bluuebunny/crossref_metadata_2025_split huggingface dataset:
Viral infections such as SARS-CoV-2, HIV, and EBV can alter nonsense-mediated decay and impact cellular processes unique to an individual's genome
Authors: Prokop Jeremy , Palo Anna , Mitchell Jackson , Cook Taylor , Bupp Caleb , Rajasekaran Surender , Chesla Dave , Hartog Nicholas 
Published: May 2023

Throughout the last few years, understanding the physiological mechanisms to viral infections has highlighted individuals' unique outcomes. While SARS-CoV-2 and other pathogens can cause hospitalization and mortality, some individuals remain asymptomatic, and others will suffer from years of altered diverse physiological pathways (such as long COVID). Our team, through transcriptomics, has built a hypothesis that many of the individual-level responses are due to the interaction of a virus with a process known as nonsense-mediated decays (NMD) and how suppression of NMD interacts with an individual's genomic variants to drive diverse physiological response. This hypothesis has been built on nearly five hundred clinical transcriptomes of infants with RSV infection, newborns with genomic disorders, kids with multiple organ dysfunction syndrome, and adults with hospitalized COVID-19 paired with >16,000 publicly deposited blood transcriptomes of broad pathologies. Several virus interactions with human genomics have been observed within our work. First, a patient with EBV had an acute activation of viral-induced genetics through suppression of NMD, resulting in elevated RNASEH2B dominant-negative human protein resulting in Hemophagocytic lymphohistiocytosis (HLH), a mechanism of a rare transient disorders. Second, we have observed multiple individuals with viral infections that resulted in either the activation or suppression of interferon cascades correlated to common variant alleles altered by NMD changes, such as ISG15 and cytokines. Third, we show that several of these cytokine modulation genetics can elevate the risk of NMD-regulated Neutrophile Extracellular Trap (NET) production associated with long-term endocrine and hemodynamic modulation. Finally, we show that when a virus suppresses NMD (SARS-CoV-2, HIV, EBV), multiple individuals with latent infections can have an elevation of the dormant virus transcripts, including EBV and Torque teno virus. Thus, individuals can have multiple viruses activated that change physiological outcomes simultaneously. Overall, it is essential to physiology and medicine to refine each individual's precision and unique outcomes based on the complex interaction of a virus with NMD and genomic variants to modify cellular, systems, and inflammatory responses. This research was funded by the Gerber Foundation, National Institutes of Health (K01ES025435 and R01AI171984), Michigan Department of Health and Human Services, and 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.
TRPC6 deficiency impairs middle cerebral artery myogenic response and brain spatial memory
Authors: Wang Zhen , Zhang Huawei , Fan Fan , Sears Jaylan , Fu Yiling , Dai Xuemei , do Carmo Jussara , da Silva Alexandre , Mouton Alan , Omoto Ana , Li Xuan , Hall John 
Published: May 2023

Transient receptor potential channel 6 (TRPC6) is a nonselective cation channel belonging to the TRP ion channel family and expressed in vascular smooth muscle cells. TRPC6 regulates calcium influx in response to vascular wall mechanical stretch. A previous study reported that TRPC6 is critical for the myogenic response of the middle cerebral artery (MCA). Impaired MCA myogenic response is implicated in cerebral blood flow dysfunction and may promote cognitive deficits. In this study, we investigated whether TRPC6 contributes to the MCA myogenic response at pressure range (from 40 to 180 mmHg) in 12-week-old male wild-type (WT) and whole-body TRPC6 knock-out (TRPC6 KO) mice (n=5-8). Cognitive function (spatial learning and reference memory) was examined at 22 weeks of age using the Morris water maze test. Myogenic response in MCA was similar in WT and TRPC6 KO mice when perfusion pressure was increased from 40 to 80 mmHg. At higher pressures (>120 mmHg), however, TRPC6 KO mice displayed significantly reduced myogenic response compared to WT mice (3 % less of myogenic tone in TRPC6 KO compared to WT) which was further exacerbated when perfusion pressure was increased to 180 mmHg (9 % less of myogenic tone in TRPC6 KO compared to WT). There were no significant differences in wall thickness, wall-to-lumen ratio, vascular distensibility, incremental distensibility, or elastic modulus curves in MCA between WT and TRPC6 KO mice. Compared to WT mice, TRPC6 KO mice displayed similar spatial learning curves after 4 days of training but showed significantly impaired reference memory (14±1 % vs 29±4 % in the target quadrant) and reduced frequency (1.0±0.3 vs 2.1±0.4 in the target area crossing) compared to WT. These findings suggest that TRPC6 deficiency impairs myogenic response at higher perfusion pressures and spatial memory, even at a young age. (AG050049 (F.F), AG057842 (F.F), AG079336 (F.F), NIDDK R00DK113280, R01DK121411, NIGMS P20GM104357 and NIGMS U54GM115428) 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.
Changes in DNA methylation patterns during high-altitude acclimatization
Authors: Frost Shyleen , Pham Kathy , Heinrich Erica 
Published: May 2023

High altitude is a physiologically stressful environment, in part due to reduced atmospheric oxygen pressure leading to hypoxemia. While the physiological changes that occur during acclimatization to high altitude are well characterized, it is unknown what role epigenetic gene regulation may play in these processes. Therefore, the objective of this study was to measure global changes in DNA methylation in response to acute high-altitude exposure, as well as changes in key hypoxia-inducible factor (HIF) pathway genes including EPAS1[E1] (HIF-2α) and EGLN1 (PHD2). Previous studies suggest that EPAS1 and EGLN1 may play key roles in high-altitude adaptation by promoting erythropoiesis, angiogenesis, and modulating metabolic pathways. We hypothesized that acute high-altitude exposure would produce global hypomethylation, as well as increased methylation of the EGLN1 promoter region and decreased methylation of the EPAS1 promoter region, resulting in increased expression of HIF-2α and increased HIF-pathway activation. To test this hypothesis, 15 (5 women, 10 men) healthy participants of sea-level ancestry were recruited (age = 25 ± 4.8). DNA was isolated from venous blood samples which were collected during fasting at sea level and over the course of three days of acclimatization to 3800 m elevation at Barcroft Station (Bishop, CA). DNA methylation levels were measured at CpG sites across the genome using the Illumina Infinium MethylationEPIC chip, and local DNA methylation for EPAS1 and EGLN1 was obtained using a high-resolution melt technique. We identified several CpG sites throughout the genome that were differentially methylated during high-altitude exposure. The top gene ontology terms for differentially methylated sites include bone cell development, DNA damage repair pathways related to p53, and myeloid cell development. There were also significant decreases in CpG sites within HIF-pathway genes such as CD44 and FOXP1. Finally, DNA methylation levels within EPAS1 and EGLN1 changed significantly throughout the process of high-altitude acclimatization, with methylation levels increasing in some regions and decreasing in others. In conclusion, high-altitude exposure leads to complex changes in DNA methylation patterns throughout the genome. These changes likely play a key role in acclimatization and adaptation to chronic hypoxia and future studies will explore these mechanisms. This work has implications for understanding the role of epigenetics in diseases associated with hypoxia such as COPD, COVID-19, sleep apnea, and reproductive diseases such as preeclampsia and endometriosis. This work was funded by a UCR Regent's Faculty Fellowship to ECH and by the UCR School of Medicine. 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.
Differential angiogenic response contributes to sexual dimorphism in right ventricular adaptation in male and female Fischer CDF rats subjected to pulmonary artery banding model
Authors: Chaudhary Ketul , Seelemann Erica , Panchakshari Sheethal , Wolverton Maxwell , Deng Yupu , Stewart Duncan 
Published: May 2023

Background: Female sex has been associated with better right ventricular (RV) adaptation and survival in patients with elevated RV afterload; however, the mechanisms underlying these differences remain unclear. Therefore, we studied the mechanisms underlying sex differences in RV remodeling and development of RHF using the rat pulmonary artery banding (PAB) model. Methods: Adult male and female Fischer CDF rats were subjected to PAB or sham surgery and echocardiography was performed at 1- or 2-weeks post-PAB to evaluate RV structure and function. RV systolic pressure (RVSP) was measured using a pressure catheter and Fulton Index (RV/ left ventricle + septum) was measured to evaluate RV hypertrophy (RVH). To explore the mechanisms, a focused PCR array was performed to assess the expression of angiogenic genes in the RV of male and female rats subjected to sham or PAB procedure. RV endothelial cells (RVECs) were isolated from Fischer CDF rats and effects of female sex hormones on angiogenic ability of RVECs was assessed using Matrigel network formation assay. We also assessed the role of sphingosine kinase-1 (Sphk1) inhibitor, PF-543, in mediating the effects of female sex hormones on angiogenic potential of RVECs. Results: At 1- and 2-week post-PAB, RVSP and RVH were significantly elevated in PAB rats compared to control rats; however, no differences were observed between male and female rats. Cardiomyocyte surface area (330 vs 234 mm2, p<0.05) and fibrosis (6.96 vs 4.58%, p<0.05) were both significantly higher in male compared to female rats. RV end-diastolic diameter was also increased in male rats compared to female rats (3.33 vs 2.05 mm; p<0.05). On the contrary, RV function was preserved in female rats as indicated by higher cardiac index and fractional area change compared to male rats. Up-regulation of angiogenic genes, including Sphk1, was observed in the RV of female rats compared to male rats at 2 weeks post-PAB. Estradiol treatment increased network forming ability of RVEC isolated from Fischer CDF rats and this effect was inhibited by PF-543. Conclusions: Female Fischer CDF rats develop adaptive RV remodeling in response to PAB compared to mal-adaptive RV remodeling in male rats. Moreover, the better RV adaptation in female rats involves increased RV angiogenesis and these effect may be mediated through Sphk1. Research Nova Scotia, Dalhousie 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.
TRPM7 contributes to TGF-ß signaling in renal fibroblast
Authors: Khan Abdul , Mankuzhy Pratheesh , Adebiyi Adebowale 
Published: May 2023

Mammalian transient receptor potential melastatin (TRPM), the non-selective cation channel subfamily, has eight members and is extensively expressed in excitable and non-excitable cells where they perform diverse functions, including sensory transduction, magnesium reabsorption, cell adhesion, and vascular reactivity. TRPM channels have been detected in the kidney, and they participate in regulating osmotic and ion homeostasis. Members of the TRPM family contribute to ischemic kidney injury, but their function in renal fibroblast, a principal mediator of renal fibrosis associated with progressive kidney failure, is unclear. Hence, this study aimed to explore the expression and function of TRPM channels in primary mouse renal fibroblast. We demonstrated that among all TRPM channels, only TRPM 4, 6, and 7 are expressed in the cells. However, the expression of TRPM7 was at least 60% more than TRPM 4 and 6. TRPM7 is a bifunctional protein characterized by ion channel and kinase activity. Treatment of renal fibroblasts with transforming growth factor β(TGF-β) increased the expression of TRPM7. Considering the critical role of renal fibroblast in the development of renal fibrosis and TGF-βas a factor that drives fibrosis in chronic kidney disease, we examined the effect of siRNA-mediated knockdown of TRPM7 on pro-fibrogenic markers and mediators. We demonstrated elevated expression of fibrotic markers fibronectin, vimentin, and collagen type 1 in TGF-βtreated renal fibroblast, an effect attenuated by TRPM7 knockdown. The TGF-β-induced increase in fibrosis markers was accompanied by activation of SMAD3- and STAT3-mediated fibrotic signaling pathways with markedly elevated expression of phosphorylated SMAD3 and STAT3. Knockdown of TRPM7 attenuated expression of phosphorylated SMAD3 and STAT3 in TGF-β-treated renal fibroblast. Migration and proliferation of the cells were elevated when treated with TGF-β. Interestingly, the knockdown of TRPM7 diminished TGF-β-induced renal fibroblast migration and proliferation. Overall, this study suggests that TRPM7 is essential for the profibrotic signaling in renal fibroblast, which is associated with activating the canonical SMAD3 and non-canonical STAT3 pathways of fibrosis. NIH: R01 HL151735-01 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.
Acute Intermittent Hypoxia and Respiratory Strength Training to Improve Respiratory Function in Individuals with Chronic Spinal Cord Injury: Preliminary Outcomes
Authors: Vose Alicia , Welch Joseph , Nair Jayakrishnan , Michela Mir , Kathryn Cavka , Wauneka Clayton , Brunetti Gina , Snyder Hannah , Demark Lou , Mitchell Gordon , Fox Emily 
Published: May 2023

Spinal cord injury (SCI) disrupts neural pathways to respiratory motor neurons, causing paralysis and breathing impairment, a major cause of illness and death in SCI. Acute intermittent hypoxia (AIH) is a promising therapeutic modality that elicits spinal synaptic plasticity, improving breathing in rodent models of SCI. AIH also elicits plasticity in limb motor systems in both rodent models and humans with chronic SCI, where functional gains are greatest when paired with task-specific training. The impact of similar combinatorial treatments on breathing ability is unknown. Here, we report preliminary breathing outcomes in seventeen adults with chronic SCI who received AIH and task-specific training (respiratory strength training; RST). Seventeen males with chronic SCI (33.7 ± 15 yrs of age; 1-28 yrs post-SCI; 12 cervical, 5 thoracic injuries; C1-T6 AIS A-D). Respiratory function was 52% ± 19% of the age-predicted normative function for expiratory pressure generation and 123% ± 32% of normative values for inspiratory function. Participants completed four random ordered 5-day protocols of AIH, Sham, RST, and AIH+RST, >3 weeks apart. AIH consisted of 15, 1-minute episodes of breathing a hypoxic gas mixture (9% oxygen), interspersed with 1.5-minute episodes of breathing room air (21% oxygen). Thirty minutes after AIH, RST involved both inspiratory and expiratory training; 4 sets of 6-12 breaths with the pressure threshold device set to 80% of each individual’s maximum. Sham treatments replicated AIH but used room air. A linear mixed model was used to test for differences in maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and forced vital capacity (FVC) prior to and 1 day post-intervention. MIP increased 10±15.6% (pre 120±34cmH20, post 129±36 cmH20) 1 day after RST (p=0.001) and 6±10.5% (pre 123±34cmH20; post 131±34cmH20) 1 day after AIH+RST (p=0.04), but did not change after AIH or Sham. MIP increased by >10% in 5/17 participants following AIH+RST and 9/17 participants following RST. Neither MEP nor FVC changed following any block. Although there were no significant differences between AIH+RST and RST intervention blocks, there was a medium effect size (0.44). Since RST and AIH+RST preliminary outcomes suggest functional respiratory benefit, future steps will determine if the combinatorial treatment elicits greater gains. Examination of biomarkers associated with outcomes will provide insight into outcome variability. Department of Defense CDMRP W81XWH1810718 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.
Putatively adaptive missense variant at Adrenergic Receptor Alpha-1A associated with decreased risk of Chronic Mountain Sickness in Andean highlanders
Authors: Gu Wanjun , Lawrence Elijah , Moya Esteban , Villafuerte Francisco , Simonson Tatum 
Published: May 2023

Andean highlanders living at high altitude (>4200 m) for hundreds of generations exhibit distinct cardiovascular and ventilatory traits in response to environmental stress. Adrenergic Receptor Alpha-1A ( ADRA1A), a gene coding for the Alpha 1-A adrenergic receptor, has been previously shown to be under positive natural selection in the Andeans. ADRA1A has also been demonstrated to have a protective effect against cardiovascular complications in other lowland populations. We hypothesized that putatively adaptive single nucleotide variants (SNVs) of strong functional impact can be found in ADRA1A and associated with cardiovascular traits in the Andean highlanders.We examined data from the Composite of Multiple Signals test in 40 high-coverage whole genomes of Andean highlanders living in Cerro de Pasco, Peru (~4340 m), specifically focusing on SNVs with strong predicted functional impact. Genetic variants of interests were then genotyped and tested for phenotypic associations in an extended Andean cohort (132 males, 46 females). The presence of Chronic Mountain Sickness (CMS), a maladaptive syndrome observed in Andean highlanders characterized by excessive erythrocytosis, and resting heart rate during hypoxia were prioritized for the regression analysis. The genotype-phenotype association analysis adapted a multivariate linear model with sex as a stratum and age as a covariate.A missense variant (rs1048101, A>G) in the second exon of ADRA1A with strong predicted functional impact was tagged by the Composite of Multiple Signals analysis. In Andean males, the rs1048101 A allele was associated with 1.52-fold decreased risk for CMS (p<0.018) and attenuated resting heart rate at room air (~10% inspired O2 ) and at 21% inspired O2 (room air: p<0.019, 21% O2 : p<0.012). In women, the association between ADRA1A rs1048101 and CMS was not significant (p>0.917). In addition, women with more copies of the putatively adaptive A allele demonstrated increased heart rate both at room air and 21% inspired O2 (room air: p<0.033, 21% O2 : p<0.044) in contrast to observations in men.In conclusion, the putatively adaptive missense variant rs1048101 at ADRA1A demonstrated a protective effect against Chronic Mountain Sickness and was further associated with decreased resting heart rate in Andean males. The lack of replicability of these associations in females suggests potential sex-dependent effect of ADRA1A. Further experiments functionalizing the variant and validating the associations in large genome cohorts may shed light on the mechanisms of the gene. This project is funded by R01HL145470. 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.
Loss of A Metalloproteinase and Disintegrin 15 leads to exacerbated myocardial hypertrophy and dilation through activation of the calcineurin pathway in male but not female micev
Authors: Aujla Preetinder , Hu Mei , Kranrod Joshua , Viveiros Anissa , Kilic Tolga , Owen Caroline , Oudit Gavin , Seubert John , Kassiri Zamaneh 
Published: May 2023

Cardiac dysfunction associated with cardiomyopathies is characterized by myocardial hypertrophy and dilation involving many cellular and molecular signalling events. A disintegrin and metalloproteinases (ADAMs) are membrane-bound proteinases with diverse functions, whose role in heart disease remains underexplored. ADAM15 is expressed in the heart and is downregulated in the failing human heart. In left ventricular (LV) specimens, ADAM15 levels did not change in patients with concentric hypertrophy (preserved ejection fraction) but was markedly decreased in hypertrophic and dilated failing cardiomyopathy. We investigated the role of ADAM15 in pressure overloaded cardiomyopathy in both male and female C57BL/6 mice. Loss of ADAM15 alone did not cause cardiomyopathy in both male and female mice up to 1 year of age. Male and female wildtype (WT) and ADAM15 knockout ( Adam15-/- ) mice were subjected to cardiac pressure overload by transverse aortic constriction (TAC) at 8 weeks of age. Adam15-/- female mice had comparable cardiac function and hypertrophy to their WT controls while, Adam15-/- male mice exhibited worsened decompensated hypertrophy and dilation with increased activation of mitogen activated protein kinases (pJNK, pERK1/2) compared to WT. Expression of integrin-α7 (but not integrin β1) increased significantly more in male Adam15-/- -TAC hearts, while the interaction of integrins with basement membrane (laminin) decreased consistent with increased LV dilation. Activity of calcineurin was higher in male Adam15-/- -TAC hearts along with greater de-phosphorylation of its target transcription factor, NFAT1. Calcineurin inhibition (cyclosporin A) blocked the excess hypertrophy and dilation in male Adam15-/- mice post-TAC. Calcineurin signalling has been shown to be inhibited by 17β-estradiol (E2), the circulating form of estrogen. Thus, the sex-dependent phenotypic differences in male and female Adam15-/- mice following pressure overload could be attributed to the inherent increased inhibition of calcineurin-mediated signalling due to the increased expression of estrogen in female mice. Research supported by Canadian Institutes of Health Research (CIHR) 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.