bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of DOCK2 and KCa3.1 in fibroblast-to-myofibroblast transformation
Authors: Stiens Sara , Bowles Doug 
Published: May 2023

Excessive fibroblast-to-myofibroblast transformation is accompanied by injurious deposition of extracellular matrix components and tissue fibrosis. Fibrosis underlies many disease processes, including systemic sclerosis, idiopathic pulmonary fibrosis, liver cirrhosis, kidney fibrosis, and heart failure. Inhibiting fibroblast transformation is a major therapeutic strategy for the attenuation of these conditions. The aim of the present study is to determine the role of two proteins, dedicator of cytokinesis 2 (DOCK2) and the intermediate-conductance calcium-activated potassium channel (KCa3.1), in fibroblast-to-myofibroblast transformation. We hypothesized that DOCK2 and KCa3.1 stimulate fibroblast transformation. Cultured NIH/3T3 fibroblasts were treated with transforming growth factor β (TGFβ) in the presence and absence of inhibitors of DOCK2 (CPYPP, 10 μM) and KCa3.1 (TRAM-34, 100 nM). After 24 hours, mRNA was collected, transcribed into cDNA, and quantified with qRT-PCR. We found that CPYPP prevented TGFβ-induced transcriptional upregulation of the genes Acta2 (4.28 ± 0.18 vs 0.30 ± 0.01, n=4, p<0.001) and Col1a (2.51 ± 0.28 vs 0.14 ± 0.01, n=4, p<0.001), both indicators of fibroblast transformation. Similarly, TRAM-34 attenuated TGFβ-induced transcriptional upregulation of Acta2 (17.27 ± 0.81 vs 12.23 ± 1.26, n=4, p<0.01) with a similar trend for Col1a (1.88 ± 0.23 vs 1.33 ± 0.07, n=4, n.s.). We also determined that the role of DOCK2 in fibroblast transformation was at the post-transcriptional level since TGFβ did not increase mRNA expression of Dock2 (n=16). We conclude that DOCK2 and KCa3.1 are both involved in TGFβ-induced fibroblast-to-myofibroblast transformation. Future experiments will determine whether there is an interaction between DOCK2 and KCa3.1 in fibroblast transformation. NIH R01 HL151444 to DKB This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Effect of obesity on the vascular response to sympathetic activation during hypoxia in female participants
Authors: Jacob Dain , Shariffi Brian , Gonsalves Anna , Harper Jennifer , Limberg Jacqueline 
Published: May 2023

Background: Activation of the sympathetic nervous system causes vasoconstriction and an acute reduction in peripheral blood flow. However, during hypoxia, sympathetically-mediated vasoconstriction is attenuated in young females without obesity. Given sustained increases in sympathetic activity associated with obesity may create a greater propensity to vasoconstrict in response to sympathetic activation, we sought to examine the effect of obesity on the vascular response to sympathetic activation during hypoxia. We hypothesized sympathetically-mediated vasoconstriction during hypoxia would be greater in premenopausal female adults with obesity when compared to females without obesity. Methods: Blood pressure (BP, finger photoplethysmography) and forearm blood flow (FBF, venous occlusion plethysmography) were assessed in premenopausal female adults with obesity (n=5, 25±3 yrs, 37±1 kg/m2, 48±1% body fat) and without obesity [n=19, 23±1 yrs, 23±1 kg/m2, (33±2% body fat, n=8)]. Data were combined from two cohorts (IRB #2022525, 2011312) to test present hypotheses. Participants completed two trials consisting of a 2-min cold pressor test (CPT) during baseline normoxia (98±1% SpO2) and following 3-5 min of steady-state hypoxia (0.10±0.01 FiO2, 82±1% SpO2). FBF was normalized for BP (forearm vascular conductance, FVC) and a change in FVC during the last 1-min of CPT was calculated (ΔFVC). The main effect of group (obese, non-obese), condition (normoxia, hypoxia) and the interaction of group and condition were compared using a two-way repeated measures ANOVA. Results: In female participants without obesity, ΔFVC during normoxia was attenuated during hypoxia (-0.57±0.19 vs +0.36±0.34 mL/dL/100mmHg/min; p=0.009). Conversely, in female participants with obesity, ΔFVC during normoxia did not differ from the response during hypoxia (-0.31±0.46 vs -0.87±0.34 mL/dL/100mmHg/min; p=0.382). Group differences in ΔFVC were not observed during normoxia (p=0.657), but were present during hypoxia (p=0.039). Conclusion: Sympathetically-mediated vasoconstriction is attenuated during steady-state hypoxia in premenopausal females without obesity, whereas this response is not observed in female adults with obesity. These preliminary data advance our understanding of the impact of obesity on hypoxic vascular control in premenopausal female participants and have implications for conditions in which hypoxia and sympathetic activation are observed ( e.g., sleep apnea, heart failure, COVID-19). NIH HL130339 (JKL), NIH HL153523 (JKL), AHA 909014 (DWJ) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Human Genetics and Dyslipidemia: From Non-synonymous Variants to Non-coding Variants
Authors: Wang Yan , Wang Yan , Liu Xiao , Liu Yinan 
Published: May 2023

Dyslipidemia has strong heritability, with over 50% of dyslipidemia is caused by genetics in general population. Previously studies identify many non-synonymous variants in genes of LDLR, PCSK9, ANGPTL3, ABCG5/8, ARH et.al, which lay the fundation for durg development. However, these known non-synonymous variants can only explain about 10-20% of genetic risks. Genome-wide association studies (GWAS) have identified hundreds of genetic variants associated with dyslipidemia in large population. However, about 95% of these variants are located in genome noncoding regions and cluster in different loci. The disease-causing variant for each locus and underline mechanism remain largely unknown. We systematically analyzed these noncoding variants and found that rs1997243 is the disease-causing variant in locus 7p22, which is strongly associated with hypercholesterolemia. The rs1997243 risk allele is associated with increased expression of GPR146 in human and specifically up regulates GPR146 expression in cultured hepatocytes. GPR146 is an orphan G-protein coupled receptor that is located on plasma membrane and responses to stimulation of heat-inactivated serum. Disrupting gpr146 specifically in the liver decreases the blood cholesterol level and prevents high-fat or high-fat high-cholesterol diets induced hypercholesterolemia in mice. Mechanistic study suggests that GPR146 regulates blood cholesterol level mainly through regulating the catabolism of cholesterol rich lipoprotein particles. Thus we uncovered a novel G-protein coupled receptor that regulates blood cholesterol levels in both humans and mice. Our results also suggest that antagonizing GPR146 function will be an effective strategy to treat hypercholesterolemia. National Key Research and Development Program of China (2018YFA0800700), the National Natural Science Foundation of China (92057207, 91754101, 32021003, 31771304) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Liver Wound Healing Is Associated with An Increase in Mfge8 Expression in Hepatocytes
Authors: Bu Heng-Fu , Geng Hua , Subramanian Saravanan , Chou Pauline , Tan Xiao-Di , Tan Xiao-Di 
Published: May 2023

Being recognized as a typical pathological feature of liver diseases, apoptosis-induced hepatocyte injury leading to sterile inflammation drives a wound-healing path in vivo. We and other researchers reported that Milk fat globule-EGF factor 8 (MFGE8) preserves tissue homeostasis, protects against tissue injury and inflammation, and attenuates nonalcoholic fatty liver disease and fibrosis. However, it is unclear whether and how MFGE8 is involved in liver regeneration from hepatocyte-apoptosis-induced injury. Our aim is to study current knowledge to this extent, we created a novel triple-transgenic mouse model, an inducible hepatocyte-specific apoptosis phenotype (namely, 3XTg-iHAP), in which the inducible hepatocyte-specific FasL expression is under control of the combined LoxP-Albumin-Cre system and rtTA Tet-On regulatory element. The liver tissues from 3XTg-iHAP and their littermates were collected at 8 h, 24 h, 48 h, 72 h, and 5 D after doxycycline (Dox, 5mg/kg, s.c., single dose) treatment and subjected to histological examination, RNAScope in situ hybridization (ISH) and qRT-PCR analysis. We first confirmed that the 3XTg-iHAP mice developed normal, viable, and fertile. Upon Dox treatment, qRT-PCR confirmed FasL expression was specifically induced in the liver tissues of 3XTg-iHAP mice (male, 7 weeks) but not in their littermates. H&E sections show the induction of hepatocyte apoptosis as early as 24 h followed by apoptosis-induced sterile inflammation and injury, hepatocyte mitosis, and regeneration in the liver parenchyma of 3XTg-iHAP mice. In the ISH assay, we found that (1) In littermate control mice, Mfge8 transcripts were localized in the intrahepatic bile duct epithelial cells (i.e., cholangiocytes) within the portal area. (2) In Dox-treated 3XTg-iHAP mice, we observed a profound increase of Mfge8 gene expression in parenchymal hepatocytes of the liver featured with apoptosis-associated sterile injury. In summary, we validated a novel 3XTg-iHAP mouse liver wound-healing model. The Mfge8 gene is constitutively expressed in the bile duct epithelial cells under the normal physiological condition, while upregulated in hepatocytes in response to the apoptosis-induced injury and repair. Our results suggest that liver wound healing is associated with an increase in Mfge8 expression in hepatocytes. The underlying mechanisms of whether and how MFG-E8 promotes the liver wound healing process need to be further studied. Grants are supported by NIH and the U.S. Department of Veterans Affairs. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
The fictional animal project: A flexible tool for helping students learn physiology
Authors: Beason-Abmayr Beth 
Published: May 2023

Several years ago, my colleagues and I developed a project-based assignment where students create a fictional animal and predict its ability to thrive in a hypothetical environment by examining the interactions between different combinations of designs for selected body systems. This assignment, which was implemented at different types of institutions and for different levels of students, can be readily adapted to either lecture-based or laboratory courses. Here I describe how students design a fictional animal as a semester-long collaborative group project in an interactive lecture course on comparative animal physiology of vertebrates. The fictional animal project aligns with several course learning goals including 1) Acquire a fundamental knowledge of “how animals work” and 2) Exercise responsibility and teamwork. Students learn integration of body systems as they choose a random fictional animal, consider if this animal can survive in a specific environment, and create the animal. Creation of the animal, which cannot closely resemble an extant animal, is scaffolded throughout the semester as students complete question sets where they describe the structure and function of the systems and consider potential trade-offs and physiological constraints. At the end of the semester, we hold a fictional animal showcase where students share highlights about their animal and its environment. Student learning is assessed through the questions sets, which are submitted as homework, and the class presentation; this group project contributes to 25% of the overall course grade and replaces more traditional assessments such as exams. Examples of fictional animals demonstrate how students must consider interactions and functions between different systems in their design; in addition, they must think about the metabolic requirements of their animal as they decide its lifestyle. Reflection data from students strongly supports that designing a fictional animal helps them understand how physiological systems function together; students gain a new or deeper awareness and appreciation of trade-offs in function as well as constraints on physiological processes. As this project continues to evolve, students will have the freedom to choose a creative format for the fictional animal showcase, such as a recorded or live oral presentation, a podcast, a tri-fold brochure, a poster, an educational game, or an illustrated story. All protocols were approved by Rice University IRB (Protocol FY2017-294). Rice University Office of Undergraduate Research and Inquiry (OURI). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Endothelial cells derived from elephant seals blunt angiogenic transcriptional signaling during hypoxia exposure
Authors: Allen Kaitlin , Torres-Velarde Julia Maria , Vázquez-Medina José Pablo 
Published: May 2023

Northern elephant seals ( Mirounga angustirostris) conduct repeated deep dives, during which arterial blood oxygen becomes depleted. Interestingly, elephant seals require little surface recovery time from these dives, and extreme hypoxemia occurs regardless of dive duration or purpose. Recent in vitro and in silica work indicates that tight regulation of the canonical hypoxia response may protect diving seals against the inflammatory injuries typically associated with repeated hypoxia exposure. In vivo assessments of these phenomena, however, remain restricted due to both technical constraints and animals' inaccessibility while diving at sea. We developed a proliferative endothelial cell culture system from expelled placental arteries to assess the real-time molecular response to hypoxia exposure in northern elephant seals. Hypoxia inducible factor 1a (HIF-1a) protein localized to the nucleus within 1 h of exposure to 1% O2 in both species[KA1]. Hypoxia increased HIF-1a protein levels to a maximum of ~70-fold over (normoxic) baseline levels in both seal and human cells (p=0.005 for both species), though the response dynamics differed between species. HIF-1a abundance in seal cells was biphasic, with an initial rapid peak occurring within 15 min of hypoxia onset. In contrast, HIF-1a levels did not peak in human cells until 1 h in hypoxia and abundance declined continuously following this peak. Interestingly, RNAseq analysis of HIF-1a target gene expression suggested that seal cells blunt angiogenic signaling and vascular remodeling during hypoxia exposure despite sustained HIF-1a protein stabilization. Seal cell expression of STC2, NHE1/SLC9A1, and PFKL lagged behind expression of these genes in human cells during hypoxia exposure, and seal cell expression of ANGPT2 and MMP14 remained stable during long term hypoxia exposure, while expression of these genes was variable or high in human cells. Cis-regulatory analyses suggested a role for altered metabolism (rather than altered oxygen delivery) in seal cells during hypoxia via FOXK1, NFKB1, JUN and ZBTB7A. In contrast, the transcriptional signature in human cells suggests altered expression of oxygen delivery pathways via homeobox A13 (HOXA13), FOS like 1 (FOSL1) and SRF, all of which regulate angiogenesis, vascular remodeling and vasodilation. Together, these data suggest that seal endothelial cells respond to hypoxia by managing metabolic factors rather than calling for increased oxygen delivery despite rapid and sustained HIF-1a stabilization. NSF GRFP and UC Berkeley startup This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Association of Osteogenic Adaptation and Sport Training in Distance Running, Soccer and Volleyball
Authors: Rocha-Rangel Jose , Rocha-Rangel Jose , Auslander Alexandra , Liang Michael , Tsai Anderson , Robles Patricia , Kwoh Yuan-Lieh , Arnaud Sara 
Published: May 2023

Purpose: The purpose of the study was to determine whether sports training comprising of 1) high-impact loading sport in volleyball (VOL), 2) odd impact loading sport in soccer (SOC), and 3) low impact sport in distance running (RUN) were associated with weight bearing tibial bending strength and calcaneus BMD, and non-weight bearing ulnar bending strength and distal radius and ulna (wrist) BMD. Method: Female athletes comprised of 13 VOL, 22 SOC and 22 RUN participated in the study. A group of 23 non-athletes (NA) served as the comparison group. Tibial and ulnar bending strength ( EI, Nm2) were assessed using a mechanical response tissue analyzer (MRTA). Calcaneus and wrist BMD were assessed using a peripheral X-ray absorptiometry. Group means differences among the study groups were determined using ANCOVA with weight, height, body mass index, ethnicity/race, and training history serving as covariates, and Tukey post-hoc test to determine the sources of the difference. Results: Tibial EI of VOL (228.3 ±138 Nm2) and SOC (208.6 ±115 Nm2) were higher (p < 0.05) than NA (101.2 ± 42 Nm2), but not RUN (144 ± 110 Nm2). Ulnar EI of VOL, SOC and RUN (43.6 ± 17, 54.9 ± 51, 33.6 ± 15 Nm2, respectively) were higher (p < 0.05) than NA (27.2 ± 9 Nm2), not among the athletic groups. Calcaneus BMD of VOL (.618 ± .0.12 g/cm2), SOC (.621 ± .009 g/cm2), and RUN (.572 ± .007 g/cm2) were higher (p<0.05) than NA (.501 ± .08 g/cm2), not among the athletic groups. Wrist BMD of VOL (.484 ± .06 g/cm2) and SOC (.480 ± .06 g/cm2) were higher (p < 0.05) than NA (.443 ± .04 g/cm2). Conclusion: The most effective mode of musculoskeletal loading activity for developing tibial bending strength and calcaneus and wrist BMD is from VOL and SOC training. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Increased dose and duration of infection with human adenovirus serotype 5 shifts amino acid, nucleic acid, TCA, and carbohydrate metabolism in human kidney cells
Authors: Sanchez Bailey-J , Grasis Juris , Fiehn Oliver , Ortiz Rudy 
Published: May 2023

Viruses are obligate intracellular parasites that overtake host cellular processes and establish an environment optimal for replication. Human adenoviruses are double stranded DNA viruses known to possess a unique tissue tropism including respiratory, gastrointestinal, ocular, and renal tissues. Furthermore, infection can result in mild to moderate symptoms with increased severity in those with dampened immunity. Disruptions to host metabolism is a well-known consequence of viral infection. Nonetheless, the relationship between adenoviruses and host metabolism remains a largely unelucidated area. Few studies have coupled metabolomic techniques with the examination of infection across the adenoviruses’ range of tissue targets. Fewer studies have investigated metabolic shifts with manipulation of viral dosage and duration of infection simultaneously. The objective for this study was to determine metabolic shifts in human kidney cells with different dosages of human adenovirus serotype 5 and couple this to duration of infection. It was hypothesized that prolonged viral infection with increased viral dosage would result in greater shifts in metabolites involved in amino acid metabolism, carbohydrate metabolism, nucleotide metabolism, and the tricarboxylic acid cycle. Three dosages of human adenovirus serotype 5 were used: 0.5. 1.0, and 2.0 multiplicity of infection. Infections were prolonged for 6, 12, 24, and 36 hours and cytosolic fractions were subsequently collected. Samples were then subjected to gas chromatography coupled to time-of-flight mass spectrometry. We found distinct separations in many primary carbon classes between uninfected controls and infected cells. Greater separation was seen in the higher dosed samples compared to the 0.5 MOI group. Analyses revealed 186 identified metabolites with significant upregulated and downregulated metabolites involved in nucleotide biosynthesis, amino acid metabolism, carbohydrate formation, and tricarboxylic acid cycle. Metabolites such as urea and pyrophosphate displayed the greatest degree of upregulation and downregulation, respectively. This was evident across all concentrations at 24 HPI. An increase in duration of infection was correlated with the emergence of more metabolites, with greater detection at increased viral concentration. Our results identify specific metabolic pathways perturbed by viral-host interactions, which have not been previously implicated in adenoviral infection and in kidney cells. Our study also provides a framework to investigate individual adenoviral protein contribution to metabolic disruptions. UC Merced USDA Hispanic Education Training Program Grant This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.