bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex Differences in the Diastolic Blood Pressure Response to Orthostasis in Obstructive Sleep Apnea
Authors: Bock Joshua , Covassin Naima , Vungarala Soumya , Sompalli Sreeja , Singh Prachi , Somers Virend 
Published: May 2023

Hypertension is commonly observed with obstructive sleep apnea (OSA), partly due to dysregulation of sympathetic activity. As OSA is considered male-dominant, potential sex differences in the sympathetic regulation of BP have yet to be explored. Hemodynamic responses to an orthostatic challenge have implications for cardiovascular risk and are sympathetically-modulated. Therefore, we tested the hypothesis that females with OSA have differential BP and HR responses to orthostasis relative to males with OSA. 160 individuals not taking antihypertensive medications completed an overnight polysomnography to identify OSA (apnea-hypopnea index ≥5 events/hr). Orthostatic responses were quantified as the changes (Δ) in BP and HR (assessed via brachial cuff) from rest (10min supine) to 60sec post-standing. Females with (n=17, 42±14yrs, 30.7±6.0kg/m2) and without (n=43, 39±12yrs, 27.6±5.7kg/m2) OSA were compared to males with (n=60, 45±11yrs, 31.4±3.8kg/m2) and without (n=40, 39±13yrs, 27.4±3.1kg/m2) OSA using a one-way ANOVA. There were no between-group differences in age (p>0.05 for post-hoc comparisons) and BMI was lower in both females, and males, without OSA relative to males with OSA (p<0.05 for both). ΔSBP did not differ between females with (1±8mmHg) and without (2±8mmHg) OSA nor between males with (4±8mmHg) and without OSA (5±12mmHg, ANOVA p=0.37). Females with OSA had a blunted ΔDBP relative to females without OSA (5±7 vs. 10±6mmHg, p<0.05), whereas males with and without OSA demonstrated similar responses (9±8 vs. 10±6mmHg, p=0.95). ΔHR did not differ between females with (8±8beats/min) and without OSA (9±11beats/min) nor between males with (13±10beats/min) and without OSA (12±10beats/min, ANOVA p=0.06). ΔDBP was not associated with the apnea-hypopnea index (Spearman's r=-0.19, p=0.47; Spearman’s r=0.23, p=0.08) nor nadir SpO2 (Spearman's r=0.27, p=0.29; Spearman’s r=0.06, p=0.64) in females or males with OSA. These data suggest that OSA influences the DBP response to orthostasis in females to a greater extent than males. As DBP is associated with sympathetic activation, this finding could indicate greater sympathetic dysregulation in females, relative to males, with OSA. This work was supported by the National Institutes of Health T32-HL007111 (JMB), HL134808 (NC), HL065176 (PS and VKS), and HL134885 (VKS). 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.
Leveling the Playing Field: Initiatives to Address Gender and Racial Inequities in NIH Funding
Authors: Tigno Xenia 
Published: May 2023

Since 1990, the number of NIH-funded training grants awarded to women at the pre- and post-doctoral levels have been steadily increasing, with women comprising 60-61% of predocs, and 55-56% of postdoctoral fellows. Similarly, women constitute the majority of career development (K) awardees (58%). Nevertheless, the proportion of R01-equivalent awards obtained by women was only 35% of all awarded R01’s in 2022, although an improvement over the 22% rate in 1998. As for research grants by race, nearly 71% were awarded to Whites as of November 2022.Aware of these disparities, the NIH as a whole and the Office of Research on Women’s Health in particular have issued a number of funding opportunity announcements that seek to mitigate some of the barriers that prevent women and other underrepresented groups from obtaining more equitable representation in the NIH-funded biomedical workforce. Many of these available funding opportunities, which are intended to increase the recruitment and retention of a diverse workforce, are often overlooked or are unknown to the underrepresented sectors of the biomedical workforce. This presentation is intended to increase awareness of some of these mechanisms and create a greater impact on promoting diversity, equity, inclusion and accessibility to disadvantaged groups. Public 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.
A novel gene therapy for familial dilated cardiomyopathy based upon disruption of PP2A -- mAKAP-beta signalosomes
Authors: Li Xueyi , Li Xueyi , Li Jinliang , Arthur Jennifer , Samuelsson Anne-Maj , Dunkenberger Logan , Ramchandani Rohin , Karakikes Ioannis , Kapiloff Michael 
Published: May 2023

Familial Dilated Cardiomyopathy (DCM) is a common inherited cause of heart failure characterized by progressive left ventricular dilatation and systolic dysfunction. Despite the discovery of novel genetic mutations causing DCM, the downstream mechanisms resulting in heart failure are still unclear, and there remains a great unmet clinical need. Contributing to the phenotype of ventricular dilatation in DCM is the lengthening of cardiac myocytes, which exhibit increased overall length to width ratio. We have shown that increasing the phosphorylation of the transcription factor serine response factor (SRF) at serine residue 103 by displacement of protein phosphatase 2A (PP2A) from the perinuclear scaffold protein muscle A-kinase anchoring protein β (mAKAPβ) can inhibit myocyte lengthening and improve cardiac function following myocardial infarction. Notably, SRF S103 phosphorylation is decreased in both human heart failure and in the hearts of transgenic mice expressing the human DCM α-tropomyosin Glu54Lys (Tm-E54K) mutant allele. We now show that, accordingly, targeting of mAKAPβ-PP2A signalosomes constitutes a new therapeutic strategy for DCM. A self-complementary serotype 9 adeno-associated virus (AAV9sc) conferring cardiac-specific expression of a mAKAPβ fragment comprising the PP2A binding domain (PBD) was used to target the signalosomes in mice. AAV9sc.PBD administration into neonatal Tm-E54K mice provided long term preservation of cardiac function and prevented ventricular dilatation. At 16 weeks of age, ejection fraction was significantly improved 14%[MK1], and wall thickness was increased for AAV9sc.PBD TM-E54K mice when compared with control AAV9sc.GFP treated TM-E54K mice. Morphometry of acutely dissociated adult mouse myocytes showed that AAV9sc.PBD treatment restored myocyte length to width ratio to that of non-transgenic animals, while western blots showed increased SRF S103 phosphorylation. The results in mice have been corroborated by PBD expression in engineered heart tissues (EHT) generated from an induced pluripotent stem cell (iPSC) line for a DCM phospholamban R14del patient. PBD expression increased SRF S103 phosphorylation and improved tissue contractility. Taken together, this study suggests that increasing SRF S103 phosphorylation by disruption of mAKAPβ-PP2A signalosomes can constitute a novel therapeutic strategy for DCM. Funded by Department of NIH Grant R01HL146111 (Dr. Kapiloff), R01 HL139679 and Leducq Foundation CurePlan (Dr. Karakikes), and the NHLBI Gene Therapy Resource Program. 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.
Assessment of metabolic flexibility by RER in the Gromphadorhina portentosa
Authors: Ebrahim Merai , Ng Madison , Sanchez Ryan 
Published: May 2023

Metabolism is the series of chemical reactions utilized by organisms to create energy to drive physiological and cellular functions. Understanding the metabolism of ectothermic organisms has been an area of interest that is widely understudied with limited model organisms. Using the Gromphadorhina portentosa (Giant Madagascar Hissing Cockroach) as a model organism, ectothermic metabolism was measured by respirometry using a closed animal chamber and iWorx gas analyzer. The metabolic rate was calculated as the Respiratory Exchange Ratio (RER), which is the ratio of carbon dioxide produced to oxygen consumed. We investigated whether changes in metabolism were allometric functions dependent on the size of cockroaches. Experiments were conducted to study the effects of high temperatures, exercise and diet on the metabolic rate of G. portentosa compared to control. Preliminary data showed significant changes in RER under several of these experimental conditions. We have also investigated whether the environmental conditions produced sex- and age-specific changes in RER. Lastly, we utilized biochemical assays to determine why several experimental groups exhibit RERs >1.0. Preliminary results show glucose and triglyceride levels in hemolymph accommodate metabolic flexibility requirements in the above experimental conditions. This work represents the most comprehensive evaluation of this ectotherm and adds to our understanding of one of the largest insects. APU 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.
Agreement of Resting Brain Perfusion using Two Different Pseudo-Continuous Arterial Spin Labeling Sequences and the Associations with Lipid Biomarkers
Authors: Decker Kevin , Sanjana Faria , Rizzi Nick , Kramer Mary , Cerjanic Alexander , Johnson Curtis , Martens Christopher 
Published: May 2023

Objective: We developed a modified pseudo-continuous arterial spin labeling (pCASL) sequence for measuring cerebrovascular reactivity (CVR) to hypercapnia in humans; however, the method has yet to be validated against an established pCASL sequence for assessing brain perfusion at rest. The purpose of this project was to compare resting brain perfusion from our modified sequence (Rest-CVR) to the pCASL sequence developed by the Human Connectome Project (HCP). The secondary purpose was to determine the association of these pCASL sequences with lipid biomarkers. Methods: Resting brain perfusion was assessed using both sequences in 7 middle-aged adult participants (56 ± 5 years old) using a 64-channel head coil inside a Siemens Prisma 3T MRI scanner. The modified Rest-CVR sequence included a shorter scan time (~3 minutes) with a single post-labeling delay and duration of 1800ms, FOV= 215mm2, slice thickness 2.27mm, TR=4510ms, and TE=20ms. Blood samples were also collected to determine the association of each sequence with circulating lipid biomarkers to test the sensitivity of each sequence to clinically relevant risk factors of cerebrovascular disease. Results: Outcomes from the two pCASL sequences were significantly correlated [R2 = 0.88; F (1,5) = 35.06 p = 0.002]. However, resting brain perfusion from Rest-CVR was significantly lower than HCP [Rest-CVR: 58.84 ± 15.22 vs. HCP: 81.12 ± 12.54 ml/min/100g; p = 0.0008]. Resting brain perfusion measurements from both sequences were negatively associated with low density lipoprotein (LDL) cholesterol (HCP: r = -0.97; p = 0.0001 and Rest-CVR: r = -0.87; p = 0.008) suggesting sensitivity of both to a clinically relevant risk factor for cerebrovascular disease. However, neither sequence was associated with total cholesterol, triglycerides, or high-density lipoprotein (HDL) cholesterol (p>0.05 for all). Conclusion: Rest-CVR was determined to be a reliable measure of resting brain perfusion in that it correlated with the HCP protocol; however, the lower magnitude relative to HCP makes it a less valid approach for accurately determining brain perfusion. Resting brain perfusion from both sequences was negatively associated with LDL suggesting both are sensitive to clinically relevant outcomes. The shorter Rest-CVR sequence may be most suitable for studies in which an exact estimate of brain perfusion is not required such as when assessing a relative change to hypercapnia. Grant Support: NIH/NIGMS - P20 GM113125 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.
Sex differences in isolated skeletal muscle force production: a spectrum of responses
Authors: Fletcher Nicole , Gee Kinley , Murrant Coral 
Published: May 2023

Whether sex differences in skeletal muscle microvascular responses differ in response to muscle contraction is currently unknown. To determine vascular responses to muscle contraction in vivo we use intravital microscopy using thin skeletal muscle models of mixed fibre types (i.e. hamster retractor muscle). However, to effectively quantify this relationship in vivo, the initial muscle contraction stimulus must be constant across the sexes and thus, we must first determine whether there are sex differences in skeletal muscle force generation. We hypothesized that sexual dimorphisms in force production would not be apparent in muscles of any fibre type composition. To test this hypothesis, we used skeletal muscles with unique fibre type characteristics and oxidative capacities. Mouse soleus (SOL: primarily type 1 >75%), extensor digitorum longus (EDL: primarily type IIB ~60%), and costal diaphragm (DIA: primarily type IIA ~55%) muscles were isolated from adult male and female CD-1 mice. The retractor muscle (RET: primarily type IIX ~58%) was also isolated from adult male and female Syrian hamsters. Muscles were electrically stimulated in vitro and force production was quantified at optimal length during a force-frequency test (1-120Hz) and twitch (1Hz) contractions. In mice, females generated greater force during the force-frequency test in SOL (10-120Hz) and EDL (30-120Hz) and generated greater twitch forces compared to males (SOL: female 34.7 ± 2.4 mN/mm2, n=21 vs male 27.8 ± 2.0 mN/mm2, n=17; EDL: female 41.2 ± 2.2 mN/mm2, n=35 vs male 32.5 ± 2.1 mN/mm2, n=29). Females generated greater force during the force frequency test in DIA at 30Hz only and no significant sex differences were observed in DIA twitch force (female 0.24 ± 0.02 g/mg, n=19 vs male 0.20 ± 0.02 g/mg, n=21). In hamster RET no significant sex differences in force were observed during the force frequency test or during the twitch contraction (female 0.13 ± 0.01 g/mg, n=19 vs male 0.14 ± 0.02 g/mg, n=20). Collectively, these findings demonstrate that sex differences in force production were observed in muscles primarily comprised of slow oxidative (type 1) and fast glycolytic (type IIB) fibres but not in muscles primarily comprised of intermediate fibres (type IIA and type IIX). These data show that on a spectrum of muscle fibres from slow oxidative to fast glycolytic, sex differences are most apparent on the extremes of the spectrum, whereas sexual dimorphisms in the middle of the spectrum are not apparent. This work is supported by NSERC. NSERC 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.
Assessing early postnatal development of the enteric glial network
Authors: Jodka Sophia , Jodka Sophia 
Published: May 2023

The enteric glial network is instrumental in intestinal barrier maintenance and repair, but is immature at birth. At birth, enteric glia are restricted to the submucosal and myenteric plexuses, and are driven to populate the lamina propria by microbial colonization and changes in microbial populations at weaning. Our lab uses a comparative pig model to describe and quantify early postnatal development of the enteric glial network. We hypothesized the density and distribution of glial cell subtypes would change within the early postnatal period, illustrating early postnatal development and maturation of the enteric glial network. Using the iDISCO three-dimensional imaging technique, the glial network in 1-, 7-, 14-, and 21-day-old pigs was analyzed by adapting an algorithm to quantify the volume, maximum and mean intensities of glial markers of GFAP, Sox10, and S100β within manually isolated villi. In the lamina propria, GFAP density by volume decreases (P=0.0228) while S100β increases (P=0.0007) from 1- to 21- days. Between 1- and 21- days old Sox 10 tends to increase (P=0.2241, one-way ANOVA) - see graph. We believe this indicates GFAP+ cells change their expression profiles over the very early postnatal period to increase production of S100β, a known inflammatory mediator, which is participating in immune responses to colonizing bacteria, while Sox10 acts as a marker of proliferation. Understanding this early postnatal development will allow for modulation of this system, accelerating maturation of repair mechanisms. 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.
Treatment with the flavonoid, luteolin, attenuates the development of placental ischemia-induced hypertension in pregnant rats
Authors: Spradley Frank , Bakrania Bhavisha , Eddy Adrian , Granger Joey , Rana Sarosh 
Published: May 2023

Preeclampsia (PE) is a disease of hypertension and systemic vasoconstriction during pregnancy. Placental ischemia is implicated in PE by release of pro-hypertensive factors, like soluble Fms-like tyrosine kinase-1 (sFlt-1). Recently, we identified the bioflavonoid, luteolin, as a potent inhibitor of sFlt-1 and hypoxia-inducible factor 1α (HIF-1α, a major positive regulator of sFlt-1) in human placental cell lines and explants. However, the impact of luteolin in models of PE is unknown. We tested the hypothesis that luteolin attenuates placental ischemia-induced hypertension and lowers circulating sFlt-1 levels. Sprague-Dawley rats were started on luteolin treatment at gestational day 14 (20 mg/kg per day) or vehicle (0.5 g peanut butter) as well as placed in Reduced Uterine Perfusion Pressure (RUPP) placental ischemic or Sham surgery groups. The ensuing 4 experimental groups were: Sham+vehicle (N=14), Sham+luteolin (N=15), RUPP+vehicle (N=14), and RUPP+luteolin (N=15). On day 18, rats were implanted with carotid catheters for measurement of conscious mean arterial blood pressure (MAP) on gestational day 19. Luteolin treatment significantly attenuated RUPP-induced rises in maternal MAP (RUPP+vehicle: 118±2 vs. RUPP+luteolin: 108±1 mmHg, P<0.05) with no effect in Sham rats (Sham+vehicle: 105±1 mmHg; and Sham+luteolin: 104±2 mmHg, P>0.05). Circulating levels of sFlt-1 were elevated in RUPP+vehicle: 1.66±0.10 pg/mL vs. Sham+vehicle: 1.01±0.08 pg/mL (P<0.05) that were significantly reduced with luteolin treatment only in RUPP+luteolin: 1.09±0.11 pg/mL and not Sham+luteolin: 1.26±0.11 pg/mL (P<0.05). Total fetal weight was lower in RUPP+vehicle: 14±2 g vs. Sham+vehicle: 26±2 g (P<0.05) but was not impacted by luteolin treatment in either group (RUPP+luteolin: 12±1 g or Sham+luteolin: 26±2 g, P>0.05). Total placental weight was less in RUPP+vehicle: 3.3±0.6 g vs. Sham+vehicle: 6.4±0.4 g (P<0.05), which was not altered by luteolin treatment in either group (RUPP+luteolin: 3.1±0.4 g or Sham+luteolin: 6.1± 0.5 g, P>0.05). Overall, luteolin significantly attenuated placental ischemia-induced hypertension and reduced circulating sFlt-1 levels suggesting that naturally occurring flavonoids can be developed as therapeutics for PE. This work was supported by NIH 1R56HL157579-01. 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.
Enhanced sensitivity to ischemia reperfusion injury in a mouse model of accelerated aging is associated with blunted upregulation of urine KIM1
Authors: Goodluck Helen , Lopez Natalia , Oe Yuji , Kanoo Sadhana , Chul Kim Young , Maher Pamela , Vallon Volker 
Published: May 2023

Objective: Advanced age enhances the risk of acute kidney injury (AKI) but the mechanisms remain unclear. Kidney injury molecule 1 (KIM1) is a sensitive measure of tubular injury (PMC2915578) but also confers a phagocytic phenotype on epithelial cells important for kidney recovery (PMC2293335), and a higher KIM1/serum creatinine (SCr) ratio was associated with better kidney recover over 6 months (PMID31646460). Here we compared the response to kidney ischemia reperfusion injury (IR) in regular C57BL6 mice with a mouse strain of accelerated aging (Senescence Accelerated Mouse-Prone 8, SAMP8). Methods: Bilateral renal artery clamping for 15 or 25 minutes (15IR, 25IR) or sham operation was performed under ketamine-xylazine anesthesia and temperature-controlled conditions (36-37°C) in 3 months old male C57BL6 and SAMP8 mice (n=6-8 mice/group). Results: In response to 25IR, none of the SAMP8 mice survived beyond day 5, while 87% of C57BL6 mice survived for 24 days (end of study) together with all 15IR and sham mice. In response to 15IR, the rise in plasma creatinine on day 1 was significantly greater in SAMP8 vs C57BL6, associated with greater urine NGAL/creatinine ratios but a blunted rise in urine KIM1/creatinine. The same phenotype was observed on day 1 in 25IR, except that the rise in urine NGAL/creatinine was likewise blunted in SAMP8. In a second set of mice we compared 15IR in SAMP8 with 25IR in C57BL6 to induce similar kidney injury in both strains as indicated by a similar rise in plasma creatinine and urine NGAL/creatinine on day 1. Also under these conditions, the increase in urine KIM1/creatinine observed in C57BL6 was absent in SAMP8. Conclusions: Mice with accelerated aging show an increased sensitivity to renal ischemia reperfusion injury. This was associated with, and potentially in part due to, blunted KIM1 expression, cleavage and/or function. Supported by National Institutes of Health (NIH) Grants RF1AG061296 (PM, VV), R01DK132690 (VV), and P30 DK079337 (VV), the Department of Veterans Affairs, and a fellowship of the Manpei Suzuki Diabetes Foundation (YO). 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.