bluuebunny/crossref_metadata_2025_split huggingface dataset:
Topographical Distribution and Morphology of Calcitonin Gene-Related Peptide (CGRP) Axons in the Flat-Mounts of the Whole Heart in Male and Female Mice
Authors: Bendowski Kohlton , Zhang Yuanyuan , Bizanti Ariege , Heal Maci , Christie Richard , Hunter Peter , Chen Jin , Cheng Zixi 
Published: May 2023

It is important to understand the topographical distribution of nociceptive axons in the heart to treat cardiac pain. While previous studies have detected nociceptive axons in the sectioned heart, their full distribution has not been fully explored, in particular, the pattern differences in male and female mice have not been determined. In this study, we performed a topographical mapping of the nociceptive afferent axons in flat-mounts of the whole heart of mice (C57BL/6J, male & female, 3-5 months, n=6 for each gender) using calcitonin gene-related peptide (CGRP) as a marker. Then, we used a confocal microscope and a Zeiss M2 Imager microscope to scan all tissues of the heart and assemble the images into complete photo montages of the heart. Furthermore, a Neurolucida 3D Digitization and Tracing System was used to trace CGRP-immunoreactive (CGRP-IR) axons and terminals in the whole heart of the male and female mice. We found that 1) CGRP-IR axons entered as large bundles near the superior/inferior vena cava, left pre-caval vein and the pulmonary veins before bifurcating into small branches, and finally formed single varicose axons and terminals which distributed throughout the tissue, including the cardiac ganglia, SA/AV nodes, auricles, and blood vessels in the right/left atria. 2) CGRP-IR axons particularly accumulated in the SA node region. 3) CGRP-IR axons entered the right/left ventricles and interventricular septum as large bundles through the base before bifurcating into small branches towards the apex. 4) CGRP-IR axons innervated the intrinsic cardiac ganglia (ICG) neurons. 5) CGRP-IR axons wrapped around the blood vessels in the atria and ventricles. 6) CGRP-IR axons presented heavily in the epicardium layer and less in the myocardium and endocardium. 7) CGRP-IR axons had a similar innervation pattern in male and female mice. 8) The representative CGRP-IR axon innervation maps will be integrated into 3D heart scaffolds (male and female). For the first time, our data provide a comprehensive topographical map for CGRP-IR axons in the hearts of male and female mice with single cell/axon/synapse resolution. Our work lays out a novel anatomical foundation for the functional mapping of nociceptive afferent axons and their pathological remodeling in cardiovascular diseases. This work will also contribute to the development of a 3D representation of a brain-heart nociceptive afferent atlas. This study was supported by NIH HEAL/SPARC U01 NS113867-01, NIH R15HL137143-01A1. NIH SPARC OT3OD025349-01 (PH). 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.
The beneficial effects of SS-31 on aging mice cerebral microvasculature
Authors: Rutkai Ibolya , Seman Abigail , Chandra Partha , Byrum Stephanie , Mackintosh Samuel , Gies Allen , Busija David 
Published: May 2023

Aging-associated structural alterations and functional decline of the brain microvasculature contribute to the development of cognitive impairment and dementias such as Alzheimer’s disease. The mitochondrial loss and dysfunction appear to play a major role in mechanisms leading to aging-associated changes of the microvasculature, including increased blood brain barrier permeability, vascular rarefication, or decreased branching. SS-31, a small, water-soluble tetra-peptide has been shown to be effective in improving the aging phenotype in healthy, aged rodents as well as in models of neurodegenerative disease. However, the beneficial effects of SS-31 have not been examined on the brain microvascular proteome.We tested the hypothesis that targeting mitochondria with SS-31 rescues aging-associated changes in the brain microvascular proteome.Aged male (> 18 months) C57Bl6/J mice were randomly assigned to the SS-31 treatment (10 mg/kg; i.p.; n = 5) or vehicle saline (n = 5) groups. Mice were treated daily for two weeks. Cerebral blood flow (CBF) was measured using laser speckle imaging at four time points (0, 3, 7, 14 days). Then, cortical microvessels (MVs) containing a mixture of end arterioles, capillaries, and venules, < 70mm, were isolated and used for Orbitrap Eclipse Tribrid mass spectrometry.During the two-week period, baseline CBF was similar between SS-31 and vehicle groups. Bioinformatic analysis showed that treatment with SS-31 resulted in significant differences in protein abundance of cortical MVs vs. vehicle. Twelve percent (107) of the identified 6,266 proteins were mitochondria associated (oxidative phosphorylation, metabolism, the antioxidant defense system) and mitochondrial dynamics were significantly differentially expressed, Our findings suggest that mitochondria are potential therapeutic targets in the aging brain microvasculature, and that changes in the proteome may contribute to the beneficial effects of SS-31 in aging. Our results warrant further study with the inclusion of female animals to investigate the role of sex-differences in the effects of SS-31. This research was supported in part by: IDeA National Resource for Quantitative Proteomics Voucher Program (R24GM137786), Tulane Brain Institute Research Fund Award to IR, NIH HL-148836, NIH AG-063345, NIH AG-075988, the Louisiana Board of Regents Endowed Chairs for Eminent Scholars program to Dr. Busija, P30GM145498, U54 GM104940. The University of Arkansas for Medical Sciences Bioinformatics Core Facility is supported by the Winthrop P. Rockefeller Cancer Institute and National Institutes of Health grant P20GM121293. 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.
Neonatal gene therapy restores breathing in a rat model of Pompe disease
Authors: Fuller David , Rana Sabhya , Pope Megan , Thakre Prajwal , Corti Manuela , Byrne Barry 
Published: May 2023

Pompe disease is a neuromuscular disorder resulting from mutations in the gene for acid a-glucosidase (GAA) – an enzyme necessary to degrade lysosomal glycogen. Early-onset disease occurs in the absence of functional GAA, which leads to cardiorespiratory failure early in life. Late-onset disease is associated with reduced GAA activity and gradual respiratory failure with preserved cardiac function. The standard of care – intravenous enzyme replacement therapy (ERT) using recombinant GAA does not effectively target the central nervous system, and can delay but not prevent respiratory failure. We used a Pompe rat model ( Gaa null) to test the hypothesis that a single intravenous AAV-GAA dose in neonate Pompe rats can drive persistent and widespread GAA expression and prevent respiratory decline over the lifespan. Male Gaa-/- rats received a single intravenous administration of AAV9-DES-hGAA (1x1014 vector genomes/kg; n=6), temporal vein injection) or sham injection (1xPBS; n=6) on post-natal day one. Ventilation was measured using a whole-body plethysmograph at age 3-, 6-, and 9-months. Rats treated with the gene therapy vector showed a striking increase in body mass over the duration of the study (2-way repeated measures analyses of variance, treatment effect, p<0.001). At age 9 mo, treated rats weighed 402±25 g and sham rats weighed 293±27 g. As rats progressed from 3- to 9-months age, tidal volume, minute ventilation, and the ratio of minute ventilation to CO2 production (i.e., VE/VCO2) were all greater in the gene therapy treated rats as compared to sham (each of these variables showed an age x treatment interaction, all p<0.001). We conclude the neonatal gene therapy with AAV9-DES-hGAA can prevent decline in body mass and preserve breathing ability over the lifespan of a Pompe rat model. Gene therapy is a promising approach for treating Pompe disease. Funding: R01HD052682 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.
Development of an in vivo correlate of lung mechanics in a rat model of spinal cord injury
Authors: Sunshine Michael , Taylor Chase , Little Brittany , Waters Christopher , Alilain Warren 
Published: May 2023

High cervical spinal cord injuries (SCI) damage of bulbospinal inputs to phrenic motor neurons results in diaphragm paresis and paralysis. Additionally, acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) is prevalent in individuals with SCI (Veeravagu et al., 2013). We have recently shown that a rat model of SCI recapitulates inflammatory and metabolic symptoms of ARDS/ALI (Huffman et al., 2021). Measurements of lung damage are typically performed at endpoint, and therefore do not allow researchers to perform longitudinal or repeated evaluations. Conversely, whole body plethysmography (WBP) is used commonly in longitudinal studies to assess changes in ventilation. WBP systems collect complex pressure waveforms, which are derived to estimate flow, and tidal volumes (Drorbaugh & Fenn, 1955). Recently, methods have been developed to capture more subtle characteristics within respiratory waveforms (Sunshine & Fuller, 2021). By grouping respiratory waveforms into clusters using principle component analysis we can track the prevalence of waveforms with similar patterns between treatment groups and across experimental protocols. In the present study we recorded WBP in adult female Sprague-Dawley rats prior to assessing lung mechanics with a flexivent. Animals were grouped into either, Shelf, Sham, C2Hx and measurements were performed at 6, 12, or 64+ weeks post-surgery. We correlated waveform cluster prevalence with metrics of lung mechanics. The waveform analysis revealed a subset of clusters with moderate correlation to lung compliance, and resistance. This suggests that this waveform analysis method may serve as an in vivo surrogate to estimate lung mechanics during longitudinal studies. NIH R21NS121966 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.
Appetite control and feed intake- Can AgRP serve as a biomarker for appetite in the teleost Atlantic salmon, Salmo salar?
Authors: Ronnestad Ivar , Lai Floriana , Kalananthan Tharmini , Tolås Ingvill , Norland Sissel , Gomes Ana 
Published: May 2023

In mammals, the main center for appetite control is the arcuate nucleus (ARC), which contains different neuronal populations. Anorexigenic neurons co-express cocaine- and amphetamine-regulated transcript ( cart) and proopiomelanocortin ( pomc) neuropeptides. The pomc peptide undergoes posttranslational modifications and one of its products, α-MSH, is released together with CART to inhibit appetite. The orexigenic neurons co-express and release neuropeptide Y (NPY) and agouti-related peptide (AgRP) to stimulate appetite. Together, these two ARC neuronal populations comprise the key neuropeptide expression of the melanocortin system (MCS).The MCS is relatively well-conserved among vertebrates, including teleost species. However, in Atlantic salmon ( Salmo salar), the salmonid-specific fourth round whole-genome duplication has resulted in the presence of several paralogous genes, some of which may have resulted in divergent functions. Our in-silico analyses have shown that in Atlantic salmon the key potential neuropeptides of the MCS repertoire comprises three npy, one agrp, ten cart and three pomc genes.Analyses of mRNA distribution of the genes for the MCS neuropeptides across brain regions in salmon reveal significant spatial and quantitative differences in their expression profile between paralogs. In situ hybridization analyses show that agrp1 is only expressed in the nucleus lateralis tuberis (NLT) region of the Atlantic salmon, the putative homolog to the mammalian ARC. In this NLT area, npya, agrp1, cart2b, and pomca are predominantly localized in distinct neurons, however, some neurons co-express cart2b/ pomca. This contrasts with what is known for higher vertebrates and show that co-expression is not required for homeostatic feeding control. Further, studies of fed and fasted fish support that agrp1 acts as an orexigenic signal in Atlantic salmon. In addition, the distinct and well-defined localization of agrp1 in the NLT region suggest that the hypothalamic agrp1 gene may serve as a biomarker for appetite and feed intake in the Atlantic salmon. Research Council of Norway (Projects# 221568; 254894, 267626, 268987, 315106, 317770) 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 lower body negative pressure on critical closing pressure and brain tissue mechanics in healthy young adults
Authors: Horvat Fiona , Kramer Mary , Johnson Curtis , Martens Christopher 
Published: May 2023

BACKGROUND: Elastography has emerged as a powerful tool for assessing the viscoelastic mechanical properties of the brain which are believed to reflect the microstructural integrity of neuronal tissue. Little is known about the influence of hemodynamic properties, including alterations of intracranial pressure (ICP) on brain tissue properties, which may be important for proper brain functioning. PURPOSE: The purpose of this study was to determine whether acute application of lower body negative pressure (LBNP) alters brain tissue mechanical properties via reductions in ICP. METHODS: 10 participants (8F/2M, age: 23±2 y; BMI: 24±2 kg/m2; BP: 111±6/73±6 mmHg) were included in this study. All participants laid supine with their lower limbs in a negative pressure chamber. Arterial blood pressure (ABP) was measured by finger plethysmography and heart rate was recorded using a 3-lead electrocardiogram (Finapres, NOVA, Medical Systems, Enschede, the Netherlands). Right middle cerebral artery blood velocity (MCAv) was assessed by transcranial Doppler ultrasound. All measures were made at rest and in response to -30mmHg LBNP, which was applied over three repeated 10-minute intervals with 10 minutes of rest in between each interval. Critical closing pressure (CrCP) was calculated as a surrogate measure of ICP using the X-intercept from a best-fit line between ABP and MCAv. The same LBNP protocol was then repeated inside a Siemens 3T Prisma MRI scanner to measure global brain tissue stiffness using magnetic resonance elastography (MRE; 3-min sequence). The last 2-minutes of vascular data for each interval was averaged for all outcomes and the effects of LBNP (off vs. on) and repeated interval (1, 2, 3) were examined using a mixed effects model. RESULTS: Heart rate was significantly elevated during application of LBNP (off: 66±23 vs. on: 76±12 BPM; p-value=0.001) confirming expected vascular effects of LBNP. There was no main effect of LBNP on either stiffness or CrCP; however, stiffness increased with each subsequent application of LBNP, resulting in a main effect of interval on brain stiffness (p-value=0.018). CONCLUSION: These preliminary data suggest brain stiffness increases with repeated application of -30 mmHg LBNP; however, this does not appear to be caused by a change in critical closing pressure and thus ICP. Future studies should further examine alternative mechanisms by which vascular function relates to brain tissue properties. University of Delaware Research Foundation 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.
Mentoring is not “Short-Term”: effective continuing mentoring strategies for undergraduate short-term summer program participants after the research experience
Authors: De Miguel Carmen , Becker Rena , Hollowell Cheyenne , Wilson Christopher , Pollock Jennifer 
Published: May 2023

Short-term summer research experiences are a “crash-course” in unique research and mentoring opportunities. Mentoring by research faculty is a key component to short-term summer undergraduate research experiences through laboratory training, one-on-one mentoring, and overall engagement in the program. Faculty members also encourage retention of these scholars in research areas. However, continuing mentorship beyond the brevity of the experience is often difficult for both the faculty mentor and the mentee, particularly if they are at different institutions. The UAB kidney, urology, and non-malignant hematology (KUH) undergraduate research experience (KURE) has been active since 2014 and since 2018 as an NIH-funded R25 Program focused on kidney research and interdisciplinary KUH experiences. UAB KURE has trained over 99 scholars (33% underrepresented in biomedical sciences) in individualized kidney physiology and pathophysiology research as well as clinical experiences. The KURE scholars were individually matched with a faculty mentor and daily supervisors or near peers to support the project and research experience. Over 32 UAB faculty members have mentored a KURE scholar in this short-term experience with 72% (23 of 32) faculty members being a mentor for 2 or more summer experiences. Many in the UAB KURE cohorts have developed a strong bond with the mentor and KUH community at UAB. Those scholars continue in research either at a distance or in future summers, a number return as gap year interns, and many are in communication for future career direction or support. This on-going mentoring and engagement with KURE Scholars as a near peer and a faculty mentor requires time and focus. Determining the most effective means and resources to continue mentoring summer scholars in the long-term is an important consideration. Continual mentoring of summer undergraduate KURE scholars has a critical impact in retaining these scholars and increasing the diversity of researchers and clinicians in the KUH larger community. Through one-on-one qualitative interviews and quantitative survey analysis, we investigated the key aspects of ongoing mentoring of short-term research scholars. We will present methods, metrics, and models for ongoing mentoring, as well as the complex nature and significance of this ongoing mentoring after the summer experience to those scholars who are underrepresented in medicine. Funded by R25 DK115353 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.
Short-chain fatty acids of the intestinal microbiota reduce mesenteric lymphatic pumping
Authors: Singh Reetu , Heaps Cristine , Muthuchamy Mariappan , Stewart Randolph , Laine Glen , Dongaonkar Ranjeet 
Published: May 2023

Short-chain fatty acids (SCFAs; acetate (AC), propionate (PP), and butyrate (BT)) are the primary metabolites of the intestinal microbiota. In addition to being an epithelial energy source, SCFAs exert numerous local effects, including maintenance of the epithelial barrier integrity and protection against inflammation, and are commonly assumed beneficial. It is also well understood that mesenteric lymphatic function is vital for normal gut health; impaired pumping leads to interstitial accumulation of fluid and immune cells, inducing intestinal edema and inflammation. Mesenteric lymphatic vessels are exposed to significantly high concentrations of SCFAs, yet the acute effects of SCFAs on lymphatic function have remained unexplored. Following earlier reports of SCFAs-induced relaxation of vascular smooth and cardiac muscle, in the present study, we tested the hypothesis that AC, PP, and BT reduce lymphatic pumping.Following our recently reported methods, pumping was characterized in vitro using rat mesenteric lymphatic vessels. Briefly, isolated vessels were cannulated, perfused, and bathed with warmed APSS. Following 60-min initial equilibration, in spontaneously contracting vessels, the effects of acute treatment with AC (10 mM), PP (10 mM), BT (10 mM), or AC+PP+BT were determined. In an additional set of vessels, the effects of short-chain fatty acid receptor antagonists (GLPG0974, FFAR2 antagonist, 1 μM and ((R)-3-Hydroxybutyric acid, FFAR3 antagonist, 1 μM) on lymphatic acute responses to AC+PP+BT were determined. Lymphatic responses were characterized using contraction frequency (CF), normalized stroke volume (difference in diastolic and systolic volume normalized to passive volume, NSV), normalized pump flow (CF*NSV, NPF), and diastolic tone (difference in passive and diastolic diameters normalized to passive diameter, DT).Treatment with AC, PP, or BT alone decreased CF and NPF significantly. Accordingly, CF and NPF were also lowered significantly after the combined treatment with the three SCFAs. Nevertheless, both indices were completely restored after FFAR2 and FFAR3 inhibition. Changes in NSV and DT after treatment with AC, PP, or BT, however, were not significant.To our knowledge, the present study is the first to demonstrate adverse chronotropic effects of the three primary SCFAs produced by intestinal microbiota on lymphatic pumping. The lymphatic responses are consistent with reports of reduced heart rate and cardiac contractile indices more than the dilation of blood vessels induced by SCFAs. Further studies are needed to reconcile the apparent conflict between the beneficial effects of SCFAs and the damaging effects of impaired lymphatic pumping. 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.