bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Relationship of Circulating Extracellular Vesicles to Small Vessel Disease in Acute Ischemic Stroke
Authors: Parray Aijaz , Akhtar Naveed , Sivaraman Siveen , Raïq Hicham , Own Ahmed , Shuaib Ashfaq , Agouni Abdelali 
Published: May 2023

The association between Extracellular Vesicles (EVs) and Small Vessel Disease (SVD) might aid in the accurate early diagnosis and prognosis of acute ischemic stroke (AIS). This may be crucial for implementing the appropriate care plan and follow-up measures to limit the risk of permanent damage and prevent future occurrences. The purpose of the present study was to investigate the connection between circulating levels of EVs from various cellular origins and AIS severity biomarkers, established risk factors, and the presence of SVD as determined by noninvasive MRI imaging.The count of total circulating medium-size EVs and their phenotyping according to cellular origins were determined by flow cytometry analysis in platelet-free plasma from healthy volunteers and patients with AIS. Then, the relationship between the circulating of EVs to SVD and other risk factors was studied.When compared with controls, AIS patients exhibited a significantly higher number of circulating EVs originating from the endothelial cells, platelets, activated platelets, erythrocytes, and granulocytes. Multinomial logistic regression analysis showed a strong association between increased numbers of EVs derived from activated platelets (CD62P+) and erythrocytes (CD235a+) and the odds risk of AIS. However, it was found that a one-unit increase in CD235a+ EVs is associated with a 0.77-unit decrease in the odds of having SVD. Most AIS patients with SVD had hypertension, white matter ischemia, silent infarct, Basis Pontis ischemia, and cerebral microbleeds. However, the most significant risk for SVD was found in patients with hypertension on admission. Patients with hypertension on admission were 9.33 times more likely to have SVD than patients without hypertension on admission.Our findings underscore the value of circulating EVs as biomarkers of cell activation and thrombosis in AIS. Furthermore, our findings suggest a potential pathophysiological role for EVs in the onset and development of SVD and an interrelationship with major risk factors for AIS such as hypertension. Altogether, the association of EVs and non-invasive MRI imaging assessment of SVD presence may represent a novel combined approach for the identification of individuals with the highest risk of AIS and patients with the highest odds of recurrent stroke. This study was made possible by Qatar National Research Fund [grant No. NPRP11S-0114-180289]. The statements made herein are solely the responsibility of the authors. 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 beta-globin is differentially expressed across mammalian species
Authors: Hakim Md Abdul , Brooks Steven , Kamenyeva Olena , Kabat Juraj , Solomon Steven , Ford Verity , Davis Jeremy , Ruhl A. Parker , Ackerman Hans 
Published: May 2023

Globin proteins interact with endothelial nitric oxide synthase at the myoendothelial junctions of resistance arteries to regulate nitric oxide signaling between endothelium and smooth muscle. Human resistance arteries express both alpha and beta globin to form heterotetrameric hemoglobin (α2β2). To better understand the role of hemoglobin in human resistance arteries, we need to identify an animal model in which both alpha and beta globin are expressed in the resistance vasculature. To identify potential candidates, we used microscopy to survey a range of mammalian laboratory animals for hemoglobin in the artery wall. We isolated arteries (100-200 μm in diameter) from mesenteric tissue collected from human patients undergoing clinically-indicated surgery and from the following laboratory animals: mouse ( Mus musculus, C57BL/6 strain), rat ( Rattus norvegicus, CD strain), African thicket rat ( Grammomys surdaster), guinea pig ( Cavia porcellus), New Zealand white rabbit ( Oryctolagus cuniculus), Beagle dog ( Canis lupus familiaris), and cynomolgus macaque ( Macaca fascicularis) after they underwent euthanasia on approved animal study protocols. We leveraged the autofluorescence of heterotetrameric hemoglobin under multiphoton excitation to visualize hemoglobin in the wall of intact, unstained, paraformaldehyde-fixed artery segments. Autofluorescent puncta representing tetrameric hemoglobin were observed in the wall of resistance arteries from the human patients, non-human primate, and canines, but not from rabbit nor any of the rodent species. The ability of beta globin to restrict endothelial NO signaling was confirmed in canine arteries ex vivo by testing a beta globin mimetic peptide that inhibited vasoconstriction to phenylephrine. In conclusion, primates and canines appear to have tetrameric hemoglobin in the resistance artery wall, whereas rodents and rabbits do not. This study highlights differences in vascular globin expression between humans and rodents and extends the recent discovery of hemoglobin in resistance arteries of humans to two additional mammalian species that may serve as models for studying the unique activities of tetrameric hemoglobin in the resistance vasculature. Funding: Intramural Research program, NIAID, NIH 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.
Overexpression of regulator of G protein signaling 2 (RGS2) in the paraventricular nucleus reduces blood pressure in angiotensin II-induced hypertensive rats
Authors: Boomer Shane , Liu Xuefei , Zheng Hong 
Published: May 2023

The hypothalamic paraventricular nucleus (PVN) is important in mediating sympathetic activity to regulate blood pressure. The regulator of G protein signaling 2 (RGS2) is a negative G protein regulator. RGS2 selectively regulates Gαq signaling, an important cause of hypertension and cardiac hypertrophy. However, little-to-no studies are being done related to G-protein-RGS2 signaling on the central mechanisms of blood pressure control and sympathetic activation. In this study, we hypothesized that central RGS2 overexpression changes blood pressure regulation by decreasing the response to angiotensin II (ANG II). We infused ANG II (200ng/kg/min) via an osmotic minipump to induce hypertension. These rats were outfitted with telemetry and measurements of blood pressure and heart rate over the next 14 days, with or without RGS2 adenovirus (AV) injection into the PVN. We found that days 3, 4, and 6 after virus transfection showed a significant difference between the group outfitted with only the ANG II pump versus those outfitted with both ANG II pumps and PVN AV injection. Results shown below are in order of ANG II pumps only, ANG II pump after AV, and ANG II pump + AV, respectively (unit in mmHg). Day 3: 155.5 +/- 9.4, 131.8 +/- 4.5, 134.3 +/-9.5, P<0.05; Day 4: 164.5 +/- 8.0, 140.3 +/- 7.0, 136.1 +/- 10.2, P<0.05; Day 6: 169.3 +/- 4.2, 144.4 +/- 4.5, 140.6 +/- 8.3, P<0.05. There was no significant difference between day 6 and the end of the experiment. Our real-time PCR and Western blot studies showed punched PVN tissue highly expressed RGS2 mRNA and protein. Further, in vitro study showed ANG II treatment affected RGS2 mRNA and protein expression in cultured hypothalamic neuronal cells. The findings suggest that RGS2 ameliorates ANG II-induced hypertension in rats, possibly via regulating central PVN-mediated blood pressure controlling and sympathetic activation. Funded by NIH R01-DK-114663 & R01-DK-129311 and USD G-RISE, NIH T32GM-136503. 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.
Acid Ceramidase as a Novel Target for Adiponectin Receptor Agonist to Abrogate NLRP3 Inflammasome Activation and Glomerular Injury during Obesity
Authors: Huang Dandan , Li Guangbi , Zou Yao , Li Ningjun , Ritter Joseph , Li Pin-Lan 
Published: May 2023

Adiponectin receptor agonists have recently been reported to protect against glomerular inflammation and injury during obesity. Nevertheless, the molecular mechanism underlying their protective action against obesity-related glomerulopathy (ORG) remains poorly understood. Given the implication of ceramide signaling pathway in the pathogenesis of ORG, the present study tested whether adiponectin receptor agonists target lysosomal acid ceramidase (AC) to inhibit NLRP3 inflammasome activation and glomerular injury during obesity. Confocal microscopy showed that NLRP3 inflammasome activation induced by visfatin, a pro-inflammatory adipokine, in murine podocytes was remarkably attenuated by adiponectin. Also, it was found that adiponectin significantly inhibited visfatin-induced formation of multivesicular bodies (MVBs) containing IL-1β in podocytes. Such inhibitory effect of adiponectin was abolished by AC inhibitors (carmofur and ARN14974) but mimicked by genistein (AC inducer) or MCC950 (NLRP3 inflammasome inhibitor). By nanoparticle tracking analysis, we measured exosomes released from podocytes in different groups, which have been reported to mediate the secretion of NLRP3 inflammasome products to extracellular space to activate inflammatory response. Visfatin-induced elevation of exosome release from podocytes was remarkably suppressed by adiponectin. This action of adiponectin was blocked by AC inhibitors but mimicked by genistein. In vivo, we showed that high-fat diet-induced T cell infiltration in glomeruli was exaggerated by podocyte-specific Smpd1 gene (gene code of acid sphingomyelinase) overexpression in Smpd1trg/Podocre mice compared to WT/WT mice. However, intraperitoneal injection of AdipoRon, a synthetic adiponectin receptor agonist, significantly decreased obesity-induced glomerular inflammatory response in both WT/WT and Smpd1trg/Podocre mice. Such anti-inflammatory effect of AdipoRon was prevented by co-treatment with carmofur. Moreover, podocyte-specific Smpd1 gene overexpression amplified HFD-induced podocyte injury, proteinuria, and glomerular sclerosis in Smpd1trg/Podocre mice compared to control littermates. These pathological changes were prevented by AdipoRon, and the effect of AdipoRon was reversed by carmofur. Taken together, our findings suggest that activation of AC signaling pathway mediates the protective action of adiponectin receptor agonists against glomerular inflammation and injury in ORG. This study was supported by NIH grants DK054927 and DK120491. 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.
Role of tyrosine phosphorylation of Mfn2 in endoplasmic reticulum-mitochondria coupling
Authors: Chaput Isabel , Kelly Madeline , Landherr Maria , Polina Iuliia , Nieto Bridget , Cypress Michael , Jhun Bong Sook , Zhang Peng , O-Uchi Jin 
Published: May 2023

Introduction: A mitochondrial fusion protein, Mitofusin 2 (Mfn2) serves as one of the major components for tethering the mitochondria and endoplasmic reticulum (ER), which regulates the exchange of lipids, Ca2+, and reactive oxygen species (ROS) across the two organelles. Several post-translational modifications (PTMs) of Mfn2 have been identified via mass spectroscopy, such as tyrosine phosphorylation (P-Tyr). However, little information is available whether any PTMs of Mfn2 can regulate mitochondrial and ER tethering function under physiological and pathological conditions. Hypothesis: P-Tyr of Mfn2 regulates Mfn2 function such as ER-mitochondrial tethering. Methods: To achieve stable activation of c-Src, we stably overexpressed c-Src or an shRNA targeting the shRNA targeted to C-terminal Src kinase (CSK), a specific negative regulator of c-Src, in HEK293T cells. Stable cell lines were used for biochemical, cell biological, and physiological assays. Results: Two computational program for phosphorylation site prediction, NetPhos and Group-Based Prediction System, predicted at least five c-Src-specific P-Tyr sites within the Mfn2 structure. Using immunoprecipitation and a phosphate-affinity electrophoresis technique (Phos-tag SDS-PAGE), we found that overexpression of c-Src, but not other Src family members, leads to P-Tyr of Mfn2. Moreover, dephospho-mimetic mutations (replacing Tyr with Phe) in Mfn2 significantly decreased the c-Src-dependent P-Tyr in Mfn2. Stable c-Src activation decreased the distance between the ER and outer mitochondrial membrane (OMM) as assessed by transmission electron microscopy and Förster resonance energy transfer between an OMM-targeted cyan fluorescent protein and an ER membrane-targeted yellow fluorescent protein the ER membrane measured by confocal microscopy. Mitochondrial Ca2+ (mtCa2+) uptake in response to cytosolic Ca2+ elevation increased with faster kinetics under c-Src activation, followed by increased mitochondrial ROS, and decreased oxygen consumption rate. Knocking down of endogenous Mfn2 by stable expression of shRNA targeting 3’ untranslated region of Mfn2 increased the distance between ER and OMM, and decreased mtCa2+ uptake. The reintroduction of wild-type Mfn2 in Mfn2-knockdown cells reversed these changes to the levels observed in cells expressing control shRNA. However, re-expression of a dephspho-mimetic mutant of Mfn2 in Mfn2-knockdown cells failed to rescue the changes in mtCa2+ uptake profile. Conclusion: P-Tyr of Mfn2 by c-Src modulates the distance between the OMM and ER, resulting in mtCa2+ elevation and oxidative stress. NIH/NHLBI R01HL136757 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.
Core temperature responses in well-healed burn survivors during exercise heat stress: effect of cooling modalities
Authors: Atkins Whitley , McKenna Zachary , Foster Josh , Belval Luke , Orth Bonnie , Johnson Elias , Benning Mayah , Watso Joseph , Hakes Courtney , Jay Ollie , Crandall Craig 
Published: May 2023

Introduction: Every year, ~150,000 patients are treated in the United States with burn-related injuries. Previously, our group has shown that ~75% of burn survivors have a maximal aerobic capacity in the lowest 20th percentile rankings, relative to sex and age-adjusted non-burned individuals. This level of impairment is strongly associated with cardiovascular-specific, as well as all cause, morbidity, and mortality. Moreover, burn injuries that require grafting impair thermoregulation, and the subsequent increases in skin and core temperature may dissuade these individuals from engaging in exercise and/or physical activity. Low-energy cooling strategies have potential to attenuate increases in core temperature in burn survivors, which may promote regular physical activity. Thus, the purpose of this study was to evaluate the efficacy of low-energy cooling modalities on thermoregulatory responses during physical activity in the heat. Methods: Twenty-four adults with NO-BURN (n = 9), MODERATE burns (20-40% body surface area burned, n = 7), or LARGE burns (> 40% body surface area burned, n = 8) walked for one hour at a moderate intensity (rate of metabolic heat production of 4.5 W/kg body mass) in an environmental chamber (39°C, 40% RH). Burn survivors were at least 2 years post-injury. Participants performed this activity four times, with the following modalities randomly applied throughout each trial on separate days: no cooling (i.e., control), fan at 4 m/s (FAN), water spray (WS, minimum 10-50 g every 5 min, scaled to burn area size), or WS+FAN. Core temperature (Tcore) was recorded throughout each trial via a telemetric pill. Final Tcore values for each cooling modality were compared against the no cooling condition. Results: For the LARGE burn group, WS reduced end-exercise Tcore by 0.37°C (range 0.09 to 0.66°C) compared with no cooling ( p = 0.01). FAN and WS+FAN did not impact end-exercise Tcore for the LARGE burn group ( p ≥ 0.48). No cooling modality affected Tcore for the MODERATE burn group ( p ≥ 0.12) or the NO-BURN group (p ≥ 0.55). Conclusion: At the assessed workload and environmental condition, the efficacy of the applied cooling modalities on Tcore responses for burn survivors appears to be dependent on both the selected modality and the size of the burn surface area. Namely, WS attenuated the increases in Tcore in participants with LARGE burn injuries, but FAN and WS+FAN did not attenuate Tcore responses in any group. Supported by NIHGrant R01GM068865 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.
Decreasing FIO2 induces spontaneous intermittent hypoxic events in mice
Authors: Kalra Hardik , Jedlicka Charles , Vasileva Anastasiia , Tomasson Michael , Bates Melissa 
Published: May 2023

Chronic intermittent hypoxia, CIH, is a feature of sleep apnea widely used in research to mechanistically examine the physiological effects of sleep apnea. These mechanistic studies commonly utilize mice as the study model. In room air, mice experience periodic apneas and arterial oxygen desaturations. Activation of the carotid body could stabilize breathing and decrease these events. Therefore, we hypothesized that C57BL/6J mice experience fewer hypoxic events with decreasing FIO2.We placed 6 C57BL/6J mice (3 male, 3 female) in an Emka® unrestrained barometric plethysmograph and measured pulse oximetry using the STARR LifeSciences MouseOx® Plus system. The mice were exposed to different levels of FIO2 for 10 minutes each: 0.21, 0.15, 0.12, 0.09, 0.30 ± 0.01. We defined a hypoxic event as 3% deviation from the average oxygen saturation at each FIO2. Mice did not show fewer hypoxic events when exposed to increasing levels of hypoxia. In fact, mice experienced more hypoxic events at 0.15 than 0.21 and 0.30 FIO2 (P<0.05). Mice also experienced more hypoxic events at 0.12 than at 0.30 FIO2. Additionally, we found that hypoxic event nadir SpO2 was significantly lower at all FIO2 levels when compared to 0.21 FIO2. Hypoxic events at all FIO2 levels had significantly lower average SpO2 compared to 0.21 FIO2. No change was observed for average SpO2 for hypoxic events at 0.30 FIO2 relative to 0.21 FIO2. Contrary to our hypothesis, intermittent hypoxic events are not stabilized by exposure to a hypoxic environment. Future work will evaluate this in other mouse strains. 1R56HL152365 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.
Effects of mental wellness training within advanced exercise physiology courses on student mental health
Authors: Leary Miriam , Bryner Randy 
Published: May 2023

Mental illness has become a prevalent health issue among college students. Within rigorous STEM based physiology programs, academic stress can negatively affect overall wellbeing. The objective of this study was to improve mental wellness and stress of undergraduate juniors in a rigorous physiology course by providing wellness trainings from campus clinicians. We hypothesized that a wellness training intervention would improve self-reported mental wellness, academic stress, and overall perceived stress of undergraduate physiology students. Students completed a survey in the first advanced physiology course at midterm in fall (F) 2021 (n=200, 99%). During the second advanced physiology course in the spring 2022 semester, students received six 30 minute wellness trainings delivered by campus counseling clinicians and were reassessed at the same time point in the spring (S) semester (n=170, 94%) as during the fall. Surveys included nonvalidated questions as well as the Perception of Academic Stress Scale and Cohen’s Perceived Stress Scale. Following the wellness intervention, more students felt satisfied with their overall mental health and wellbeing (F 21%, S 41%), and fewer reported feeling anxious (F 89%, S 50%) and depressed (F 58%, S 26%). Students still felt academics were a significant sources of stress (F 96%, S 96%), but were less likely to feel academics negatively impacted their mental health (F 73%, S 47%). While responses improved over time on the Perception of Academic Stress Scale (34.7 ± 8.5 vs. 53.7 ± 11.5, p<0.001), there were no differences on the Cohen’s Perceived Stress Scale (20.0 ± 6.8 vs. 20.6 ± 6.7, p=.0.20). In conclusion, wellness trainings embedded into rigorous physiology courses can positively impact undergraduate physiology students’ mental wellbeing. Potential mechanisms may include learning and practicing stress management techniques for academic stress. 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.