bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vascular Signaling Plasticity Reprograms Blood Delivery Mechanisms to Meet Fluctuating Neuronal Energy Needs
Authors: Weir Nick , Xiang Liuriumin , Vigderman Abigail , Isaacs Dominic , Qadir Houman , Patton Michael , Mathur Brian 
Published: May 2024

Neuronal computation is metabolically expensive and depends on precision delivery of energy substrates—oxygen and glucose—via tightly coordinated blood flow to ensure that energy demands are continually met. This is facilitated by neurovascular coupling (NVC)—a range of mechanisms matching neural activity to local blood flow. These NVC mechanisms are typically considered invariant, and whether they are reshaped according to ever-changing neuronal metabolic needs has not been examined. We present evidence that neural activity continually reprograms the blood flow control mechanisms embedded in the local vasculature, a process we refer to as ‘vascular signaling plasticity’ (VSP). Using an established enrichment paradigm, we find that animals housed in conditions that increase input to the barrel cortex for 7 days exhibit profound neuronal plasticity in this region. This resculpts local vascular reactivity to elevate blood delivery. Indeed, VSP results in increased basal capillary blood flow and augmented activity of vasodilatory agents in vivo manifesting as increased red blood cell (RBC) flux responses to capillary stimulation and upstream diameter changes measured using 2-photon laser scanning microscopy. Moreover, the sensitivity of capillaries to stimulation is also dramatically elevated in an ex vivo isolated capillary-arteriole preparation. Using K+-mediated capillary-to-arteriole electrical signaling as a springboard to study the molecular underpinnings of VSP, we find that this process induces a ~70% increase in the density of strong inward rectifier K+ (Kir2.1) currents in capillary endothelial cells, which profoundly augments the retrograde hyperpolarization generated by these channels to control upstream diameter at the level of the penetrating arteriole. Through whole-cell patch clamp electrophysiology, we characterize the mechanism of VSP induction and recapitulate this phenomenon in vitro. We validate our findings through Crispr/Cas9-mediated endothelial cell-specific knockout of the transcription factor responsible for VSP induction. Our data thus recast the vasculature as a plastic, brain-wide activity sensing network that is continually reshaped at the molecular level by local neuronal input, leading to precisely-tuned blood delivery to meet continually fluctuating neural energy needs. VSP represents a new dimension to brain plasticity that may underpin a range of vital physiological processes and is likely disrupted in numerous brain pathologies with a blood flow component. This work was supported by the American Heart Association (23POST1023086), and NIH grants 1DP2NS121347, 1R01AG066645, and 5R01NS115401. 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.
Sex Is Not a Transcriptomic Binary: Towards a Broad Physiologic Omics Insight Into Sex Chromosome Genes
Authors: Das Akansha , Bhargava Disha , Prokop Jeremy 
Published: May 2024

Background: As social definitions of sex and gender expand, there is a greater demand for understanding the clinical challenges of intersex individuals, transgender individuals, and those with hormonal and transcriptomic profiles that do not align with traditional binary standards. Larger population studies are elucidating comorbidities associated with Klinefelter’s Syndrome, Turner’s Syndrome, 47XXX, 47XYY, and other sex chromosome syndromes even though the sex chromosomes are underpowered in traditional GWAS. Though research has focused on how estrogen and testosterone supplementation can influence comorbidity risk, we identify a need for greater understanding of isoform and tissue-specific expression and functions of X and Y genes to understand their potential interactions with hormones and inform physiological outcomes. Methods: Analysis of RNA-Sequencing data quantified in transcripts per million (TPM) from GTex (extracted June 2022, n = 17,382), NCBI SRA Blood PAXgene tube analysis (extracted June 2021, n = 12,559), and NCBI SRA “skin” RNA sequencing (extracted June 2021, n = 8,274). Results: We display an expression panel of 572 isoforms of 73 sex-biased genes across 54 male (n = 11,588) and female (n=5,798) tissue samples and highlight isoform-specific expression differences within the brain, arteries, heart, skeletal muscle, and gastrointestinal tract. Six X/Y gene pairs show broad ratios over tissues highlighting the role of X-chromosome dosage and X-chromosome inactivation escape differences in various tissues. Several genome-wide eQTLs across multiple tissues have sex differences and are found within X/Y chromosome transcription factor binding sites such as ZFX/ZFY. Stratifying blood and skin RNA-Sequencing data by XIST/KDM5D ratios to determine transcriptomic “sex”, we conduct an exploratory analysis of bioprojects with five or more outliers of X:Y chromosome expression ratios (Males: PRJNA683803 (HIV), PRJNA768419 (Sepsis), PRJNA492829 (Vaccine trial), PRJNA496323 (Psoriasis and atopic dermatitis), PRJNA699562 (COVID-19). Females: PRJNA683803 (HIV), PRJNA794277 (Sepsis), PRJNA492965 (Vaccine trial), PRJNA526259 (Myalgic encephalomyelitis)).Conclusion: Transcriptomics enables broader insights to sex chromosomes and their contributions to physiology outside of the binary male/female knowledge. This work was supported by the NIH NIAID and OD grant R01AI171984. 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.
Pathway analysis for functional characterization of microRNAs
Authors: Hatzigeorgiou Artemis , Skoufos Giorgos , Miliotis Marios 
Published: May 2024

DIANA-miRPath webserver enables the exploration of combined miRNA effects using predicted or experimentally supported miRNA interactions. Its latest version (DIANA-miRPath v4.0, http://www.microrna.gr/miRPathv4 ), introduces the capacity to tailor its target-based miRNA functional analysis engine towards specific biological/experimental contexts. Via a modular interface with rich interaction, annotation and parameterization options, users can perform enrichment analysis on Gene Ontology (GO) terms, KEGG and REACTOME pathways, gene sets from Molecular Signatures Database (MSigDB) and PFAM. Included miRNA interaction sets are derived from state-of-the-art resources of experimentally supported (DIANA-TarBase v8.0, miRTarBase and microCLIP cell-type-specific interactions) or from in silico miRNA-target interactions (DIANA-microT-2023 and TargetScan predictions). Bulk and single-cell expression datasets from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression project (GTEx), as well as single-cell expression atlases can be used to assess expression change of targeted genes within terms, across a wide range of states. A discrete module to perform miRNA-tailored CRISPR knock-out screen analyses deems possible the investigation of selected miRNAs within conditions under study. Hellenic Foundation for Research and Innovation (HFRI) under the 1 st Call for HFRI Research Projects to Support Faculty Members & Researchers and Procure High-Value Research Equipment grant (Project Number 2563). 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.
IL-6 Contributes to Impaired Nitric Oxide and Increased Mitochondrial ROS Production in Human Aortic Endothelial Cells
Authors: Velusamy Prema , Greaney Jody L. , Case Adam J. , Fadel Paul J. , Trott Daniel W. 
Published: May 2024

Background: Major Depressive disorder (MDD) is associated with chronic low-grade inflammation with elevated proinflammatory cytokines. Notably, elevated inflammation is a known contributor to cardiovascular dysfunction and disease. Interleukin (IL)-6 has been shown to be elevated in rodent models of depression. Additionally, preliminary data from our lab suggests that there is a greater proportion of IL-6 producing CD8+ T cells in adults with MDD. Although IL-6 has been reported to be increased in adults with MDD and known to have a direct effect on vascular endothelial cells, the exact mechanism by which IL-6 interacts with the endothelium is unknown. Therefore, we tested the hypothesis that IL-6 treatment will decrease nitric oxide (NO) production and increase mitochondrial ROS (mitoROS) in endothelial cells. Methods: Human aortic endothelial cells (HAECs) were used to study the effects of IL-6 on NO production. The HAECs were treated with vehicle or 10 ng/mL IL-6 for 16 hours, and then stimulated with Acetylcholine to induce NO production and the real time NO production was measured using a commercially available assay. We also measured mitoROS in HAECs treated with or without IL-6. Results are expressed as mean ± SEM (n=3-6 replicates) and group differences were assessed by one-way ANOVA followed by Tukey’s post-hoc test. Results: L-6 was found to significantly lower NO production in the cells (Control: 276.24 ± 7.01; IL-6: 215.19 ± 6.07 MFI, p=0.022). Acetylcholine stimulation resulted in greater NO production in the control cells (Control: 276.24 ± 7.01; Control + Ach: 354.28 ± 6.26 MFI, p=0.0005) whereas this increase was abolished in the IL-6 treated cells (IL-6: 215.19 ± 6.07; IL-6 + Ach: 225.21 ± 5.16 MFI, p=0.955). Additionally, we also found greater mitoROS in the IL-6 treated cells (Control: 683.02 ± 32.98; IL-6: 840.86 ± 38.63 MFI, p=0.002). Conclusion: These preliminary results suggest that IL-6 reduces NO production in endothelial cells, which may be in part due to elevated mitoROS. This work is supported by grants from NIH K01AG061271, R01AG060395 and AHA940023 (DWT). 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.
Links between systemic inflammation and the chemoreflex control of breathing following COVID-19
Authors: Penuelas Veronica , Pham Kathy , Frost Shyleen , Harahap-Carillo Indira , Vargas Abel , Bergersen Kristina V. , He Yuxin 
Published: May 2024

The emergence of SARS-CoV-2 resulted in millions of hospitalizations and 6.9 million deaths to-date. Many individuals who recover from COVID-19 report prolonged dyspnea, with this symptom persisting for months following recovery. Furthermore, data suggests COVID-19 has been linked to systemic and neuronal inflammation which may have downstream impacts on the neural control of breathing. As such, we hypothesized that individuals recovered from COVID-19 may exhibit changes in their ventilatory chemosensitivity to CO2 and/or O2 and that these changes may be linked to higher levels of systemic inflammation. To test this hypothesis, we measured baseline ventilatory patterns and chemoreflex sensitivity using a modified rebreathing technique in individuals recovered from COVID-19 (n = 77), as well as an age and sex-matched control group (n = 41). Peripheral blood samples were also collected for inflammatory profiling. Recovered participants demonstrated lower ventilatory responses to hypercapnia, particularly under a combined hypoxic stimulus (p = 0.032). Furthermore, higher levels of plasma IL-1β and IL-6 were associated with lower hypoxic ventilatory responses (R2 = -0.53, p = 0.025; R2 = -0.49, p = 0.04), highlighting a potential link between systemic inflammation and ventilatory chemoreflex sensitivity. When separated by time-post-recovery, we observed a decreased ventilatory recruitment threshold (VRT) beginning at 4 months post-recovery (p = 0.019) that returned to baseline after one-year post-recovery. A decrease in sensitivity to CO2 was also noted immediately after recovery with no return to baseline observed within the two-year tested time frame (p = 0.023). Overall, this data indicates that (1) COVID-19 may have impacts on the neural control of breathing, and (2) systemic inflammation may play a role in modulating ventilatory chemoreflex sensitivity. These findings may have implications for the pathology of long-COVID symptoms, including sleep disturbance and prolonged dyspnea. This work was funded by the Health Disparities Research Center and the OASIS center at University of California, Riverside. 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.
A Role for the Gastrointestinal Tract in Sodium Dysregulation Associated with the Salt Sensitive Phenotype in the Dahl S Rat
Authors: Otmanowski Emily , Keith Caullin , Bearss Nicole , Joe Bina , Reznikov Leah , Zubcevic Jasenka 
Published: May 2024

Introduction: Salt sensitive hypertension in the Dahl S rat (SS) has traditionally been attributed to elevated renal sodium reabsorption, largely mediated by the renal epithelial sodium channel (ENaC). Considering the role of ENaC in the distal colon epithelium in sodium absorption in the gastrointestinal tract, we hypothesized that the salt sensitive phenotype of SS rats may in part be attributable to increased absorption of sodium in the distal colon. Methods: Adult male SS and its control, the SR rats (12-14wo), were administered either low sodium diet (LS; 0.3% NaCl, Teklad) or moderately high sodium diet (HS; 2.0% NaCl, Teklad) ad libitum for two weeks. At endpoint, fecal samples were collected, dried for 72 hours at 70°C, weighed, and homogenized in deionized water. Fecal levels of sodium per gram of dry fecal weight were measured using flame photometry. Segments of distal colon wall were dissected and mounted in the Ussing chamber filled with warm, oxygenated Kreb’s solution containing D-glucose. Amiloride hydrochloride, a selective ENaC inhibitor, was applied to the tissue apical side in increasing concentrations (0-100μM) at 10-minute intervals. Total ionic currents (Isc, A) were measured under voltage clamp and presented as change from baseline. Results: We observed significantly lower fecal sodium levels in the SS compared to SR rats on LS diet (p<0.05), and a similar trend in fecal sodium levels between the SS and SR on HS diet (P=0.1). This was associated with significantly elevated amiloride-sensitive current in the distal colon of SS compared to the SR on LS and HS diets (p<0.01 and p<0.0001, respectively). Conclusion: Elevated amiloride-sensitive sodium current in the distal colon of SS rats is associated with decreased fecal sodium levels. This suggests increased sodium absorption in the SS rats and proposes a role for the gastrointestinal tract in sodium dysregulation associated with the salt sensitive phenotype in Dahl S rats. 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.
Effects of CBD on the Phosphorylation of Cardiac Insulin Receptor in Rat Model of Metabolic Syndrome
Authors: Zapet Bamac Daisy , Wilson Jessica , Mendez Dora A. , Ortiz Rudy M. 
Published: May 2024

Metabolic syndrome (MetS) comprises a cluster of conditions that include obesity, insulin resistance, dyslipidemia, hypertension, pro-inflammation, and pro-thrombosis. In the United States, approximately one in three adults is afflicted with MetS. If left unmanaged, it can lead to type 2 diabetes (T2D), which would increase the risk of cardiovascular diseases (CVD). The insulin signaling pathway is critical to regulate glucose homeostasis in the body. During insulin resistance, the pathway is downregulated, and glucose remains in the bloodstream leading to a hyperglycemic state. Recent studies on the benefits of cannabidiol (CBD) have shown it can mitigate CVD risk factors, but its impact on glucose metabolism within the heart remains unclear. To investigate this, the Otsuka Long Evans Tokushima Fatty (OLETF) rat, a model of MetS, and its healthy strain-control, the Long Evans Tokushima Otsuka (LETO) rat, were used. Rats were assigned to three groups (n=8/group): (1) untreated LETO, (2) untreated OLETF, and (3) OLETF + H4CBD (200mg/kg/day x 4 weeks). CBD treatment did not impact the nascent insulin receptor nor the nascent protein kinase B, but the effects of CBD on the phosphorylation and activation of these insulin signaling components have yet to be determined (analyses ongoing). Because CBD has been shown to improve glucose homeostasis previously, we anticipate it is by increasing the activation by phosphorylation of the insulin receptor. A better examination of the effects of CBD on the insulin signaling pathway in the heart will provide greater insight on its therapeutic potential during diabetic cardiomyopathy. USDA Hispanic Education Training Program, Center for Medical Cannabis Research. 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.
Assessments from the first year of an underrepresented undergraduate internship program
Authors: Barnett Vincent , Wu Steven , Anderson Lisa 
Published: May 2024

To enhance our service to a diverse student population our faculty created the INtegrative biology and Physiology Undergraduate Training (INPUT) program. This research focused initiative solicited applications from first- and second-year students undergraduates of our large, urban, land-grant university. Selection criteria included academic aptitude, self-reported socioeconomic and cultural challenges, interest in physiological research and letters of support. Six students were selected from our initial cadre of applicants. The students were matched with faculty research mentors and provided a paid research opportunity for the spring semester of 2023. At the end of the term, an assessment of the experience by both each student and mentor determined whether a second semester experience was offered by the department. All of our faculty mentors were favorably impressed by the progress made by their INPUT scholars and five of the six students requested and were granted a second semester research opportunity. The five INPUT students continued their mentored research in the areas of neurophysiology, skeletal muscle physiology, and adipose biology. The one outlier stated that while she enjoyed the experience and that it encouraged her to continue in research. She also found that her scientific passion was in chemistry rather than physiology and moved to a different program. Based on the overall positive outcomes a second semester opportunity was offered to the five students who expressed an interest in continuing their physiology-focused projects. The second term experiences were completed either during the summer or fall of 2023. We will encourage our initial group of INPUT scholars to serve as ambassadors for other underrepresented students who are interested in physiology research and use their end of experience assessments to help shape the future of our INPUT program. We will report on the opportunities discovered and the challenges faced in launching the INPUT program as well as the prospects for continued outreach. Our hope is that our experiences with INPUT will encourage others to attract, encourage and prepare a robust and representative group of young scientists and clinicians to enter the 21st century biomedical community. Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN 55455. 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.
Mitigating Female Aging Kidney Damage from Ischemic Reperfusion Injury Using Renal Progenitor Cells
Authors: Parker Alexander , Pushpakumar Santhnur B , Sen Utpal 
Published: May 2024

Acute kidney injury (AKI) is a sudden event that damages the kidney and disrupts normal function by various causes, such as ischemia, exposure to substances, or obstructions. With AKIs affecting 1 out of 5 hospitalized patients and their association with increased risk of chronic kidney disease (CKD), finding an effective treatment for AKIs is of vital importance. One possible treatment for AKIs could be found within the realm of progenitor cell therapy. Progenitor cells are currently used in the treatment of hematological diseases with the burgeoning information on their possible uses for other disorders. The purpose of this study was to determine whether there is a resident population of renal progenitor cells (RPCs) within the kidney and if these cells can be utilized as an effective treatment to mitigate aging AKI by decreasing inflammation through alteration of the M1:M2 macrophage ratio. This study utilized 75-78 weeks old C57BL/6J female mice to determine if RPCs can reduce the damage caused by ischemic reperfusion (IR)-induced AKI. Kidneys were harvested from young female (40 days old) mice and digested in collagenase type 1 to remove connective tissue. Cells were sorted by flow cytometry, positively selected for c-Kit using magnetic nanoparticles, and subsequently stained for Sca1 and Oct4. Aging female mice underwent renal IR injury (IRI) by clamping off the renal artery and vein for 27 minutes. Following reperfusion, the triple-positive cells were suspended in DMEM and injected into the kidney over the course of 8 minutes to reduce the possibility of pressure necrosis. A separate group of mice was injected with saline to serve as control. The mice were monitored for 3 days at which point kidney function was assessed and tissue harvested for biochemical analysis. Our results indicated an increase in inflammatory cytokines IL-17, NF-κB, and IL-6 in IRI mice which were mitigated with RPCs treatment along with an increase in anti-inflammatory marker IL-10. Furthermore, an increase in M1 macrophage markers was measured in IRI, and a trending increase in M2 macrophage markers in IRI animals treated with RPCs. The kidney function of IRI animals treated with RPC showed improvement compared to IRI control. In summary, we found a population of cells positive for three progenitor cell markers: c-Kit, Sca1, Oct4, and treating IRI aging female kidney with these cells reduced inflammatory markers along with an increase in kidney function, suggesting RPCs promote recovery from AKI by reducing inflammation. Grant Support: DK116591. 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.