bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex-Specific Regulation of Catecholamine Signaling in Rats Exposed to Dexamethasone In Utero and Angiotensin in Adulthood
Authors: Alvarez Jared , Sharma Arpan , Madhavpeddi Lakshmi , Hale Taben 
Published: May 2024

Pregnant women who are at risk of pre-term delivery are given the synthetic glucocorticoid dexamethasone (DEX) to stimulate fetal lung development as it is not degraded by 11ß-hydroxysteroid dehydrogenase, enabling DEX to freely cross through the placenta and act on the developing fetus. Our lab has previously found that in-utero DEX exposure increases stress-induced blood pressure and heart rate responses in female, as well as autonomic dysregulation in the adult offspring. Angiotensin II (Ang II) induces hypertension and cardiac remodeling in part through activation of the sympathetic nervous system. Given these prior findings, this project explores whether prenatal DEX exposure alters the response of Ang II on cardiac sympathetic nervous system regulation. Pregnant rats were administered either vehicle (20% w/v 2-hydroxypropyl ß-cyclodextran) or the glucocorticoid DEX (0.4 mg/kg body weight, i.p) on gestation days 18-21. When offspring reached ~15 weeks of age, groups were administered either subcutaneous AngII (200 ng/kg per min) as a cardiovascular challenge or saline as experimental control for four weeks. To measure local sympathetic signaling, tyrosine hydroxylase (TH) was analyzed as it serves as the rate limiting step of catecholamine synthesis while catechol-O-methyltransferase (COMT) was selected as it catalyzes catecholamine breakdown. Gene expression of adrenoreceptor ß1 ( Adrb1) was measured to assess receptor availability for sympathetic activity. Data were analyzed by 3-way ANOVA with sex, prenatal treatment (i.e., DEX vs. Vehicle), and postnatal treatment (i.e., saline vs. AngII) as the variables. There was an overall main effect of prenatal DEX treatment to reduce TH expression in the LV (p=0.018), an effect that was more pronounced in males. COMT expression was found to be significantly impacted by sex, prenatal treatment, and post-natal treatment (3-way interaction, p=0.016). Thus, the degree to which DEX and Ang II impacted COMT expression differed by sex. There was a sex x postnatal treatment interaction (p=0.013) on ADRB1 expression whereby expression was increased by Ang II only in female hearts. Although prior studies have shown that Ang II can increase local sympathetic activity in the heart, the present data suggest that prenatal treatments disrupt this response in a sex-specific manner. Moreover, sex and prenatal treatment were greater drivers of local sympathetic regulation than Ang II. NIMH/ORWH 1U54MH118919. This is the full abstract presented at the American Physiology Summit 2024 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.
High Fat Diet Induced Lipid Deposition and Perilipin 2 Expression in Mouse Liver Is Attenuated by Endothelin-1 Receptor A Blockade
Authors: Sileshi Yamrot , Wilson Natalie , Mills Megumi , Speed Joshua 
Published: May 2024

Obesity is associated with dyslipidemia and lipid deposition into liver tissue. Circulating endothelin-1 (ET-1) is elevated in patients with obesity, and our lab has demonstrated that ET-1 is increased in liver of mice fed high fat (HFD). Interestingly, treatment with atrasentan attenuates reduces circulating triglycerides and free fatty acids and reduces lipid deposition into liver of mice fed HFD for 10 weeks; however, the mechanisms are not known. Perilipin 2 (Plin2) is a protein expressed in adipocytes and hepatocytes that is integral to lipid droplet formation by forming a coating around the droplet. We hypothesized that ET-1 receptor blockade reduces liver lipid deposition in obese mice by reducing Plin2 expression. To test this hypothesis, mice were fed normal (NMD) or HFD for 10 weeks and treated with the ET-1 receptor A (ETA) antagonist atrasentan for weeks 9-10. ET-1 receptor expression was significantly increased in HFD fed mice compared to NMD. As previously demonstrated, HFD fed mice had significantly higher liver triglyceride content compared to NMD controls, and this was attenuated in mice treated with atrasentan (ATR). As expected, Plin2 expression in liver tissue was significantly elevated in HFD mice compared to NMD (91.7±17.4 vs. 60.8±14.4 copies/pg RNA), an affect that was abolished in mice treated with atrasentan (NMD, 60.8±14.4; HFD, 91.7±17.4; NMD + ATR, 70.2±10.8; HFD + ATR, 26.3±5.8 copies/10pg RNA). These data suggest that ET-1 promotes lipid accumulation in liver of obese mice by reducing Plin2 expression. Funding: R01 DK124437, P30GM149404, and T32HL105324. This is the full abstract presented at the American Physiology Summit 2024 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.
Genomic Insights into Diving Adaptations of Extreme Pinniped Divers: A Comparative Study of Elephant and Weddell Seals
Authors: Moreno Santillan Diana , Vazquez-Medina Jose Pablo , Hindle Allyson 
Published: May 2024

Extreme pinniped divers are extraordinary models to study adaptations to hypoxia/reoxygenation events derived from extreme fluctuations in oxygen levels during deep diving. We analyzed the evolutionary adaptations of the Weddell seal ( Leptonychotes weddellii) and the Northern and Southern elephant seals ( Mirounga angustirostris and M. leonina), which have exceptional diving abilities, reaching depths of over 1000 meters for extended periods up to 90 minutes. To understand the molecular mechanisms underpinning these remarkable adaptations, we conducted a comprehensive comparative genomic analysis of thirteen pinniped species. Our gene family evolution analyses revealed a significant loss of function in genes involved in the enzymatic degradation of glutathione, an endogenous antioxidant that our functional analysis have previously shown to increase rapidly in response to hypoxia exposure in primary cells derived from extreme divers, likely to protect cells against oxidative damage. We also detected adaptive signatures in pathways involved in the optimization of mitochondrial respiration, energy metabolism, DNA repair and cardiovascular regulation in these extreme divers. Notably the Weddell seal exhibited more genes under positive selection compared to the Elephant seals, possibly reflecting adaptations to extreme environmental pressures. Pathways enriched in Weddell seals include those related to fat metabolism, oxidative damage against hydrogen peroxide and membrane lipid remodeling. Our analysis sheds light on the remarkable genomic adaptations that enable extreme pinniped divers to tolerate oxygen fluctuations associated with deep diving while offering valuable insights into their unique physiological and biochemical strategies for overcoming the challenges posed by hypoxia and reperfusion damage. NSF OPP 2020664. This is the full abstract presented at the American Physiology Summit 2024 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 Role of Microvascular Rarefaction in Dysfunctional Pericardial Adipose Tissue
Authors: Fopiano Katie Anne , Cotton Claire M , Patel Vijay S , Bagi Zsolt 
Published: May 2024

Pericardial adipose tissue (PAT) in obesity has been shown to be an independent risk factor for coronary heart disease but the underlying mechanism remains incompletely understood. We aimed to elucidate the interrelationship between PAT expansion and the adipose tissue vascularization. PAT samples were collected from patients with coronary heart disease (19 patients; age: 48-79; BMI: 22.29-41.09). Tissue samples were stained using H&E and the number and size of adipocytes was quantified using unbiased techniques via AdipoCount and ImageJ. PAT samples, cut 40 μm thick, were immunolabelled using DyLight 594 fluorescent tomato-lectin dye followed by quantification of the tissue vasculature using an unbiased, automatic 3D reconstruction (Vesselucida360). Angiogenesis was quantified using an ex vivo angiogenic assay whereby pericardial vessels were isolated, cut, and embedded in a collagen matrix sustained with growth factors; number of sprouts were used as a measure of angiogenic potential and were further analyzed for length and branching in ImageJ. Patients exhibited an increased adipocyte size as BMI increased with measures of vascularization, such as number of branching nodes and total vessel length, showed a negative correlation to increasing BMI. Vessel volume and vessel surface area showed no correlation to patient BMI. Angiogenic potential, measured by the number of vessel sprouts, sprouting length, branching length, and branching interval, showed a significant association with increasing BMI. Our data show that while adipocyte size increases with an increasing BMI, the PAT vascularization had a negative correlation to increasing BMI. These results suggest that the vasculature is insuffcient to supply the increasing PAT demand, leading to impaired perfusion and eventual adipose tissue dysfunction. However, there was a significant increase in angiogenic potential that shows that when provided with growth factors, these vessels have the ability to increase their angiogenic potential, yet in vivo the vascular angiogenic response may be hindered, which needs to be further studied. T32 HL155011 (KAF) F31 NS132564 (KAF). This is the full abstract presented at the American Physiology Summit 2024 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.
Muscle function and structure in a mouse model of dysfunctional central nervous system myelin
Authors: Manzoor Iman , Dagostino Gino , Alshawabkeh Zaid , Tajaldeen Jawad , Greger Devin , Gow Alexander , Roche Joseph 
Published: May 2024

INTRODUCTION. Claudin-11(CLDN11)-deficient mice have been reported to have dysfunctional central nervous system myelin, and altered motor control and muscle tone in their hindlimbs. OBJECTIVE. We compared CLDN11-deficient mice with strain-, age-, and sex-matched controls (CLDN11-suffent mice). We hypothesized that CLDN11-deficient mice will have reduced muscle strength and will show a greater resistance to high stretch velocities compared to their CLDN11-suffcient counterparts. METHODS. We studied the ankle dorsiflexor and plantarflexor muscles in a convenience sample of ten CLDN11-deficient and four CLDN11-suffcient mice (3-4 months, males). We recorded the maximum isometric contractile torque of the ankle plantarflexor and dorsiflexor muscles measured in milli-Newton-millimeter (mNmm), and the maximum contractile torque at low (100 °/s) and high (1200 °/s) muscle stretch velocities during eccentric contractions to assess spasticity. We also studied structural changes in muscle cross sections stained with hematoxylin and eosin. RESULTS. Data are reported as mean ± SD. Maximum plantarflexor contractile torque was 7800 ± 1651 mNmm and 9646 ± 2637 mNmm in CLDN11-deficient and -suffcient mice, respectively. Maximum dorsiflexor contractile torque was 1956 ± 347 mNmm and 2975 ± 195 mNmm in CLDN11-deficient and -suffcient mice, respectively. Spasticity assessed as the ratio of maximum eccentric torque measured at 1200 °/s to 100 °/s was 0.94 ± 0.07 and 0.93 ± 0.01 in the plantarflexors of CLDN11-deficient and -suffcient mice, respectively, and 1.41 ± 0.19 and 2.1 ± 0.33 in the dorsiflexors of CLDN11-deficient and -suffcient mice, respectively. One-way ANOVAs indicated that CLDN11-deficient and -suffcient mice were not statistically different (p>0.05) in maximum torque production and spasticity. CLDN11-deficient mice showed no remarkable alterations in muscle structure. CONCLUSION. Claudin 11 deficiency in mice does not affect maximum contractile torque and stretch-velocity-dependent muscle tone when studied by robotic dynamometry under general anesthesia, nor does it prominently affect muscle structure. We thank the WSU UROP funding mechanism for supporting Ms. Iman Manzoor’s involvement on this project. We thank the Wayne State University Doctor of Physical Therapy (DPT) Program for supporting student research and providing research training through coursework and research experiences. We thank Dr. Alexander Gow for sharing mice and mentorship. This is the full abstract presented at the American Physiology Summit 2024 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.
Cells expressing POLG loss-of-function variants can decrease mtDNA copy number and increased growth rates in neighbouring A7r5 and HeLa cells
Authors: Poburko Damon , Rothwell Samantha , Taha Omnia , Ng Irvin , Baniqued Angelica , Paris Italia , Shalchy-Tabrizi Sophia 
Published: May 2024

Mitochondrial disfunction promotes vascular disease, and mitochondrial diseases offer valuable insights into the pathological mechanisms of mitochondrial dysfunction. We previously described a patient cohort with variants in the mitochondrial DNA gamma polymerase (POLG) that were prone hypertension. We hypothesized that the POLG variants promote hypertrophy or hyperplasia of vascular smooth muscle cells in a way that stiffens or thickens blood vessels to explain the high rate of resistant hypertension in this cohort. The objective of this study was to assess the cellular phenotype of cells over-expressing POLG variants: pathogenic Y955C and variants of unknown significance; R964C, I1098N, Y1138C. We transiently expressed human FLAG-tagged POLG variants in rat A7r5 and HeLa cells for 2-4 days. Transfection effciency ranged from 20-30% in A7r5 and >60% in HeLa cells. POLG variants increased cell density by nuclear counting (20-60%) and growth rates measured by 48-72 h of live-cell imaging (Y955C > R964C > I1089N » Y1138C). Compared to wild-type, Y955C and R964C reduced mtDNA copy number (mCN) measured by droplet digital PCR by 10-20%. Imaging mtDNA nucleoids (anti-dsDNA) and the FLAG-tag showed that reduced mCN was not restricted to transfected cells. Addition of a P2A-T2A-nuclear-EGFP to the POLG constructs demonstrated that faster growth rates were not specific to transfected cells. Resting and oligomycin-stimulated mitochondrial membrane potential imaged with TMRM were unaffected by Y955C and R964C. Mitochondrial ROS (mitoSox) was similar between cultures transfected with Wild-type versus POLG variants and lower than levels stimulated by antimycin-A’s inhibition of complex III. Notably, we found a linear relationship between mCN and cell density that was not simply due to smaller cell size at higher densities. Using Hoescht-33342 staining to assess cell cycle, no clear difference in cell-cycle distribution was evident in unsynchronized cultures. We conclude that modest reduction of mCN induces a mitogenic effect, likely via a diffusible messenger that further reduces mCN in a cell population. The signalling mechanism of this phenomenon remains to be identified, but our results confirm that POLG malfunction can alter smooth muscle physiology in a way that could support pathogenic vascular remodelling and could promote enhanced growth in cancerous cells. Funded by the Natural Sciences and Research Council of Canada. This is the full abstract presented at the American Physiology Summit 2024 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.
Chlorpyrifos-Induced Airway Hyperreactivity in Rats Is Dependent on NK1 Receptor Signaling
Authors: Grodzki Ana Cristina , Schelegle Edward , Lein Pamela 
Published: May 2024

Occupational and environmental exposures to organophosphorus pesticides (OP) are associated with increased asthma incidence. While the canonical mechanism of OP neurotoxicity is acetylcholinesterase (AChE) inhibition, we previously demonstrated that the OP chlorpyrifos (CPF) causes airway hyperreactivity (AHR) in adult rats 24 h after exposure at levels that do not significantly inhibit AChE. Here we further investigated the persistence of CPF-induced AHR at 7 days post-exposure and tested the hypothesis that neurogenic inflammation contributes to CPF-induced AHR. Eight-week-old male Sprague Dawley rats were administered 30 mg/kg CPF subcutaneously, and AHR was assessed at 24 h or 7 days post-exposure using a Flexivent mechanical ventilator during electrical stimulation of the vagus nerves. CPF significantly increased airway resistance and elastance at 24 h and 7 days post-exposure. The NK1 antagonist SR140333 was used to evaluate the involvement of substance P and its receptor NK1 in CPF-induced AHR. SR140333 was injected into rats 1 h before mechanical ventilation and vagal stimulation. NK1 receptor inhibition decreased vagally stimulated bronchoconstriction in CPF-exposed male animals to that observed in vehicle controls, at 24 h and 7 days post-CPF exposure. These data suggest that substance P signaling contributes to both acute and persistent CPF-induced AHR. These findings have significant implications for assessing the risk to human health and safety of CPF, and potentially other OPs, and indicate a potential new therapy for mitigating AHR in intoxicated individuals. This work was supported by the NIH (grants R01 ES017592 and T32 HL07013). This is the full abstract presented at the American Physiology Summit 2024 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.
Development of a Case/Problem-Based and Teamwork-Focused Applied Physiology Course to Graduate Students Planning to Apply to Dental School
Authors: Schonhoff Christopher , Lopez Marisol , Lehman William , Young Aaron 
Published: May 2024

The Master of Science in Oral Health Sciences (OHS) at Boston University Chobanian & Avedisian School of Medicine is explicitly designed for students who wish to improve their academic preparedness for dental school admission. Oral Health Sciences students take some courses, including the first-year Dental Physiology course, alongside dental students at Boston University Henry M. Goldman School of Dental Medicine (GSDM). Since students in the OHS program often struggle in the largely lecture-based Dental Physiology course, we developed a case/problem-based and teamwork-focused Applied Physiology course that ran parallel to the Dental Physiology course in the fall of 2023. The primary goal of the Applied Physiology course is to provide additional instruction and academic support and to present course material in a team-based learning mode for the OHS students. We hypothesized this approach to learning physiology would help to improve student mastery of physiology content critical to their future success. The objective of the current study was to assess the effectiveness of the new Applied Physiology course in enhancing OHS students' motivation and academic performance in the Dental Human Physiology course. We are evaluating the benefits of this course by comparing Dental Physiology final grades and individual exam grades between dental students and OHS students. In addition, we are comparing course performance for OHS students from previous class years who did not take the Applied Physiology course against students from the current academic year who took the course. Our preliminary results indicate students who took the Applied Physiology course in the fall of 2023 performed better in the Dental Physiology course than last year’s OHS students. The mean grade for Dental and OHS students in Dental Physiology in the fall of 2023 was 82.3% ± 12.3% and 80.3% ± 13.9% respectively. In contrast, the mean grades for Dental students in the fall of 2022 was 82.7% ± 8%, while OHS students’ mean was much lower at 74.7% ± 11%. Analysis and comparisons for individual course exams for the dental and OHS students are ongoing. In addition, analysis of a validated survey containing Likert-style questions to quantify how the new course enhances motivation, engagement, and perceived benefits of student learning is underway. Our results indicate that additional team and case/problem-based support can improve academic performance for students hoping to gain admission to Dental School. No funding for this project. This is the full abstract presented at the American Physiology Summit 2024 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.
Unraveling the Interplay of p21, Autophagy, and Mitophagy in Mitigating Skeletal Muscle Dysfunction during Aging and Obesity
Authors: Kim Siyun , Noh Sung Gi , Wang Lichao , Xu Ming , Kwon Oh Sung 
Published: May 2024

Introduction: The accumulation of senescent cells accelerates aging, a process further exacerbated by obesity. The decline of muscle function is a hallmark of this progression due to muscle atrophy stemming from dysregulated autophagy and mitochondrial function in skeletal muscles. p21 is one of the major regulators, which accumulates in tissues with aging and obesity. Previous studies have demonstrated that the elimination of p21-highly-expressing ( p21high) cells improves muscle function. However, the connection between p21 and its influence on muscle function remains unclear. One possible explanation is associated with alternations in autophagy and mitophagy through mitochondria dysfunction and increased reactive oxygen species. Therefore, this study investigated the link between autophagy, mitophagy, and p21 in the context of aging and obesity. Methods: Four 18-month-old male p21-Cre/+; +/+ (P) and p21-Cre/+; DTA/+ (PD) mice, fed by high-fat diet for 15 months were administered with tamoxifen for twice. We previously observed the P group with accumulation of p21high cells, which were effectively eliminated in PD group. Soleus muscles were collected for subsequent immunoblotting analysis, employing primary antibodies targeting key proteins involved in autophagy and mitophagy cellular processes. Results: Our study elucidates dynamic changes driven by eliminating p21high cells in autophagy and mitophagy marker levels within the soleus muscles of mice exposed to a high-fat diet for 15 months. There was no significant difference in the body weight of P and PD mice (65.1±2.58 g vs. 64.3±2.22 g). In P mice, an increase in the upstream autophagy initiator, Beclin1, was observed, along with elevated levels of ATG4A, ATG7, and the ATG12-ATG5 complex, indicating elongation of autophagosome formation. Despite increased autophagosome marker p62, the LC3-II/LC3-I ratio remained unchanged. Lysosomal markers, LAMP1 and LAMP2, were both elevated in P mice. Conversely, PD mice exhibited heightened mitochondrial damage elimination markers, Parkin, VDAC1, and DRP1. Although PINK1 levels were not significantly changed, they showed an increasing trend. Conclusion: Our results suggest that eliminating p21high cells may be the potential therapeutic approach to enhance skeletal muscle function in the context of obesity and aging, possibly through autophagy and mitophagy. This is the full abstract presented at the American Physiology Summit 2024 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.