bluuebunny/crossref_metadata_2025_split huggingface dataset:
Piezo1 regulates expression of BK and TRPV4 channels in mouse cortical collecting duct (CCD)
Authors: Carattino Francisco , Mutchler Stephanie , Dalghi Marianela , Apodaca Gerard , Satlin Lisa , Kleyman Thomas , Carrisoza-Gaytan Rolando 
Published: May 2023

Within the CCD, an acute increase in tubular fluid flow rate (TFFR) leads to an immediate high amplitude increase in [Ca2+]i, due to release of IP3-sensitive internal Ca2+ stores coupled to extracellular Ca2+ entry at the basolateral membrane in both principal (PC) and intercalated (IC) cells therein (Liu et al., 2003, 2005, 2007). This is followed by a decay in [Ca2+]i to a sustained plateau elevation due, at least in part, to luminal Ca2+ entry through TRPV4 (Berrout et al., 2012). This flow-induced increase in [Ca2+]i is necessary for BK channel-mediated flow induced K+ secretion (FIKS) in the microperfused mammalian CCD. We generated a mouse with IC-specific targeted deletion of the mechanosensitive Ca2+ permeable channel, Piezo1, which is expressed on the basolateral membranes of PCs and ICs in the mouse CCD (Dalghi et al., 2019). Microperfused CCDs isolated from these IC-PIEZO1-KO mice fed a high K (HK, 5% K+) diet and subject to an increase in TFFR did not exhibit either a peak or plateau elevation in [Ca2+]i in response to flow, and FIKS was eliminated. The absence of FIKS and the plateau elevation in [Ca2+] during sustained flow in the CCDs of KO mice led us to examine whether BK and TRPV4 channel expression was impacted by deletion of PIEZO1.Indirect immunofluorescence (IF) staining was performed to examine expression and localization of the BK and TRPV4 channels in PCs and ICs of IC-PIEZO1-KO mice. Whole cell and apical + subapical fluorescence intensities in cryosections were analyzed using LAS X software from a total of 3 male and 3 female control mice and 3 male and 3 female IC-PIEZO1-KO mice fed HK diet x 10d.IF analysis showed reduced whole cell BKα expression in ICs of both male (p≤0.05) and female (p≤0.01) IC-PIEZO1-KO mice. We also saw reduced BKα expression in PCs from female but not male KOs. In addition, ICs in female but not male KO mice had reduced whole cell TRPV4 expression vs. controls (p≤0.01). Also, whole cell expression of TRPV4 in PCs from female KO mice was reduced vs. female controls (p≤0.01). The ratio of apical-to-whole cell expression of BKα was similar in PCs and ICs of KO and control mice. Male, but not female, KO mice had modestly reduced apical TRPV4 expression in PCs vs. controls (p≤0.01). Piezo1 plays a role in the regulation of BK and TRPV4 channel expression in CCDs. In addition, sex differences exist in whole cell expression of these channels in response to IC-selective deletion of PIEZO1. R01 DK038470 (TK, LMS); R01 DK129285 (TK, LMS); P30 DK079307 (TK) 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.
Chimeric constructs confer the human CFTR chloride channel with the properties of mouse CFTR
Authors: Sheppard David , Cai Zhiwei , Lea-Smith David , Stevenson Barbara , Doherty Ann , Davidson Heather , Porteous David , Boyd A 
Published: May 2023

Mouse cystic fibrosis transmembrane conductance regulator (CFTR) differs from human CFTR in several important respects: altered gating pattern distinguished by prolonged residence in a sub-conductance state, reduced single-channel conductance and strong inward rectification. Transfer of the regulatory (R) domain of mouse CFTR to human CFTR was without effect, whereas transfer of both nucleotide-binding domains (NBDs) endowed human CFTR with greatly prolonged channel openings without conferring human CFTR with the sub-conductance state, single-channel conductance and inward rectification of mouse CFTR. We therefore hypothesised that the membrane-spanning domains (MSDs) determine these differences between human and mouse CFTR. To test this idea, we constructed the human-mouse CFTR (hmCFTR) chimeras hmTM1-6, hmTM7-12 and hmTM1-6:TM7-12 containing MSD1, MSD2 and MSD1+2 of mouse CFTR on a human CFTR background and studied them in excised inside-out membrane patches from transiently transfected CHO cells. For single-channel studies, we used a large Cl- concentration gradient ([Cl-]i, 147 mM; [Cl-]e, 10 mM) and clamped voltage at –50 mV, whereas for macroscopic studies, we used symmetrical Cl--rich solutions. All intracellular solutions contained PKA (75 nM) and ATP (1 mM) to activate and sustain CFTR activity; temperature was 37 °C. The three hmCFTR chimeras possessed a gating pattern intermediate between human and mouse CFTR. Both the single-channel conductance and open probability of the full open-state decreased in the rank order: human CFTR > hmTM7-12 > hmTM1-6 ≥ hmTM1-6:TM7-12 (n = 5-10). Like human CFTR, hmTM7-12 rarely transitioned to sub-conductance states, whereas hmTM1-6 sojourned to multiple sub-conductance states and hmTM1-6:TM7-12 resided in a tiny sub-conductance state resembling that of mouse CFTR. Human CFTR Cl- currents exhibited weak inward rectification, whereas those of mouse CFTR strongly inwardly rectified. Transfer of both MSDs of mouse CFTR to human CFTR in the chimeras hmTM1-6:TM7-12 reproduced the strong inward rectification of mouse CFTR (n = 4). Interestingly, the inward rectification of hmTM1-6 closely resembled that of mouse CFTR, whereas that of hmTM7-12 was intermediate between human and mouse CFTR (n = 6-9). Taken together, our data demonstrate that sequences from both MSDs specify the gating, conduction and rectification properties of CFTR with sequences from MSD1 playing a dominant role in determining the different rectification behaviour of human and mouse CFTR. Supported by the Biotechnology and Biological Sciences Research Council and Cystic Fibrosis Trust. 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.
Investigating the Role of Neurovascular Coupling on Brain Function and Health
Authors: Larios Alyssa , Gu Chenghua 
Published: May 2023

The brain consumes a disproportionate amount of energy, receiving 20% of the total cardiac output despite accounting for only 2% of the body’s weight. While total cerebral perfusion is homeostatically held constant, the neurovascular network dynamically modulates regional blood flow to deliver more nutrient-rich blood to highly active brain areas. Activity-dependent focal increases in cerebral blood flow, or neurovascular coupling (NVC), ensure that energy delivery is commensurate with neuronal metabolic demands. It is widely thought that neurovascular coupling is critical for normal brain function, as neurons lack energy stores and may require increases in oxygen or glucose delivery from the blood supply to fuel signaling operations that consume high levels of ATP. However, it is unknown which features of neuronal signaling are supported by NVC, if any. We are investigating this important question by using a genetic mouse model with NVC specifically impaired. This study will reveal new insights on how NVC supports normal brain function and health. HHMI, NHLBI 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.
Effects of volumetric muscle loss injury on contractile function, and bone structure and functional capacity in male C57BL/6J mice
Authors: Schifino Albino , Cooley Marion , Zhong Roger , Heo Junwon , Hoffman Daniel , Warren Gordon , Greising Sarah , Call Jarrod 
Published: May 2023

Skeletal muscles and bones are structurally and functionally linked, such that bone strength is primarily determined the frequency and magnitude of the mechanical strain derived from muscular contractions. Volumetric muscle loss (VML) injury results in a significant loss of muscle tissue and a non-recoverable loss of muscle strength. However, the extent to which limbs that sustain a VML injury have associated changes to bone structure and functional capacity is unknown. This study’s objective was to investigate whether VML injury affects the adjacent tibial bone structure and functional capacity in adult male C57BL/6J mice. At 12 weeks of age, mice (n=14) underwent a unilateral VML injury (4mm diameter muscle biopsy) to the left hindlimb plantar flexor muscles, while the right limbs served as uninjured controls. At 20 weeks of age (2 months post-VML injury), mice were bilaterally tested for in vivo peak-isometric plantarflexion torque. Post-mortem analyses of tibial bone structure and mechanical properties was assessed via μCT and 3-point bending tests, respectively, at the mid-diaphysis. Statistical analyses were performed between injured and uninjured limbs via paired t-test, with an α-level of 0.05. At 2 months post-injury, VML-injured limbs had significantly less gastrocnemius muscle mass (28%), and peak-isometric torque (35%) as compared to uninjured limbs (p<0.001). Tibial bone strength, as measured by ultimate load, demonstrated a trend in VML-injured limbs to be 3% lower than that in uninjured limbs (p=0.055). Most notably, the cross-sectional moment of inertia (CSMI), the principal structural determinant of the bone’s ultimate load was 9% smaller in VML-injured limbs as compared to uninjured limbs (p=0.035). Additional structural changes in cortical bone were detected: notably, less cortical bone thickness (4.5%), volume (6.6%), and cross-sectional area (4.9%) in VML-injured limbs as compared to the uninjured limb (p≤ 0.025). Bone-to-muscle functional ratio (i.e., ultimate load:peak-isometric torque) was 38% greater in VML-injured limbs compared to uninjured limbs (p<0.001) indicating the deficits in muscle far outweigh that of bone at 2 months post-injury. Future research directions include determining if more time post-VML injury has a greater effect on bone ultimate load and exploring the extent to which the uninjured limbs in VML-injured mice experience compensatory or related changes to bone structure and function. W81XWH-20-1-0885 to JAC and SMG 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.
Impact of Metformin on Cardiometabolic risk factors in Polycystic Ovary Syndrome: Comparison between races
Authors: Chatakondi Raksha , Salau Faridah , Pruett Jacob , Romero Damien , Yanes-Cardozo Licy 
Published: May 2023

Purpose: Polycystic Ovary Syndrome (PCOS), the most common endocrine disorder in reproductive-age women, is characterized by androgen excess and ovarian dysfunction. PCOS women have an increased prevalence of metabolic syndrome components, such as an increased blood pressure (BP), insulin resistance (IR), and obesity. Metformin is the most frequently prescribed insulin sensitizer in women with PCOS. Recent evidence suggests that Black Women (BW) with PCOS have an increased incidence of cardiometabolic (CM) risk factors compared to their White Women (WW) counterparts. It is unclear if metformin has a different effect in BW versus WW with PCOS. Thus, the aim of the current study is to elucidate whether the effect of metformin on CM risk factors is different between BW with PCOS and WW with PCOS at the University of Mississippi Medical Center (UMMC). Hypothesis: CM risk factors will be more pronounced in BW with PCOS compared to WW with PCOS. There will be no difference in the impact of metformin on CM risk factors when comparing BW with PCOS to WW with PCOS. Methods Used: UMMC de-identified patient data from 2013-2022 were obtained from electronic medical records (EMR) using UMMC's Research Data Warehouse. The ICD-10 code of PCOS, E28.2, and code for Type 2 Diabetes Mellitus (T2DM), E11.9, were used to filter patients and encounters. Metformin users were then identified. CM risk factors were analyzed and compared between BW and WW with PCOS. Data are expressed as averages and statistical analysis was performed using SPSS, with p <0.05 considered significant. Summary of Results: From 2013 to 2022, EMRs of 3,260 PCOS patients were analyzed. Of these, 322 patients were co-diagnosed with T2DM. A total of 169 patients were identified as metformin users. BW with PCOS were younger than WW with PCOS (27 yo versus 34 yo). Compared to WW with PCOS, BW women with PCOS have significantly higher body mass index (45.5 vs. 41.16, p<0.001). There was no difference in BP between groups. The rate of current or former smoking doubled in WW with PCOS compared to BW with PCOS. BW with PCOS presented with an HbA1c of 7.5% whereas WW with PCOS presented with an HbA1c of 7.1%. Conclusions: BW with PCOS on metformin have a significantly higher body mass index than WW with PCOS. In contrast, former and current smoking status was more prevalent in WW with PCOS. Race/ethnicity plays a significant role in the CM risk factors in women with PCOS. Implementing strategies to ameliorate cardiovascular diseases in women with PCOS should consider the impact of race in clinical manifestations. No external funding sources 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.
Does hyperoxia stimulate breathing?
Authors: Huggard Joshua , Guluzade Nasimi , Duffin James , Keir Daniel 
Published: May 2023

Hyperoxia has been shown to stimulate ventilation (V̇E) in a dose-dependent manner. Whether this occurs due to an oxygen (O2)-specific mechanism or secondary to carbon dioxide (CO2) retention at the central chemoreceptors (via the Haldane effect) remains unclear. This study measured the ventilatory response to isoxic-hyperoxic CO2 modified rebreathing (an estimate of central chemoreflex sensitivity) with O2 clamped at increasingly higher hyperoxic pressures. We hypothesized that the slope of the V̇E versus PCO2 relationship is fixed and independent of hyperoxic severity. Fourteen healthy participants (6 females; mean ± SD age: 25 ±7 years) visited the laboratory on four occasions to perform three repetitions of modified rebreathing in four isoxic-hyperoxic conditions: “mild”: PO2=150 mmHg; “moderate”: PO2=200 mmHg; “high”: PO2=300 mmHg; and “extreme”: PO2=700 mmHg. The level of isoxic-hyperoxic PO2 was randomized between visits. Throughout rebreathing, breath-by-breath V̇E, end-tidal PCO2 (PETCO2) and O2 (PETO2) were measured by pneumotach and dual gas analyser. For each trial, the PETCO2 at which V̇E began to rise was identified as the ventilatory recruitment threshold (VRT, mmHg). The V̇E data prior to VRT provided baseline V̇E (V̇Ebsl, L∙min-1) and the slope of the linear response above VRT estimated central respiratory chemoreflex sensitivity (V̇ES, L∙min-1∙mmHg-1). For each hyperoxic condition, VRT, V̇Ebsl, and V̇ES from like-trials were averaged and between condition comparisons were assessed by repeated measures analysis of variance. There was no effect of PETO2 on V̇Ebsl (mild: 6.7±3.4 L∙min-1; moderate: 5.9±3.0 L∙min-1; heavy: 5.5±1.6 L∙min-1; extreme: 6.1±3.2 L∙min-1; p=0.35), VRT (mild: 42.7±3.2 mmHg; moderate: 42.0±2.2 mmHg; heavy: 42.2 ±2.4 mmHg; extreme: 41.5±2.4 mmHg; p=0.17) or V̇ES (mild: 5.04±2.78 L∙min-1∙mmHg-1; moderate: 4.64±1.90 L∙min-1∙mmHg-1; heavy: 4.68±1.92 L∙min-1∙mmHg-1; extreme: 4.49±1.72 L∙min-1∙mmHg-1; p=0.47). The hyperoxic V̇E versus PCO2 relationship was unaltered across a range of PO2 spanning mild to extreme. These data indicate that hyperoxia is not an independent stimulant of breathing. Supported by 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.
Blood pressure responses by fitness status following a physical activity intervention in sedentary adults
Authors: Leicht Zachary , Weeldreyer Nathan , Adams Marc , Angadi Siddhartha 
Published: May 2023

Background: Blood pressure and peak oxygen uptake (VO2peak) are strong independent predictors of all-cause and cardiovascular mortality. A VO2peak of 8 METs or greater is associated with greater cardiovascular health and probability of survival, whereas individuals with a VO2peak less than 8 METs are at greater risk for cardiovascular and all-cause mortality. Increasing physical activity in insufficiently active adults is associated with improvements in blood pressure (BP). Additionally, the relationship between an individual’s baseline VO2peak and BP responses following a walking intervention are unknown. Therefore, we examined the change in BP in individuals stratified based on baseline VO2peak (< 8 METs & ≥ 8 METs). We hypothesized that those with a VO2peak < 8 METs would see greater blood pressure responses compared to those with a VO2peak ≥ 8 METs. Methods: Cross-sectional, secondary analyses were carried out on data from a previously conducted clinical trial that included insufficiently active (as determined by accelerometry) individuals (N=518). Subjects underwent BP measurements, anthropometric testing, and a treadmill-based VO2peak test with ventilatory gas exchange assessment to determine VO2peak. Subjects with missing data were excluded from analyses. Additionally, only valid VO2peak tests (≥90% age-predicted HRmax, RER > 1.0) were included. Three hundred and sixty nine individuals had BP measured and met the criteria for a valid VO2peak test. Subjects were then stratified based on baseline VO2peak: low fit (<8 METS), and high fit (≥8 METS). Linear mixed model analyses were carried out to examine main effects (time and VO2peak category) of the walking intervention on BP. The interaction of time and VO2peak category was examined as well. Data are presented as means ± SD with α set at 0.05. Results: Eighty-one individuals had a VO2peak greater than or equal to 8 METs (age = 41.9±10.0 years; BMI = 28.8±4.8; VO2peak = 31.1±3.1 mL/kg/min; Males/Females = 55/26). Two-hundred and eighty-eight individuals had a VO2peak less than 8 METs (age = 45.9±8.6 years; BMI = 34.4±6.5; VO2peak = 22.4±3.2 mL/kg/min; Males/Females = 75/213). There was a significant group by time interaction effect for changes in systolic BP (≥ 8 METs: Pre = 120.8±1.4, Post = 123.0±1.6 mmHg, < 8 METs: Pre = 122.1±0.7, Post = 120.4±1.0 mmHg) (p = 0.03). There was no significant effects found for DBP. Conclusions: These secondary analyses found that SBP significantly decreased following a 6-month walking intervention in individuals with low-fitness. These data suggest that those with lower baseline CRF are likely to have greater declines in SBP. Supported by NIH R01CA1989 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 Phosphodiesterase-9A inhibitor PF04447943 improves coronary microvascular rarefaction via Peroxiredoxin-5 in the ZSF1 rat model of HFpEF
Authors: Fopiano Katie Anne , Pearson William , Buncha Vadym , Lang Liwei , Hamdani Nazha , Bagi Zsolt 
Published: May 2023

Coronary microvascular dysfunction contributes to the development of left ventricular (LV) diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF), a prevalent symptom that has limited targeted treatment options. Selective pharmacological inhibitors of phosphodiesterase 9A (PDE9A), such as PF04447943, have emerged as a potential therapeutic approach for the treatment of cardiometabolic diseases, in part, owing to their antioxidant effects. We hypothesized that PDE9A inhibition has beneficial effects on the coronary microvasculature, thereby improving LV diastolic function in HFpEF. In order to study this, the Obese diabetic Zucker fatty/spontaneously hypertensive heart failure F1 hybrid (ZSF1) rat, a model of human HFpEF, was employed in which it was found that progressively developing coronary microvascular rarefaction, as quantified by an unbiased, three-dimensional reconstruction of the coronary microvascular network (Vesselucida360), as well as vasodilator coronary arteriole dysfunction are associated with the development of LV diastolic dysfunction, which were improved by the treatment with the selective PDE9A inhibitor, PF04447943 (3 mg/kg/day, oral gavage for 2 weeks). These coronary microvascular changes were accompanied by an increase in cardiac 3-nitrotyrosine, a marker of nitrosative stress, which was also mitigated by PF04447943 treatment. Furthermore, mass spectrometry-based proteomics and pathway analyses identified peroxiredoxin-5 (PRDX5) as one of the predominantly downregulated antioxidants in the heart of the obese ZSF1 rats, which was augmented after PDE9A inhibition. From this data, it was concluded that PDE9A inhibition, potentially through augmenting the PRDX-5 antioxidant mechanism, improved coronary vascular rarefaction and vasodilator function, thereby restoring LV diastolic function in obese ZSF1 rats. T32HL155011 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.