bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microbial Indole Metabolites Provide a Novel Pathway for Regulation of Intestinal Homeostasis
Authors: Alexeev Erica E. , Kao Daniel J. , Mills Krista B. , Lanis Jordi M. , Lee J. Scott , Dowdell Alexander S. , Schaefer Rachel E.M. , Onyiah Joseph C. , Colgan Sean P. 
Published: June 2021

Inflammatory bowel disease (IBD) is a multifactorial chronic condition that result in numerous perturbations in the gastrointestinal mucosa. IBD is characterized by the continual breakdown of the intestinal epithelial barrier leading to an inappropriate immune response towards intestinal microbiota. This exposure promotes inflammation and continued mucosal injury, though the pathogenesis of the disease remains unknown. There is currently significant interest in understanding the role of gut microbiota in IBD. Loss of commensal bacteria and their metabolites may play a role in homeostasis of the intestinal epithelia. Microbes benefit the host through the local synthesis of numerous metabolites. One such metabolite is indole. Indoles are gut microbiota‐derived tryptophan metabolites that are abundant in the healthy mammalian gut and positively influence intestinal health. Using an unbiased metabolomics profiling approach, we identified a selective reduction in microbiota‐derived indole metabolites in active murine colitis. We have developed HPLC‐based technologies to validate these results and quantify indole and indole‐derived metabolites within murine and human colitis samples. We show that exposure of intestinal epithelial cells to indole metabolites induces genes important in formation and maintenance of intestinal barrier. For instance, the anti‐inflammatory cytokine IL‐10 functions through binding to the IL‐10 receptor alpha subunit (IL‐10R1), and colitis is strongly associated with the induction of the epithelial IL‐10R1. Our results have revealed a prominent induction of IL‐10R1 mRNA and protein expression following treatment of intestinal epithelial cells with indole metabolites. We also show a potential role for selective indole metabolites, particularly indole‐3‐propionic acid (IPA), to alleviate disease severity and decrease inflammatory mediators in models of murine colitis. Together, these data suggest that microbial‐derived indoles play a central role in mucosal homeostasis. Based on these findings and ongoing studies, we show that microbial‐derived indole metabolites inhibit inflammation‐induced damage and promote mucosal homeostasis. These studies elucidate a novel role for microbial metabolites in innate immune responses during intestinal inflammation using in vitro and in vivo models. This work will provide new insight and identify possible avenues to utilize indoles as therapeutic approaches for treating IBD.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Molecular Genetics of Human Sleep Behaviors
Authors: Fu Ying‐Hui , Ptacek Louis John 
Published: June 2021

Sleep plays an essential role in our total well‐being and survival. Long‐term shift working schedule and frequent transmeridian travel have become inevitable for many in the current society. These factors lead to the out‐of‐sync condition of the sleep timing with the internal body clock, and thus significantly contribute to many health conditions that we are facing. Our group uses human genetics approach to identify genes/mutations that give rise to unusual sleep timing trait in human. Mouse models recapitulating human condition, coupled with in vitro molecular studies, offer new insight into the underlying mechanism. Because the fundamental role that sleep plays in our health, part of the pathways for regulating sleep are intertwined with pathways for regulating other functions. Our method also offers opportunities to investigate how sleep can impact other conditions including mood and pain regulations. These genes/mutations have provided unique opportunities to reveal the molecular mechanism of human sleep timing regulation and beyond. Previously, we have reported mutations on PER2, CRY2, PER3, and CK1delta that cause familial advanced sleep phase in human. Interestingly, the main components of molecular clock are mostly conserved from flies to mammals; however, the role of mammalian Timeless remains ambiguous. We recently identified a mutation on human TIMELESS gene for advance sleep phase trait. Behavioral and molecular characterizations of these mutations will be presented.Support or Funding InformationThis work was funded by NIH grants NS072360 and HL059596 to Y‐H.F. and L.J.P., NIH grant P30 DK063720, and by the William Bowes Neurogenetics Fund.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Radiation Cystitis Modeling: a Comparative Study of Bladder Radiation‐Induced Fibrosis in Different Mouse Strains
Authors: Zwaans Bernadette MM , Wegner Kyle A , Bartolone Sarah N , Chancellor Michael B , Vezina Chad M , Lamb Laura E 
Published: June 2021

Introduction and ObjectiveRadiation cystitis (RC) is a severe side effect from radiation therapy that can occur in pelvic cancer survivors (e.g. cervical and prostate cancer) and results in a fibrotic bladder. However not all patients treated with pelvic radiation will develop RC. Different mouse strains can be used for exploring genetic variability with respect to human biology. We aimed to assess the fibrotic response of the bladder to radiation in various genetic mouse strains to determine if genetic background variation may explain differences in risk for patients developing RC after radiation treatment.MethodsFemale C57BL/6, C3H and Balb/c mice were given a single dose of 40 Gy irradiation using the Small Animal Radiation Research Platform (SARRP) to deliver a gamma‐irradiation to the bladder while limiting toxicity to neighboring tissue. Weekly micturition measurements were performed. Mice were sacrificed one‐year post irradiation and bladders were processed for histology. Fibrosis was determined using Mason's trichrome and Picrosirius Red stains.ResultsAll mice tolerated the radiation treatment well ‐ no changes in weight or behavior were noted. Micturition measurements were performed in C57BL/6 and Balb/c mice only, as C3H mice destroyed the filter paper. Increased number of voids, and decreased average and primary void size developed in both strains, though occurred earlier in the C57BL/6 strain. Hematuria developed in all strains. Mild to severe radiation‐induced fibrosis was visible in Balb/c and C57Bl/6 mice, with the highest degree of fibrosis in the latter. Fibermetrics analysis indicated higher number of collagen fibers in C57Bl/6 and Balb/c mice, but only Balb/c mice showed increased collagen fiber length and diameter. Ongoing studies will determine changes in specific collagen proteins using antibody specific fluorescent staining.ConclusionUsing SARRP, we can create bladder dysfunction in mice modeling symptoms of chronic human RC including hematuria, fibrosis, and micturition frequency. Radiation‐induced fibrosis in the bladder is strain dependent, suggesting that there may be a genetic predisposition to radiation sensitivity of the bladder. These results are essential in determining the right preclinical model for future RC studies and understanding which cancer patients are at risk for RC.Support or Funding InformationThis project was in part supported by the U Can‐Cer Vive Foundation, NIDDK K01 career development award DK114334 (BMMZ), NIDDK specialized center cooperative agreement award U54DK104310, and NIEHS predoctoral research award F31ES028594 (KW)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Self‐Antigen‐Specific T Cell Receptor Activation of CD4+ T Cells in the heart is required for Maladaptive Cardiac Remodeling in Pressure Overload Induced Heart Failure
Authors: Ngwenyama Njabulo , Carrillo‐Salinas Francisco , Aronovitz Mark , Alcaide Pilar 
Published: June 2021

Cardiac pressure overload is associated with an adaptive immune response that drives maladaptive cardiac remodeling. CD4+ T cells are activated and expanded specifically in the heart‐draining mediastinal lymph nodes (mLNs) and infiltrate the left ventricle (LV) in response to transverse aortic constriction (TAC), a well‐established mouse model of heart failure (HF). In contrast, T cell deficient mice (Tcrα−/−) do not develop HF in response to TAC. Classic CD4+ T cell activation occurs upon cognate antigen recognition on antigen presenting cells, such as dendritic cells (DCs), through the T cell receptor (TCR). However, the specific mechanisms triggering T cell activation during the progression of HF remain unknown. We hypothesized that TCR‐dependent activation of CD4+ T cells by self‐antigens initiates and sustains maladaptive cardiac remodeling during the progression of TAC induced HF. We report a three‐fold increase in DC activation by flow cytometry in both the LV and mLNs in response to TAC, as compared to Sham surgery. Major histocompatibility complex class II deficient (MhcII−/−) mice, which lack the ability to present antigens to CD4+ T cells, did not develop cardiac dysfunction upon reconstitution with effector CD4+ T cells in the onset of TAC, despite developing some signs of adverse cardiac remodeling. A similar phenotype was observed in transgenic OT‐II mice, which undergo TCR activation only in response to exogenous ovalbumin (OVA), upon immunization with OVA during TAC. We next directly assessed whether CD4+ T cells respond to endogenous antigens in the heart using Nur77GFP mice, which transiently express GFP upon TCR stimulation. Strikingly, GFPhiCD4+ T cells were present in the LV, and increased in number as maladaptive remodeling and cardiac dysfunction progressed over time. TCR clonal analysis by next generation sequencing of TCR‐activated GFP+CD4+ T cells sorted from the LV demonstrated a limited repertoire of TCR clones relative to the periphery, suggesting that an antigen‐restricted response occurs in the LV in response to pressure overload. Taken together, our results indicate that CD4+ T cell recognition of self‐antigens through the TCR is required for maladaptive cardiac remodeling and cardiac dysfunction. Ongoing studies are focused on the identification of specific self‐antigens generating this clonal CD4+ T cell response in the heart.Support or Funding InformationNIH R01 HL123658‐01, T32 AI007077‐34, F31 HL140883‐01A1, AHA 19PRE34020084This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Defining the Role of the Sympathetic Nervous System in Leukocyte Migration In Vivo
Authors: Weber Jasmin 
Published: June 2021

The nervous system and the immune system are intricately linked, with neurotransmitters controlling many aspects of leukocyte biology. Recently, we have shown that leukocyte migration patterns from murine blood to tissues fluctuate over 24h, exhibiting peak numbers in blood during the day and a trough in the night. How neural signaling pathways are involved in these circadian oscillations remains to be elucidated. Here, we investigated the effect of sympathetic nervous system manipulations on the circadian migration behavior of leukocyte subsets in vivo. Stimulation of specific β‐adrenoreceptors drastically influenced blood leukocyte numbers in a subset‐specific manner. Using systematic adoptive transfer assays of leukocytes combined with flow cytometric analyses we could attribute this to an increased capacity of blood leukocyte subsets to emigrate into organs. We furthermore investigated this migratory homing behavior of leukocyte subsets in real time using intravital microscopy of different tissues and focusing on the effect on different steps of the leukocyte adhesion cascade. Together, our investigations provide mechanistic insights into the leukocyte‐subset specific migration behavior after sympathetic stimulation.Support or Funding InformationWe are very thankful for our funding agencies: European Research Council (ERC), Deutsche Forschungsgemeinschaft (DFG), Integrated Research Training Group 914 / Sonderforschungsbereich 914 of the Ludwig‐Maximilians‐Universitaet Muenchen, International Max Planck Research School for Life SciencesThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Bacteria degrade the specialized basal lamina attaches the gingiva to teeth
Authors: Fouillen Aurélien , Grenier Daniel , Barbeau Jean , Baron Christian , Moffatt Pierre , Nanci Antonio 
Published: June 2021

IntroductionThe junctional epithelium is a specialized portion of the gingiva that seals off the tooth supporting tissues from the oral environment. This relationship is achieved via a specialized basal lamina (sBL). Three unique proteins ‐AMTN, ODAM and SCPPPQ1‐ together with Laminin‐332 structure the supramolecular organization of this sBL and determine its adhesive capacity. Despite its critical and strategic importance and continued exposure to bacteria, little is known on the susceptibility of the sBL to bacterial activity.MethodsThe objective of this study was to evaluate the impact of various oral bacteria on the sBL using molecular biology and complementary imaging approaches.ResultsSDS‐PAGE and western blot analysis of degradation assays with trypsin like proteases as well as incubation with Porphyromonas gingivalis (P. gingivalis) revealed that all sBL constituents, except SCPPPQ1, were rapidly degraded. Mass spectrometry also confirmed that SCPPPQ1 was not degraded. We have previously shown that mixing the recombinant sBL proteins results in the formation a supramolecular network that mimicked the sBL. To observe the impact of oral bacteria on this ‘reconstituted’ sBL network, we exposed it to P. gingivalis and observed the results by atomic force microscopy and scanning electron microscopy (SEM). The bacteria destroyed the supramolecular network in their vicinity creating a peripheral space around them. SEM imaging further showed the presence of fine filamentous residual matrix on the exposed HOPG surface, suggesting the incomplete degradation of some component and a layered destruction of the network. Finally, to determine the effect of P. gingivalis on the native sBL itself, we exposed it ex‐vivo to bacteria. After two hours of exposure, SEM analysis revealed the presence of a shallow depression around the bacteria and after 6 h, the affected peri‐bacterial area became deeper and cavitated , suggesting active degradation of the native sBL as well.ConclusionWe show here for the first time that enzymes and P. gingivalis, one of the major bacteria implicated in chronic periodontitis, can attack the individual components of the sBL as well as alter the supramolecular organization of this critical adhesive extracellular matrix. Because destruction of the sBL would open the door to bacterial infiltration around teeth. These results highlight the importance of the sBL in PD and open the door for new treatment paradigms.Support or Funding InformationThis work was supported by CIHR, Canada Research Chair, RSBO, and Shriners Hospital.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Methicillin‐resistant Staphylococcus aureus causes sustained collecting lymphatic vessel dysfunction
Authors: Jones Dennis , Padera Timothy 
Published: June 2021

Methicillin‐resistant Staphylococcus aureus (MRSA) is a major cause of morbidity and mortality worldwide and is a frequent cause of skin and soft tissue infections (SSTIs). Lymphedema—fluid accumulation in tissue caused by impaired lymphatic vessel function—is a strong risk factor for SSTIs. SSTIs also frequently recur in patients and sometimes lead to acquired lymphedema. However, the mechanism of how SSTIs can be both the consequence and the cause of lymphatic vessel dysfunction is not known.Here, we used the endemic USA300 strain of community‐associated MRSA (CA‐MRSA), a common cause of serious bacterial infections in the United States, to establish a model of localized MRSA infection. We used intravital imaging to determine whether MRSA infections inhibit lymphatic vessel contractility and lymph flow. In vivo studies used C57BL/6, iNOS−/− C57BL/6, MyD88−/− C57BL/6, LysMgfp/gfp C57BL/6, and alpha SMAP‐DsRed/C57BL/6 mice to assess the effects of host‐derived molecules to lymphatic contractility after infection. Alpha SMA‐DsRed transgenic mice were visualized and immunofluorescence staining of alpha SMA+ lymphatic muscle cells (LMCs) of WT mice was performed to analyze LMC coverage of lymphatic vessels on multiple days after infection. To define the molecular mechanisms related to this response, we performed cell viability and cell lysis assays and measured killing of LMCs by MRSA‐conditioned supernatant from wild type and mutant MRSA strain(s). Similar experiments were performed using recombinant MRSA toxins.Intravital imaging in mice revealed an acute reduction in both lymphatic vessel contractility and lymph flow after localized MRSA infection. Moreover, chronic lymphatic impairment is observed long after MRSA is cleared and inflammation is resolved. Associated with decreased collecting lymphatic vessel function was the loss and disorganization of lymphatic muscle cells (LMCs), which are critical for lymphatic contraction. In vitro, incubation with MRSA‐conditioned supernatant led to LMC death. Proteomic analysis identified several accessory gene regulator (agr)–controlled MRSA exotoxins that contribute to LMC death. Infection with agr mutant MRSA resulted in sustained lymphatic function compared to animals infected with wild‐type MRSA.Our findings suggest that agr is a promising target to preserve lymphatic vessel function and promote immunity during SSTIs.Support or Funding InformationThis work was supported by the National Institutes of Health under award numbers R21AI097745, DP2OD008780, R01CA214913, and R01HL128168 to Timothy Padera. Dennis Jones was supported in part by the UNCF‐Merck Science Initiative Postdoctoral Fellowship, Burroughs Wellcome Fund Postdoctoral Enrichment Program Award, and NIH NCI F32CA183465.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Clinical Cases Review: Hand Innervation and Function using a Hand Model
Authors: Elmansoury Amr , Pessina Monica 
Published: June 2021

Objective

To improve the understanding of the anatomy of the hand muscles and its nerve supply.
To understand the different types of nerve injuries of the hand
Application of the theoretical knowledge on a hand model
Material and MethodsTwenty‐eight first‐year medical students had a 55 minutes educational session that included

‐ A pretest
‐ Ten minutes focused power point presentation.
‐ An interactive simulation of hand deformities using a color labelled hand model
‐ Post test
‐ Feedback questions
ResultsTwenty‐eight students participated in the session. Scores were measured on a scale from 0–8. The mean pretest score was (3.4 +/− 1.7) while the posttest score was (5.07 +/− 2.25). The posttest scores were higher than the pretest scores, and that was statistically significant using a paired t‐test of P = 0.002ConclusionUsing a short presentation and an interactive simulation of the hand function impairment and anatomy was effective in teaching various nerve injuries of the hand.Support or Funding InformationNo funding was received
Pre and Post Test Score ChartimagePre and Post Test Score ChartThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
A review of U.S. medical schools promotion standards for excellence in education
Authors: Hoffman Leslie , Lufler Rebecca , Brown Kirsten , DeVeau Kathryn , DeVaul Nicole , Fatica Lawrence , Mussell Jason , Byram Jessica , Dunham Stacey , Wilson Adam 
Published: June 2021

PurposeThe number of medical science educators, who commit the majority of their time to education‐related duties, is ostensibly on the rise. Given the growing role separation between teaching and biomedical research faculty in medical education, it is timely to examine how institutions communicate their promotion criteria related to educational excellence and scholarship. This study investigates the extent to which medical schools' promotion criteria align with published standards for documenting educational activities.MethodsPromotion guidelines from U.S. allopathic and osteopathic medical schools were collected mostly from institutional websites and were systematically analyzed according to a predefined data extraction rubric adapted from previously published standards for documenting educational activities. After 10 researchers each independently reviewed and extracted data from 1/5 of all guidelines, researchers compared their findings in pairs and reached consensus on all identified discrepancies prior to final data submission. Descriptive statistics were used to determine the frequency of cited promotion criteria.ResultsPromotion‐related documents were retrieved for 110 (59%) of the 185 allopathic and osteopathic U.S. medical schools. Fifteen percent of schools were cited as lacking explicit direction for education focused faculty to attain academic advancement. Across seven education‐related domains, ‘educational measurement and evaluation’ was the least represented with only 37% of schools referencing this domain in their guidelines. The other domains including teaching, curriculum/program development, mentoring/advising, educational leadership/administration, research/scholarship, and service were referenced by at least 59% of schools. Overall, only 20% of schools were judged to have above average or very comprehensive criteria for excellence in education.ConclusionsWhile most medical schools acknowledge education within their promotion criteria, only three fully embraced the educational excellence standards recommended in the literature. These data should be concerning to current teaching faculty who may be evaluated for promotion based on vague and/or incomplete promotion criteria. With greater awareness of how educational excellence is currently documented and how promotion criteria can be improved, more schools may be compelled to embrace change and to follow recommended best practices.Support or Funding InformationNoneThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.