g; p < 0.05) in HFD‐fed, but not in chow‐fed mice. VWR distance, duration, and speed were not affected by diet. VWR increased energy expenditure (EE) with both diets equally, but energy intake (EI) only increased in chow‐fed mice. VWR decreased overall off‐wheel activity (OWA) regardless of diet.These data demonstrate that 9 days of VWR cause weight loss in HFD‐fed mice but not mice fed a chow‐diet. Because VWR did not vary between diets, the efficacy of VWR in HFD‐fed mice could instead be attributed to resistance to specific behavioral compensations (i.e. increased food intake) that occur with the introduction of VWR in lean mice.Support or Funding InformationDSL (16POST29910001); D.H.W. (NIH DK054902 and DK076169)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Heart Failure with Reduced Ejection Fraction Causes Limb Muscle Atrophy in Males, but Not Female Rats
Authors: Noriega Andrea M. , Kelley Rachel C. , Goldberg Emma , Ferreira Leonardo F. 
Published: June 2021

Fatigue and muscle weakness are common symptoms in chronic heart failure that significantly compromise patients' quality of life. Skeletal muscle abnormality is an important contributor to these symptoms, independent of cardiac function. Heart failure with reduced ejection fraction (HFrEF) causes histological changes in limb muscles, including changes in muscle fiber type distribution and fiber atrophy. Metabolic alterations often accompany these changes, and several reports show shifts from oxidative to glycolytic fiber phenotype. There are conflicting reports on HFrEF‐related abnormalities in limb muscle. There are approximately 3–4 million patients with HFrEF in the United States, and while the disease is more prevalent in males, it affects a large number of females. Animal studies have largely focused on effects of HFrEF in males whereas studies in humans have included mostly males with mild or moderate HFrEF. We conducted the current study to determine whether the effects of HFrEF on limb muscle abnormalities are dependent on sex and disease severity. We performed myocardial infarction to induce HFrEF or Sham surgery in 8–9 week old male and female Sprague Dawley rats. Animals that underwent MI surgery were grouped into either moderate or severe HFrEF; severe HFrEF was determined by 1) transmural infarct ≥35% of left ventricle and septal area and 2) right ventricle hypertrophy. We have used SMASH code (MatLab) to analyze fiber type distribution and cross‐sectional area (CSA) in cryogenic sections of tibialis anterior of males and females Sham, moderate, and severe HFrEF rats (n=3–4 per group). Compared to Sham, type IIb/x CSA decreased in males with moderate (28% ± 11%) and severe HFrEF (39% ± 5%) (P < 0.05). Female rats with moderate and severe HFrEF had fiber CSA similar to Sham. Fiber type distribution did not change for either males or females animals with CHF compared to Sham. Overall, our initial data show that HFrEF causes muscle atrophy in males independently of disease severity, but not in females. However, we cannot exclude the possibility that limb muscle atrophy occurs in post‐menopausal females with HFrEF.Support or Funding InformationR01‐HL130318 to LFFThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Evolutionarily Conserved Notch‐Dependent and Independent Mechanisms Regulating Hypoxia Tolerance
Authors: Zhou Dan , Xue Jin , Hsiao Yu‐hsin , Stobdan Tsering , Haddad Gabriel G. 
Published: June 2021

Hypoxia tolerance is an important trait for human populations living at high altitude. It is also clinically important for patients suffering from illnesses in which hypoxia represents a critical element in the pathogenesis, such as ischemic stroke, myocardial infarction and solid tumors. Our previous studies and those of others have shown that the mechanisms underlying hypoxia tolerance are polygenic and evolutionarily conserved. Indeed, we and others have found that Notch signaling regulates hypoxia tolerance in both Drosophila melanogaster and humans. However, the mechanistic details underlying Notch‐conferred hypoxia tolerance are largely unknown. By comparing candidate genes identified through whole genome sequencing analysis of hypoxia‐adapted fruit flies and those from genome‐wide single nucleotide polymorphism data from four high‐altitude human populations (i.e., Sherpas, Tibetans, Ethiopians and Andeans), we have identified several, evolutionary conserved genes involved in hypoxia tolerance. In the current study, we developed a novel dual‐USA/Gal4 system to determine genetic interactions between Notch signaling and these conserved genes in terms of hypoxia tolerance. This unique system allows us to activate Notch signaling in the Eaat1 positive cells, which dramatically enhances hypoxia tolerance in flies, and, simultaneously, knockdown a candidate gene in the same glial cells. Using this system, we discovered that Notch‐conferred hypoxia tolerance requires HES1/hairy, FOXC1/croc and ZNF521/Oaz. In contrast, KCND2/Shal and EGFR/Egfr regulate hypoxia tolerance in a Notch‐independent manner. Furthermore, Notch activation can partially rescue lethality under hypoxic condition with FGF/bnl down regulation. In summary, we identified evolutionarily conserved, Notch‐dependent and independent mechanisms regulating hypoxia tolerance. These mechanisms have strong potential to be translated into humans and serve as novel targets for developing therapeutic strategies to treat hypoxia‐related diseases.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Hormonal Drive of Cardiomyocyte Proliferative and Regenerative Potential Loss During the Acquisition of Endothermy
Authors: Huang Guo N. 
Published: June 2021

Across phylogeny and ontogeny, pronounced differences are evident in the ability of organisms to regenerate damaged tissues and organs. However, the underlying mechanisms driving this phenomenon remain enigmatic. Mammalian hearts lose regenerative potential due to cardiomyocyte cell‐cycle withdrawal and polyploidization coinciding with the development of postnatal endothermy. Our phylogenetic analysis of cardiomyocyte ploidy in 41 vertebrate species including those from the clades of the smallest and largest mammals reveals that diploid cardiomyocyte abundance inversely correlates with standard metabolic rate and body temperature, suggesting that cardiac regenerative potential declines during the evolution of endothermy. In a targeted chemical screen we identify thyroid hormones, major metabolic regulators hypothesized to drive the ectotherm‐to‐endotherm transition, as potent triggers of mammalian cardiomyocyte cell‐cycle arrest in vivo. Further pharmacological and genetic manipulations in mice and zebrafish show thyroid hormones inhibit cardiomyocyte proliferation and heart regeneration. Collectively, our data supports a model where species‐specific regulation of thyroid hormone levels determines cardiomyocyte proliferative and regenerative capacity, suggesting that during the acquisition of endothermy in ontogeny and phylogeny, increases of thyroid hormones drive loss of cardiomyocyte regenerative capacity.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Glucocorticoid‐Receptor Mediated Signaling Regulates Lipolysis in Northern Elephant Seal Pups
Authors: Juarez Pablo , Vasquez‐Medina Jose Pablo , Lee Debby , Croker Daniel E. , Ortiz Rudy 
Published: June 2021

Northern elephant seals (NES) experience prolonged 2–3 month fasting periods, relying primarily on the oxidation of fatty acids to meet their energetic needs (RQ=0.71). Although fasting periods are characterized by an increase in circulating cortisol (F) and non‐esterified fatty acids (NEFA's), the functional relevance such increase in cortisol in NES is not defined. We hypothesized that F lipolysis is regulated through glucocorticoid receptor signaling (GR) in NES. The contributions of F and the GR were assessed by exogenous infusions of ACTH and/or concurrent blockade of the GR in the following groups: (1) untreated control, (2) ACTH (80 units intramuscular injection (IM)) and (3) ACTH + GR blocker (RU486) (80 units IM + 400mg RU486 in time release pellets). Plasma, and adipose and muscle biopsies were collected at days 0 (T0; immediately prior to infusion) and 6 (T6). Mean plasma NEFA levels increased 38% (0.84 ± 0.13 vs 1.16 ± 0.06mM) from T0 to T6 with ACTH infusion suggesting glucocorticoids contribute to increased lipolysis. ACTH infusion increased mean adipose HSP90 expression by 92%±18.2 while decreasing mean muscle HSP90 expression by 39%±14.5 from T0 to T6 suggesting that HSP90 may participate in GR‐mediated lipolysis in adipose while contributing to conserving lipid sources in muscle. Mean muscle CD36 expression decreased 46%±12.2 from T0 to T6 with ACTH infusion suggesting that there is a reduced intake of NEFA's by skeletal muscle, contributing to increased circulating NEFAs during lipolysis. These data suggest that the fasting‐associated increase in GR signaling is imperative for sustaining elevated levels of lipolysis during the post weaning fast, and is dependent upon the functional role of cortisol and HSP90.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Leucine Supplementation in Mice during Pregnancy Does not Affect Birthweight or Offspring Growth prior to Weaning
Authors: McGuckin Molly Mae , Bartak Sarah Ann , Marini Juan , Peterson Daniel G. , Manjarin Rodrigo 
Published: June 2021

Advances in nutritional care of low‐birth weight infants have significantly improved the outcome of premature infants; nonetheless, low‐birth weight still represents the main cause of newborn deaths in the U.S. Based on studies in cells and rodents demonstrating anabolic effects of branched‐chain amino acids, there is potential for use of supplementary leucine to improve muscle growth in children and adults. However, the effect of supplemental leucine during fetal development remains unknown. We tested the hypothesis that leucine supplementation during pregnancy would increase pup weight at birth and subsequent growth prior to weaning. Twenty‐five female CD‐1 strain mice were fed ad libitum 1 of 3 diets containing 5.5, 11 and 22 g/kg leucine throughout gestation. Alanine and sucrose were added to make the three diets is nitrogenous and isoenergetic. Diets were formulated to otherwise meet nutrient requirements during gestation. Feed intake was measured daily throughout pregnancy for 21 d. After parturition, litters were normalized to 8 pups, and average pup weight was collected every other day for 21 d until weaning. Statistical analysis was performed using linear mixed models which included treatment, time and their interaction as fixed effects, mouse nested within treatment as repeated measures, replicate as a random effect, and initial body weight, feed intake, and litter size as covariates. There was no significant effect of leucine on average birth weight (1.24 ± 0.05, 1.24 ± 0.06, 1.22 ± 0.05 for 5.5, 11 and 22 g/kg leucine, respectively; P = 0.36) or pup growth over 21 d of lactation (0.54 ± 0.06, 0.54 ± 0.05, 0.53 ± 0.04 g/d; P = 0.96). Number of pups born alive was positively correlated with total amount of feed consumed over 21 d gestation (R=0.64 and P=0.0003). Our results indicate that supplemental leucine during gestation does not improve birth weight or offspring growth in mice. However, these results do not preclude the effects of leucine on muscle fiber dynamics, fetal programming or the regulation of metabolic pathways related to muscle development, which may warrant further investigation.Support or Funding InformationARI#58982 and Cal Poly Summer Undergraduate Research ProgramThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Parallel genomic analysis: Hi‐C analysis pipeline for open‐source Torque resource manager
Authors: Stodola Timothy , Liang Mingyu , Greene Andrew 
Published: June 2021

Genomic sequencing has become more available as technology has advanced and costs have decreased, making efficient data analysis crucial for keeping up with the rate of data generation. This is particularly true when generating 3D maps of chromatin structure using Hi‐C datasets, which can generate terabytes of data per experiment. One of the best ways to do this is with parallel computing, distributing a single job across multiple cores in single server or a large cluster of networked computers. We have adapted the Hi‐C software, Juicer, designed by Durand et al to run on a computing cluster managed by the open‐source Torque Resource Manager software. Juicer is a pipeline that converts fastq reads to Hi‐C maps and operates using only a single command line input making it amenable to a parallel computing environment. Using this implementation does not require the user to purchase server time or license distributed computing software. Through parallel computing it is possible to optimize the efficiently of determining alignment, sorting, duplicate identification, and data analysis necessary for Hi‐C. The software works as a pipeline, but is modular and can be used parallelize more conventional alignment jobs, and easily optimized as an individual user requires.Support or Funding InformationNIH HL121233, Advancing a Healthier Wisconsin EndowmentThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.