bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unraveling Molecular and Metabolic Gut‐Brain Signalling Disruptions and Potential Therapy in New Bardet‐Biedl Syndrome Mouse
Authors: Singh Arashdeep , Haq Naila , Luckey Shelby , Mansouri Samira , Gogoi Himanshu , Rourk Katelyn , Jin Lei , Christou‐Savina Sofia , de Lartigue Guillaume 
Published: May 2022

Obesity is a cardinal feature of Bardet‐Biedl syndrome (BBS), a syndromic ciliopathy caused by mutations in genes for BBS 1‐21. BBS proteins control the function of primary cilia that act as a sensory antenna on virtually all mammalian cells. The mechanisms of BBS‐induced obesity remain poorly understood, resulting in a lack of therapeutic options for these patients. The overarching goal of the study was to define underlying mechanisms involved in the pathogenesis of BBS‐induced obesity and use this knowledge to identify novel therapeutic targets. Given the importance of cilia in interoceptive and homeostatic sensing, we hypothesized that disruption of cilia function by BBS mutation would impair negative feedback resulting in a proinflammatory microenvironment in adipose tissue and disruption of neuroendocrine control of feeding in hypothalamus.In this study, we first characterized the metabolic phenotype of a novel BBS5 knockout mouse (BBS5‐/‐; n=6‐12/strain/gender). Next, we performed immunophenotyping of adipocytes and unbiased RNA sequencing of the hypothalamus of BBS5‐/‐ and WT mice. To validate the predictions from transcriptomic data, we performed pharmacological‐based feeding experiments and tested a putative therapeutic for BBS‐induced obesity.We found that BBS5‐/‐ mice exhibits all the classic symptoms observed in human patients with BBS, including hyperphagia, cognitive impairments, glucose, and insulin intolerance, and 3 to 4‐fold increased fat mass on chow diet compared to wildtype mice (p<0.001). BBS5‐/‐ mice had increased proinflammatory M1 macrophages and decreased functional regulatory T‐cells in adipocytes suggesting that extrinsic factors promote fat mass gain. Pathway analysis of the transcriptomics data revealed altered endocrine receptor signaling in the hypothalamus of BBS5‐/‐ mice. Feeding experiments confirmed the development of both leptin and cholecystokinin resistance independent of body weight (p>0.05). The receptor for glucagon‐like‐peptide‐1 (GLP1) was found to be upregulated in the hypothalamus of BBS5‐/‐ mice (p<0.001). Chronic daily pharmacological administration of GLP1 receptor agonist (Semaglutide) for two weeks significantly reduced food intake, body weight, elevated glucose levels, and fat mass (p<0.001).In conclusion, BBS5‐/‐ mice are a valuable new translational tool to elucidate interoceptive and homeostatic gut‐brain axis alterations in BBS‐induced obesity. We identify adipose inflammation, and impaired hypothalamic leptin, insulin, and cholecystokinin signalling as underlying mechanisms for the metabolic pathogenesis of ciliopathy. Our results support using GLP1 receptor agonist as a novel therapeutic strategy for treating obesity in patients with BBS.
Ethanol Inhibits the Metabolism of the Multiple Sclerosis Drug Dimethyl Fumarate to its Active Metabolite and Decreases Brain Exposure
Authors: Yang Bing , Parker Robert B. , Meibohm Bernd , Srivastava Ashish , Temrikar Zaid H. , Laizure S. C. 
Published: May 2022

HypothesisDimethyl fumarate is primarily metabolized to the monomethyl fumarate active metabolite by carboxylesterase 1 and is subject to inhibition by ethanol.MethodsA pharmacokinetic study was conducted to determine the effect of ethanol on dimethyl fumarate disposition in ES1e mice, a strain that is a better model of human carboxylesterase drug metabolism than typical rodent strains. The disposition of dimethyl fumarate and monomethyl fumarate, the purported active metabolite, was determined in a control group (n=30) receiving 100 mg/kg of dimethyl fumarate via oral gavage versus an ethanol group (n=30) receiving 3 g/kg of ethanol by oral gavage 10 minutes prior to dosing with 100 mg/kg of dimethyl fumarate. The area‐under‐the‐curve (AUC) and maximum plasma concentration (Cmax) were determined in plasma and brain tissue from the drug and metabolite concentrations determined by LC‐ mass spectrometry. The AUC and Cmax were compared between the control and ethanol group.ResultsLike dimethyl fumarate disposition in humans, only monomethyl fumarate concentrations were quantifiable in the plasma in the control group. In the ethanol group, dimethyl fumarate was quantifiable in both the plasma and brain tissue.

Control
Ethanol

DMF
MMF
DMF
MMF

AUCPLASMA(ng/ml*min)
ND
6072
4629
3948

CmaxPLASMA(ng/ml)
ND
210
64
65

AUCBRAIN (ng/ml*min)
ND
980
20
787

DMF=dimethyl fumarate; MMF=monomethyl fumarate (active metabolite); ND=not detectedThe terminal elimination half‐life of monomethyl fumarate in the control and ethanol groups was 14.4 and 44.3 minutes, respectively.ConclusionsEthanol inhibits the hydrolysis of dimethyl fumarate to active monomethyl fumarate by carboxylesterase 1 and has a drastic effect on the disposition of dimethyl fumarate and monomethyl fumarate. The therapeutic effect of dimethyl fumarate is likely to be significantly altered by the consumption of ethanol or other drug that inhibits carboxylesterase 1 potentially altering the beneficial effect of chronic dimethyl fumarate therapy on Relapsing‐Remitting Multiple Sclerosis.
Insights Into the Na+‐Dependent Anion Exchange in the SLC4 Family From the Cryo‐EM Structure of the Sodium‐Driven Chloride/Bicarbonate Exchanger SLC4A8
Authors: Zhekova Hristina R. , Wang Weiguang , Tsirulnikov Kirill , Kayık Gülru , Khan Hanif M. , Azimov Rustam , Abuladze Natalia , Kao Liyo , Newman Debbie , Noskov Sergei , Tieleman D. P. , Zhou Z. H. , Pushkin Alexander , Kurtz Ira 
Published: May 2022

SLC4 transporters are involved in the transport of HCO3‾, CO32‾, Na+, Cl‾ and H+ required for regulation of pH and ion homeostasis in several important physiological processes. Dysfunction of these transporters can lead to acid‐base abnormalities, pH dysregulation, and various disease processes. Understanding of their transport mechanism is therefore critical for development of pharmacological strategies for SLC4‐related diseases. The studies of the SLC4 transport mechanisms have been hindered by lack of information on the specific substrate binding sites within the protein matrix. No binding sites have been resolved in the two previously published structures of SLC4 proteins, the chloride/bicarbonate anion exchanger 1 (AE1, SLC4A1) and the electrogenic sodium carbonate cotransporter 1 (NBCe1, SLC4A4), although putative binding sites have been identified on the basis of these structures from computational modelling and functional mutagenesis experiments. Here we present a new cryo‐EM structure at 3.4Å of the outward facing open (OF) conformation of the sodium dependent chloride/bicarbonate exchanger (NDCBE, SLC4A8) [1], which exchanges Na+‐CO32‾ for Cl‾, combining the feature functionalities of both AE1 and NBCe1. The structure resolves for the first time a Na+ and a CO32‾ ion bound at the center of the protein in the area of the previously identified putative binding site S1 in NBCe1 and AE1. Mutation of the residues involved in ion binding leads to significant impairment of NDCBE transport. Computational modelling with the new NDCBE structure outlines two separate ion pathways for cations and anions in the OF cavity and demonstrates that a Na+ ion bound at D800 is necessary for anion binding in site S1 and that a Na+‐CO32‾ ion pair in this site is the most likely ion load. A second anion binding site, S2, is also identified in the permeation cavity in proximity to site S1. We conclude that Na+‐dependent transport in the SLC4 family is influenced both by thermodynamic effects at the S1 binding site and by permeation effects governed by the residues lining the cation and anion permeation pathways in the OF cavity and site S2.[1] Wang W, Tsirulnikov K, Zhekova HR, et al. Cryo‐EM structure of the sodium‐driven chloride/bicarbonate exchanger NDCBE. Nat Commun. 2020;12: 5690
Anatomical Structures Object Library of the Human Reference Atlas
Authors: Börner Katy , Quardokus Ellen M. , Browne Kristen 
Published: May 2022

The Human BioMolecular Atlas Program (HuBMAP) aims to create a computable, open Human Reference Atlas (HRA) [1]. This HRA will redefine our understanding of the human body by recovering multi‐scale tissue organization from the human body to the single cell resolution. In the initial three years of the project, we created an authoritative ontology of anatomical structures, cell types, and biomarkers; this anatomical structure terminology was then linked to three‐dimensional reference objects in the size and shape of human organs, functional tissue units, and anatomical micro‐structures [2]. Many of the current 52 reference organs were derived from the Visible Human Project data. An initial subset can be explored at https://hubmapconsortium.github.io/ccf/pages/ccf‐3d‐reference‐library.html. The growing collection of reference objects form the basis of tissue data registration via the Registration User interface (RUI, https://hubmapconsortium.github.io/ccf‐ui/rui); registered tissue data can be explored in the context of the atlas via the Exploration User Interface (EUI, https://portal.hubmapconsortium.org/ccf‐eui).We are in the process of developing standard operating procedures and design style guides for the HuBMAP Reference Object Library and would like to present first drafts of both at the AAA meeting to benefit from feedback by the larger expert community.References

Snyder MP, Greenleaf WJ, Ahadi S, Nevins SA, Lee H, Esplin E, et al. The human body at cellular resolution: the NIH Human Biomolecular Atlas Program. Nature 2019; 574:187–92.
Börner K, Teichmann SA, Quardokus EM, Gee JC, Browne K, Osumi‐Sutherland D, et al. Anatomical structures, cell types and biomarkers of the Human Reference Atlas. Nat Cell Biol 2021; 23:1117–28. https://doi.org/10.1038/s41556‐021‐00788‐6.
Digital Dissection with CT Scans Enhances Anatomy Education: First‐year Medical Students’ Perception of Radiology Teaching During the Covid‐19 Pandemic
Authors: Spouge Rebecca , Forster Bruce B. , Tsai Olivia , Gil‐Mohapel Joana , Darras Kathryn E. 
Published: May 2022

OBJECTIVEThe aim of this study was to evaluate students’ perceptions of the educational value of online, interactive anatomy radiology laboratories.HYPOTHESISDigital dissection is performed with computed tomography (CT) scans on near life‐size anatomy visualization tables and has been used to teach radiology anatomy at our institution. These sessions were pivoted to online delivery in response to COVID‐19. With the ongoing movement towards technology integration in medical education, if home access to these online laboratories is made available then we hypothesize the perceived learning experience should be preserved.METHODS290 first‐year medical students participated in 10 weekly digital radiology anatomy laboratories, which employed 3D CT scans to emphasize the clinical applications of anatomy. Students reviewed the cases at home prior to the lab on a mobile platform and labs were delivered synchronously via the Zoom platform in a facilitated large‐group format. After the course, a voluntary anonymous online survey was distributed assessing learner satisfaction, task value, emotional achievement, and cognitive load.RESULTSSurvey response rate was 44%. Most participants reported the labs improved their knowledge of anatomy (82%), disease (81%) and clinical decision making (65%), including surgical knowledge (76%). The large group, synchronous learning format was found to be the most effective (68%). Positive emotional achievement was reported (mean 2.98). The extraneous cognitive load of the at‐home mobile technology and lack of time were perceived as the greatest programmatic challenges.CONCLUSIONSynchronous digital dissection labs were perceived as a valuable addition to the first‐year medical curriculum, enhancing learners’ clinical decision making and preparation for medical sub‐specialties. This format of radiology anatomy education can be integrated into blended learning environments to provide students with additional learning opportunities.
Variants and Cellular Functional Verification of CITED2 Gene Promoter Region in Patients with Atrial Septal Defect
Authors: Chen Zhuo , Chen Huan‐Xin , Yin Xiu‐Yun , Han Jun , Yang Qin , He Guo‐Wei 
Published: May 2022

ObjectivesCongenital heart disease (CHD) is a common disease of human birth defects, and atrial septal defect (ASD) is the most common form of ASD. Genetic variants in the coding region of the CITED2 gene is known to be significantly correlated with cardiac malformations, but variants of the CITED2 promoter region and its relationship with the formation of ASD are still unclear. We hypothesize that the variants of the CITED2 promoter may be related to pathogenesis of ASD. The purpose of this study was to screen variants in the promoter region of the CITED2 gene and to verify the effect of the variants on gene expression at the cellular level.MethodsThe blood samples of 332 ASD patients and 293 unrelated healthy children used as controls were studied. The total DNA of all subjects was extracted, and the CITED2 promoter variants were screened by PCR combined with Sanger sequencing. The luciferase activity of the CITED2 promoter was measured by a dual luciferase reporter at the cellular level. Electrophoretic mobility change assay (EMSA) and bioinformatics analysis were used to test the effect of CITED2 promoter changes on transcription factor binding sites.ResultsFour variants in the promoter region of the CITED2 gene were found only in the 332 ASD patients with zero occurrence in the 293 control subjects. These included one novel heterozygous variant (g.4933C>A) and three SNPs [1 case of g.4078 A>C(rs1165649373), 4 cases of g.4935C>T(rs111470468), 2 cases of g.5027C>T (rs112831934)]. The cellular functional analysis showed that these four variants significantly changed the transcriptional activity of the CITED2 gene promoter in HEK‐293 cells (P<0.05). In addition, EMSA results and database analysis showed that these variants created or destroyed a series of possible transcription factor binding sites, resulting in changes of the expression of CITED2 protein.ConclusionThe variants of CITED2 promoter sequence in ASD patients affect transcriptional activity and are likely involved in the occurrence and development of ASD. These findings may provide new perspectives on the molecular pathogenesis and potential therapeutic insights of ASD patients.
Plasma Concentrations of Trace Elements Selenium and Cobalt During and After Coronary Artery Bypass Grafting Surgery
Authors: Zhou Jia‐Yi , Hou Hai‐Tao , Wang Shi‐Fu , Yang Qin , He Guo‐Wei 
Published: May 2022

ObjectivesTrace elements selenium (Se) and cobalt (Co) have been known to be essential in the human body and the correlation between Se and cardiac surgery has been suggested. The present study was designed to investigate the plasma concentration of Se and Co during and after coronary artery bypass grafting (CABG) surgery under cardiopulmonary bypass (CPB).MethodsFrom December 2019 to January 2020, preoperative plasma samples from isolated first‐time CABG patients (N=20; 10 males and 10 females) were prospectively collected at five points: after anesthesia and before CPB (T1), 45 min after CPB started (T2), 90 min after CPB started (T3), postoperative day1 (T4), and day 4 (T5), respectively. The concentration of Se and Co was measured.ResultsThe concentration significantly decrease for Se at T2 (105.24 ± 4.08 vs. 68.56 ± 2.42μg/L, P < 0.001) and T3 (105.24 ± 4.08 vs. 80.41± 3.40μg/L, P < 0.001) and for Co at T4 (0.35 ± 0.19 vs. 0.26 ± 0.13μg/L, P < 0.01) and T5 (0.35 ± 0.19 vs. 0.23 ± 0.11μg/L, P < 0.001). There was no operative mortality or major morbidity except that five patients developed atrial fibrillation (AF).ConclusionsThis study for the first time identified the alteration of plasma concentration of Se and Co during and after CABG surgery. The findings may suggest that supplementation of Se before or during CABG and that of Co after CABG may become necessary for patients undergoing CABG. Further studies are warranted.
Role of GBP5 in NLRP3 inflammasome mediated intestinal inflammation in Crohn’s disease
Authors: Li Yichen , Lin Xutao , Cheng Sijing , Wang Wenxia , Huang Yibo , Ke Jia , Zhu Lixin 
Published: May 2022

BackgroundNLRP3 inflammasome is implicated in the pathogenesis of inflammatory bowel diseases (IBD). Since guanylate binding protein 5 (GBP5) induces the NLRP3 inflammasome activity, we aim to investigate the potential role of GBP5 in IBD pathogenesis.MethodsThe expression of GBP5, NLRP3 inflammasome and related cytokines and chemokines were examined in two cohorts of IBD patients and healthy controls, by microarray transcriptome analysis, quantitative real time PCR, Western blot and Luminex Multi‐Analyte Profiling technology. Cellular and subcellular localization of GBP5 in colonic biopsies were examined by immunohistochemistry and immunofluorescence with confocal microscopy. For functional studies, GBP5 expression was induced by IFNγ or silenced by siRNA or CRISPR/CAS9 technique.ResultsExpression of GBP5 was elevated in colonic mucosa in two geographically and culturally distinct IBD cohorts. In colonic tissues of IBD patients, the expression of GBP5 was mainly confined to immune cells and the levels of GBP5 expression were correlated with those of the inflammatory cytokines and chemokines. In cultured T and macrophage cells, expression of proinflammatory cytokines and chemokines were increased when GBP5 was induced, while GBP5 deficiency leads to decreased expression of the proinflammatory mediators including gasdermin D, caspase 1 and pro‐IL1β.ConclusionsGBP5 is required in the expression of many inflammatory cytokines and chemokines in intestinal immune cells. In addition, GBP5 may up‐regulate inflammatory reactions through an inflammasome mediated mechanism. Highly elevated GBP5 expression at the inflamed colonic mucosa in two geographically and culturally distinct IBD cohorts indicates that GBP5 plays a common and important role in IBD pathogenesis, and therefore, is a potential therapeutic target for the management of IBD patients of various genetic and environmental backgrounds.
Interaction of epithelium and myofibroblasts through ERBB3‐PDGF growth pathways crosstalk drive the maturation of distal lung epithelium in late stage lung development
Authors: Zhang Xin , Heydarian Motaharehsadat , Voss Carola , Sucre Jennifer , Hilgendorff Anne 
Published: May 2022

RationaleThe last stage of lung development is realized by coordinated growth of septae from the alveolar walls to subdivide the distal saccules into alveoli, resulting in the expansion of surface area for gas exchange. The process is accompanied by microvascular maturation and underlying matrix formation of the interstitial scaffold. Secondary septation is driven by the orchestration of the distal epithelium, endothelium, and fibroblasts through the spatial and temporal distribution of various growth pathways and their crosstalk.This study investigated the role of the receptor tyrosine kinases 3 (ERBB3) pathway in the fibroblast‐epithelial crosstalk during septation using both in vitro co‐cultures and ex vivo organoid model as well as transgenic mice.MethodsPrimary myofibroblasts were extracted from neonatal C57BL/6wildtype (WT) mice at postnatal day 7 (PND7) and co‐cultured with a murine epithelial cell line (MLE12) in transwell inserts for 24h before sample collection. Gene expression was analyzed by quantitative PCR. Neonatal lung organoids were generated from primary lung epithelial cells (CD45‐/CD31‐) from neonatal C57BL/6 WT mice (PND7) and cultured in matrigel together with primary myofibroblasts from neonatal WT mice (PND7) as well as age matched mice heterozygot for the Platelet‐derived growth factor receptors (PDGF‐Rα+/‐). After organoid formation, cultures were treated with Neuregulin (NRG), an activating ligand of the ERBB3 receptor. We measured organoid number and size and Erbb3 signaling was assessed by immunofluorescence and quantitative gene expression analyses.ResultsProximal culture with myofibroblasts upregulated the expression level of ERBB3 receptor in epithelial cells, as well as homeodomain‐only protein homeobox (HOPX), GATA‐binding factor 6 (GATA6), both of which are essential in the differentiation of distal epithelial cells and surfactant production during late stage lung development. In neonatal lung organoids, myofibroblasts with reduced PDGFRα expression led to reduction in organoid size and number. Treatment with the Erbb3 ligand NRG significantly increased both the expression and phosphorylation of Erbb3 in epithelial cells together with an upregulation of surfactant C (SPC) expression, and an increase in myofibroblasts PDGF‐R α expression.ConclusionActivated Erbb3 signaling results from the interaction with fibroblasts involving PDGF‐Rα signaling and drives distal epithelium maturation.
In‐Silico Investigation of Castration on Vas Deferens Smooth Muscle Electrophysiology
Authors: Mahapatra Chitaranjan , Manchanda Rohit 
Published: May 2022

OBJECTIVEThe vas deferens smooth muscle (VDSM) generates spontaneous contractions for the sperm transportation. The underlying electrical activities of the VDSM cell are prominently correlated with these contractions. According to a recent experimental study, the castration has down regulated the A‐type K+channel activities in the VDSM cell. However, the modulating properties of castration into VDSM electrophysiology are not investigated yet. In the present time, the in‐silico study plays a key role in understanding various complex physiological systems. To explore the quantitative contribution of castration to the VDSM membrane action potential (AP), a biophysically detailed single VDSM in‐silico cell model is simulated.METHODSThe in‐silico guinea‐pig VDSM cell model is constructed after incorporating a voltage‐gated Na+ ion channel, two voltage‐gated Ca2+ ion channels, a hyperpolarization‐activated ion channel, two voltage‐gated K+ ion channels, a Ca2+‐activated K+ ion channel, and a nonspecific background leak ion channel. All ion channel models are validated by comparing the simulated currents and current‐voltage relationship with those reported in the experimental studies. The modulating properties of the castration are simulated by mimicking the A‐type K+ channel on VDSM cell excitability.RESULTSThe ion channel conductnaces are set to maintain the resting membrane potential (RMP) at ̶ 50 mV as the physiological range of RMP in VDSM cell varies from ̶ 45 mV to ̶ 70 mV (Figure 1). The AP and membrane depolarization are generated in the whole cell model by applying an external current stimulus (10‐30 pA), as a brief square pulse of 10 ms duration. The A‐type K+ current is elicited by a 1000 ms depolarizing‐voltage‐step between ̶ 70 and +40 mV from a holding potential (̶ 80 mV) with 10 mV increments. The maximum conductance of A‐type K+ channel is altered to observe the changes in VDSM AP. The RMP, AP width, and AP peak are elevated by 2 mV, 15 ms, and 1 mV respectively after the castration (Figure 1). It reveals that the VDSM cell is more electrically excited due to the castration.CONCLUSIONSThe present in‐silico model, constrained heavily by physiological data, provides a powerful tool to investigate the ionic mechanisms underlying the genesis of VDSM electrical activity. In the guinea‐pig, following castration, the VDSM cell is excited by membrane depolarization, which causes to evoke more spontaneous contractions. The new biological insight from this investigation shows the agonist of the A‐type K+ channel might control the much‐diminished sex drive experiences for men after the castration.