bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
Arterial baroreflex control of heart rate in young and older adults and in patients with heart failure with preserved ejection fraction
Authors: Bunsawat Kanokwan , Holwerda Seth , Alpenglow Jeremy , Broxterman Ryan , Francisco Michael , Craig Jesse , Iacovelli Jarred , Weavil Joshua , Iannetta Danilo , Inglis Erin , Tuday Eric , Harrison Jonathan , Ma Christy , Ryan John , Wray D. Walter 
Published: May 2023

Background: The arterial baroreflex (ABR) plays an important role in evoking appropriate cardiovascular adjustments in response to perturbations such as exercise. The ABR control of heart rate (HR) becomes attenuated with advancing age and in a variety of patient populations, but limited information is available in patients with heart failure with preserved ejection fraction (HFpEF). The present study tested the hypothesis that the ABR control of HR is attenuated to a greater extent in patients with HFpEF compared to older and young controls. Methods: Six patients with HFpEF (71±6 years; 35.3±6.6 kg/m2), 4 older controls (68±4 years; 25.1±3.4 kg/m2), and 7 young controls (27±4 years; 26.6±3.9 kg/m2) underwent sequential bolus infusions of sodium nitroprusside (50-100 μg) and phenylephrine (150 μg) (modified Oxford technique) to provoke acute hypotension (“BP falls”) and hypertension (“BP rises”), respectively. Cardiac baroreflex gain was quantified as the weighted linear regression slope between the R-R interval and systolic blood pressure (BP). Results: Compared to young controls (10.7±3.4 ms/mmHg), overall cardiac baroreflex gain was reduced in older controls (3.4±1.6 ms/mmHg) and patients with HFpEF (2.1±1.8 ms/mmHg) (p<0.05), with no difference between the older controls and patients with HFpEF (p=0.718). During BP falls, cardiac baroreflex gain was not different between groups (p=0.06), but was qualitatively lower in patients with HFpEF (0.6±1.5 ms/mmHg) compared to young (5.3±5.5 ms/mmHg) and older controls (5.2±1.9 ms/mmHg). During BP rises, cardiac baroreflex gain was not different between older controls (2.6±0.8 ms/mmHg) and patients with HFpEF (2.3±2.0 ms/mmHg) (p>0.05); however, responses in patients with HFpEF were attenuated compared to young controls 10.7±5.8 ms/mmHg) (p<0.05). Conclusion: These findings suggest an age-related attenuation in the overall ARB control of HR that does not appear to be further exacerbated in patients with HFpEF. However, patients with HFpEF may exhibit a selective attenuation in ABR-mediated tachycardia in response to acute reductions in BP that may pose an increased risk of hypotension and frank syncope. This work was funded in part by the U.S. Department of Veterans Affairs (RX001311, to D.W.W.; IK2RX003670, to 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.
Role of paraoxonase 3 (PON3) in regulating ENaC-mediated sodium transport in distal nephron
Authors: Shi Shujie , Mutchler Stephanie , Whelan Sarah Christine , Marciszyn Allison , Kleyman Thomas 
Published: May 2023

PON3 is expressed in the aldosterone-sensitive distal nephron, where ENaC plays an essential role in maintaining Na+/K+ homeostasis in the kidney. The aims of our study were to determine the physiological roles of PON3 in renal Na+ and K+ handling. We hypothesize that PON3 functions as a molecular chaperone to regulate ENaC expressionand Na+ reabsorption in the kidney. We have obtained a Pon3 global knockout mouse model and examined the effect of PON3 on ENaC functional expression using several approaches, including biochemistry, immunohistochemistry, electrophysiology, and whole animal metabolic cage studies. Pon3 KO mice have normal kidney histology without evidence of inflammation or injury. At baseline, Pon3 KO mice have a significantly lower blood [K+] and higher blood [Na+] when compared to WT littermates. Amiloride-induced natriuresis was significantly greater in the KO mice, reflecting, in part, an upregulation in ENaC-dependent Na+reabsorption in the absence of the PON3. Immunoblotting of whole kidney lysates indicated that the total abundance of ENaC subunits was not altered in KO mice. Single channel recordings of ENaC in split-open tubules freshly isolated from WT or Pon3 KO mice kidneys demonstrated that open probability ( P O) was similar between the two groups of animals. However, the number of active channels per patch ( N) was significantly higher in Pon3 KO mice, resulting in a higher ENaC activity ( NP O) in the distal nephron segments of Pon3 KO mice. Consistent this notion, we found that ENaC γ subunit surface abundance was increased in mCCD cells when PON3 expression was knocked down by siRNA.Together, our data suggest that Pon3 KO mice have upregulated Na+ reabsorption and K+ secretion, likely a result of increased ENaC functional expression in the absence of PON3. This study was funded by NIH grants R01 DK130901 (to SS), R01 DK111380 (to SS), R01 HL128053 (to TRK and SS), R01 HL147818 (to TRK), and P30 DK079307 (the Pittsburgh Center for Kidney Research). SMM was supported by T32 DK061296, T32 DK007052, and a grant from Relypsa. 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.
Underrepresentation of Women Participants in Exercise Science and Physiology Research is Associated with Authorship: A Historical Perspective
Authors: Linde Jessica , Klevenow Emilie , Atkinson Mira , Vosters Emma , Bueckers Elizabeth , Quinn Meagan , Hunter Sandra 
Published: May 2023

The historically low representation of women as participants in exercise science and physiology research has led to a lack of understanding in the response of women to exercise and other therapeutic interventions. We hypothesize (1) the number of women authors and participants will increase over the last 30 years, and (2) a larger representation of women authors will be associated with an increase in the number of women participants. METHODS: Original research articles (n = 971) were analyzed from three journals (Journal of Applied Physiology, Medicine and Science in Sports and Exercise, and British Journal of Sports Medicine) in 1991 and 2021. These journals were chosen based on the following inclusion criteria: consistently ranked in the top 15 exercise science and physiology research journals, impact factor >3.5, ≥50 years of publications, and were accessible online. Articles were chosen from the following inclusion criteria: original research and not a review, included humans and not animals and did not solely use computational models. ANOVA and modified Pearson-Filon (ZPF) were used to statistically analyze the data. Data are reported as mean ± standard deviation. RESULTS: The number (percentage) of women authors was less in 1991 than 2021 (16 ± 22% vs. 31 ± 24%, p < 0.001) as well as the number of women participants (22 ± 32% vs. 36 ± 30%, p < 0.001). The percentage of women participants were less when the last author was a man compared to when the last author was a woman in 1991 (20 ± 30% vs. 34 ± 42%, p = 0.002) and in 2021 (32 ± 28% vs. 52 ± 33%, p < 0.001). Of all studies, 51% were authored by men only in 1991, which declined to 18% in 2021. In contrast, 1.8% in 1991 and 1.1% in 2021 were authored by women only. The correlation between authorship gender (number of women/total authors ratio) and participant gender (number of women/total participants ratio) grew between 1991 and 2021 (r = 0.27 vs. r = 0.42, p = 0.020). CONCLUSION: While the number of women authors and participants increased from 1991 to 2021, these numbers do not represent the current number of women in the population (~51%). Our data shows the historical underrepresentation of woman authors influences the low number of woman participants. Specifically, women authors included participants of both genders (men and women) at equitable numbers in exercise science and physiology research in 2021. The low representation of women as participants in exercise science and physiology research could be resolved by encouraging authors who are men to research equitable numbers of each gender. 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.
Pressure Regulation of Vascular L-type Calcium Channels
Authors: Mironova Galina , Baudel Miguel , Flores-Tamez Victor , Brett Suzanne , Navedo Manuel , Welsh Donald 
Published: May 2023

Myogenic tone is dependent upon the activation of L-type Ca2+ channels and the rise in cytosolic [Ca2+]i. While L-type Ca2+ channel activation is often singularly linked to arterial depolarization, sparse evidence suggests that pressure itself may also enhance functional activity, through cooperative gating and trafficking. In this context, this study explored whether intravascular pressure indeed tune the myogenic response by enhancing the L-type Ca2+ channel trafficking and amplifying cooperative gating.Experimentation began in isolated smooth muscle cells (whole cell/single-channel patch clamp; immunohistochemistry; proximity ligation assay) and extended to intact arteries (pressure myography and Ca2+ measurements). Whole-cell electrophysiology revealed the ability of pressure stimuli to increase the L-type Ca2+ current, a response dependent on the intact cytoskeleton and enzymes tied to functional coupling (PKCα, AKAP150, PKA). Cell-attached electrophysiology confirmed whole-cell observations, registering increased coupling among L-type Ca2+ channels when cells were pressurized. Ensuing experiments on isolated arteries subsequently revealed linkage between intravascular pressure and enhanced L-type Ca2+ channel activity, independent of membrane depolarization.In closing, our results suggest there is more to L-type Ca2+ channel regulation than voltage gating and that pressure itself can enhance functional activity. Work continues to precisely define the pressure-sensitive signaling complexes within vascular smooth muscle. Supported by the Canadian Institute for Health Research, National Institute of Health and the Rorabeck Chair in Vascular Biology and Neuroscience. 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.
Temporal and kinematics changes in jaw movement during feeding following chemoradiation to the rat submental muscles
Authors: King Suzanne , Scott Nathan , Smiley Brittany 
Published: May 2023

Head and neck cancer patients treated with chemoradiation can develop radiation-induced dysphagia, which can significantly impact their quality of life. The submental muscles of the floor of mouth, such as the mylohyoid and geniohyoid, are at high risk for radiation-associated impairments in swallowing function. Prior work has shown that irradiating the submental muscles reduces the rate of tongue movement. During feeding, there is functional linkages between the jaw and tongue; therefore, an alteration in jaw movement could influence the position/shape of the tongue. The purpose of this study was to determine if chemoradiation treatment to the submental muscles alters jaw movement during eating. We hypothesized that the jaw speed and distance of movement during feeding would be modified following radiation treatment. Videofluoroscopic swallow study (VFSS) was performed on 18 Sprague-Dawley rats 1-month after chemoradiation, radiation alone or no treatment. Radiation was targeted to the submental muscles (12 fractions of 4Gy given three days a week for four weeks). Four cycles of 1mg/kg of cisplatin were administered concurrently with radiation. Rodents were provided peanut butter with 40% w/v barium and video recordings were taken at 250 frames per second with a customized c-arm. Jaw position along the xy axis was measured relative to the hard palate. Temporal and kinematic measures of the vertical movement of the jaw were analyzed. Significant decreases in jaw distance (p<0.03) and speed (p<0.02) traveled during licking were observed post treatment compared to untreated controls. The distance traveled during opening and closing phases of the jaw cycle were found to be decreased (both p<.03) following chemoradiation and radiation treatment. Results demonstrate that radiation-based treatments to the submental muscles impair jaw movement. The observed changes in jaw kinematics could potentially influence tongue position and shape during feeding. The Ar-Hale Family Foundation; Jewish Heritage Fund for Excellence Grant 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.