bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of statin therapy on vascular reactivity in patients with Heart Failure with Preserved Ejection Fraction
Authors: Iacovelli Jarred , Alpenglow Jeremy , Bunsawat Kanokwan , Ma Christy , Ryan John , Wray D
Published: May 2023

Background: HFpEF is characterized by peripheral vascular dysfunction, which likely underlies clinical presentations such as dyspnea on exertion and severe exercise intolerance in this population. HMG-CoA reductase inhibitors, also known as “statins,” can exert beneficial pleiotropic effects on the vasculature that may be related to improvements in nitric oxide (NO) signalling. However, it has yet to be investigated whether statin therapy can improve vascular function in patients with HFpEF. We hypothesized that 30-day statin therapy would improve upper limb conduit vessel and microvascular function, as determined by brachial artery flow-mediated dilation (FMD) and reactive hyperemia (RH), respectively, and improve locomotor muscle microvascular responsiveness, as determined by passive limb movement (PLM). Methods: Using a double-blind, parallel design, patients with HFpEF were studied before and after randomization to 30 days of statin therapy (atorvastatin, 10 mg; QD, n = 4) or placebo ( n = 3). FMD, RH, and PLM testing was performed via ultrasonography according to published guidelines. Results: Compared to baseline values, FMD tended to improve following statin therapy (2.8 ± 2.4% to 4.7 ± 1.5%, day 0 to day 30, P=0.06), with no change following placebo (P=0.87). FMD adjusted for shear also tended to improve following statin therapy (0.09 ± 0.08AU to 0.15 ± 0.03AU, day 0 to day 30, P=0.07), with no change following placebo (P=0.79). RH was unchanged following both statin (P=0.24) and placebo (P=0.31) interventions. PLM AUC appeared to improve following statin therapy (98 ± 62ml to 184 ± 111ml, day 0 to day 30, P=0.22), with no change following placebo (P=0.64). The peak blood flow response to PLM was unchanged in both statin (P=0.31) and placebo (P=0.28) groups. Conclusions: While no statistically significant differences were observed, qualitative analyses suggest that statin therapy may improve upper limb conduit vessel function and locomotor muscle microvascular responsiveness in patients with HFpEF, supporting the potential efficacy of this drug class to improve vascular function. These improvements in vascular reactivity provide preliminary evidence for improved NO bioavailability that may translate to improvements in functional capacity and exercise tolerance in this patient group.

Funded in part by grants from the U.S. Department of Veteran’s Affairs (1I01CX002152, D.W.W., 1IK2RX003670, K.B.) and the National Institutes of Health (5T32HL139451, K.B.).

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.
TRPV4 and mechanosensitive regulation of hemichannel function in ocular nonpigmented ciliary epithelium
Authors: Shahidullah Mohammad , Delamere Nicholas
Published: May 2023

Purpose: Previously we reported a mechanosensitive ion channel, TRPV4, along with functional connexin hemichannels on the NPE basolateral surface. In the lens, we have evidence of TRPV4-mediated hemichannel opening as part of a feedback mechanism that enables the lens to sense and respond to swelling. The present study was undertaken to test the hypothesis that TRPV4 and hemichannels might function as a mechanosensor in ocular nonpigmented ciliary epithelium (NPE). Methods: Porcine NPE cells were cultured on either plastic culture plates to study effects of osmotic swelling stretch, or on flexible membranes (Flexcell) to study effects of axial cyclic stretch. ATP release and the uptake of the large molecule propidium iodide (PI) from the bathing medium were taken as indicators of hemichannel opening and determined by luminescence and fluorescence. Results: NPE cells subjected to cyclic stretch for 1-10 min (10%, 0.5 Hz) significantly increased ATP release (CTRL 0.3±0.002 vs Stretch 0.7±0.004, nmoles/mg protein, n=6, p<.0001) into the bathing medium. The same stretch stimulus also increased uptake of large molecule propidium iodide (PI) from the bathing medium (CTRL 1.5±0.09 vs stretch 2.49±0.09, Fl unit/mg protein, n=6, p<0.001). The ATP release and PI uptake responses both were prevented by a TRPV4 antagonist, HC067047 (10 μM) and a connexin blocking peptide, GAP27 (200μm). Cells subjected to a hypoosmotic stimulus (200 mOsm) also displayed a significant increase in PI uptake (CTRL 4.65±0.24 vs Hypo 8.26±0.43 nmoles/mg protein, n=5, p<0.001) and the response was abolished by HC067047. The TRPV4 agonist GSK1016790A (10 nM) markedly increased ATP release (CTRL 0.56±0.03 vs GSK 1.24±0.06 nmoles/mg protein, n=12, p<0.001) and PI uptake (CTRL 1.83±0.05 vs GSK 3.69±0.09 Fl unit/mg protein) in the absence of any swelling or stretch stimulus and both responses were abolished by GAP27. Conclusion: The findings are consistent with TRPV4-dependent connexin hemichannel opening in response to mechanical stretch. The TRPV4-hemichannel mechanism may act as mechanosensor that facilitates release of ATP and other autocrine or paracrine signaling molecules that influence fluid (aqueous humor) secretion by the NPE.

This research was funded by an NIH (NEI) grant, R01EY029171.

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.
Student Performance in Cardiovascular and Respiratory Physiology is Unaffected by the Number of Courses Tested at Once
Authors: Johnson Fruzsina , Johnson Robert
Published: May 2023

Physiology has been a foundational course in medical curriculums for several decades. At William Carey University College of Osteopathic Medicine (WCUCOM), Medical Physiology is taught in both semesters of the first-year curriculum. Cardiovascular and respiratory physiology are the first two major organ systems we teach after the foundational lectures and take up most of the Fall semester. An ongoing debate at our school is whether to test foundational courses by themselves or rather via combined (“integrated”) exams that more closely resemble the board exams. The students prefer the smaller exams, but often end up setting up cycle studying patterns only focusing on one course at a time that ends up hurting them in the second year where combined integrated exams are standard in our curriculum. Going from the 2020-2021 to the 2021-2022 academic year we moved from combined integrated exams where four courses were tested at once to smaller exams where one to two courses were tested at one time. We were also undergoing the second stage of a planned class size increase from 150 students to 175 students, but we previously reported that the first stage of the class size increase did not adversely affect physiology outcomes. In this study, we compared overall student performance on the traditionally challenging cardiovascular and respiratory physiology sections between the Fall 2020 and Fall 2021 student cohorts. In 2020, 156 students completed the Fall semester at WCUCOM. Their average exam score on the cardiovascular questions was 83.11±9.51%, and the average exam score on the respiratory questions was 82.63±11.12%. In 2021, 182 students completed the Fall semester at WCUCOM. Their average exam score on the cardiovascular questions was 84.73±8.06%, and the average exam score on the respiratory questions was 84.42±10.12%. The increase in the mean exam score between cohorts was not statistically different between the two groups (P=0.354, Mann-Whitney rank sum test for cardiovascular questions, and P=0.177, Mann-Whitney rank sum test for respiratory questions). These findings show that student performance on the cardiovascular and respiratory sections of the Medical Physiology course at WCUCOM were similar between the Fall 2020 and Fall 2021 semesters. Our results suggest that the number of courses tested at once may not significantly affect student performance.

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 IBD-candidate gene, PTPN2, Regulates Goblet Cell Number and Expression of Intestinal Epithelial Cell Markers in a Regional-specific Manner in Mice
Authors: Canale Vinicius , McCole Declan
Published: May 2023

Loss-of-function variants in the Protein Tyrosine Phosphatase non-receptor Type 2 ( PTPN2) gene are associated with increased risk of Inflammatory Bowel Disease (IBD). PTPN2 encodes T Cell Protein Tyrosine Phosphatase (TCPTP), a negative regulator of intracellular signaling pathways including JAK-STAT. PTPN2 is critical for intestinal epithelial cell (IEC) barrier maintenance, IEC-macrophage crosstalk, and modulating the gut microbiota in mice and IBD patients. Aim: To determine if Ptpn2 loss compromises IEC subtypes that restrict gut dysbiosis. Methods: Ileal and colonic IEC subtypes and their function were assessed by PAS staining of goblet cells and immunostaining. RNA isolated from colonic IECs of whole-body Ptpn2-wild-type (WT), heterozygous (Het) and KO mice was assayed by two separate Nanostring® panels: PanCancer and AutoImmune totaling >1500 targets. Flow cytometry was performed to evaluate abundance of mucosal-associated immune cells. Results: Goblet cells were reduced in the ileal and cecal crypts compared with WT mice (p<0.05; n=5) while numbers in the proximal and distal colon were variable. Ki-67 immunostaining revealed increased proliferating cells in the proximal and distal colon (p<0.01; n=3). Nanostring analysis had 1399 targets with detectable expression. Notably, expression of growth factors Egf and Fgfr3, differentiation factors Atoh1 and Mycn, tuft cell marker Dclk1, and intestinal stem cell marker Lgr5, were all downregulated in colonic IECs from Ptpn2-KO mice compared with WT (p<0.05; FDR<0.1; n=4). Moreover, abundance of mucosal neutrophils, macrophages, CD4+ expressing IFN-γ, CD8+ expressing TNF/IFN-γ, and CD4+ expressing IL-22 T-cells were higher in colon and cecum of Ptpn2-KO mice compared with WT and HET mice (p<0.01; n=5), whereas abundance of IL-4 expressing CD4+ cells, and Tregs expressing IL-10 were decreased in all intestinal segments of Ptpn2-KO mice (p<0.01; n=5). Conclusion: Ptpn2 loss negatively impacts abundance of IEC subtypes in a region-specific manner, affecting epithelial proliferation and expression of critical differentiation/cell markers. The elevated abundance of immune cells expressing pro-inflammatory signals accompanied by decreased levels of cells expressing IL-4 and IL-10, could contribute to a skewed abundance of IEC subtypes and their function. The observed effects may contribute to the increased susceptibility to infection and the dysbiotic microbiota in Ptpn2-deficient mice, and partly explain association of PTPN2 variants with dysbiosis in clinical IBD.

Supported by NIH 2R01DK091281, 1R01AI153314-01, R21AI152017 and R01AI165490 (DFM).

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.
Using Simplex (an online writing tool) to assist students when simplifying complex ideas towards various audiences: a pilot project
Authors: Zubek John , Murali Gokul , Chinoy Natasha , Joseph Jackson , Shaltry Christopher , Krishnan Arjun
Published: May 2023

Professional skills development is an increasingly emphasized part of the undergraduate curriculum. Both physiology instructors and students of STEM place a high importance on effective communication of scientific information to a variety of audiences. However, it can be difficult for students to simplify technical jargon and ensure a clear message. Simplexalpha is an online writing tool to identify scientific jargon and assist the writing simplification process. The goal of this pilot project was to evaluate whether Simplexalpha assisted students when reducing scientific writing, improving knowledge retention, and increasing the effectiveness of communication. Participants in this study included 129 undergraduate science majors from Michigan State University. Each participant was given the same scientific abstract to rewrite and assigned to one of three groups. Group A utilized the Simplexalpha online tool, Group B was provided minimal feedback, and Group C was given no feedback. A knowledge assessment was completed, and participants were later asked to rate five random rewritten de-identified abstracts as to their perceived “effectiveness” based on the writing prompt. Group A performed slightly better on the knowledge assessment than groups B and C (89.3% vs. 88.3% vs. 86.9%). More participants in Group B simplified the abstract to the lowest grade levels vs. Groups A and C. There was a statistically significant difference in the effectiveness scores between the groups as Group B slightly outperformed Group C, while Groups B and C significantly outperformed Group A (P=0.004). Students using the Simplexalpha tool were highly complementary to its ease of use and the benefits of identifying technical jargon for simplification. However, Group A did not achieve as favorable “effectiveness” outcomes as those participants in Group B and Group C (minimal and no feedback respectively). It is not known whether the tool itself or the time spent attempting to simplify writing can be of greatest benefit. Further attenuation of the methods may need to be evaluated.

Department of Physiology, Michigan State University

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.
Effect of coronary artery disease on myocardial blood flow during passive heat stress
Authors: Barry Hadiatou , Chaseling Georgia K , D'Oliviera-Sousa Caroline , Iglésies-Grau Josep , Harel François , Pelletier-Galarneau Matthieu , Gagnon Daniel
Published: May 2023

INTRODUCTION. Extreme heat is associated with a greater risk of cardiovascular mortality in older adults. However, the pathophysiology that links extreme heat and cardiovascular mortality remains unknown. One possibility is that myocardial oxygen requirements during heat exposure surpass the capacity for myocardial oxygen delivery, thereby predisposing to myocardial ischemia. This may notably occur in individuals with coronary artery disease (CAD), because it reduces the capacity of the coronary arteries to dilate (i.e., coronary flow reserve). However, it is unknown to what extent myocardial blood flow (MBF) increases during heat exposure and whether this increase is altered by CAD. OBJECTIVE. This study tested the hypothesis that passive heat stress increases myocardial blood flow in older adults and that this increase is attenuated in older adults with CAD. METHODS. Healthy older adults (n=19, 68 ± 7 years) and older adults with CAD (n=12, 72 ± 6 years) were passively heated (water-perfused suit) until rectal temperature increased 1.5°C above baseline values. Myocardial blood flow was measured at baseline and at each 0.5°C increment in rectal temperature during heating by positron emission tomography following intravenous infusion of 82-Rubidium. Heart rate (ECG) and blood pressure (automated auscultation) were also measured to calculate rate pressure product (heart rate × systolic blood pressure). MBF reserve (MFR) was calculated by dividing the MBF at 1.5°C by baseline MBF. Adults with CAD were asked to withhold β-blockers, calcium channel blockers and nitroglycerin for 24h prior to the study. RESULTS. At a 1.5°C increase in core temperature, myocardial blood flow increased from 0.85 ± 0.20 to 1.51 ± 0.40 mL/min/g in healthy older adults and from 0.87 ± 0.19 to 1.37 ± 0.48 mL/min/g in adults with CAD. The change in myocardial blood flow at a 1.5°C increase in rectal temperature did not differ between groups (healthy: 0.66 ± 0.31 mL/g/min, CAD: 0.49 ± 0.42 mL/g/min, p=0.25. Furthermore, healthy adults and adults with CAD displayed a similar MFR at an increase in rectal temperature of 1.5°C (healthy: 1.8 ± 0.4 vs. CAD: 1.6 ± 0.6, p=0.25). CONCLUSION. These results demonstrate that passive heat stress increases myocardial blood flow nearly 1.6 times in older adults, and that this increase is not affected by CAD. These results will help determine if the increase in myocardial blood flow during passive heat exposure is sufficient to predispose to myocardial ischemia in individuals with low coronary flow reserve.

Canadian Institutes for Health Research, Montreal Heart Institute Foundation.

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.
Critical role of long non-coding RNAs in excessive erythropoietic response in Monge's disease
Authors: Azad Priti , Zhou Dan , Haddad Gabriel
Published: May 2023

Excessive erythrocytosis (EE) is a major hallmark of patients suffering from chronic mountain sickness (CMS, Monge’s disease) and is responsible for major morbidity and even mortality in early adulthood. We took advantage of unique populations, one living at high altitude (Peru) showing EE, while another population, at the same altitude and region, shows no evidence of EE (non-CMS). We have built an in-vitro human iPS-derived model system to study the genetic and epigenetic mechanisms related to pathology of excessive erythropoetic response in these Monge's disease patients. Through RNA-seq, we identified and validated the function of a group of long non-coding RNA (lncRNAs) that regulate erythropoiesis in Monge’s disease. Among the lncRNAs, we found that LINC02228 specifically played a critical role in erythropoiesis the CMS cells and non-CMS based on our functional assays in our in-vitro model systems. We observed that LINC02228 has a huge impact on erythriod colony production (>50% reduction in colonies p<0.001 with the control vs LINC02228-KD). Furthermore, we have also assessed the downstream target genes for these lncRNA (Eg. CSNK2B) and mechanism(s) of erythropoetic regulation by these lncRNAs and found an important role and mediation of erythropoetic transcriptional factor GATA1. We conclude that LINC02228 mediate erythropoesis in Monge's diseases through critical downstream effectors (CSNK2B and GATA1).

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.
Gunryeong-tang extracts protect against diabetes and heart dysfunction by reducing levels of inflammation and fibrosis in db/db mice
Authors: TAI AILIN , Yoon Jung Joo , Han Byung Hyuk , Lee Ho Sub , Kang Dae Gill
Published: May 2023

Diabetes mellitus (DM) is one of the most common metabolic disorders known to result from abnormal secretion of insulin and/or resistance to insulin. DM is characterized by hyperglycemia, decreased function of pancreatic islet cells and reduced insulin secretion. DM causes many types of complications, among which heart complications are a serious cause of death in people with diabetes. Gunryeong-tang (GRT, 君苓湯) is a traditional oriental herbal formula for the treatment of acute and chronic nephritis, which is used to promote water retention and reduce swelling. However, no study has been conducted on the cardioprotective effects of GRT in diabetes, so this study was investigated whether GRT alleviated diabetes and diabetic heart injury in db/db mice. The experiment was conducted for 8 weeks, distributed into four different groups: db/m control, db/db control, db/db treated with vildagliptin (50 mg/kg/day) or db/db treated with GRT (200 mg/kg/day). As a result, GRT has an impact in lowering high blood glucose levels and insulin resistance in db/db mice. GRT significantly improved cardiac function in db/db mice by inhibiting LDH, CK-MB, and CPK. After 8 weeks of GRT-treatment, M-mode echocardiography was performed to confirm whether GRT had effect on cardiac function. GRT significantly up-regulated impaired LV EF and FS in db/db mice. In addition, GRT was also confirmed to improve histopathological changes (hypertrophy, fibrosis and inflammation) and protein expression levels of related factors caused by diabetes. Furthermore, GRT remarkably improved the expression of factors involved in cardiac apoptosis in db/db mice. Taken together, our results suggest that GRT improves cardiac function and diabetic complications through suppression of cardiac fibrosis and inflammation. Therefore, it is believed that GRT can be developed as a new treatment for diabetes, especially heart complications.

This study was supported by a National Research Foundation of Korea (NRF) Grant funded by the Korean government (MSIP) (2017R1A5A2015805) (2021R1C1C2009542).

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.
Vagal nerve activity and sympathetic nerve activity are suppressed by alpha-2 adrenergic receptor agonists in conscious rats
Authors: Miki Kenju , Ikegame Shizuka , Yoshimoto Misa
Published: May 2023

Vagal nerve activity (VNA) and sympathetic nerve activity (SNA) have been known to influence each other and changes in their activity directly, but details on this remain unknown. This study used an alpha-2 adrenergic receptor agonist (dexmedetomidine) to study how SNA affects VNA in the conscious state. Electroencephalography, electromyography, electrocardiography, cervical VNA, renal SNA, and catheters for arterial pressure measurement and intravenous drug administration were measured after male Wistar rats were anesthetized and implanted with electrodes. Dexmedetomidine (50 micro g/kg) was intravenously administered in conscious rats. Cervical VNA decreased and reached its lowest values about 10 min after intravenous dexmedetomidine administration. However, renal SNA, electromyography, and heart rate decreased immediately after administration, whereas arterial pressure increased immediately. These results show that alpha-2 adrenergic receptor agonists simultaneously inhibit VNA and SNA. Furthermore, the present data suggest that excessive SNA activation increases norepinephrine release, inducing an increase in the concentration of circulating norepinephrine, which in turn inhibits SNA via negative feedback and suppresses VNA.

JST (JPMJMS2023)

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.
Electrophysiological assessment of patients recovered from COVID-19 infection
Authors: Almazidi Sarah , Al-Subieh Ahmed , Al-Sabti Areej , Al-Mutairi Abdullah , Al-Yahya Asmaa , Al-Taweraqi Reema , Al-Dakhil Lina , Al-Ahmari Abdulla , Al-rouq Fawzia
Published: May 2023

Background: Neurological manifestation associated with Coronavirus-19 (COVID-19) is commonly reported. However, these patients were not routinely referred for electrophysiological testing. Many studies reported abnormalities in nerve conduction studies (NCS) in patients who recovered from COVID-19 infection. Aim: we aimed to investigate the effect of COVID-19 infection on patients who performed NCS prior to the COVID-19 pandemic and after recovering from COVID-19 illness. Methods: A cohort retrospective study was conducted, which included males and females (average age 50.6 years old) participants who performed NCS before the pandemic and were not hospitalized during their COVID-19 illness. We assessed sensory and motor NCS for the ulnar, median, peroneal, tibial, and sural nerves. A total of 14 ulnar and median nerves and six tibial, peroneal, and sural nerves were assessed. Results: All tested parameters were normal in most of our participants. However, there was a significant increase in amplitude and decrease in conduction velocity (CV) in sensory NCS in median nerves ( p <0.005) and ulnar nerves ( p <0.05). There is an increase in amplitudes and a decrease in the CV in the lower limbs' sensory and motor NCS and the motor ulnar and median nerves, but this did not reach a significance level. Conclusion: This is the first study to assess the effect of COVID-19 on the same nerves (before and after COVID-19 infection). Although all NCS parameters were normal, the paired analysis showed that the median and ulnar sensory nerves are the most affected by COVID-19. Standardized electrodiagnostic guidelines are recommended to be established for recovered COVID-19 patients for early diagnosis of neural functions to ensure optimal recovery.

This research was not funded.

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.
Sodium density associates with nighttime systolic blood pressure in young healthy adults
Authors: Axler Michael , Lobene Andrea , Kaseman Kathryn , Awayes Yasmine , Lennon Shannon
Published: May 2023

Cardiovascular disease (CVD) is influenced by diet quality, such that poor diets generally lead to increased risk. In particular, diets high in sodium have been shown to raise blood pressure (BP) and can lead to arterial stiffening subsequently increasing CVD risk. Current sodium recommendations aimed at lowering CVD risk are given in absolute amounts and do not account for total energy intake. This makes it difficult for individuals with greater energy intakes to meet daily recommended targets. Dietary sodium density (i.e., mg sodium/kcal energy) has been suggested to be a stronger determinant of BP than absolute sodium intake; however, the relation between sodium density and vascular health has yet to be studied in normotensive adults. Our objective was to examine the association between sodium density and ambulatory BP and arterial stiffness in young, healthy, normotensive adults. We hypothesized that sodium density would relate to 24-hour BP and arterial stiffness just as absolute sodium intake does. Sixty-two participants (23M/39W, age 27±6 years, BMI 23.4±2.7 kg/m², BP 112±11/69±9 mmHg) recorded their habitual diet for three days and wore an ambulatory BP monitor to assess 24-hour, daytime, and nighttime BP. Arterial stiffness was assessed by pulse wave velocity (PWV) and wave reflection with augmentation index (AIx). Associations between absolute sodium intake and sodium density with BP and stiffness measures were assessed using bivariate and partial Pearson correlations. On average, participants consumed 2029±547 kcals and 3250±1231 mg sodium. Daytime BP was 118±11/70±7 mmHg and nighttime BP was 106±14/58±9 mmHg. Sodium intake (r=0.31, p=0.03) and sodium density (r=0.35, p=0.01) both correlated with nighttime systolic BP but not nighttime diastolic BP nor daytime or 24-hour systolic or diastolic BP. After controlling for age and sex, both sodium intake (r=0.44, p=0.01) and sodium density (r=0.56, p<0.001) remained significantly associated with nighttime systolic BP. There were no significant correlations between sodium intake or sodium density and PWV or AIx (all p>0.05). These findings indicate sodium density is associated with elevated BP, specifically nighttime systolic BP, in healthy young men and women, suggesting sodium density relates to BP as strongly as absolute sodium intake.

Supported by NIH Grant 1R01HL145055 and P20GM113125.

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.
Single-cell mRNA expression profiling of chemosensitive locus coeruleus neurons from American bullfrogs
Authors: Amaral-Silva Lara , Santin Joseph
Published: May 2023

The locus coeruleus (LC) is a cluster of neurons in the midbrain that, among other roles, participates in the control of breathing by sensing CO2 and evoking hyperventilation, which is observed in mammals, amphibians, and reptiles. The LC is considered the major noradrenergic nucleus of the brain, but in addition to norepinephrine, the mammalian LC also produces glutamate and GABA. Yet, little is known about the neurotransmitter phenotypes of chemosensitive LC neurons in other vertebrates. Thus, we investigated the neurotransmitter profile of neurons responsible for CO2/pH chemoreception in American bullfrogs. For that, 19 LC neurons from 5 American bullfrogs ( Lithobates catesbeianus) brains were analyzed. Chemosensitivity was ensured by monitoring the increase of firing in response to hypercapnia (switching from 1.5% to 5% CO2) in whole-cell patch clamp. A hypercapnic response was observed in all neurons recorded, which were then aspirated into the recording pipette and preserved. Single-cell quantitative PCR was performed to measure the mRNA copy number of markers for glutamatergic (glutamate transporter, VGLUT2), GABAergic (GABA catalytic enzyme, GAD1), and norepinephrinergic (norepinephrine biosynthetic enzyme, DBH) neurons. In addition, we measured the expression of genes with a potential role in pH/CO2 sensitivity; KCNK5 that encodes TASK-2, an alkaline-activated K+ channel; ASIC2 that encodes an acid-sensing cation channel; and KCNJ16 that encodes Kir 5.1, a K+ channel inhibited by acidosis. All LC neurons expressed both VGLUT2 and DBH, while GAD1 had a minimal expression, supporting the role of cotransmission using glutamate and norepinephrine in chemosensitive neurons. KCNK5 and ASIC2 were expressed in most neurons, while KCNJ16 was not. This result suggests that TASK-2 and ASIC2 proteins may contribute to CO2/pH chemosensitivity of LC neurons. Moreover, the expression of these pH sensing related genes ( KCNK5 and ASIC2) had expression linearly correlated to the noradrenergic marker DBH ( e.g., when DHB was high, KCNK5 was high and vice versa) but were not correlated to VGLUT2. Our results point to a transcriptional program that links the noradrenergic cell identity, but not the glutamatergic identity, with the capacity to sense CO2/pH. Given the comparable role of LC in regulating blood gases across vertebrates, our results suggest that the cotransmission of norepinephrine and glutamate from chemosensitive LC neurons plays a role in CO2/pH sensing.

This research was funded by the Department of Defense (W911NF2010275) and NIH (R01NS114514)

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.
Cystathionine gamma lyase (CSE) deficiency promotes increased contraction of the corpus cavernosum
Authors: Azeez Tooyib , Pierrre Clifford , La Favor Justin
Published: May 2023

Cystathionine γ lyase (CSE) is the primary enzyme responsible for hydrogen sulfide (H2S) production in the vasculature. Although, it is known that H2S is a vasodilator systemically, little is known about the effect of CSE on the arteries and tissues responsible for erectile function. Adequate relaxation of the pre-penile arteries and corpus cavernosum are important for effective penile erection, while excessive contraction impedes erectile response. The aim of our study was to determine the effect of CSE deletion on pre-penile vessels and erectile tissue reactivity. We hypothesized that CSE deletion will impair vascular relaxation of these tissues. We used 12 CSE KO mice and 12 age matched controls for this study. The mice were fed with normal chow and water ad libitum and sacrificed at 1 year of age. The distal internal pudendal arteries (dIPA), internal iliac arteries (IIA) and corpus cavernosum (CC) were harvested and used for ex vivo functional assessment. Tissue and wire myography studies were carried out to assess adrenergic and endothelium-dependent vasoconstrictions using cumulative dose-responses to phenylephrine (PE), endothelin, U-46619 and electrical stimulation (E-stim). Endothelium-dependent relaxation was assessed by acetylcholine (ACh) and endothelium-independent relaxation was assessed using Sodium nitroprusside (SNP). Na2S was used to assess the vascular reactivity to H2S. Finally, Non-adrenergic non-cholinergic (NANC) transmission was assessed using E-stim; 20V of electrical impulses were delivered to the tissues with frequency ranging from 0.5 to 16Hz following the administration of atropine, guanethidine and pre-constriction with PE. There were no significant differences observed in the relaxation due to ACh, SNP or NANC-stimulation in any tissue type. However, we found that the loss of CSE increased the contraction of the CC in response to electrical stimulation (p=0.024) and U-46619 (p=0.030). These results indicate that chronic deficiency of CSE increases sensitivity to two prominent vasoconstriction pathways in the CC, which may result in increased vascular resistance in the penis rather than the arteries that supply blood to the penis. Chronic H2S deficiency may thus result in impaired erectile function.

This work was supported in part by National Institute of Health grant R03DK131242

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.
Metabolic Consequences of Skeletal Muscle Specific High Expression (SM-HE) of mu-Crystallin Following Low-and High-Fat Diet Interventions are Diet and Sex-Specific
Authors: Noland Kaila , Li Yi , Aja Susan , Bloch Robert
Published: May 2023

mu-Crystallin is a thyroid hormone binding protein but its role in metabolism is poorly understood. Our previous work on mice with skeletal muscle- specific high expression (SM-HE) of mu-crystallin ( Crym-tg), showed a shift towards oxidative metabolism away from glycolysis (13.7%, as measured by RER via indirect calorimetry), as well as increased expression of slow twitch muscle fiber genes as identified via RNA-seq.Here we report the effects of challenging both male and female, Crym-tg and wildtype littermates to low- and high-fat diets (LFD or HFD). Mice were placed on either diet for 16 weeks, and then subjected to QMR for body composition analysis as well as glucose and insulin tolerance tests (GTT and ITT). Mice were then acclimated to CLAMS cages and studied by indirect calorimetry during ad libitum and fast/refeed conditions. Voluntary wheels were then introduced, and indirect calorimetry measures were again collected, GTT and ITT testing was repeated before harvesting tissue for mRNA and protein interrogation.Our results show sex- and diet-specific differences between Crym-tg and WT littermates. Male Crym-tg mice on LFD weigh significantly less than their WT counterparts due to differences in lean mass. Female mice on LFD show no change in overall mass or body composition compared to controls. Female Crym-tg mice on HFD weigh significantly less than WT, again due to changes in lean mass. Males on HFD did not show significant changes in overall mass or body composition. We found no distinct patterns in the parameters monitored by indirect calorimetry that could account for these changes.Following design of a qPCR array for metabolic genes of interest (GOI) (chosen from the RNA-seq data of our previous work in male Crym­-tg mice on normal chow) we saw a distinct difference in expression profiles. Selected GOI showed little variation in mice on LFD. However, dramatically significant differences were seen in mice on HFD. GOIs, when assayed for the male mice, showed a significant decrease in expression across the group for Crym-tg mice as compared to wildtype. Concomitantly, female Crym-tg mice when assayed for the same GOIs showed a significant increase in expression across the group.The work presented here highlights the need for continued studies interrogating sex-specific differences in metabolism. Our results suggest that obesity is not strictly defined by diet and exercise, but also depends on genetic factors, including the levels of expression of Crym.

MMPC subcontract from the University of Georgia (R. McInroe, P.I.)

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.
Commensal microbiota regulate gene expression in the kidney, liver, and large intestine
Authors: Moore Brittni , Pluznick Jennifer
Published: May 2023

Commensal bacteria influence host gene expression not only in the colon (J. Allen, Genome Medicine, 2019), but also at distal sites (B. Weger, Cell Metabolism, 2019). Although microbial metabolites are linked to renal pathologies and diseases, a role for commensal organisms to regulate renal gene expression has not been explored. To address this question, we performed bulk RNA sequencing (RNA-Seq) to compare renal gene expression in C57Bl/6 mice that are germ-free (GF; lacking microbiota; n=8, equal number of males and females) versus conventionalized (Conv; with gut microbiota; n=8 equal number of males and females). For comparison, we also examined gene expression in liver and large intestine (n=6 GF and n=6 conventionalized, equal numbers of males and females). Our results demonstrate that host gene expression is influenced by the presence versus absence of microbiota in a sexually dimorphic manner. Differentially expressed genes (DEGs) were defined as log2fold change ≥ ±0.5, p<0.05, and basemean≥15 transcripts/million. We identified 918 DEGs (Conv/GF) in kidney, 1701 in liver, and 1324 in large intestine. The pattern of DEGs were sex-specific: 85%, 90%, and 89% of DEGs changed in kidney, liver, and large intestine (respectively) in either males or females, but not both. Furthermore, the DEGs in the kidney were different from the DEGs in both the liver and the large intestine, indicating that the influence of commensal bacteria on gene expression is tissue specific. However, a small population of genes (n=4 in males, n=6 in females) were differentially regulated in all three tissues examined, including genes associated with metal binding ( Mt1 and Mt2). Mt1 and Mt2 were the only genes to be upregulated in absence of microbiota in all three tissues, and in both males and females. Previous reports show that Mt1 and Mt2 are increased in GF mice; however, these studies were only performed in female mice (J. Breton, Toxicology Letters, 2013). We observe that metallothionein gene expression is more pronounced in males compared to females (in the kidney, log2fold changes for Conv/GF males: Mt1 = +1.1, Mt2 = +1.4; in females: Mt1= +0.6 and Mt2= +0.8). Furthermore, preliminary ICP-MS analysis in liver demonstrates increased trace metal concentrations (manganese, iron, copper, zinc, and cadmium) in GF mice compared to Conv. In sum, we demonstrate microbiota regulates kidney, liver, and large intestine gene expression, and that these changes are poised to impact host physiology and function.

National Science Foundation Graduate Research Fellowship (DGE-1746891 to BM), the NIDDK Diabetic Complications Consortium (RRID:SCR_001415m www.diacomp.org ), grants DK076169 and DK 115255 (subaward to JLP), and R56DK107726 (to JLP).

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.
Heavy metal-laden particulate dust disrupts intestinal epithelial stem cells and lineage differentiation
Authors: Atanga Roger , Castillo Eliseo , Campen Matthew , In Julie
Published: May 2023

Chronic heavy metals exposure has been associated with intestinal inflammation and higher incidences of colorectal cancer, however there is no molecular evidence that metal laden-particulates can cause injury to the gut epithelia. Communities that live adjacent to abandoned uranium mines have higher incidence of metabolic and digestive diseases; however, the cause is unknown. The goal of this study is to characterize particulate dust containing non-fissile uranium as an environmental toxicant that damages intestinal epithelia and characterize the subsequent transcriptomic changes. We hypothesized that non-fissile uranium will alter the differentiation pattern of progenitor cells in the crypt biasing them towards the secretory lineage. Human colonoids derived from healthy adult colonic biopsies (UNM IRB approved study 18-626 and 18-171) were established and shown to physiologically model the intestinal epithelia. Colonoids were acutely exposed (24h) to non-fissile uranium dust obtained near the Jackpile uranium mine in New Mexico, one of the largest open pit uranium mines in the US, located on the Laguna Pueblo. Control and dust-exposed colonoids (n=3 unique donors) were dissociated into single cells and processed for droplet-based single cell sequencing (scRNAseq). scRNAseq identified significant changes in the secretory lineage in uranium dust-exposed colonoids. Specifically, there was a four-fold expansion of enteroendocrine cells (EEC) with increases in EEC hormones serotonin and PYY in all colonoid lines. Proliferative pathways, such as Wnt signaling and negative regulation of apoptosis were upregulated in these EECs. These transcriptomic changes in EECs and proliferative cells and increased basolateral secretion of secretory granules and serotonin was validated in colonoids (˃5 biologically unique human donors) via RNA FISH, immunofluorescence and ELISAs. Our results demonstrate that acute uranium dust exposure directly induces transcriptomic and cellular changes in intestinal epithelia independently of microbiota, stroma, and immune cells. These results indicate that adult human colonoids are a relevant model for investigating environmental toxicants on intestinal epithelia and provide an improved understanding of uranium dust as a model of intestinal injury.

This study was funded by NIDDK (K01DK106323), NIEHS (R56ES034400, P42ES025589), and NIGMS (P20GM121176, P20GM130422).

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.
Cerebrovascular function is protected in hepatic xanthine oxidase knockout mice under chronic stress
Authors: Prahbu Saina , Oudomvilay Crystal , Burrage Emily , Lewis Sara , Hanshew Alec , Childers Ryan , Maxwell Brooke , Wood Avery , Choueiri Matthew , Sissoko Mouhammad , Walsh Caleb , Kelley Eric , Chantler Paul
Published: May 2023

Americans have been facing a mental health crisis that is predicted to impact and yield long-term psychological and physiological consequences negatively. We have shown that exposure to chronic stress can induce a pro-oxidative environment leading to cerebrovascular dysfunction and cognitive impairment. Xanthine oxidoreductase (XOR) is an enzyme that generates xanthine oxidase (XO) and xanthine dehydrogenase (XDH). Under hypoxic or pro-inflammatory conditions, XO produces excessive amounts of hydrogen peroxide and superoxide, which plays an important role in this stress-induced cerebrovascular dysfunction. Pharmacologically inhibiting XO with Febuxostat (50 mg/L) prevented stress-induced cerebrovascular dysfunction. XO is found in multiple tissues/organs; however, the liver is the major source of XO. Thus, this study aimed to understand how XO produced from the liver impacted cerebrovascular function during chronic stress. We hypothesize that liver XO production mediates stress-induced cerebrovascular dysfunction. To test our hypothesis, we exposed wild-type (WT) and hepatic XO knockout mice (HXO) to eight weeks of unpredictable chronic mild stress (UCMS) with or without Febuxostat (Feb). Groups were separated by HXO-control, HXO-UCMS, HXO-UCMS+Feb, WT-con, WT-UCMS, and WT-UCMS+Feb. During terminal procedures, the middle cerebral artery (MCA) was isolated and assessed using pressure myography to test the endothelial-dependent (EDD) and endothelium-independent dilation (EID) to acetylcholine (ACh) and sodium nitroprusside (SNP). The isolated MCA was kept under physiological conditions (pH 7.4±0.2; 70±2 mmHg, 37±1℃). In WT mice, UCMS decreased by 50% EDD (p<0.0001) and did not affect EID compared to WT-con, whereas the WT-UCMS+Feb group was fully protected, with similar EDD and EID values compared to WT-con. In contrast, HXO mice were partially protected from UCMS, reflected by only a 24% decrease (p<0.0001) in EDD and no change in EID. However, the HXO-UCMS+Feb group was fully protected with similar EDD and EID values to control mice. Our data shows that the liver significantly contributes to stress-induced cerebrovascular dysfunction. However, additional sources of XO circulation within the cerebrovasculature need further investigation.

NIH, NINDS BINP R01 NS1117754, Psychosocial Stress-Induced Vascular Contributions to Cognitive Impairment and Alzheimer's. Disease: The Role of Xanthine Oxidase, NIH F31 Diversity Award, US DHHS-NIH-National Institute on Aging, Role of Xanthine Oxidase on Vascular Contributions to Cognitive Impairment

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.