bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interactions Between Carotid Arterial Stiffness, Amplitude of Cerebral Blood Flow Oscillations, and Cerebral Tissue Oxygenation During Simulated Hemorrhage in Humans
Authors: Hudson Lindsey , Davis K. Austin , Anderson Garen , Rosenberg Alexander , McKeefer Haley , Bird Jordan , Pentz Brandon 
Published: May 2024

Introduction: Inducing 0.1 Hz (10-s cycle) oscillations in cerebral blood flow attenuates the reduction in cerebral tissue oxygenation during simulated hemorrhage in humans. It is unknown, however, how stiffness of the cerebral feed arteries influences the magnitude of cerebral blood flow oscillations, and/or the protection of cerebral tissue oxygenation. When 0.1 Hz oscillations are induced during simulated hemorrhage, we hypothesize that: 1) arterial stiffness of the internal carotid artery (ICA) will increase from rest; 2) the amplitude of 0.1 Hz oscillations in cerebral blood flow will be higher in individuals with stiffer arteries, and; 3) the reduction in cerebral tissue oxygenation will be smaller with higher amplitude of cerebral blood flow oscillations. Methods: 8 healthy human participants (age: 30.1±7.6 y) underwent a 10-min hypovolemic oscillatory lower body negative pressure (OLBNP) protocol, where chamber pressure oscillated every 5-s between -30 mmHg and -90 mmHg (i.e., 0.1 Hz). ICA beta stiffness index was calculated from measurements of ICA diameter (via ultrasound imaging), and arterial pressure (via finger photoplethysmography). Middle cerebral artery velocity (MCAv) was measured using transcranial doppler ultrasound, and cerebral tissue oxygenation (ScO2) was measured with near infrared spectroscopy. Fast Fourier transformation was used to quantify oscillations in mean MCAv at ~0.1 Hz. Results: While Mean MCAv 0.1 Hz oscillations increased from baseline to OLBNP (N=8, 34.0±33.9 (cm/s)2 vs. 104.7±58.1 (cm/s)2, p=0.01), ICA beta stiffness did not increase (N=5, 6.1±0.7 au vs. 8.2±2.7 au, p=0.21). There was no relationship between baseline ICA beta stiffness and the percent change in mean MCAv 0.1 Hz oscillations (N=5; r=0.44, p=0.46). ScO2 decreased from baseline to OLBNP (N=8, 66.5±2.9 % vs. 64.8±2.9 %, p=0.03), but there was also no relationship between the percent change in mean MCAv 0.1 Hz oscillations and the decrease in ScO2 (r=0.28, p=0.50). Conclusions: Based on these data, 0.1 Hz OLBNP does not affect ICA stiffness, and there is no relationship between ICA stiffness, amplitude of induced 0.1 Hz cerebral blood flow oscillations, and the reduction in cerebral tissue oxygenation during simulated hemorrhage. However, as this analysis was performed retrospectively, and arterial stiffness was not initially an outcome measure, there was limited data available for analysis. This limitation will be addressed in a project currently in progress in our laboratory. American Heart Association Grant in Aid. 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.
Phosphatidylserine supplementation as a potential strategy to improve endothelial function in type 2 diabetes
Authors: Augenreich Marc , Ramirez-Perez Francisco I. , Imkaew Natnicha , Ferreira-Santos Larissa , Power Gavin , Martinez-Lemus Luis A. , Padilla Jaume 
Published: May 2024

Endothelial dysfunction represents a causal factor in the pathogenesis of cardiovascular disease associated with type 2 diabetes (T2D), including hypertension. Previous work has revealed that endothelial mechanosensing structures are degraded in T2D, resulting in impaired shear stress mechanotransduction and decreased flow-mediated dilation (FMD). One well-known mechanosensor that is susceptible to cleavage is glypican-1, a prominent proteoglycan member of the endothelial glycocalyx. In this regard, recent evidence from a proteomic analysis suggests that glypican-1 is a substrate of the proinflammatory enzyme ADAM17 (a disintegrin and metalloproteinase-17), which is elevated in the vasculature of T2D. Recent work has revealed that exogenous phosphatidylserine (PS) inhibits in vitro ADAM17 sheddase activity, which may aid in retaining the membrane-bound glypican-1. Therefore, we hypothesized that oral administration of PS in diabetic mice (db/db) would enhance shear stress mechanotransduction, as assessed by FMD, and that this would be accompanied by greater presence of glypican-1 on the endothelial surface. We further hypothesized that PS would reduce blood pressure. We tested this hypothesis in ~10-week-old db/db male mice that were randomized to receive a daily peanut butter pellet as vehicle control or the pellet mixed with soy-derived PS (200 mg/kg/day) for 28 days. A third group of untreated age-matched wild-type C57BL/6J male mice served as healthy controls. Excised mesenteric arteries were used for assessment of FMD using pressure myography, while femoral arteries were used for determining presence of glypican-1 content on the endothelial surface using confocal microscopy. Blood pressure was assessed using the tail-cuff method. All reported differences are significant at p<0.05. Compared with wild-types, untreated db/db mice had impaired FMD, reduced presence of endothelial glypican-1, and increased blood pressure. Notably, these effects were not observed in db/db mice treated with PS. These findings suggest that oral PS may be effective at improving indices of endothelial dysfunction in T2D, an effect likely mediated by the retention of endothelial mechanosensor glypican-1 via reduced ADAM17 sheddase activity. No support to disclose. 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.
HSP47 complements cholesterol synthesis-independent HMGCoA-reductase pathway-mediated fibroblast bioenergetics
Authors: Salem Salsabeel , Benjamin Ivor , Ross Gracious , Vodanovic-Jankovic Sanja 
Published: May 2024

Fibrosis, characterized by excessive extracellular matrix (ECM) components deposition, is a common pathological process underlying numerous chronic diseases. Differentiating fibroblasts into myofibroblasts leads to the deposition of fibrous proteins like collagen in the ECM. Heat shock protein 47 (HSP47) is a molecular chaperone protein that assists in the folding of collagen. Recent studies show that inhibition of cholesterol synthesis-independent HMGCoA-reductase pathway enzyme geranylgeranyl pyrophosphate synthase 1 (GGPS1) decreases fibroblast differentiation and its bioenergetics. However, the role of HSP47 in this pathway is unknown, although recent observations show that HSP47 is decreased when GGPS1 is inhibited. Hence, we tested the hypothesis that HSP47 promotes cellular respiration in myofibroblasts. Seahorse assays were performed on different fibroblasts/myofibroblasts repeatedly and the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were measured in the presence and absence of HSP47 inhibitor (HY124817). Complex V of the electron transport chain was measured by immunoblotting ATP-5A. HY124817 tends to decrease the OCR, basal respiration rate, ATP-linked, and spare respiratory capacity. Co-incubation with HY124817 and digeranyl bisphosphonate (DGBP), an inhibitor of GGPS1, significantly (P = 0.043) inhibited further the ATP-linked OCR compared to the TGF group. Immunoblotting showed that Complex V did not change significantly across treatments. These results suggest that HSP47 is involved in fibroblast bioenergetics related to ATP-linked OCR in both differentiated myofibroblasts and normal fibroblasts. Inhibition of HSP47 complements the decrease in myofibroblast cellular respiration caused by the GGPS1 inhibition. This finding is novel in that HSP47 plays a role in fibroblast bioenergetics regulated by the cholesterol synthesis-independent HMGCoA-reductase pathway. Further research is necessary to identify what HSP47 targets and regulatory elements involved in this process. This would provide more insight into the mechanisms that underlie critical fibrosis conditions like myocardial fibrosis and potential therapeutics. This experience was supported by the Medical College of Wisconsin's Advancing Student Potential for Inclusion with Research Experiences (ASPIRE) program. The program is funded by a federal grant from the National Heart, Lung, and Blood Institute. 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.
Normobaric Hyperoxia Treatment after Mid-cervical Contusion Injury in Rats
Authors: Deegan Kyle M. , Rana Sabhya , Martinez Robert , gonzalez Isabelle , Thakre Prajwal , Fuller David 
Published: May 2024

Severe hypoxia at or near the site of spinal cord injury (SCI) contributes to necrosis and secondary tissue damage. Prior studies of O2 therapy after SCI have primarily used pressurized hyperoxic exposure ( i.e., hyperbaric oxygen). We tested the hypothesis that daily exposure to 100% O2, delivered at atmospheric pressure ( i.e., normobaric hyperoxia) could accelerate the recovery of inspiratory tidal volume after cervical SCI. Three groups of adult male Sprague Dawley rats received a 150 kdyn impact right lateral C4 cervical SCI. In group 1, normobaric hyperoxia (100% O2 at 1 atmosphere pressure, 2 hours) was initiated within 20 min of SCI and continued daily for 7 days. In group 2, the same normobaric hyperoxia paradigm was initiated on day 8 post-injury and continued until day 14. A third group received a sham treatment, consisting of exposure to normobaric normoxia (21% O2, 1 ATA) daily for 14 days. Whole-body plethysmography was used to examine breathing patterns before-, 1-, and 2-weeks post-SCI. All three groups lost and then gained body mass at similar rates over days 1-14 post-SCI. Mortality rates during the first week after SCI were 23% (5/22) in rats not exposed to hyperoxia, and 10% (1/10) in the daily hyperoxia group. Tidal volume (VT) and breathing rate were compared using 2-way repeated measures ANOVA. The breathing rate (br/min) was similar between groups at 1-week post-injury. We observed a trend (p=0.182) for reduced breathing rate at the 2-week time point in the week-1 hyperoxia group (69±18) compared to the week-2 hyperoxia group (89±21) and the normoxia group (83±17). Inspiratory VT (mL/breath) was elevated in the week-1 hyperoxia group (0.59±0.08) as compared to the week-2 hyperoxia (0.44±0.05) and normoxia groups (0.44±0.06) at 1-week post-SCI (p=0.002). When VT was normalized to body weight (mL/breath/kg) the same effect of O2 exposure was observed (p=0.001). The effect was transient, however, and at day 14 post-SCI VT was similar across the three experimental groups (p>0.50). We conclude that normobaric hyperoxia treatment during the first week after cervical SCI alters the pattern of breathing, and may have benefit to recovery. R01HL153140-04. 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.
Divergent Effects of IL-18- and IL-18R-deficiency on Angiotensin II-induced Abdominal Aortic Aneurysm Formation
Authors: Sherriff Ashleigh-Georgia , Dinh Quynh Nhu , Thomas Jordyn , Figueiredo Galvao Hericka , Imyage Dona Malathi , Wickramasinghe Buddhila , Diep Henry 
Published: May 2024

Currently, there are no pharmacological treatments for abdominal aortic aneurysms (AAA), and AAA rupture is fatal in ~90% of patients. Aortic inflammation is strongly correlated with the expansion of AAA and recently the NLRP3 inflammasome has been implicated in thedevelopment of AAA. Interleukin (IL)-18, an inflammasome-derived cytokine, exerts pro-inflammatory responses when bound to its cognate IL-18 receptor (IL-18Rα). The current project aimed to determine the effect of IL-18- and IL-18Rα-deficiency on the incidence of angiotensin (Ang) II-induced AAA. Ten-week-old male C57BL/6 (WT), IL-18-deficient ( Il18−/−) and IL-18Rα-deficient ( Il18r1−/−) mice were infused with Ang II (1.44 mg/kg/day, s.c.) for 28 days via osmotic minipump. Ang II-induced AAA incidence differed in all strains. While 52% of WT mice developed AAA (including premature deaths due to rupture), no AAAs were detected in Il18−/− mice (p<0.05, n=20-23). Strikingly, Il18r1−/− mice exhibited a higher incidence of AAA and associated mortality compared to WT mice(88%; p<0.05, n=23-25). Consistent with this finding, in vivo ultrasound imaging confirmed advanced dilation of the abdominal aorta at d7 after Ang II-treatment in Il18r1−/− mice cf. WT mice (1.49 ± 0.13 vs 1.15 ± 0.05 mm; p<0.05; n=23-25). Single cell RNA-sequencing of Ang II-infused mouse aorta revealed Il18r1 gene expression was limited to gamma-delta T cells, suggesting these cells may be driving IL-18 mediated AAA formation. In summary, IL-18-deficiency affords protection from AAA formation, while AAA incidence and severity were augmented in Il18r1−/− mice. Neutralisation of IL-18, but not IL-18Rα inhibition, may represent a novel therapeutic strategy to treat AAA. NHMRC (GNT1143674). 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.
Coordinated Regulation of Myonuclear DNA Methylation, mRNA, and miRNA Levels Associates with Mitochondrial Function During an Acute Skeletal Muscle Growth Stimulus
Authors: Ismaeel Ahmed , Thomas Nicholas , Wen Yuan , von Walden Ferdinand , Murach Kevin 
Published: May 2024

The central dogma of molecular biology dictates the general flow of molecular information from DNA that leads to a functional cellular outcome. In skeletal muscle fibers, the extent to which global myonuclear transcriptional alterations, accounting for epigenetic and post-transcriptional influences, contribute to an adaptive stress response is not clearly defined. In this investigation, we leveraged an integrated analysis of the myonucleus-specific DNA methylome and transcriptome, as well as myonuclear small RNA profiling to molecularly define the early phase of skeletal muscle fiber hypertrophy. The analysis of myonucleus-specific mature miRNA and other small RNA species provides new directions for exploring muscle adaptation and complemented the methylation and transcriptional information. Our multi-omics interrogation revealed a coordinated myonuclear molecular landscape during muscle loading that coincides with an acute and rapid reduction of oxidative metabolism. This response may favor a biosynthesis-oriented metabolic program that supports rapid hypertrophic growth. Y.W. was supported by the National Institutes of Health (K99 AR081367) K.A.M. was supported by the National Institutes of Health (R00 AG063994 and R01 AG080047). F.v.W. was supported by the Swedish research council (2022-01392), AFM-Telethon (23137), SMDF, Åke Wiberg, Swedish Medical Association, and the Swedish Research Council for Sport Science (2022/10). 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.
Focal adhesion kinase (FAK) inhibition induces aquaporin 2 (AQP2) plasma membrane accumulation in renal epithelial cells by remodeling the actin cytoskeleton
Authors: Tchakal-Mesbahi Asma , He Jinzhao , Zhu Shuai , Yu Kevin , Huang Ming , Huang Huihui , Bouley Richard 
Published: May 2024

The actin cytoskeleton is involved in the cellular traffcking of the AQP2 water channel in kidney collecting duct (CD) principal cells (PC): this plays an important role in water homeostasis. Focal adhesion kinase (FAK) is known to modulate the actin cytoskeleton through small GTPase-mediated pathways and we, therefore, investigated the potential role of FAK in AQP2 traffcking. We and others have previously shown that AQP2 constitutively traffcs and recycles independently of vasopressin (VP) and that this involves actin depolymerization/polymerization; therefore, FAK could regulate AQP2 traffcking through actin remodeling, bypassing the VP-V2R (cAMP/PKA) signaling pathway. To examine this, we used small molecule FAK inhibitors, VS-4718, GSK2256098 (GSK), or Defactinib-Hydrochloride (DH). We used immunofluorescence staining, a transferrin endocytosis assay ± cold block treatment, a fluorometric exocytosis assay using cells expressing secreted yellow fluorescent protein (ssYFP), a RhoA activity assay, and western blotting. Inhibiting FAK with 1mM VS-4718 for 30 min increased AQP2 membrane accumulation in LLCPK1 and IMCD kidney epithelial cells expressing AQP2. VS-4718 resulted in reduced clathrin-mediated endocytosis, as well as increased vesicle exocytosis, both mechanisms contributing to increased AQP2 membrane accumulation. This effect of FAK inhibition was independent of vasopressin/cAMP signaling and did not require phosphorylation of the Serine 256 residue of AQP2, since AQP2 membrane accumulation also occurred in cells expressing the constitutive dephosphorylation AQP2 S256A mutant. The FAK inhibitor VS-4718 promoted actin depolymerization (phalloidin staining assay) which would facilitate AQP2 vesicle exocytosis into the plasma membrane. We then examined the activity of the small GTPase, RhoA, whose activity increases actin polymerization and vesicle traffcking in the exocytic and endocytic pathways. We found that FAK inhibition by VS-4718 downregulated RhoA activity using GST-RBD, a substrate that binds to active RhoA, as seen by western blotting using phospho-specific antibodies. Similar results were obtained with GSK and DH. In summary, our study revealed that the interaction between FAK and cytoskeletal architecture plays a crucial role in regulating AQP2 recycling and its subsequent entry into the endocytic pathway. Thus, targeting FAK could be a potential therapeutic strategy for water balance disorders involving defective AQP2 reabsorption, such as nephrogenic diabetes insipidus. This work was supported by NIDDK R01DK096015 (JHL) and DK096586 (DB). 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.
Targeting Cardiomyocytes with Adeno Associated Viruses to Protect Hearts from Trastuzumab-induced Cardiotoxicity
Authors: Reichelt Melissa , Ho Uda , Bunt Kelsey , Watson Sophie , Patel Kinjal , Bradford Julia , Thomas Walter G 
Published: May 2024

Amplification of HER2 occurs in 20% of breast cancers. HER2 (known as ErbB2 in mouse) belongs to the Epidermal Growth Factor Receptor (EGFR) family that is responsible for cell growth and survival. While HER2 does not bind ligands, it forms heterodimers with HER1 (also known as EGFR) in the presence of its ligand EGF, and HER4 following stimulation with Neuregulin. In HER2-positive breast cancer where HER2 expression is high, HER2 homodimerizes leading to excessive activation of downstream signalling and cell proliferation. Current HER2-positive breast cancer treatment involves chemotherapy with drugs called anthracyclines, such as Doxorubicin, and an antibody targeting HER2 called Trastuzumab. This combination is effective in killing HER2-positive breast tumours, however, Trastuzumab alone or in combination with anthracyclines leads to severe cardiotoxicity and heart failure in 2.6-11% of cases, making it a dose-limiting side effect. We hypothesise that cardiac toxicity can be mitigated by targeting cardiomyocytes exclusively to express a mutated (but functional) version of HER2 that is not recognised by trastuzumab. We designed 3 HER2 variants wherein the trastuzumab binding domain was mutated to disrupt binding. These HER2 mutants were transfected into HEK293T cells, and we confirmed that all 3 successfully localised to the cell membrane, and did not bind trastuzumab. We have used bioluminescence resonance energy transfer to examine the capacity of all 3 mutants to activate recruitment of Grb2 to the HER2 as part of HER1/HER2 and HER4/HER2 heterodimers; Western blotting also confirming mutants were capable of stimulating ERK and Akt phosphorylation. Future studies will evaluate the effcacy of using AAVs to instruct cardiomyocytes to express these HER2 mutants in a murine model of breast cancer. We predict that this new therapy would not only mitigate cardiac toxicity, but would also permit higher doses of trastuzumab to be used to treat breast cancer. This work is supported by Australia's National Health and Medical Research Council and the Australian Research Council. 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.
Exploring the Impact of Fibroblast Growth Factor 17 on Functional Recovery and Neuroinflammation in Spinal Cord Injury
Authors: Devine Caroline , Sunshine Michael , Alilain Warren 
Published: May 2024

Spinal cord injury (SCI) affects more than 300,000 people in the United States, making it a significant and widespread problem. This includes injuries at the cervical level, which pose greater challenges due to respiratory in addition to mobility issues. Though there is a large societal impact there is still standard of care following spinal cord injury. While previous preclinical research has shown benefits from FGF1 and FGF2, there is weak data to suggest their clinical effcacy. A related compound, Fibroblast Growth Factor 17 (FGF17), has recently been described as a component within the CSF of young animals that when delivered to aged animals improved cognitive function. These improvements were associated with oligodendrogenesis. Spinal cord injury results in secondary demyelination, which may be mitigated by increasing oligodendrogenesis; this led us to examine how FGF17 may be used as a therapeutic agent following SCI. We used a rat C2 hemisection injury model to evaluate the effects of FGF17 at 4 hours, 2 and 6 weeks after injury. FGF17 was administered via intrathecal infusion at 25 μg/μl for 14 days at 0.5 μL/hour or a single application of 20 μL (4-hour timepoint). Following treatment, whole body plethysmography was performed weekly. Tissues were collected at endpoint to assess brainstem neuroinflammation via immunohistochemistry and molecular signaling pathways via western blotting. As anticipated, animals that were not treated with FGF17 had reduced tidal volume following spinal cord injury. Treatment with FGF17 partially preserved tidal volume as early as 3 days post injury. 6 weeks following spinal cord injury we observed a reduction in GFAP+ and IBA1+ staining in the brainstem near regions associated with respiratory control in animals treated with FGF17. Further, when we quantified the protein content in the spinal cord near the lesion epicenter we saw an increase in p-ERK 1/2 in all injured animals. However, in FGF17 treated animals we saw an increase in downstream transcription factors, STAT6 and Serum Response Factor. Serum Response Factor was implicated in oligodendrogenesis, ongoing studies will directly address this. These data suggest that FGF17 may be a viable alternative to the traditional fibroblast growth factor family members when treating spinal cord injury. R21NS121966, R01NS116068. 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.