bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of Claudin-3 Impairs Intestinal Barrier Function and Gut Microbiota to Promote Colitis
Authors: Singh Amar , Ahmad Rizwan , Thapa Ishwor , Kumar Balawant , Bastola Dhundy , Dhawan Punita 
Published: May 2023

Objective: Inflammatory Bowel Disease (IBD) is multifactorial autoimmune disorder where dysregulation of the gut barrier and gut microbiota (Dysbiosis) play critical role in disease onset and progression. A leaky gut often coexists with the dysbiotic gut microbiota, however a pathobiological integration is not well understood. Intestinal claudin-3 expression is robust, and we have reported that its loss promotes gut permeability and colon cancer. Increased gut permeability and colon cancer risk characterize Inflammatory Bowel Disease (IBD). The current study was undertaken to delineate the status and role of claudin-3 expression in IBD. Methods: Multiple murine models of colitis and IBD patient biopsy were used. Claudin-3KO mice were used to determine causal role. Multiplex ELISA, RNAseq and 16S DNA sequencing helped determine inflammatory cytokines, transcriptomic changes, and gut microbiota diversity, respectively. Fecal microbiota transplantation (FMT) and antibiotic treatment studies were done to test the role of claudin-3/gut dysbiosis axis in promoting IBD. Results: A significant decrease in claudin-3 expression was observed in IBD patient samples or the colon of mice subjected to DSS- (2.5% w/v) or C. rodentium-colitis (5 x108 CFU/oral). colitis (p<0.001). To test the causal role, claudin-3KO mice were subjected to DSS-colitis (acute and chronic), and infectious colitis. A significant change in the body weight, colon thickness, and mucosal injury score (p<0.001) characterized the colitis challenged claudin-3KO versus WT mice. P-Stat3 expression was highly upregulated in colitis challenged claudin-3KO mice. Interestingly, administration of an antibiotic cocktail rescued the colitis severity in claudin-3KO mice. The 16s metagenomics further revealed that the gut microbiota of claudin-3KO mice is diverse and clustered distinctly from the WT mice. To determine if gut dysbiosis in claudin-3KO mice promotes susceptibility to colitis, we performed FMT from naïve Claudin-3KO mice to germ-free WT mice. When subjected to DSS-colitis, germ-free mice transplanted with Claudin3-KO gut microbiota showed significantly higher colitis severity versus WT (p<0.05). Conclusion: We summarize that the loss of colonic Cldn3 deregulates mucosal barrier integrity to induce gut dysbiosis and susceptibility to IBD. We propose that claudin-3 can be a novel therapeutic target in strengthening the gut barrier integrity to diminish IBD susceptibility. National Institute of Health, Veterans Administration 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.
Insight on the loading-mediated regulation of Runx1 in skeletal muscle
Authors: Koopmans Pieter , Jones Ronald , von Walden Ferdinand , Vechetti Ivan , Murach Kevin 
Published: May 2023

Skeletal muscle adaptation during conditions of dynamic muscle loading such as resistance-type exercise occurs in conjunction with pronounced changes in gene expression. The objective of this study was to comprehensively evaluate gene expression at the onset of rapid muscle hypertrophy in mice. We analyzed the global, nascent, stable, and myonuclear transcriptome utilizing RNA-sequencing. C57BL6/J mice were treated with 5-ethenyl uridine at the end of 72 hours of synergist ablation mechanical overload of the plantaris muscle to assess transcriptional dynamics; sham mice served as controls. Mice with in vivo fluorescent myonuclear labeling were used to obtain RNA-sequencing in exclusively myonuclei from overloaded and sham mice. In these analyses, RUNX family transcription factor 1 ( Runx1, or Aml1) was significantly elevated in all conditions (adj. p<0.05x10-15) and was among the most induced genes across datasets. These findings allude to Runx1 as a highly regulated mediator of muscle hypertrophy that is enriched specifically in muscle fibers during loading. Myonucleus-specific global DNA methylome analysis also report exon and intron CpG hypomethylation in the Runx1 gene after overload. As gene body methylation can mediate alternative splicing, we subsequently hypothesized Runx1 may be subject to alternative splicing and conducted preliminary analyses of RNA splice isoforms present after acute overload. We found that a non-canonical isoform of Runx1 ( Runx1-202, coding for a 387 amino acid protein) was relatively more induced than the Runx1-201 transcript that codes for the full-length 465 amino acid protein (30- versus 17-fold induction, respectively), while Runx1 is essentially not expressed in sham muscle. Ongoing analysis will validate Runx1 splice variant expression during overload in muscle, the potential influence of DNA methylation, and the impact of the Runx1 short isoform on muscle hypertrophy. This work is supported by the National Institutes of Health under grant R00 AG063994 to Kevin A. Murach. 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.
Sex differences in swallowing response to Gaussian stochastic surface electrical stimulation
Authors: Morimoto In , Frazure Michael , Iceman Kimberly , Koike Takuji , Pitts Teresa 
Published: May 2023

One of the rehabilitation methods in practical use for dysphagia is electrical stimulation therapy, usually by stimulating the anterior neck muscles via surface electrodes. Electrostimulation therapy does not directly induce swallowing, but is used as resistance training or to alter drive to swallow muscles. Techniques to stimulate the sensory nervous system have been investigated as possible rehabilitation methods to activate the entire swallowing reflex circuit (such as direct magnetic stimulation of the primary somatosensory cortex). We hypothesized that electrical stimulation of the posterior thoracic region using surface electrodes on the back could work in a similar way to magnetic stimulation therapy to improve swallowing movements. We placed stimulating electrodes at three different locations on the back, neck, and subclavian region of adult Sprague Dawley rats ( n = 18). Using a stochastic paradigm, Gaussian probability electrical stimulation was applied to each site at a median frequency of 300 Hz. Natural swallow was evoked by oral water infusion, and swallow activity was recorded with electromyogram (EMG) wires placed in three swallow-related muscles: mylohyoid (laryngeal elevator), thyroarytenoid (laryngeal adductor), and thyropharyngeus (pharyngeal constrictor). A total of four 120 second electrical stimulus trials were applied with a median frequency of 300 Hz in a Gaussian distribution. EMG amplitudes during swallows after each stimulus were compared to those generated during control swallows. Results showed stimulator placement on the back facilitated all three muscles (mylohyoid, thyroarytenoid, and thyropharyngeus) in all male rats, and in some female rats. Stimulation placed on the lateral neck affected only the thyropharyngeus in male rats, and only the thyroarytenoid in female rats. EMG amplitudes were unchanged following subclavian stimulation. In conclusion, our finding that Gaussian electrical stimulation of the back activated a complement of swallowing muscles in male rats suggests that this may represent a novel swallowing treatment method. Additionally, male and female rats responded differently to simulation, indicating that potential sex differences need to be further elucidated. This work was supported by NIH grants HL 111215, HL 103415 and OT20D001983, the Craig H. Neilsen Foundation Pilot Research Grant 546714, Kentucky Spinal Cord and Head Injury Research Trust, and the Commonwealth of Kentucky Challenge for Excellence. 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.
Chronic exercise in pigs shifts post-transcriptional control of the myocardial inflammasome
Authors: Samani Stephanie , Barlow Shayne , Freeburg Lisa , Jones Traci , Sarzynski Mark , Zile Michael , Shazly Tarek , Spinale Francis 
Published: May 2023

Background: Chronic exercise protocols have demonstrated a beneficial effect on overall cardiovascular health, however, the direct effects on left ventricular (LV) function and the relation to changes in post-transcriptional regulatory checkpoints, that is the microRNAs (miRs), and what downstream processes may be affected, remains unexplored. Accordingly, this study developed a chronic exercise protocol in mature pigs and examined LV function and myocardial mRNA profiles. Methods and Results: Pigs (n=9; 25 Kg) underwent a treadmill protocol (4 weeks, 10° elevation, 2.5 mph, 10 minutes) in which LV ejection fraction (LV EF) and end-diastolic volume (LV EDV) were measured by echocardiography. Age matched, non-exercise pigs (n=6) served as referent controls. LV myocardial samples were subjected to an 84 miR array using rt-PCR. All results are reported as mean ± SEM. LV EDV (54.8 ± 3.1 vs 67.4 ± 3.3 mL, p≤0.05) and LV EF (66.4 ± 1.8 vs 82.0 ± 0.7 %, p≤0.05) increased with exercise indicative of a successful training effect. A total of 25 miRs were significantly upregulated (56%) or downregulated (44%) following exercise. Using miR mapping algorithms, miR-22 and miR-30e, which fell by over 3-fold change with exercise (rt-PCR, -3.07 ± 0.92 and -3.28 ± 1.08 respectively, p≤0.05), mapped to the NLRP3 inflammasome. NLRP-3 mRNA (rt-PCR) levels fell by over 2-fold with exercise (-2.65 ± 0.62, p≤0.05). Conclusion: A chronic exercise protocol in pigs induced a unique miR profile that was associated with changes in LV geometry and function. In particular, several miRs mapped to regulatory elements of the local inflammatory pathway- the inflammasome. These unique findings demonstrated a clear shift in post-transcriptional pathways occur with chronic exercise and reduces LV myocardial inflammasome profiles. This work was supported in part by National Institutes of Health grant R01HL130972-01A1 (F.G.S.) & R01HL5949 (F.G.S.) as well as a Merit Award from the Veterans Health Administration, BX000168-10A1 (F.G.S.) & BX005320 (F.G.S.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 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.
Prospective assessment of nighttime respiratory disturbance in multiple myeloma patients
Authors: Jedlicka Charles , Haasl Calista , Witherell Carly , Tomasson Michael , Bates Melissa 
Published: May 2023

Chronic intermittent hypoxia, a feature of sleep apnea, is a potent driver of solid tumor cancers and promotes lethal engraftment of malignant plasma cells in a mouse model. The objective of this study was to investigate if nighttime respiratory disturbances affect clinical outcomes in a multiple myeloma patient population. To do so, we prospectively assessed nighttime respiratory disturbance index (RDI) in 44 patients (27 male, 17 female) diagnosed with multiple myeloma at the University of Iowa Hospitals and Clinics. Following this assessment, we categorized patients by RDI and utilized electronic medical records to explore differences in routine myeloma clinical measures. We found 93% of the patients had an RDI equal to clinical sleep apnea. 39% of patients had a moderate or severe RDI. In comparing these patients to those with low RDI, there were no statistical differences in any clinical performance indicator. Additionally, there were no differences in disease symptoms, multiple myeloma staging, or antibody type between these groups. However, patients with a higher nighttime RDI were less likely to respond to induction chemotherapy (p=0.046), a predictor of poor disease prognosis. These data support the hypothesis that nighttime respiratory disturbances negatively impact multiple myeloma patients, but this impact may not be evident in routine clinical tests of patient performance. This research is supported by NIH award R01CA244271 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.
Age and sympathetic transduction to blood pressure
Authors: Bigalke Jeremy , Cleveland Emily , Young Benjamin , Fadel Paul , Carter Jason 
Published: May 2023

Aging has been associated with reduced sympathetic transduction using multiple methodologies, including signal-averaging, in which the change in mean arterial pressure (MAP) following a muscle sympathetic nerve (MSNA) burst is tracked for 10-15 cardiac cycles. Recent reports suggest that this methodology is impacted by the location of an MSNA burst relative to the average resting blood pressure. The current study examined age differences in MSNA burst dispersion around the average MAP and its potential impact on sympathetic transduction. We hypothesized that aging would be associated with more MSNA bursts occurring at MAP values above mean resting MAP, contributing in part to reductions in sympathetic transduction. Beat-to-beat blood pressure and MSNA were recorded during 5-minute supine rest in 27 young (YA; 13F, age: 25±1 yrs, BMI: 25±1 kg/m2) and 26 older (OA; 15F, age: 59±1 yrs, BMI: 26±1 kg/m2) adults. Resting beat-to-beat MAP values were split into low (T1), middle (T2), and high (T3) tertiles, and transduction of bursts occurring within each tertile was calculated using signal-averaging. OA exhibited higher resting MSNA burst frequency (YA: 24±2 vs. OA: 33±2 bursts/min, P<.001). OA exhibited blunted overall sympathetic transduction (YA: Δ1.5±0.1 vs. OA: Δ0.9±0.1 mmHg, P=.005). When separated by MAP tertiles, age differences in transduction were only observed in T3 (YA: Δ-0.4±0.1 vs. OA: Δ-1.0±0.1 mmHg, P=.005) but not T1 (YA: Δ2.3±0.1 vs. OA: Δ2.2±0.2 mmHg, P=.456) or T2 (YA: Δ0.7±0.1 vs. OA: Δ0.4±0.1 mmHg, P=.337). Since age differences were only observed at T3, we next examined only bursts occurring above the average MAP. A greater proportion of bursts occurred above the average MAP in OA (YA: 30±2 vs. OA: 40±1 %, P<.001), and a larger proportion of these bursts were associated with a depressor response in OA (65±2%) compared to YA (56±2%, P=.005). Nevertheless, assessment of bursts occurring above the average MAP that were associated with a pressor response revealed a blunted transduction in OA (YA: Δ2.7±0.3 vs. OA: Δ1.7±0.2 mmHg, P=.016). These results indicate an age-related increase in MSNA burst occurrence above the average resting MAP, with a greater majority of these bursts being associated with depressor responses in OA. Further, age-associated reductions in transduction are observed following MSNA bursts associated with a pressor response occurring above the average resting MAP. Support: NIH (AA-024892, U54GM115371; P20GM103474, 2TL1 TR002318) 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.
Manipulating thyroid hormone levels alters development of skeletal muscle mitochondria in nestling red-winged blackbirds
Authors: Dzialowski Edward , Sirsat Tushar , Sirsat Sarah , Pineda Megan , Price Edwin , Crossley Janna 
Published: May 2023

Thyroid hormones are key regulators of development and metabolism in vertebrates. Red-winged blackbirds are an altricial species that exhibit an increase in plasma 3,3’, 5-triiodo-L-thyronine (T3) levels during the first 5 days post-hatch (dph), begin to develop endothermic metabolic responses by 7 dph, and fledge within 10 days of hatching. To better understand the role thyroid hormones play in the endothermic metabolic development in an altricial species, we treated nestling red-winged blackbirds on 2, 3, and 5 dph with either methimazole to induce hypothyroidism or supplemental T3 to induce hyperthyroidism. We examined mitochondria function in breast and thigh skeletal muscle at 5, 7 and 9 dph in permeabilized muscle fibers. Hypothyroid conditions prior to day 5 post-hatching induced lower oxygen flux during oxidative phosphorylation through complexes I and II than controls in both breast and thigh skeletal muscles of 7 and 9 dph nestlings. Elevating thyroid hormones during the first 5 dph resulted in greater leak respiration but no change in oxidative phosphorylation respiration later in the nestling period. These data suggest that thyroid hormone levels play a role in development of skeletal muscle mitochondrial function and may be a foundational mechanism by which endothermic capacity is achieved by neonate altricial birds. NSF 1146758 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.
Effects of chronic neonatal hyperoxia-induced bronchopulmonary dysplasia on breathing, energy expenditure, and growth in young, adolescent, and adult mice
Authors: Mouradian Gary , Dir Brooke , Grobe Connie , Reho John , Grobe Justin , Segar Jeffrey 
Published: May 2023

Bronchopulmonary dysplasia (BPD) is a common chronic lung disease associated with preterm birth. Growth failure is common in infants with BPD and is associated with increased resting metabolic rate (RMR). Whether increased RMR and growth failure are a consequence of BPD lung pathology per se, or a consequence of clinical interventions remains unknown. Herein, we sought to determine the effects of BPD-like lung injury on breathing, growth, and energy expenditure in C57BL/6J male mice exposed to chronic hyperoxia (Hx; 70% O2; n=5) or normoxia (Nx; n=6) in the neonatal period (postnatal day (P) 0-14). Consistent with prior reports and human BPD, Hx lungs at P21 had reduced alveoli and alveolar density indicated via H&E lung sections. Also, Hx mice had altered respiratory responses to acute hypoxia (10 min; 12% O2) including a reduced hypoxic ventilatory response (108±6 Nx vs 89±4 % Hx; p<0.05) and drive to breathe (tidal volume/inspiratory time; 0.98±0.06 vs 0.76±0.04; p<0.05). The pattern of breathing during the acute challenge favors longer inspiratory time (132±6 vs 170±9 ms, p<0.05) which may reflect a compensatory response to reduced alveoli. Despite these differences, no differences in body composition (body, fat and fat-free masses, and total body water) were observed at P21, 6wks, or 8wks of life. Furthermore, there were no differences in ingestive behaviors, or total or resting aerobic heat production (kcal/h) at 8 wks of age, yet Hx mice had reduced locomotor activity (199±10 vs 154±11 m/d; p<0.05) which may indicate reduced exercise capacity. In a subset of mice (n=2/group), a 20% increase in right ventricular mass was noted, consistent with some degree of pulmonary hypertension, along with a 3% decrease in hematocrit, which may reflect a programmed change in hematopoiesis after early-life Hx. Together, these data document the impact of BPD-like lung injury on key physiological parameters and support the iconoclastic concept that BPD pathology per se does not drive increased RMR or growth failure. By extension, other factors – possibly including side-effects of well-intentioned clinical interventions – may underly growth failure in children with BPD. We speculate that sodium depletion resulting from diuretic therapy, which is common for this condition and known to impact infant growth, may be an important contributor to growth failure in infants with BPD. GCM: AHA 20CDA35310121; JLG: DK133121, HL134850, and HL084207; JLS: DK133121 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.
Embedding design thinking, career planning and teamwork into the curriculum better prepares life science students for research and alternate science careers
Authors: French Michelle , Miliotis Helen , Andreopoulos Stavroula , Laposa Rebecca , Arnot Michelle 
Published: May 2023

Many undergraduates have either a narrow or vague idea of their career path which causes stress and can result in them leaving science. In addition, they often lack confidence or the knowledge needed to pursue independent research project courses in their senior year. To broaden student career perspectives, promote adaptability and build research skills, we developed a third-year course: Research Readiness and Advancing Biomedical Discoveries. This flipped course features online pre-class modules and extensive in-class group work. Online module topics include: writing a research proposal, project management and attributes of a successful scientist ( https://experientialmodules.utoronto.ca/research-readiness/ ). We also incorporated design-your-life ( http://lifedesignlab.stanford.edu/ ) team activities (DYL) such as brainstorming, articulating alternate life plans (Odyssey planning), and networking to help students develop novel scientific research proposals and to support their own creative career planning. To assess student perceptions of course components, we conducted anonymous student surveys three times in each offering of the course using both 5-point Likert scales and open-ended prompts for student feedback (Univ. Toronto REB#18345). Responses to open-ended survey questions were independently analyzed for broad themes by two third-party research assistants. Over the three years of course offerings, 86% of students reported feeling better prepared for research and other opportunities after graduation, 87% of students reported being encouraged to consider flexible career paths, and 87% reported they have realized the importance of teamwork (n=121). Written comments included: “ The research proposal was an incredible assignment because it gave me insight into what I would be doing in research and let me think of my own idea.” and “ [Odyssey planning] helps me to rethink my choices. Why can’t I make different choices? What is holding me back?. I think I need more diverse experience in area of biomedical science to answer these questions. ” Thus, students perceive that our novel course better prepares students for research and alternate science careers. Learning and Education Advancement Fund (LEAF) Impact grant, University of Toronto, Career Readiness Fund, Faculty of Arts and Science, University of Toronto, Online Undergraduate Course Initiative Fund, University of Toronto 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.