bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex-dependent cAMP signaling domains in vascular smooth muscle
Authors: Nieves-Cintron Madeline , Pereira Da Silva Eric Aian , Navedo Manuel F 
Published: May 2024

The ubiquitous second messenger 3’,5’ monophosphate (cAMP) is essential for regulating vascular smooth muscle (VSM) function. Despite the overwhelming number of studies examining cAMP signaling compartmentalization in multiple cell types, no study has examined how biological sex regulates discrete cAMP pools and the functional implications in VSM. In this study, cAMP biosensors targeted to the cytosol (cyt), plasm membrane (PM), and sarcoplasmic reticulum (SR) were used to examine subcellular cAMP domains using live-cell FRET imaging. We uncovered a sex-specific distribution of cAMP signaling domains where cAMP pools are constrained in the SR of male but not in female mice. To test whether sexually dimorphic cAMP pools are mediated by sex hormones, we used WT male and sham or ovariectomized (OVX) WT female mice. cAMP subcellular distribution was like that of males in VSM from OVX female mice. Interestingly, aortic rings from males and OVX females showed less relaxation responses to isoproterenol compared to sham females. Our study highlights sex-dependent segregation cAMP pools in VSM that could contribute to the sex-specific regulation of vascular reactivity. American Heart Association award 852984 Research Supplement to Promote Diversity in Science 23DIVSUP1069345. 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.
Effects of Lifelong Exercise on Body Composition and Bone Density
Authors: Hughes Ryan , Raue Ulrika , Trappe Todd , Trappe Scott 
Published: May 2024

Objective: The purpose of this study was to compare body composition and bone density among young exercisers (YE), lifelong exercisers (LLE), and old healthy non-exercisers (OH), as well as between men (M) and women (W). Hypothesis: A hierarchal pattern will emerge (YE > LLE > OH) for healthy body composition and bone density. Both body composition and bone density will differ between M and W. Methods: Healthy adults were separated into three groups: YE (n=20, 10M, 25±1yr, 67±10kg), LLE (n=28, 21M, 74±2yr, 75±12kg), and OH (n=20, 10M, 74±2yr, 77±14kg). Daily physical activity was indirectly assessed using a pedometer (YE: ~10,000steps/day; LLE: ~9,000steps/day; OH: ~6,000steps/day). LLE individuals completed aerobic exercise regularly ~5 days/week (~7 hrs/week) for 52±1yr. Further analysis was done between men and women to investigate potential sex differences (M: n=41, 62±25yr, 80±10kg; W: n=27, 58±28yr, 62±7kg). Dual X-ray absorptiometry (DXA) was used to assess body composition (fat and lean mass) and bone mineral density. Results: There was a hierarchal pattern of beneficial body composition related to total body fat (YE: 21±6% < LLE: 25±6% < OH: 37±7%; p<0.05) and lean mass (YE: 79±6% > LLE: 74±6% > OH: 62±7%; p<0.05). In addition, there were sex differences for both total body fat (M: 24±7%; W: 32±9%; p<0.05) and lean mass (M: 75±7%; W: 67±10%; p<0.05). Bone mineral density was not different among the three groups (YE: 1.26±0.10g/cm2; LLE: 1.27±0.18g/cm2; OH: 1.22±0.14g/cm2; P>0.05) but was different between men and women (M: 1.33±0.12g/cm2; W: 1.14±0.11g/cm2; p<0.05). Conclusion: These data suggest lifelong endurance exercise was beneficial for body fat and lean mass in both men and women. Bone mineral density, generally thought to decrease with age, was not impacted by aging or exercise status in this cohort. Women had lower bone mineral density compared to men, regardless of age, which may be related to distinct hormonal regulation between the sexes. Funding Sources: This research was supported by the National Institutes of Health Grant R01-AG038576 and the Ball State University Human Bioenergetics Program. 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.
Peripheral Endothelial and Microvascular Function with Repeated Far-infrared Sauna in Adults with Obesity
Authors: Reed Emma , De Leenheer Merel , Famiano Alex , Singh Jaidon , Uzoekwe Colleen , Halliwill John , Minson Christopher 
Published: May 2024

Obesity can lead to vascular dysfunction and elevated cardiovascular risk. Repeated far-infrared sauna bathing has improved cardiovascular function in cardiac patients. It is unknown if repeated far-infrared sauna bathing improves vascular function in adults with obesity. Purpose: We hypothesized that brachial artery flow-mediated dilation (FMD) and post-occlusion reactive hyperemia would be improved after 30 far-infrared sauna sessions in adults with obesity. Methods: Five adults with obesity (4 men, 1 woman; age: 33 ± 11; BMI: 36.3 ± 4.2 kg/m2) were assigned to a heat therapy (n=3) or time-control group (n=2). The heat therapy group completed 30 sessions of far-infrared sauna bathing (43 ± 4 min at 54 ± 2°C) at 3-4 times/week for 9 weeks. Peripheral vascular function was assessed before (PRE) and after (POST) the intervention. Brachial artery diameter and blood velocity were recorded via Doppler ultrasound for 1 min of baseline, 5 min of forearm occlusion, and 3 min of post-occlusion. FMD was calculated as the percent change from baseline diameter to peak diameter during post-occlusion. Relevant shear rate was calculated as the area under the curve (AUC) to peak dilation. Peak post-occlusion reactive hyperemia was defined as the peak blood flow during post-occlusion. Total post-occlusion reactive hyperemia was calculated as the AUC for blood flow above baseline for 3 min. Results: Baseline diameter did not differ at PRE vs. POST or between Control (3.76 ± 0.08 vs. 3.78 ± 0.09 mm) and Heat (4.25 ± 0.03 vs. 4.25 ± 0.02 mm) (all p > 0.3977). FMD did not differ at PRE vs. POST and between Control (11.2 ± 5.2 vs. 10.6 ± 10.2%) or Heat (2.8 ± 2.4 vs. 6.2 ± 4.2%) (all p > 0.2684). Relevant shear rate AUC did not differ at PRE vs. POST or between Control (27,412 ± 7,506 vs. 31,251 ± 20,608 a.u.) and Heat (16,538 ± 11,617 vs. 24,952 ± 10,639 a.u.) (all p > 0.2577). Peak post-occlusion reactive hyperemia did not differ at PRE vs. POST or between Control (396 ± 42 vs. 387 ± 17 ml/min) and Heat (464 ± 40 vs. 441 ± 32 ml/min) (all p > 0.1049). Total post-occlusion reactive hyperemia AUC was lower in Heat (140 ± 7 ml) vs Control (262 ± 12 ml) at PRE but did not differ across time or between groups at POST for Heat (212 ± 35 ml) vs Control (246 ± 66 ml). Conclusions: These preliminary data suggest there is no effect of 30 sessions of far-infrared sauna bathing on peripheral endothelial and microvascular function in adults with obesity. This may be due to the duration, frequency, and intensity of the far-infrared sauna compared to other passive heating modalities that have generated beneficial vascular adaptations in other studies. AHA 19TPA34890033. 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.
Mast cell degranulation is greater when exposed to dialysate collected from exercising skeletal muscle
Authors: Abbotts Kieran , Mangum Joshua , Wiedenfeld Needham Karen , Sieck Dylan , Ely Matthew , Larson Emily , Minson Christopher 
Published: May 2024

The effect of histamine is multifaceted and potentially triggers a broad range of cellular adaptations contributing to vascular function, cellular maintenance, metabolism, and inflammation. During exercise, histamine is released from skeletal muscle. This response and the subsequent actions of histamine appear important in obtaining many of the beneficial adaptations to exercise. Increases in exercising skeletal muscle histamine release, in part, occur due to mast cell degranulation. However, the direct effect of exercise on mast cell degranulation has yet to be elucidated. To that end, this preliminary study aimed to quantify in vitro mast cell degranulation when cells are exposed to dialysate taken from exercising and non-exercising skeletal muscle. We hypothesized that greater mast cell degranulation would occur when exposed to dialysate collected from exercising skeletal muscle compared to dialysate collected from non-exercising muscle. Ten subjects (5M/5F, age 26 ± 5 years, weight 76 ± 17 kg, height 168 ± 12 cm) completed 60 minutes of single-leg dynamic knee extension exercise. Prior to exercise, a microdialysis probe was inserted into the vastus lateralis of the exercising and non-exercising legs and perfused with saline at a rate of 5 uL/min. Dialysate was collected before and every 20 minutes during exercise and the subsequent one-hour recovery period. In the exercising skeletal muscle, mast cell degranulation (quantified via b-hexosaminidase release) was greater when exposed to dialysate during exercise versus dialysate collected pre-exercise (P < 0.05). Compared to non-exercising leg dialysate, degranulation was greater for exercising leg dialysate taken between minutes 20 and 40 into exercise (20.6 ± 2.7% vs 15.8 ± 2.0%, P < 0.05) and 40 and 60 into exercise (24.0 ± 2.6 % vs 15.0 ± 2.7 %, P < 0.001) and remained greater for dialysate taken in the first 20 minutes of recovery (21.4 ± 2.8% vs 15.2 ± 3.0%, P < 0.05). These data suggest that there is a soluble factor released from exercising skeletal muscle that causes mast cell degranulation in vitro. These preliminary findings establish a bioassay for further exploration of the identity of the soluble factor released from exercising skeletal muscle, which is responsible for mast cell degranulation in vivo. This research was supported in part by National Institutes of Health Grants AG072805 and HL115027. 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.
A Meta Analysis of Whole-Body and Heart Mass Effect Sizes From a Long-Term Artificial Selection Experiment for High Voluntary Exercise
Authors: Schwartz Nicole , Garland Theodore 
Published: May 2024

Effect sizes are a quantitative measure of the magnitude and direction of a phenomenon. These estimates can be compiled across multiple studies to summarize the weight of evidence for a particular alternative hypothesis, which is generally termed a meta-analysis. A meta-analytic approach allows one to summarize information from a wide array of similar studies and reach conclusions that may not be apparent on a case-by-case basis (e.g., to determine the overall effectiveness of a drug). Meta-analyses may be particularly useful in selection experiments, where the magnitude of a correlated response is necessarily expected to increase across generations, perhaps eventually reaching a plateau. Here, we examined the effect of artificial selection for high voluntary wheel running on heart mass in mice, which was expected to increase with selection for aerobic exercise behavior. The experiment spans nearly 30 years and 100 generations. All 4 of the replicate High Runner (HR) lines reached selection limits around generations 17-27, running approximately 2.5-3-fold more revolutions per day than the 4 non-selected Control (C) lines. These selection limits cannot be explained simply by a complete loss of heritability. Functional studies have tried to elucidate subordinate traits that affect motivational and/or ability for endurance exercise and have shown that HR mice differ from C in several other behavioral, physiological, and morphological traits. Several studies of heart ventricle mass have reported larger values in HR mice (with body mass as a covariate), but the differences often do not reach statistical significance (p<0.05). We compiled Least-Square Means, standard errors, F-statistics, degrees of freedom, and p-values from multiple studies. We also recorded pertinent information, such as: covariates used, age, generation, and whether other main effects were present (e.g., sex, wheel access). We calculated a common measure of effect size (Pearson’s R) and associated confidence intervals. This work is part of a larger meta-analysis to quantify effects of selection on various traits across multiple levels of biological organization. Preliminary results indicate that, despite a lack of statistical significance in many generations, HR mice have evolved larger hearts and smaller bodies relative to Controls. Moreover, a plateau in effect sizes for both of these traits coincide with the generational range during which the selection limit for wheel-running behavior was reached. NSF IOS-2038528. 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.
In Vivo Silencing of Intestinal DMT1 Mitigates Iron Loading in β-thalassemia Intermedia (Hbbth3/+) Mice
Authors: Yu Yang , Yang Chunghua , Delellis Regina , Lee Jennifer , Ebea-Ugwuanyi Pearl , Shine Jacob , He Yue 
Published: May 2024

β-thalassemia is an iron-loading anemia caused by homozygous mutations in the hemoglobin subunit beta gene. In β-thalassemia major, frequent blood transfusions and elevated absorption of dietary iron can lead to iron overload, which exacerbates pathological outcomes. Iron absorption is inappropriately high due to blunted expression of the iron-regulatory hormone hepcidin. Low hepcidin potentiates iron export from duodenal enterocytes by ferroportin (FPN); cellular iron depletion then secondarily increases expression of the iron importer, divalent metal-ion transporter 1 (DMT1). High expression of both transporters drives excessive iron absorption and ultimately, iron overload. In non-transfusion-dependent, β-thalassemia intermedia (βTI), hepcidin suppression and high iron absorption are the sole causes of iron loading. In this investigation, two parallel hypotheses were tested in βTI ( Hbbth3/+) mice: 1) Intestinal DMT1 drives elevated iron absorption and precipitates iron overload; and 2) In vivo silencing of intestinal DMT1 mitigates iron loading. Initial experiments revealed that intestine-specific ablation of DMT1 caused a pathophysiological shift from iron overload to an iron-deficiency phenotype with exacerbated anemia, thus proving that intestinal DMT1 is required for iron absorption in Hbbth3/+ mice. Subsequent studies utilized folic acid-coupled, ginger nanoparticle-derived lipid vectors to deliver functional DMT1 siRNAs to the duodenal epithelium of 4-week-old Hbbth3/+ mice daily for 16 days to assess the impact on iron loading. Knockdown of intestinal DMT1 blunted iron loading in Hbbth3/+ mice, thus supporting hypothesis 2. These notable experimental outcomes establish intestinal DMT1 as a plausible therapeutic target to mitigate iron overload in βTI and possibly other non-transfusion dependent, iron-loading anemias. This work was supported by grants R01 DK074867 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and R01 DK109717 from NIDDK and the Offce of Dietary Supplements (to JFC). 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.
Optogenetic Engineering of STING Signaling to Remotely Control anti-Tumor Immunity
Authors: Liu Siyao 
Published: May 2024

The cGAS-STING signaling pathway is regarded as a promising target for cancer therapeutics development. Here we present an ultra-light-sensitive optogenetic device, designated LiSmore for light-inducible SMOC-like repeats, that remotely control STING activation and downstream gene expression in antigen-presenting cells to mount innate immunity. We demonstrate that noninvasive light-triggered STING modulation effectively promotes dendritic cell (DC) maturation and antigen presentation, allowing T cells to be effectively sensitized to engage tumor antigens, thereby photo-boosting anti-tumor immune response. Importantly, combining LiSmore with immune checkpoint blocker (ICB) synergistically enhances antitumor effcacy in an immunosuppressive lung cancer model, which otherwise remains largely unresponsive to ICB treatment. Our findings establish that targeted optogenetic activation of STING signaling allows for the remote control of DC functions by boosting anti-tumor immunity at the tumor sites. Hence, LiSmore sets the stage for the development of wireless optogenetic immunomodulatory therapies in a light-switchable manner. Acknowledgment: This work was supported by the Welch Foundation (BE-1913-20220331 to Y.Z.), the Cancer Prevention and Research Institutes of Texas (RP210070 to Y.Z.), and the National Institutes of Health (R01GM144986 to Y.Z., R01HL134780 to R01 Y.H., R01HL146852 to Y.H., and R01CA240258 to Y.H.). Images were created by Biorender.com. 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.
Chloroquine Treatment Causes Diaphragm Muscle Denervation
Authors: Gulbronson Chloe I. , Jahanian Sepideh , Gransee Heather M. , Sieck Gary C. , Mantilla Carlos B. 
Published: May 2024

Chloroquine (CQ), an antimalarial agent, inhibits autophagy by preventing the autophagosome from fusing with the lysosome, emulating the effects of aging. Autophagy is a cellular digestion process that contributes to homeostasis through degradation of cytoplasmic structures in the cell. Aging effects include autophagy impairment, leading to the accumulation of altered proteins and organelles, thus contributing to subsequent cell damage and death. Previous studies in phrenic motor neurons show an age-dependent increase in key autophagy proteins LC3 and p62, reflecting autophagy impairment and autophagosome accumulation. In addition, acute chloroquine administration in old mice decreases maximal transdiaphragmatic pressure generation, suggesting a neuromuscular effect in aging. We hypothesized that treatment with the autophagy inhibitor chloroquine alters pre-synaptic morphology and increases the proportion of denervated diaphragm muscle fibers. Adult male and female 6-month C57BL6 mice were used to examine diaphragm muscle neuromuscular junction (NMJ) morphology and denervation. The autophagy inhibitor chloroquine (10 mg/kg/d) or vehicle was administered via daily intraperitoneal injections for 7 days. Confocal microscopy was used to compare pre- and post-synaptic morphology and denervation. There was evidence of a decrease in pre-synaptic volume without evidence of post-synaptic volume changes in chloroquine treated mice compared to vehicle. As expected, vehicle treated mice did not show evidence of substantial denervation. In contrast, chloroquine treated mice showed an increased proportion of denervated NMJs. The morphological changes observed were similar to those previously reported in the diaphragm muscles of 24-month-old mice. These findings reveal the effects at the neuromuscular junction of inhibiting autophagy and implicate impaired autophagy as a mechanism of aging effects. Supported by NIH R01 AG057052 and Mayo Clinic. 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.
Role of adipocyte-hepatic stellate cell cross talk in liver fibrosis
Authors: Morgan Angelina , Herbert Lea , Robinson Takeriah , Kim Paul , Kim Audrey 
Published: May 2024

Hepatic stellate cells (HSCs) are located in the space of Disse, between sinusoidal epithelial cells and hepatocytes. When the liver is injured chronically by alcohol, toxins, viruses, or nonalcoholic steatohepatitis, HSCs are activated. Activated HSCs are transdifferentiated into proliferative myofibroblasts which secrete extracellular matrix and exhibit contractile properties. HSCs may be an effective target to treat liver fibrosis. HSCs can communicate with neighboring cells such as hepatocytes, sinusoidal endothelial cells, Kupffer cells, and immune cells that regulate the activation of HSCs. The secretion of cytokines has led to HSC activation by the cell types mentioned, adipocytes are also known to release cytokines. The role of adipocytes in HSC activation has been rarely reported. This research aims to explore the roles of adipocyte-hepatic stellate cell crosstalk in liver fibrosis. At this annual meeting preliminary gene expression of activation markers, α-smooth muscle actin and type I collagen fiber, in HSCs will be discussed. Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant #P20GM103424-21. Grambling State University Title 3 Program (Award #P01B220013). 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.
Allelic modulation of large (second-order) mesenteric artery mechanical properties in adult APOE3 & APOE4 Mice
Authors: Walton Isaiah , McMurray Shelby , Gusek Brikena , Stimpson Anna , Jones Carleton , Eckman Delrae 
Published: May 2024

Previous studies from our lab have demonstrated age-related changes in vascular structure/function in posterior cerebral arteries (PCA) and left common carotid artery (CA) in male and female mice expressing human-APOE targeted replacement of APOE3 (B6.129P2-APOEtm2(APOE*3)MaeN8) and APOE4 (B6.129P2-APOEtm3(APOE*4)MaeN8) (Taconic Labs). Therefore, we hypothesize that similar changes may be observed in the systemic circulation. We isolated second-order mesenteric arteries (MA) from adult (6-month-old) male and female mice expressing APOE3 (n=3) and APOE4 (n=4). Mesenteric artery segments (5-8 mm in length) were rapidly isolated and cannulated on an arteriograph to assess mechanical properties: lumen diameter (LD), wall thickness (WT), wall:lumen ratio (W:L), distensibility, stress, strain, and stress versus strain (SvS) in the presence of Ca2+-free Krebs + diltiazem at intraluminal pressures ranging from 10mmHg–140mmHg. Phenylephrine and potassium-induced contractions were assessed in Ca2+-containing Krebs at intraluminal pressures ranging from 10-140mmHg. Data were analyzed using two-way ANOVA, Student’s t-test, and analysis of nonlinear fit. Values were considered statistically different at p<0.05. Our preliminary data indicated APOE4 mice had a greater WT and W:L compared to APOE3. Interestingly, there were no significant differences in the remaining passive mechanical properties (LD, distensibility, stress, strain, SvS). In addition, phenylephrine and potassium-induced contractions were similar in the APOE3 and APOE4 mice. This data suggests changes in passive mechanical properties in APOE4 mice which may resemble premature aging. ABRC/ADHS18-205211 (DME, CBJ), Arizona Alzheimer’s Consortium (funded by the Arizona Department of Health Services, Contract No. CTR040636) and matching funds from Midwestern University (DME), Biomedical Sciences Program (IW, SM, DME), Biomedical Sciences Start-up Funds (DME). 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.