bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metabolomic and transcriptomic alterations in the colon of mice with metabolic syndrome in the absence of inflammation
Authors: Rivas Jaclyn , Castillo Eliseo , Scieszka David , Peralta-Herrera Eduardo 
Published: May 2024

Metabolic syndrome (MetS) is characterized by a cluster of conditions including abdominal obesity, elevated blood pressure, altered lipid profiles and high blood sugar levels. These factors collectively elevate risks for cardiovascular diseases, diabetes, and metabolic dysfunction associated steatotic liver disease (MASLD). MetS impacts approximately a third of the US populace and a quarter of the global population. Despite its widespread prevalence, there are no existing medications to specifically treat MetS. With the global rise in MetS cases, understanding its underlying mechanisms is paramount. Our research emphasizes the potential physiological and metabolic disruptions within the gastrointestinal (GI) tract that might contribute to MetS manifestation. Using a mouse model of MetS (MS NASH) and healthy lean controls (C57BL/6J), we investigated the colon environment. 16S rRNA sequencing from fecal samples revealed a distinct microbiota profile in MS NASH mice, highlighted by an increase in the Lactobacillus genus. Colonic metabolome and transcriptome in MS NASH mice displayed an upregulation in anabolic pathways, like glycolysis, the pentose phosphate pathway, and the tryptophan/kynurenine pathway. Subsequent integrated analysis of these datasets unveiled potential compensatory mechanisms and pathway crosstalk, within the colonic environment. Despite these alterations, MS NASH mice showed no signs of intestinal inflammation, a finding confirmed through detailed histological and LCN-2 assessments. Additionally, there were no changes detected in genes typically associated with increased intestinal inflammation or permeability. This study provides insight in the nuanced relationship between the metabolic state, gut microbiota, and potential progression towards other metabolic disorders. Our findings highlight the significance of multi-omics data convergence in understanding the changes within the colonic environment and their implications for MetS onset and/or progression. Supported in part by the National Center for Research Resources and the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) through grant no. UL1TR001449 (E.F.C.) and in part by NIH grant P20GM121176 (E.F.C.), and the University of New Mexico Comprehensive Cancer Center with grant P30CA118100. This is the full abstract presented at the American Physiology Summit 2024 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 Compliance during Progressive Hypotension in Patients with Autonomic Failure
Authors: Sajid Aleena , Shoemaker Leena , Schondorf Ronald , Shoemaker Kevin 
Published: May 2024

Background: Cerebral perfusion during reductions in arterial pressure (AP) can be supported transiently by a Windkessel mechanism that increases cerebrovascular compliance (Ci). This defense mechanism exists in healthy participants during rapid standing and in patients during vasovagal syncope. However, it remains unknown whether the rise in Ci with falling AP exhibits a threshold effect. Thus, we tested the hypothesis that increased Ci is passive to a reduction in AP and starts to increase only after a threshold has been reached. To test this hypothesis, it was necessary to study a population that tolerates progressive large reductions in BP without a loss of consciousness. Therefore, we analyzed Ci changes during a graded head-up tilt (HUT) from patients with autonomic failure (AF). Methods: Finger AP and right middle cerebral artery blood velocity (MCAv) were recorded from 5 AF patients (n = 5 male, 61 ± 23 years, 25 ± 5 kg/m2) at supine rest and during graded-HUT (30, 45, 60 degrees). Tilt gradients increased incrementally every 5 minutes until AP reached a critically low value prompting termination of HUT. The total time in HUT was 11 ± 4 min. Individual AP and MCAv waveforms during supine rest and graded HUT (one waveform every 5 s) were assessed with a modified Windkessel model to calculate Ci and cerebrovascular resistance (CVR). Pulse pressure (PP) was calculated as systolic AP − diastolic AP. A threshold value for the increase in Ci was determined as five consecutive cardiac cycles greater than the average supine Ci plus 2 standard deviations. Results: Graded HUT resulted in an overall reduction in AP (85 ± 18 to 50 ± 7 mmHg), PP (72 ± 22 to 32 ± 19 mmHg), mean MCAv (62 ± 12 to 35 ± 7 cm/s), and CVR (1.4 ± 0.1 to 1.0 ± 0.3 mmHg/cm/s; all p < 0.05 vs supine). Ci increased by 905 ± 756% (p = 0.04 vs supine). The threshold effect was evident as Ci began to increase progressively after PP fell by 15 ± 3 mmHg and AP fell by 12 ± 2 mmHg. Conclusions: Our results provide evidence that Ci increases after a threshold reduction in PP and AP in the apparent absence of autonomic support. These data support the idea that increasing Ci during reductions in AP represents a pressure-dependent Windkessel mechanism. Of interest, our findings provide clinical insight into how AF patients compensate for such large reductions in pressure without the assistance of CVR as a defense mechanism. NSERC USRA — Western University, Natural Sciences and Engineering Research Council of Canada (NSERC, Grant No. RGPIN-2018-06255). This is the full abstract presented at the American Physiology Summit 2024 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.
Dietary Effect on Peripheral and Cerebral Vascular Function in Adults with Non-Alcoholic Fatty Liver Disease
Authors: Wang Tianyu , Chen Lin-Sheng , Gallagher Isabelle , Li Yanrong , Caillaud Marie , Park Jessica , Alhalimi Taha 
Published: May 2024

Objective: Non-alcoholic fatty liver disease (NAFLD) is a recognized independent risk factor for cardiovascular and cerebrovascular dysfunction. The present study evaluated the effect of dietary interventions on peripheral and cerebral vascular function in individuals with NAFLD. Methods: We studied 30 middle-aged adults (55±9 years) with NAFLD or with elevated NAFLD risk (with prediabetes symptoms). Liver fat content was assessed via 1H magnetic resonance spectroscopy. NAFLD was defined as liver fat proton density fat fraction (PDFF) exceeding 5%. Participants were randomly assigned to a low-carbohydrate diet (carbohydrate intake <30 g/d) or a low-calorie diet (30% calorie intake reduction). Arterial stiffness (via brachial-ankle pulse wave velocity-baPWV), carotid artery intima-media thickness (IMT), endothelium-dependent vasodilation (via flow-mediated dilation-FMD), cerebrovascular reactivity (CVR) in the middle cerebral artery (MCA), and blood concentrations of cardiovascular risk factors were measured before and after a two-week dietary intervention. Results: Participants with NAFLD represented 70% of the current cohort. Following the dietary interventions, participants had significant reductions in body weight (95%CI [-3.22, -1.41 kg]) and fat mass (95%CI [-1.64, -0.56 kg]), accompanied by decreased liver fat content (95%CI [-2.62, -0.79%]). These changes were only evident in the NAFLD group with no significant differences between the two dietary interventions. Systolic and diastolic blood pressure as well as pulse pressure significantly decreased in both NAFLD and non-NAFLD groups. Total cholesterol (95%CI [-22.2, -1.5 mg/dL]) and triglyceride (95%CI [-30.4, -0.9 mg/dL]) concentrations decreased in those with NAFLD assigned to the low-carbohydrate diet. baPWV decreased (95%CI [-78.6, -12.4 cm/s]) only in individuals with NAFLD assigned to the low-calorie diet. FMD significantly increased (95%CI [0.5, 5.1%]) only in individuals with NAFLD assigned to the low-carbohydrate diet. Lower baseline liver fat content was associated with greater improvement in FMD (r=-0.60, p=0.008) in the NAFLD group. Carotid IMT and cerebrovascular parameters (e.g., pulsatility index, CVR, MCA blood flow velocity) remained unchanged in any groups. Changes in vascular function were not associated with the corresponding changes in liver fat content. Conclusion: The two-week dietary intervention involving either a low-carbohydrate or low-calorie diet elicited significant reductions in liver fat content and improvements in peripheral arterial stiffness and endothelium-dependent vasodilation in adults with NAFLD. UT Aging Initiatives. This is the full abstract presented at the American Physiology Summit 2024 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.
Little Brown Bats and White Nose Syndrome: Predicting Colony Outcomes from Cytokine Biomarkers
Authors: Gerber Belle , Klink Amy C , Hindle Allyson G , Richardson Christopher S 
Published: May 2024

White Nose syndrome (WNS) is the disease caused by a fungal pathogen, Pseudogymnoascus destructans ( Pd) that has been decimating 13 species of North American bat populations since 2006. Little brown bats, Myotis lucifugus, are severely threatened by this pathogen with population declines over ninety percent in some colonies after exposure to the fungus. Because immune function is suppressed during hibernation, this disease is able to ravage bats throughout the winter. Pathogen surveillance is an essential component of studying and managing WNS in North American bats. As part of a larger study on predicting how maternity colonies are recovering from WNS, we aim to validate and calibrate a suite of biomarkers to better understand the health of individual bats within colonies that are currently affected or recovering from Pd, which can help predict disease occurrence and prevalence. One set of biomarkers is the host individual’s inflammation responses, measured by mRNA expression of cytokines known to respond to Pd infection in Myotis ( IL-6, IL-17ɑ, IL-1). This study compares host cytokine expression across 8 colonies with varied exposure to the Pd pathogen from a non-invasively collected sample (guano, n=355 bats) and a minimally invasive biosample (wing biopsy, n=33 paired samples). Host mRNA isolated from guano represents a non-invasive but also indirect metric of host health, and cytokine mRNA could be detected in 353 of 369 samples from Myotis guano. Significant differences in the relative expression of IL-17a (F7,275=2.494, p=0.017) and IL-1B (F7,288=2.278, p=0.03), but not IL-6 (F7,293=1.166, p=0.322), were detected among colonies in the guano samples using one-way ANOVA. This comparison will help in the development of a non-invasive colony assessment tool using known disease state and fungal load to assess the likelihood of colony recovery. Funded by the US Fish and Wildlife Service. This is the full abstract presented at the American Physiology Summit 2024 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.
Knockout of DEPDC5, the gene associated with drug-resistant focal temporal epilepsy, causes abnormal Ca2+-waves in human iPS cell-induced neurons
Authors: Horiuchi Yuna , Inaba Haruka , Hando Tetsuya , Ai Tomohiko , Miida Takashi 
Published: May 2024

Genetic variants in the DEP domain containing 5 (DEPDC5) are one of the most common causes of inheritable drug-resistant temporal focal epilepsy. Epilepsies caused by DEPDC5 variants are often associated with brain malformations and sudden unexplained death in epilepsy (SUDEP). It has been reported that the DEPDC5 genes regulates cell growth via rapamycin complex 1 (mTORC1) pathways. Though several animal models showed knockout of the DEPDC5 causes epilepsy, the underlying mechanism(s) by which DEPDC5 variants cause neuronal excitations remains unelucidated in human cells. To examine whether knockout of DEPDC5 causes abnormal excitations in human iPS cell (iPSC)-induced neurons, DEPDC5 was knocked out using CRISPR-Cas9 gene editing methods. Expression of DEPDC5 peptides was confirmed by a mass spectroscopy. Then, the cells were differentiated into neurons by Dual Smad Inhibition. Spontaneous cellular excitation was evaluated by Ca2+-imaging (AquaCosmos/Ratio imaging system, Hamamatsu Photonics). DNA sequencing of the DEPDC5-knockout cells showed a truncated change, c.251_258delCTTTGGGG:(p.Gly15Glyfs*5), in one allele. The DEPDC5 peptides encoded by exon 7 were decreased to less than half in the DEPDC5-knockout cells compared to the wild type (WT) cells. Ca2+-imaging showed abnormal Ca2+ bursts in neurons derived from the DEPDC5-knockout cells, while the WT cells did not show any abnormal Ca2+ waves. These results indicate that haploinsuffciency of DEPDC5 can cause abnormal excitation in human iPSC-induced neurons. Currently, we are planning to further investigate cellular excitations in iPSC-induced cardiomyocytes to dissect underlying mechanisms of SUDEP. This work was supported in part by a Grant-in-Aid for Scientific Research (C) [grant number 18K08900 and 21K08135 (to T.A.)] and a Grant-in-Aid for Young Scientists [grant number 22K15694 (to Y.H.)] from the Japan Society for the Promotion of Science. This is the full abstract presented at the American Physiology Summit 2024 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.
Sarcoplasmic reticulum (SR)-mitochondria tethering is lost in human heart failure
Authors: Latchman Nadina , Margulies Ken , Prosser Ben , Elrod John 
Published: May 2024

Sarcoplasmic reticulum (SR)-mitochondria (SR-mito) tethering facilitates communication between these organelles and regulates many physiological processes critical for cardiomyocyte function. Recent evidence suggests that alterations in SR-mito tethering impacts cardiac metabolism and calcium handling which contributes to cardiovascular pathologies, such as heart failure (HF). To characterize SR-mito apposition in cardiac disease we obtained electron microscopy (EM) images of individual cardiomyocytes freshly isolated from failing hearts explanted from ischemic (ICM), ischemic-dilated (ICM-DCM) and dilated cardiomyopathy (DCM) patients undergoing transplantation and nonfailing control hearts. Topographical EM analysis revealed a significant increase in the mean SR-Mito distance, as well as an increase in the minimum SR-mito distance (closest approximation of any single mitochondrion to SR) in ICM, ICM-DCM and DCM cardiomyocytes, compared to nonfailing controls. Results from the EM analysis also revealed that in DCM there was a decrease in mean mitochondrion perimeter in contact with the SR, as well as a decrease in SR in approximation with mitochondria at a distance <50-nm. In agreement, nonfailing hearts had a greater length of outer mitochondrial membrane in close contact (<20-nM) with the SR, as compared to failing cardiomyocytes. ICM and DCM cardiomyocytes displayed an overall reduction in mitochondrion perimeter and circularity, suggesting smaller and more fragmented mitochondria. Surprisingly, failing cardiomyocytes exhibited an overall increase in mitochondrial area compared to nonfailing controls. To define the molecular changes that may underlie loss of SR-mito tethering, we evaluated the expression of several proposed linkers. qPCR analysis of left ventricular samples revealed that mRNA expression of mitofusin 2 is significantly decreased in both hypertrophic cardiomyopathy (HCM) and DCM. Further, other proposed tethering components including FUNDC1, BAP31, DJ-1 and VAPB demonstrated decreased mRNA expression in HCM, DCM and ischemic HF samples, compared to nonfailing controls. IP3R1 displayed increased mRNA expression in HCM and DCM human HF samples, whereas IP3R2 and VDAC1 displayed increases in expression in HCM and ICM. These results highlight that transcriptional remodeling of the components mediating SR-mito tethering and communication may contribute to the observed structural changes in inter-organelle approximation in cardiomyocytes. These studies provide rationale for causal interrogation of the structural mechanisms regulating SR-mito communication in the context of HF progression. Fellowship in Biomedical Sciences, Lewis Katz School of Medicine. This is the full abstract presented at the American Physiology Summit 2024 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.
Oxidative stress: A driving force in CKD induced heart failure
Authors: Sen Payel , Hamers Jules , Sittig Theresa , Zhang Hengliang , Zandbergen Lotte , Merkus Daphne 
Published: May 2024

Background: Several clinical investigations have shown that individuals with renal impairment are more likely to experience heart failure. Cardiac remodeling happens relatively early in the course of kidney injury, yet research into identification of common markers of cardiorenal signaling remains insuffcient. This may be because studies conducted in small animal models do not accurately reflect the complexity of the disease. To bridge the translational gap, we developed a swine model for chronic kidney disease (CKD) Aim: We employed proteome studies to clarify the pathophysiological impact of chronic kidney disease (CKD) on the heart and correlate to cardiac function and perfusion in order to offer mechanistic insights. Methods: We used microspheres to embolise both kidneys of swine at 10-12 weeks of age while sham operated swine served as controls. Post 6 months, we performed pressure volume loops to assess cardiac function, while coronary flow reserve (CFR) was measured by intracoronary infusion of adenosine in control and CKD. (LC-MS-MS based proteomic analyses of left ventricular tissue was performed. Paraffn embedded myocardium and kidney tissues were histologically examined for interstitial fibrosis and oxidative stress. Results: Renal embolization resulted in mild chronic kidney injury as evidenced by increased fibrosis staining and urinary NGAL (24±4 vs 48±9 pg/ml). Hemodynamic parameters showed increased wall stress (20±3 vs 40±7 ml*mmHg/g) as well as increase of end diastolic volume (1.5±0.1 vs 1.9±0.1 ml/kg) indicating dilation of the left ventricle in CKD. Quantitative proteomic analysis detected significant differences in the left ventricle of the controls when compared to those with CKD and STRING pre-ranked functional analysis showed enrichments in pathways related to reactive oxygen species. Furthermore, we detected alterations of pathways associated with remodeling of the extracellular matrix (ECM), Oxidative stress and ECM remodeling were confirmed histologically. Interestingly, in CKD we found that mitochondrial proteins like cytochrome oxidase (MT-CO2) and ATP5 synthase subunit were downregulated suggesting mitochondrial dysfunction which was associated with higher basal coronary blood flow (0.48±0.05 vs 0.87±0.11 ml/min/g). Conclusions: Our proteomic data in swine model provides strong evidence that mild CKD can induce early alterations in mitochondrial function along with oxidative stress and ECM remodeling. Thus, we aim to further our understanding by applying our proteomic findings in conjunction with functional hemodynamic data in this swine model of cardiorenal disease. German Center for Cardiovascular Research (DZHK81Z0600207 to D.M. and P.S.). This is the full abstract presented at the American Physiology Summit 2024 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.
Lumbar epidural electrical stimulation enhances respiration in mice
Authors: Huang Ruyi , Yamamoto Mark T , Zhou Yan , Jin Benita , Bao Yunrui , Masari Tamara , Zhao Yimeng 
Published: May 2024

Spinal cord epidural electrical stimulation (EES) has emerged as a novel approach to modulate and interrogate the neural circuit(s) underlying sensorimotor functions in the past few decades. Recent studies have revealed that cervical EES can regulate respiration in both human subjects and animal models. Furthermore, coupled cervical and lumbar stimulations significantly increased the rhythmic motor outputs in both the cervical and lumbar spinal cord. We hypothesize that the lumbar and cervical coupling is underpinned by cervico-lumbar synaptic connections, and thus, EES at level of the lumbar spinal cord alone may also facilitate respiration via the cervico-lumbar circuit. In this study, we applied EES to the dorsal surface of the lumbar spinal cord between levels 1 and 6 (L1-6) in anesthetized mice. We found that rostral lumbar (L1-2) EES at a stimulation intensity of 0.5 mA elicited significantly higher respiratory frequency, tidal volume, and minute ventilation responses compared to the other lumbar levels (L3-4 and L5-6) tested at intensities ranging from 0.1-1.0 mA. The increased respiratory activity elicited by lumbar stimulation persisted even after the stimulation ceased. Using the optimal stimulation parameters that we identified, we further investigated the underlying mechanism of the lumbar EES-induced respiratory response by examining the neuronal activation patterns. Using immunostaining, we detected c-fos signals, a marker of neuronal activity, in the cervical spinal cord and brainstem after EES at L1-2 using 0.5 mA at 30Hz. This indicates that focal lumbar stimulation elicits remote neuronal activation in cervical spinal cord and brainstem, regions that contain respiration-related neural circuits. These findings suggest that lumbar EES may facilitate respiration by recruiting paraspinal respiratory circuits and potentially supra-spinal respiratory central pattern generator(s). This study provides insights into the development of novel approaches to restore normal respiratory patterns for patients with respiratory disorders, particularly spinal cord injuries. This work was supported by The Louis and Harold Price Foundation, H & H Evergreen Foundation, Jonathan and Susan Dolgen Foundation, the National Institute of Drug Abuse (R01DA047637), and the National Institute of Neurological Disorders and Stroke (UH3NS119772) in the National Institutes of Health. This is the full abstract presented at the American Physiology Summit 2024 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.