bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationship of body surface area (BSA) and BSA·mass-1 ratio on exertional heat stroke risk in healthy young men and women
Authors: Giersch Gabrielle , Taylor Kathryn , Caldwell Aaron , Epstein Yoram , Charkoudian Nisha 
Published: May 2023

Exertional heat stroke (EHS) is an ongoing challenge for military personnel, for athletes and for individuals with occupational stressors that involve prolonged activity in hot environments. We recently showed that body mass index (BMI) was significantly associated with increasing risk for EHS in a cohort of activity duty U.S. Soldiers between 2016-2021. During exercise, heat is generated primarily by contracting skeletal muscle (and other metabolically active body mass) and dissipated based on body surface area (BSA). Thus, in compensable environments, a higher BSA·mass-1 ratio would be a benefit to heat dissipation & decrease risk of EHS. The purpose of the present analysis was to test the hypothesis decreasing BSA·mass-1 ratio is more strongly associated with increased EHS risk compared to increasing BMI in a cohort of healthy young men and women using the USARIEM Soldier Performance, Health and Readiness (SPHERE) database. We employed a matched case-control approach, where each individual with a diagnosis of EHS was matched to 5 controls based on calendar time, unit ID, and job category, for a total of 744 EHS and 3720 controls). As such, we captured control individuals who were matched to EHS events by location, time, and activity. We used a multivariate logistic regression model including variables of BSA·mass-1, age, military rank, and race. Results show that BSA·mass-1 was a significant predictor of EHS risk (P < 0.02), such that people with higher BSA·mass-1 were at lower risk of developing EHS when controlling for other potential factors such as age and race. These data suggest biophysical factors play an important role in EHS risk, with more research needed to better elucidate the role of age and race in this population. Funded by USAMRDC; author views not representative of the Army/ DoD. 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.
Daunorubicin-induced arterial stiffness in Down syndrome
Authors: Buckman Michelle , Vasileva Anastasiia , Vasilyev Mikhail , Jedlicka Charles , Kalra Hardik , DeRuisseau Lara , Tomasson Michael , Bates Melissa 
Published: May 2023

Children with Down syndrome have a high risk of leukemia and are at a higher risk for delayed early onset heart failure after treatment. Cardiac toxicity is more severe in female patients. Traditional risk factors for cardiovascular diseases in the general population may not be predictive of chemotherapy-induced heart failure in the Down Syndrome population. We used the Ts65Dn Down syndrome mouse model to investigate the impact of the chemotherapy agent daunorubicin on survival and arterial stiffness, a predictor of heart failure risk. We hypothesized that arterial stiffness will be increased in Ts65Dn mice treated with daunorubicin. Four-month-old Ts65Dn (n=12) and control wild-type Ts65Dn (WT Ts65Dn, n=8) mice were treated with low (2mg/kg), high (4mg/kg) dose of daunorubicin, or saline. Mice were injected twice over two weeks. Following treatment, we measured pulse wave velocity (PWV) weekly for 8 weeks using the Indus mouse Doppler flow velocity system. There was a significant decrease in PWV in mice treated with high-dose daunorubicin (p<0.001). Additionally, high-dose daunorubicin treatment resulted in a decreased survival in Ts65Dn mice (p<0.01). Overall, high-dose daunorubicin reduced PWV and survival in Ts65Dn and WT Ts65Dn mice. Daunorubicin has a dose-dependent impact on PWV in Ts65Dn and WT Ts65Dn mice. High-dose daunorubicin decreased aortic stiffness and increased mortality in Ts65Dn and WT Ts65Dn mice. This is the first demonstration that daunorubicin, the well known cardiotoxic agent, significantly impacts the conducting vasculature in Down syndrome as well. NIH R21 HD099573 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.
Loss of Nr4a3 results in increased adipose mass and impaired adipocyte respiration
Authors: Carter Jared , Ellsworth Peter , Herring Jacob , Tessem Jeffery 
Published: May 2023

Diabetes is a chronic disease that affects millions of people and will affect millions more in the coming generation. Symptoms of type 2 diabetes (T2D) include weight gain, impaired glucose tolerance, and impaired insulin secretion. Nuclear receptor Nr4a3 controls gene expression of targets essential for fuel metabolism and respiration. In patients with type 2 diabetes Nr4a3 promoter is hypermethylated, and Nr4a3 expression is downregulated. Here we demonstrate the effect of systemic Nr4a3 loss. Full body Nr4a3 KO animals were fed a standard diet. Male, but not female, Nr4a3 KO mice demonstrate impaired glucose and insulin tolerance. Male Nr4a3 KO mice have normal muscle, liver, and kidney respiration rates, while adipose tissue respiration is impaired. The impaired adipose respiration corresponds with increased mass of all adipose depots, increased adipocyte size, and increased lipid droplet size. Our data demonstrate the critical role of Nr4a3 in adipose tissue. 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.
Implementation of a 10-meter radius centrifuge model into a simulator of the human cardiovascular system: Effect on heart rate, stroke volume, and aortic pressure
Authors: Holcomb Matthew , Kilburg Jackson , Wellens Zach , Detwiler Trevin , Harycki Katya , Petridis Athanasios , Luttrell Meredith 
Published: May 2023

Greater interest in long term space travel is creating demand to develop artificial gravity systems that minimize the negative effects of long-term microgravity exposure. However, due to practical constraints of understanding the physiological effects of artificial gravity systems, we propose a cardiovascular simulation to better understand the physiological impacts of an artificial gravity gradient created through the centrifugal force of a rotating spacecraft. The purpose of these simulations is to understand the effects of artificial gravity systems during space travel. We hypothesized that an artificial gravity system will not have significant effects on the cardiovascular system if it induces the same gravity gradient in an upright human as exists on Earth. For this reason, a 10-meter radius, 1 radian/second centrifuge system was chosen to mimic the effect of the gravity gradient on Earth. We used a modified version of the CVSIM program developed to model cardiovascular responses to orthostatic challenges ( https://physionet.org/content/cvsim/1.0.0/ ). CVSIM is a 21-compartment, lumped parameter model with control systems for the cardiopulmonary and arterial baroreflexes. The existing tilt test simulation within the CVSIM program was modified to create a simulation of the centrifuge. A 500-second-long simulation resulted in an average heart rate of 79 beats/minute, an average stroke index of 46 mL/beat/m2, and average pressures in the ascending aorta of 99 mmHg during systole, and 72 mmHg during diastole. These values were achieved by 150 seconds into the 500-second simulation. In comparison, prior to the onset of the centrifugation, initial heart rate, stroke index, and ascending aortic pressure compliance were set at 70 beats/min, 46 mL/beat/m2, and 0.28 ml/mmHg, respectively, based on published norms in humans. These preliminary data suggests that this artificial gravity system may produce viable physiological conditions for the cardiovascular system. Further research, especially with longer simulations, is necessary to determine if a rotating spacecraft could ease the negative impacts of microgravity over an extended time. This work is supported by Iowa Space Grant Consortium/NASA BASE grant No.103428-19-20 (AP, MJL) 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 WNK-SPAK/OSR1 kinases and NKCC1 control epithelial barrier function by regulating claudin-2 expression
Authors: Koumangoye Rainelli , Delpire Eric 
Published: May 2023

Conditions that cause the loss of epithelial barrier integrity are often accompanied by dysregulation of tight junction protein expression and/or localization. Recently, we have reported that patients with mutations in SLC12A2; the gene encoding the basolateral Na+-K+-2Cl- cotransporter (NKCC1), suffer from severe gastrointestinal deficits, including chronic gastrointestinal inflammation, gastrointestinal hemorrhage, intestinal obstruction, and constipation. Although the intestinal inflammation observed in patients with loss of NKCC1 function may or may not be due to tight junction dysfunction, we investigated whether the loss of NKCC1 function affects paracellular ion transport and epithelial barrier function. Wild-type HT29-MTX-E12 and CRISPR/Cas9-mediated NKCC1 knockout HT29 clones were tested for tight junction protein expression and localization. Tightness of epithelial cell monolayer was assessed by measurement of transepithelial resistance and permeability of molecular tracers in transwell filters. Tight junction protein localization was assessed by immunofluorescence. Loss of NKCC1 expression strongly increases the expression of claudin-2. Genetic deletion of WNK1, WNK4, SPAK and OSR1 resulted in a substantial increase in claudin-2 expression, confirming an essential role of WNK-SPAK/OSR1 pathway in tight junction regulation. Loss of NKCC1 significantly reduces the transepithelial electrical resistance (TER) indicating an increase in paracellular ions flux, consistent with upregulation of the cation-selective and channel-forming claudin-2. In addition, NKCC1-KO monolayers showed a significant increase in the paracellular flux of small molecules like fluorescein (0.33 kDa), while the permeability of higher molecular weight TRITC-Dextran (4 kDa and 70 kDa) remained unchanged. Thus, NKCC1 regulates tight junction protein expression and loss of NKCC1 function affects epithelial barrier integrity. 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.
Filling the Gaps: implementation of two programs to engage highly motivated scholars at crucial gaps in their careers
Authors: Becker Rena , Watts Makayla , Wilson Christopher , Gutierrez Orlando , Pollock Jennifer 
Published: May 2023

Providing opportunities to engage highly motivated scholars in kidney, urology, and non-malignant hematology (KUH) research areas is of great need to advance research and practice in these underserved fields. High school, undergraduate, pre-doctoral and post-doctoral programs have helped improve interest and connection with the areas, however, there are gaps in education at crucial career decision points that are often overlooked. We developed and implemented two training programs during this pre-matriculation “gap.” The UAB KUH Gap year INternship (GAIN) program and the PRedOctoral PhD and MD research training in teams (PROmoTE) program engage scholars as pre-matriculates, after their undergraduate or master’s education and prior to their professional education for PhD studies or MD education. Through creating opportunities for in-depth training and exposure to KUH research areas at this crucial space in their careers, highly motivated individuals work with highly engaged mentors to be introduced and engaged in KUH research. The GAIN program, initiated in 2021, connects interested and motivated scholars who have recently completed their undergraduate or master’s degree to commit 1-2 years in a UAB KUH laboratory for scientific and laboratory training opportunities through seminars, laboratory research training, and mentorship. The PROmoTE program provides a summer research experience for pre-matriculating UAB PhD and MD scholars. The NIH R25 short-term experience is team-based with pre-matriculating PhD and MD students paired with PhD and MD mentors in a translational research project. Thus, the pre-matriculants are engaged in KUH research directly with both clinical and basic science researchers for the summer prior to their UAB PhD program or UAB MD education. The PROmoTE program seeks to engage pre-matriculating scholars to continue their careers in KUH research areas, to inspire translational research, as well as to promote the careers of underrepresented individuals. PROmoTE has engaged with 26 pre-matriculating scholars of which 46% are underrepresented individuals, with 9 scholars (3 PhD students, 6 medical students) continuing to engage in KUH research. We will address the opportunities these programs provide to enhance engagement and diversity in KUH research areas, challenges and obstacles overcome when developing and enhancing the programs, and provide preliminary outcomes. In addition, we will address how these programs have enhanced connection to peers, the institution, and ultimately the KUH scientific community. NIH R25 DK112731 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.
Contribution of smooth muscle-derived vascular progenitor cells to atherosclerosis
Authors: Dubner Allison , Lu Sizhao , Jolly Austin , Noble Tysen , Moulton Karen , Nemenoff Raphael , Weiser-Evans Mary 
Published: May 2023

Purpose: Atherosclerosis is a major cause of morbidity and mortality worldwide, but current therapies fail to adequately meet clinical needs. Emerging evidence implicates the outer layer of the blood vessel, the adventitia, in the pathogenesis of atherosclerosis. Specifically, it has been suggested that expansion of adventitial microvessels, the vasa vasorum (VV), drives atherosclerosis by facilitating inflammatory cell infiltration. Our group previously identified a unique population of multipotent resident vascular stem cells (AdvSca1-SM cells) that derive from mature vascular smooth muscle cells (SMCs) and reside in the vessel adventitia, where they are poised to respond to vascular injury. The goal of this project was to determine the contribution of AdvSca1-SM cells to the chronic vascular injury response. We hypothesized that in the setting of atherosclerosis, AdvSca1-SM cells contribute to plaque growth or VV expansion to drive disease progression. Methods: We generated a highly specific lineage tracing mouse model to track AdvSca1-SM cells in vivo over time. Lineage tracing mice were placed on either normal chow or modified Western diet (combined with PCSK9 AAV) for 8 to 30 weeks, then vascular tissue was analyzed using IF microscopy, scRNA-Seq, and flow cytometry. Results: scRNA-Seq and flow cytometry revealed a large reservoir of AdvSca1-SM cells in a stem-like state in the setting of atherosclerosis, but these cells showed significant phenotypic shifts compared to control conditions. Additionally, genetic modulation of the AdvSca1-SM cells influenced the transcriptional profiles of non-AdvSca1-SM-derived cells, indicating a signaling role for AdvSca1-SM cells in the vascular microenvironment. When AdvSca1-SM cells differentiate into other cell types, they primarily become mature SMCs, modulated SMCs, and myofibroblasts. These AdvSca1-SM-derived SMCs and myofibroblasts can be found in the core of the plaque, the fibrous cap, and the media wall. Additionally, these cells can be associated with adventitial microvessels in plaque regions, suggesting a role in plaque neovascularization. Contrary to our preliminary data, AdvSca1-SM cells very rarely differentiate into endothelial cells or macrophages. Conclusions: These studies emphasize the dynamic nature of AdvSca1-SM cells in the vascular injury response, demonstrating the potential of these cells to both differentiate into a variety of cell types as well as signal to other cells in the vascular wall. Ongoing studies will further characterize the distinct contributions of AdvSca1-SM cells to atherosclerosis. NHLBI F31 (Dubner, HL160149-01); NHLBI R01 (Weiser-Evans, HL121877) 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.
Blockade of mTOR stimulates hyperglycemia but inhibits severe proteinuria in obese SS rats prior to puberty
Authors: Mandal Sautan , Ekperikpe Ubong , Safir Sarah , Johnson Tyler , Cooper Jonita , Cornelius Denise , Williams Jan 
Published: May 2023

Prepubertal obesity (PPO) is a public health problem that is now associated with renal injury. Recently, we reported that the obese SSLepRmutant rat develops inflammation and renal injury before puberty. Moreover, the progression of renal disease in the SSLepRmutant rat is associated with the increased renal expression of the mammalian target of rapamycin (mTOR). Previous studies have shown that the mTOR pathway contributes to inflammation and renal disease. Therefore, this study tested the hypothesis that rapamycin (a mTOR inhibitor) will attenuate renal inflammation and early progressive renal injury in SSLepRmutant rats. Four-week-old SS and SSLepRmutant rats were treated with either vehicle (saline) or rapamycin (1.5 mg/kg/day, ip) for 4 weeks. At baseline, body weight was significantly higher in SSLepRmutant vs SS rats and remained elevated throughout the study. Treatment with rapamycin significantly decreased body weight in SSLepRmutant rats without affecting SS rats. While blood glucose levels were in the normal physiological range throughout the study in SSLepRmutant and SS rats (≤120 mg/dL), treatment with rapamycin only increased blood glucose in SSLepRmutant rats (561±54 mg/dL) without affecting SS rats (116±23 mg/dL). At the end of the study, we observed significant elevations in plasma insulin in SSLepRmutant vs SS rats, and treatment with rapamycin significantly decreased insulin levels by >50% in SSLepRmutant rats. At baseline proteinuria was significantly higher in SSLepRmutant vs SS rats (72±52 vs. 6±6 mg/day), and it remained higher throughout the study (500±125 vs. 26±12 mg/day). Interestingly, treatment with rapamycin only decreased proteinuria in SSLepRmutant rats (62±8 mg/day). Glomerular injury and renal fibrosis were markedly greater in SSLepRmutant vs SS rats, and treatment with rapamycin ameliorated these histological changes. At the end of the study, we observed increased GFR (via creatinine clearance) in SSLepRmutant vs SS rats (3.93±0.5 vs. 0.56±0.2 mL/min/gkwt), and treatment with rapamycin reduced GFR in SSLepRmutant rats (0.47±0.1 mL/min/gkwt). While there were no detectable differences in the renal expression of IL-4 in SSLepRmutant vs SS rats, there was a significant decrease in the renal expression of IL-10 in SSLepRmutant vs SS rats. Treatment with rapamycin significantly increased the renal expression of IL-4 and IL-10 in SSLepRmutant rats, while not affecting SS rats. In conclusion, although rapamycin causes hyperglycemia, it prevents early progressive proteinuria by reducing GFR and increasing renal anti-inflammatory cytokines during PPO. Funding: DK109133 and HL151407 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.
Voltage-gated ion channels regulate ion and fluid transport in Malpighian tubule epithelia of larval lepidopterans
Authors: Dates Jocelyne , Castaneda Alexis , Kolosov Dennis 
Published: May 2023

Insects account for ~80% of the world’s species, translating to approximately 200 million insects for every human. Moths and butterflies, from the order Lepidoptera, belong to second most diverse order of insects. The Cabbage Looper, Trichoplusia ni, is a prolific crop pollinator. Unfortunately, its larvae are worldwide agricultural pests because they consume copious quantities of food, eating 3-4 times their body weight in food daily, and growing 1000-fold in just a few weeks. These invasive agricultural crop pests are generalist feeders (eating >160 beneficial host plants) and consume large quantities of food to support their rapid growth. Rapid larval growth requires specialized regulatory mechanisms and an efficient excretory system. The Malpighian tubules (MTs) function as the insects’ primary excretory organ (equivalent to the vertebrate kidney), regulating ion and fluid transport, and xenobiotic and metabolic waste excretion. MT epithelium of larval lepidopterans is of particular interest because it can rapidly (~10 min) switch between ion reabsorption (where ions are transported from tubule lumen to hemolymph) and ion secretion (where ions are transported from hemolymph to tubule lumen). Recent studies have shown that this switch has been shown to be regulated in part by voltage-gated ion channels (VGICs). In larval T. ni, CaV1 channels expressed in the MTs distal ileac plexus region (DIP) have been shown to directly regulate K+ secretion. Pharmacological inhibition of voltage-gated ion channels (Kir1, HCN1, Cav1) independently from each other altered cell-based K+ transport. In the current study, biological assays measured changes in fluid secretion rate and membrane potential of MT epithelia of larval lepidopterans in response to pharmacological inhibition and/or activation of VGICs. In addition, immunohistochemistry assay using custom-made antibodies, revealed cellular and membrane localization of voltage-gated TRPA/ painless in the epithelia of the MT’s. In the current study we demonstrate that activating and inhibiting voltage-gated K+ and Ca2+ channels altered fluid secretion rate and membrane potential in the MTs of larval lepidopterans. VGICs have been extensively studied in excitable tissues. In contrast, their roles in the regulation of ion transport in the non-contractile, non-innervated epithelia of animals remains largely understudied. The novel data obtained in this study provides further insight about the fast-acting response mechanisms of VGICs, and how they play a vital role in the regulation of ion and water transp California State University startup and seed grant funding 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.