bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of total parenteral nutrition and antibiotics on hepatic and intestinal homeostasis in pediatric murine model
Authors: Pierre Joseph , Mims Tahliyah , Kumari Roshan , Joseph Sydney , Leathem Cameron , Antunes Karen , Al Abdallah Qusai , Henry Lydia , Ferstl Danielle , Jamieson Sophia , Sabbar Austin , Willis Kent , Talati Ajay , Elabiad Mohamad , Hibl Brianne 
Published: May 2023

Parenteral nutrition (PN) prevents starvation and supports metabolic requirements intravenously when patients are unable to feed enterally. Adult rodents and piglets have been used in PN research for decades, while almost no research has used adolescent mice. Clinically, human neonates are frequently provided PN in intensive care settings along with exposure to antibiotics (ABX) to minimize infection during care. Since PN bypasses the intestine, intravenous alimentation impacts metabolism and may alter organ growth and programming during critical early life developmental windows. Utilizing our newly established adolescent murine PN model, we first administered ABX or controlled drinking water to time pregnant dams to disrupt maternal microbiome. Resulting pups (post-natal day 9, n=6-8/group) were then randomized to PN or sham surgery controls for 72 hours with or without prior ABX exposure. ABX or PN decreased liver and brain organ weights, intestinal length, and mucosal architecture compared with controls. PN significantly elevated hepatic proinflammatory cytokine expression, neutrophils, macrophages, and bacterial colony forming units, which was blocked by ABX. However, PN+ABX uniquely elevated metabolic regulatory genes, FXR, CYP27A1, SPEBP1, and FASN, resulting in accumulation of hepatocyte lipid vesicles and altered circulating bile acid pools. Within the gut, PN elevated the relative abundance of Akkermansia, Coprococcus and decreased Lactobacillus compared with enteral controls, while ABX enriched Enterobacteriaceae and Adlercrutzia. We conclude that even brief PN feeding elevates hepatic inflammatory stress in an early life model. While concurrent ABX exposure protects against PN associated inflammatory responses, the dual therapy modulates bile acid and lipid metabolism, which may contribute to the progressive hepatic dysfunction observed in human neonates unable to wean from PN. This study serves as the first demonstration of PN and ABX exposures upon hepatic metabolism and inflammation in an early life murine model. Institutional Start Up Funding 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 Spike protein of SARS-CoV-2 exacerbates cardiac mitochondrial dysfunctions in obese mice: mechanistic evidence for cardiomyopathy in post-acute sequelae of COVID-19
Authors: Nguyen Vi , Cao Xiaoling , Tsai Joseph , Tian Yan , Zhang Yuping , Gao Chao , Carver Wayne , Kiaris Hippokratis , Cui Taixing , Tan Wenbin 
Published: May 2023

Background: As the pandemic persists, post-acute sequelae of CoV-2 (PACS) including cardiovascular manifestations have emerged as a new health threat. Obesity is an established risk factor for acute COVID-19 severity. Evolving evidence has suggested its contributive roles in the pathogenesis of PACS. However, whether and how obesity can exacerbate PACS-related cardiomyopathy is unknown. Methods: A Spike protein-pseudotyped (Spp) virus with the proper surface tropism of SARS-CoV- 2 was developed for viral entry assay in vitro and administration into high fat diet (HFD)-fed mice. The systemic viral loads and cardiac transcriptomes were analyzed at 2 and 24 hrs, 3, 6, and 24 weeks post infection (wpi) using RNA-seq or real time RT-PCR. Echocardiography was used to monitor cardiac functions. Results: Low-density lipoprotein cholesterol enhanced viral uptake in endothelial cells, macrophages, and cardiomyocyte-like H9C2 cells. Selective cardiac and adipose viral depositions were observed in HFD mice but not in normal-chow-fed mice. The cardiac transcriptional signatures in HFD mice at 3, 6, and 24 wpi showed systemic suppression of mitochondria respiratory gene families including ATP synthases and nicotinamide adenine dinucleotide:ubiquinone oxidoreductase gene members, upregulation of stress pathway-related crucial factors such as nuclear factor-erythroid 2-related factor 1, and increases in expression of glucose metabolism-associated genes. Cardiac ejection fraction and fractional shortening were significantly decreased, while left ventricular end-systolic diameter and volume were significantly increased, in HFD mice at 24 wpi as compared with the age-matched HFD control mice. Conclusion: Our data demonstrated that chronic cardiac inflammations were persisted and exaggerated in HFD mice after viral infection, leading to mitochondrial metabolic perturbations and myocardial contractile impairment. This work was supported by grants from the National Institutes of Health (AR073172 and NIH COBRE (P20GM109091) pilot study to W.T., NSF EPSCoR (OIA1736150) to H.K., HL160541 to T.C.). 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.
Three levels of enhanced inspired CO2 or fasted-state on stress response activation in behaviorally inhibited humans and rats
Authors: Wolf Olivia , Harshberger Mary , Apostoli Giana , Ehlert Luke , Wiseman Connor , Martino Paul , Miller Daniel , Miller Justin , Terrill Sarah , Hodges Matthew , Allen Michael 
Published: May 2023

Behavioral inhibition (BI) is believed to be a genetically determined trait that affects roughly 33% of the human population. These individuals tend to respond to stressful situations differently than their non-behaviorally inhibited (NBI) counterparts. In the rodent population, a similar behavioral/stress model exists. The Sprague-Dawley (SD) strain often acts as a “control” among rat strains and can be considered to be the rat equivalent to NBI individuals, and the Wistar-Kyoto (WKY) strain is the rodent equivalent to BI individuals. The differences in the activation of the sympathetic nervous system between chronically stressed and non-stressed populations remain unknown. Our current study tested the hypothesis BI individuals and WKY rats will have increased stress responses. In humans, we tested physiological responses to increasing levels of carbon dioxide (CO2) through analyses of breathing, heart rate, and blood pressure. The Adult Measure of Behavioral Inhibition (AMBI) survey was used to determine the presence of BI. A 15-minute control period baseline was completed followed by an acquisition period of five minutes of each 3%, 5%, and 7% CO2, respectively. Preliminary results were analyzed through a CO2 sensitivity slope (inspired minute ventilation ((L/min) / end-tidal CO2) and show that BI individuals had increased, exaggerated responses to the respiratory stressors across the three levels of enhanced CO2. In the rodent model, signaled lever-press avoidance was used to examine the activation of stress responses. Rats were trained to avoid mild foot shock using a tone warning signal. As demonstrated previously, WKY rats acquired a higher level of avoidance responses. Rats were then food-deprived overnight and subsequently retested on signal lever-press avoidance. Food deprivation did not affect the high rate of avoidance seen in WKY rats; however, food deprivation increased the SD rate of avoidance to nearly the level of WKY rats. Our data suggest that WKY rats do not respond to food deprivation when paired with lever-press avoidance; however, SD rats do. Simply, the addition of a stressor causes SD rats to behave more similarly to their WKY counterparts. 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.
Role of Sphingosine Kinase 1 in the Pathogenesis of Idiopathic Pulmonary Fibrosis: Identification of Novel Transcription Factors as Potential Therapeutic Targets by in silico Analysis
Authors: Krishnan Yashaswin , Sudhadevi Tara , Ramachandran Ramaswamy , Natarajan Viswanathan 
Published: May 2023

Introduction: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with no definitive treatment. However, a bioactive lipid mediator, sphingosine-1-phosphate (S1P) has been identified to have a role in the pathogenesis of IPF. S1P is synthesized from sphingosine by iso-enzymes sphingosine kinase (SPHK) 1 & 2. In animal models of IPF, genetic knockout of Sphk1 or inhibition of SPHK1 protected the lungs from fibrosis induced by inciting agents. SPHK1 expression is upregulated in IPF; however, the mechanism(s) of its upregulation remain unclear. Hypothesis In silico analysis can predict transcription factors (TFs) that could bind to the promoter region of mouse Sphk1, upregulating its transcription. This could help predict therapeutic targets for IPF in mouse models. Methods: MatInspector® software tool of Genomatix Inc. (Germany) was used for in silico analysis of TF binding sites in Sphk1. This tool uses the available pool of data for TF binding sites to predict probable binding sites in the DNA nucleotide sequence. Results A search for Sphk1 transcript in mouse using gene ID 20698 with accession numbers GXP_6660985, 9541363 and 10224577 yielded 2,119 matches in chromosome 11. GXP_6660985, with the highest probability of TF binding, was the main transcript. The top 100 TF binding sites were analyzed. Among these, 24 binding sites relevant to lung tissue had a very high probability of binding with matrix similarity of 0.98 to 1.0. The TFs included GREF, STAT, SMAD and FKHD. Among these, seven TFs and their binding sites were not cited in the literature according to MatInspector®. Conclusions: A total of 12 TFs were identified in lung tissue as potential members of transcription initiation complex for Sphk1 gene in mouse.Future direction: In silico analysis of TF binding for human SPHK1 is in progress. Modulation of these TFs could serve as a potential therapeutic tool for IPF. 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 BBSome Regulates Mitochondria Dynamics and Function
Authors: Guo Deng , Merrill Ronald , Qian Lan , Zhang Qi , Lin Zhi , Thedens Daniel , Usachev Yuriy , Grumbach Isabella , Sheffield Val , Strack Stefan , Rahmouni Kamal 
Published: May 2023

The essential role of mitochondria in physiology and many pathologies has garnered enormous interest in understanding the mechanisms controlling the function of this organelle. The BBSome, a protein complex composed of eight Bardet-Biedl syndrome (BBS) proteins including BBS1, has emerged as an important regulator of various cellular processes. The similarity in the phenotypes evoked by disruption of the BBSome and mitochondria function led us to hypothesize that the BBSome plays an important role in the regulation of mitochondria dynamics and function. To test this, we used a multidisciplinary approach that include CRISPR/Cas9 technology-mediated generation of stable Bbs1 gene knockout cell lines (N39-BBS1KO and IMCD3-BBS1KO) and analysis of the phenotype of global and conditional BBSome deficient mice. Disruption of the BBSome caused mitochondria hyperfusion in cell lines, fibroblasts derived from BBS patients as well as in hypothalamic neurons and brown adipocytes of mice. The morphological changes in mitochondria translate into functional abnormalities as indicated by the altered mitochondrial distribution, reduced oxygen consumption rate and calcium handling responded to PDGFbb stimulation (340/380 ratio, cytosolic Ca2+ 44.0±,5.4 in N39 cells vs 19.5±3.0 in N39-BBS1KO cells, and mitochondria Ca2+, 75.7±4.4 in N39 cells vs11.8±2.1 in N39-BBS1KO cells, P<0.01). Mechanistically, we found that absence of the BBSome caused ~25% decrease (P<0.01) in phosphorylation at Serine 616 site of dynamin-like protein 1 (DRP1), a key regulator of mitochondrial fission. Notably, rescuing the decrease in DRP1 activity through deletion of one copy of the gene encoding A-kinase anchoring protein 1 (AKAP1) was effective to normalize the defects in mitochondrial morphology and DRP1 activity induced by BBSome deficiency. Importantly, this was associated with improvement in several of the phenotypes caused by loss of the BBSome such as the neuroanatomical abnormalities including motile cilia morphology and hydrocephalus. Loss of AKAP1 also rescued the obesity phenotype as indicated by the reduced body weight (35.4±1.6 in males, 30.5±1.5g in females) relative BBS mice (40.6±1.6 g in males, 32.3±1.5g in females, P<0.05). These findings demonstrate a critical role of the BBSome in the modulation of mitochondria and point to mitochondrial defects as a key disease mechanism in BBS. NIH RO1 and VA for K.R 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.
Neutrophil developmental defects cause hyperinflammation in cherubism
Authors: Cao Ziming , Karlinsey Keaton , Sah Shyam Kishor , Flynn William , Reichenberge Ernst , Zhou Beiyan , Chen I-Ping , Fan Zhichao 
Published: May 2023

Cherubism is a rare autosomal dominant disease caused mainly by a P416R point mutation of Src homology 3 Domain Binding Protein 2 (SH3BP2). Though macrophages and osteoblasts were thought to be the major contributors to the pathology in the past, the involvement of neutrophils in cherubism has been demonstrated by the increasing neutrophil infiltration and extensive neutrophil extracellular trap formation in the lesion recently. Here, we observed decreased expression of lineage marker Ly6G and impaired integrin activation on neutrophils, indicating a developmental defect of neutrophils in cherubism mice carrying the SH3BP2 P416R mutation. Furthermore, we performed single-cell RNA sequencing and compared transcriptomes between blood neutrophils, bone marrow neutrophils, and bone marrow leukocyte progenitors from wildtype and SH3BP2 P416R mice. RNA velocity and pathway analysis show that mutated neutrophils have stalled in the early stage of neutrophil development and failed to mature into granzyme pathway-enhanced, NET-formation-restrained mature neutrophil population in wildtype. Together, our study first illustrates the neutrophil development defects in cherubism as a mechanism for hyperinflammation characterized in cherubism. Ziming Cao and Keaton Karlinsey contributed equally. Beiyan Zhou, I-Ping Chen and Zhichao Fan are co-corresponding authors. This research was supported by grants from the National Institutes of Health, National Heart, Lung, and Blood Institute, USA (R01HL145454), and a startup fund from UConn Health. 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.
AAV-driven expression of channelrhodopsin-2 in lingual myofibers enables light activation of lingual electromyogram activity
Authors: Singer Michele , Benevides Ethan , Rana Sabhya , Martinez Robert , Barral Brian , Sunshine Michael , Byrne Barry , Fuller David 
Published: May 2023

Contraction of the tongue muscles is needed for effective swallowing, speaking and breathing. Thus, inadequate tongue muscle activation can contribute to devastating conditions such as dysarthria, dysphagia, and obstructive sleep apnea. Existing treatments for these clinical conditions are often ineffective and/or poorly tolerated. Optogenetic technology allows for exceptional temporal and spatial precision for stimulating cells and may therefore provide a tool activating the tongue muscles to promote airway patency or enhance swallow function. The purpose of the current study was to test the hypothesis that lingual injection of an AAV9 vector encoding channelrhodopsin-2 (ChR2) would enable light-induced activation of tongue motor units during spontaneous breathing. An AAV9 vector (pACAGW-ChR2-Venus-AAV9, 8.29E11vg) was injected into the posterior tongue in adult C57BL/6Jmice, targeting the genioglossus. After 12 weeks, mice were anesthetized and posterior tongue electromyographic (EMG) activity was recorded during spontaneous breathing. Photostimulation of the tongue was achieved using a high-powered 473 nm light emitting diode positioned near the injection site. Single pulse as well as pulse train stimulation paradigms of varied intensity and duration were performed. Light-evoked EMG responses increased with the intensity (1-way ANOVA on ranks, p=0.002) and duration (1-way ANOVA on ranks, p<0.001) of single light pulses. Trains of light pulses were able to evoke lingual EMG bursts that were comparable to endogenous tongue muscle activation with XII nerve intact. Experiments were repeated after bilateral transection of XII nerve, and light stimuli were still effective at activating lingual EMG. Histology confirmed lingual myofiber transgene expression that was concentrated near the site of AAV injection. These experiments demonstrate the feasibility of using optogenetic stimulation to activate tongue musculature. This novel approach could potentially have application in clinical conditions in which reduced lingual muscle activity is problematic. 2R01HD052682-11A1 (DDF, BJB), MBI Graduate Fellowship Award (MLS) 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 neural basis for fasting activation of the hypothalamic-pituitary adrenal axis
Authors: Resch Jon , Douglass Amelia , Madara Joseph , Kucukdereli Hakan , Yizhar Ofer , Grama Abhinav , Yamagata Masahito , Yang Zongfang , Lowell Bradford 
Published: May 2023

Fasting initiates a multitude of adaptations to allow survival. Activation of the hypothalamic-pituitary-adrenal (HPA) axis and subsequent release of glucocorticoid hormones is a key response that mobilizes fuel stores to meet energy demands. Despite the importance of the HPA axis response, the neural mechanisms that drive its activation during energy deficit are unknown. Here, we show that hypothalamic agouti-related peptide (AgRP)-expressing neurons trigger and are essential for fasting-induced HPA axis activation. AgRP neurons stimulate activity of the HPA axis via projections to the paraventricular hypothalamus (PVH), where, in a mechanism not previously described for AgRP neurons, they presynaptically inhibit the terminals of tonically active GABAergic afferents from the bed nucleus of the stria terminalis (BNST) that otherwise restrain activity of corticotrophin-releasing hormone (CRH)-expressing neurons. This disinhibition of PVH-Crh neurons requires GABA (γ-aminobutyric acid)/GABA-B receptor signaling and potently activates the HPA axis. Importantly, stimulation of the HPA axis by AgRP neurons is independent of their induction of hunger, showing that these canonical ‘hunger neurons’ drive multiple parallel adaptations to the fasted state. Together our findings identify the neural basis for fasting-induced HPA axis activation and uncover a unique means by which AgRP neurons activate downstream neurons – via presynaptic inhibition of GABAergic afferents. Given the potency of this disinhibition of tonically active BNST afferents, other activators of the HPA axis such as psychological stress may work via a similar mechanism. NIH R01DK096010, NIH R00HL144923, AHA 935362 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.
Airway inflammation and cough hypersensitivity induced by tumor necrosis factor alpha in mice
Authors: Lee Lu-Yuan , Lee Lu-Yuan , Lin Ruei-Lung , Lin An-Hsuan , Athukorala Ashami , Khosravi Mehdi 
Published: May 2023

Tumor necrosis factor alpha (TNFα), a pro-inflammatory cytokine, plays a significant role in the pathogenesis of asthma and bronchial hyperrresponsiveness. We have previously reported that TNFα pretreatment elevated the sensitivities of vagal bronchopulmonary C-fibers to chemical irritants in mice (Lin et al., Front Physiol 8: 411, 2017). More recently, we have demonstrated that inhalation of sulfur dioxide (SO2), a common irritant gas and a major industrial air pollutant, can elicit cough by activating these bronchopulmonary C-fibers (Lin et al., J Physiol 585: 1093-1108, 2020). Based upon these previous findings, we carried out this study to test the hypothesis that the cough response to inhaled SO2 is enhanced by pretreatment with TNFα. Coughs were recorded via a telemetry sensor implanted in the intra-pleural space in awake mice moving freely in a recording chamber. Our results showed: 1) Intra-tracheal instillation TNFα (10 μg/ml; 0.03 ml) into the lung induced airway inflammation 24 h later, as shown by 2.9-fold increase in the total leukocyte count in the bronchoalveolar lavage fluid, and 12.8- and 28.4-fold increases in the percentages of eosinophils and neutrophils, respectively, compared to vehicle-treated mice. 2) The TNFα pretreatment significantly elevated the cough responses to SO2 inhalation challenges (300 and 600 ppm, 8 min) in the same animals; e.g., the average cough frequencies during the SO2 (600 ppm) inhalation were 1.1 ± 0.2 and 3.1 ± 1.0 (min-1; n=7, P<0.05) before and three days after the TNFα pretreatment, respectively. This TNFα-induced increase in cough sensitivity slowly declined toward the baseline after 6-8 days. 3) The same TNFα pretreatment did not cause any significant increase in cough responses to SO2 inhalation challenges in p55/p75 (TNF receptors)-null mice. Pretreatment with the vehicle of TNFα (0.03 ml of PBS) also failed to induce cough hypersensitivity to inhaled SO2 in wild-type mice. In conclusion, intra-tracheal instillation of TNFα induced airway inflammation and a long-lasting elevation of cough responses to inhaled SO2. This action of TNFα was mediated through the activation of TNF receptors. NIH grants AI123832 and ES026529-04S1, and Merck MISP100107 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.