bluuebunny/crossref_metadata_2025_split huggingface dataset:
Absence of Mast Cells in the Kidneys of Rats Subjected to Fat Embolism Despite their Presence in the Lungs and Heart
Authors: Patel Chirag , Fletcher Amanda N , Poisner Alan M , Siddiqi Ahsan , Arif Dauod , Hamidpour Soheila , Ponnapureddy Rakesh , Molteni Agostino 
Published: November 2023

In a rat model of fat embolism (FE) induced by i.v. injection of triolein (T), we have shown that the lungs, hearts and kidneys demonstrate severe histopathological damage characterized by organ inflammation and arterial constriction. 1,2,3 Such damage is present up to 10 weeks after injection.1 The renin angiotensin system (RAS) plays a role in the pathogenesis of the damage since captopril (an ACE inhibitor) and losartan (Los), an angiotensin‐II type 1 receptor blocker, prevented the damage.4 After T injection, an increase in renin stain was observed in the kidney juxta‐glomerular apparatus (JXTG)5 and in the lungs.6 The renin overexpression may be related to an increased number of mast cells (MCs),7 and indeed we found an increased number of these cells 10 weeks post T injection in the lungs of the rats.8 MCs in lower numbers were also observed in hearts of the same rats, but LOS did not reduce their number.9 On the basis of these observations, we decided to evaluate the potential presence of MCs in kidneys after T injection.Twenty‐two Sprague Dawley rats (~300 gm BW) received either T (0.2 mL i.v.) or saline. Six weeks later, half of the rats were given i.p. injection of Los and the remainder received saline. Four weeks later (10 weeks post T injection), rats were anesthetized with isoflurane, sacrificed, and necropsied. Tissues were fixed in 10% formalin and stained with H&E (morphometric scoring), Trichrome (fibrosis) and CD 11‐c kit (MCs). On each slide, 10 photographs were taken at random at 400× and MCs evaluated by two pathologists unaware of the slide identity.After T injection, we observed severe arterial damage with increased medial thickness and reduced lumen patency. Glomeruli showed increased cellularity, thickening of basal membrane, and crescent formation. Scattered chronic inflammatory cells and erythrocytes were seen in the tubuli. The damage was moderately reduced by Los treatment. MCs were not seen in any of the animals.In the kidneys, despite the high presence of renin in the JXTG and severe vasculitis after T injection, we could not identify MCs at 10 weeks even with a very specific staining method. This is in contrast with the presence of MCs that we have found in the lungs and heart. The absence of MCs in the kidneys at 10 weeks may reflect different pathogenic mechanisms or a time course different from that of the lungs or heart.Support or Funding InformationM. K. Geldmacher Foundation, St. Louis, MO; This work was supported by a CTSA grant from NCRR and NCATS awarded to the University of Kansas Medical Center for Frontiers: The Heartland Institute for Clinical and Translational Research # TL1TR000120. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH, NCRR, or NCATS.
Increased Indoleamine 2,3‐dioxygenase expression in the renal fibrogenesis induced by unilateral ureteral obstruction
Authors: Matheus Luiz Henrique Gomes , Simão Gislene Mendes Simão , Amaral Taíssa Altieri do , de Oliveira Brito Rodrigo Barbosa , Malta Camila Soares , Matos Yves Silva Teles , Souza Diego Mota , Dellê Humberto 
Published: November 2023

Chronic kidney disease (CKD) is a progressive and high prevalent disease worldwide. Its prevalence doubled on USA on the last decade and as such, deserves attention and a worry to better know its mechanisms.Renal fibrosis is a lead event happening in CKD, and is characterized by an extensive inflammatory process with vast macrophage migration and extracelular matrix accumulation, those leading to damages on the kidney architecture and renal function, and thus worsening the patient condition.In this frame, Indoleamine 2,3‐dioxygenase (IDO), a tryptophan‐catabolizing enzyme with immunomodulatory properties, seems to be deeply associated with mechanisms leading to a bad prognostic to fibrotic and inflammatory conditions. Because IDO may be modulated by Transforming growth factor‐β (TGF‐ β), a key cytokine in the development of renal fibrosis, we hypothesized the relationship between IDO and renal fibrogenesis.In the present study, our objective was to analyze IDO activity and expression in a model of renal fibrogenesis induced by unilateral ureteral obstruction (UUO), and correlate it with markers of epitelial‐mesenchymal transition.Wistar rats were submited to 7 days of UUO. The unobstructed kidneys of the UUO (CL) and the kidneys from SHAM operated rats were used as control. Increased interstitial collagen deposition was remarkable in UUO kidneys. Immunohistochemistry analysis revealed a significant increase in the number of macrophages in UUO kidneys, accompanied by reduction of tubular e‐cadherim expression. Markers of mesenchymal cells (alphaSMA and vimentin) were increased in UUO kidneys, in particular in the renal interstitium and in tubules. These findings characterize the epitelial‐mesenchymal transition process and were accompained by increased TGB‐beta 1 expression (qRT‐PCR). Finally, IDO was markedly expressed in cortical and medular tubules of the UUO kidneys. In addition, IDO activity was accessed from renal tissue, being significantly higher in UUO kidneys. These data demonstrated that IDO is increased during renal fibrogenesis and associated with an increased number of macrophages as well as an upregulation of mesenchymal cell markers, sugesting an association between IDO and EMT.Support or Funding InformationFAPESP (2012/04423‐0)
Clomiphene Citrate and Male Infertility: Investigation of Treatment on Spermatogenesis and Testicular Histomorphology in a Rat Model
Authors: Gibson‐Corley Katherine , Kogan Paul , Wald Moshe 
Published: November 2023

Clomiphene citrate (CC) is used off‐label as a treatment for selected cases of male infertility, acting as a competitive selective‐estrogen receptor modulator. Although CC is used clinically, there have only been a small number of randomized controlled human studies that have yielded inconclusive findings. Here we have used a prospective animal model for studying CC treatment to determine if this drug increases spermatogenesis for treatment of male infertility. We treated sexually mature Sprague‐Dawley rats with CC via oral gavage for either 1 or 2 rat spermatogenic cycles (13 days for 1 cycle or 26 days for 2 cycles) at a dose of 0.6 mg/kg. This dose was chosen as it is a similar dose to what is clinically used in humans. Testes were weighed and sperm counts were measured from rats treated with CC and control animals. Testes were fixed in modified Davidson's solution and stained with HE for histopathological and morphometric analysis. No differences in sperm count and no histomorphologic differences were noted in the testes treated with CC as compared to control. Seminiferous tubule minimum diameter and tubular epithelial height were measured and the number of retained spermatozoa was also scored with no significant differences compared to control. Although previous studies have shown that rats treated with much higher doses of CC (>20 mg/kg) have decreased spermatogenesis, we can conclude that CC treatment at a therapeutic dose of 0.6 mg/kg in rats does not appear to have an effect on spermatogenesis. That said; CC may play a more indirect role in male infertility which may include changes in accessory reproductive organs or alterations in hormonal levels.Support or Funding InformationInternal funding; Department of Urology, University of Iowa
The Effect of the Baby Friendly Hospital Initiative on Exclusive Breastfeeding Rates in Hospitals
Authors: Patterson Julie Ann , Olson Beth H , Keuler Nicholas S 
Published: November 2023

BackgroundExclusive breastfeeding is associated with an increased level of protection from maternal and infant morbidity and mortality. The Baby Friendly Hospital Initiative (BFHI) was launched in 1991 to positively influence breastfeeding outcomes by recognizing hospitals with optimal practices in mother/infant care. There is limited research examining the influence of the BFHI on exclusive breastfeeding rates, and how these rates may be influenced by other factors.Study ObjectiveThe aim of this study is to examine the relationship between population demographics, including poverty and race, and exclusive breastfeeding outcomes in hospitals with and without the BFHI designation.MethodsData was obtained from the Joint Commission, a leading agency in hospital accreditation, and included 283 BFHI hospitals and 1071 hospitals without the BFHI designation. Demographic variables were applied to the data set and included total population; proportion of white, African American, Hispanic, Asian; educational status and household income, as computed for the zip code surrounding each hospital. Relationships were explored using linear regression. We additionally built a multiple linear regression model in an attempt to determine how well we can predict exclusive breastfeeding rates.ResultsThe proportion of whites, number of residents with a bachelor's degree, and income were all positively related to exclusive breastfeeding rates within the hospital (p<0.0001). By contrast, the proportion of African Americans, proportion of Hispanics, and number in the population at less than 200% of the poverty line were negatively related to exclusive breastfeeding rates within the hospital (p<0.0001). Hospitals with BFHI designation had exclusive breastfeeding rates that were on average 10–15% higher than hospitals without BFHI designation, regardless of demographics. Using a multiple linear regression model we were able to explain 22% of the variability in exclusive breastfeeding rates.ConclusionsBFHI designation is associated with significantly higher exclusive breastfeeding rates independent of demographic variables. However, we recognize that our model was limited in its ability to explain the variability in the exclusive breastfeeding rates. We suggest areas for improvement of the model, including additional possible explanatory variables, which could be the subject of future research.Support or Funding InformationNo funding was received for this research.
Organic Cation Transporter Novel Type‐1 (OCTN‐1) And Pulmonary Responses To Secondhand Tobacco Smoke (SHS)
Authors: Milner Dallin C. , Lewis Joshua B , Winden Duane R , Gassman Jason , Monson Troy , Broberg Dallin , Arroyo Juan A , Reynolds Paul R 
Published: November 2023

Oxidative stress is involved in the pathogenesis of lung disorders such as asthma, COPD, acute lung injury, pulmonary fibrosis and lung cancer. The antioxidant amino acid ergothioneine and its highly specific transporter, OCTN‐1 (organic cation transporter novel type‐1) play important roles in antioxidant cellular defence. The goal of this project was to understand the role of OCTN‐1 in protecting the lung from oxidative stress caused by secondhand tobacco smoke (SHS). The current research evaluated the in vivo effects of SHS exposure in OCTN‐1 null and control mice compared to identical animals exposed to room air only for three months. Mice were subjected to daily secondhand tobacco smoke (SHS) via a nose only inhalation system (Sireq industries) from PN20‐110. Q‐PCR and immunoblotting confirmed no OCTN‐1 expression in nulls regardless of exposure, but a significant decrease in expression following SHS exposure. Bronchoalveolar lavage fluid (BALF) procured from OCTN‐1 null and control animals revealed SHS‐induced increases in total cell counts and protein compared to controls. Inflammatory mediators including TNF‐alpha and IL‐1beta were also significantly increased in SHS‐exposed OCTN‐1 nulls compared to smoke exposed controls. As a general theme, inflammatory status and remodeling were increased in OCTN‐1 nulls exposed to SHS compared to smoked controls. Such differences included histological simplification of the distal lung, decreased abundance of non‐ciliated cells in the proximal lung, elevated PMNs, and augmented inflammatory cytokines including TNF‐alpha and IL‐1beta. Of particular interest, increased thickness and volume density of alveolar septa and inflammatory cell infiltration were observed in OCTN‐1 lungs exposed to SHS compared to controls. These data reveal intriguing insight into potential mechanisms related to oxidative stress that may be key factors in SHS‐mediated inflammation.Support or Funding InformationThis work was supported by a grant from the Flight Attendant's Medical Research Institute (FAMRI, PRR) and a BYU Mentoring Environment Grant (PRR).
Molecular Mechanism Of DNA Interstrand Crosslink Repair
Authors: Smogorzewska Agata , Kottemann Molly , Conti Brooke , Thongthip Supawat , Rickman Kimberly , Lach Frank 
Published: November 2023

The focus of our research is to understand the mechanism of DNA repair during DNA replication. I will discuss how DNA interstrand crosslinks (ICLs) are repaired as well as describe our early studies to understand the response of replication fork machinery to stalling at difficult to replicate regions.Most of our research concentrates on ICL repair with the overall goal to gain insights into the cellular and organismal consequences of deficiencies in this type of repair. I will discuss the role of FAN1 in assuring proper DNA repair. FAN1 is a nuclease important for ICL repair, whose deficiency results in kidney disease. To help elucidate the cellular and tissue maintenance functions of FAN1, we generated Fan1 knockout mice. Fan1−/− mouse embryonic fibroblasts (MEFs) display Mitomycin C (MMC)‐induced proliferation defect. The crosslink sensitivity of Fan1−/− cells is not as significant as the level observed in Fanca, Fancd2 or Slx4 (Fancp)‐deficient cell lines. Wild type mouse FAN1 cDNA but not the variants with inactivating mutation in the SAP or nuclease domains complement ICL sensitivity in Fan1−/− MEFs. As we previously described for a human protein, the mutation in the UBZ domain, which is essential for the interaction with FANCD2, is completely dispensable for the crosslink‐repair function of FAN1. At high level of crosslink insult, deficiency in Fan1 can additively enhance the degree of MMC‐induced chromosomal abnormality in Fancd2−/− MEFs. Karyomegalic nuclei are detected in the kidney and liver of Fan1 mice from the age of 6 months with the level of renal karyomegaly intensifying with age. Fan1−/− mice, when treated with MMC, display hypocellular bone marrow and are hypersensitive to MMC treatment.In the second part of my talk, I will discuss proteins at the active replication fork that are important for proper response to replication stress and describe a regulatory network that is called upon when DNA damage is encountered during replication.Support or Funding InformationSupported by NIH RO1grant HL120922, grant # 8 UL1 TR000043 from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) program, and by Rita Allen Foundation Scholars grant.
Chromatin Replication And Epigenome Maintenance
Authors: Groth Anja 
Published: November 2023

In dividing cells, faithful duplication of the genome must be accompanied by reproduction of the chromatin landscape on newly synthesized DNA. Our research focuses on how human cells replicate chromatin and ensure transmission of genetic and epigenetic information during cell division.Recently, we have developed an explorative proteomic approach, Nascent Chromatin Capture (NCC), to profile chromatin replication in human cells (Alabert et al., 2014). NCC relies on biotin‐dUTP labeling of replicating DNA and cross‐linking, followed by affinity‐purification of tagged chromatin and quantitative proteomics. By comparing nascent newly synthesized chromatin with mature post‐replicative chromatin, we have provided an extensive resource to understand DNA replication and restoration of chromatin organization (Alabert et al., 2014). In addition, we have used NCC technology combined with pulsed SILAC labeling to comprehensively address transmission of histone marks across the cell cycle. We find that histone PTMs are propagated by two distinct mechanisms in human cells (Alabert et al., 2015), which hasimplications for how cell proliferation is linked to cell fate decision. To understand how histones are handled at active and damaged replication forks, we are doing histone chaperone structure‐function analysis (Huang, Stromme et al., 2015). I will discuss the roles of MCM2, ASF1 and TONSL‐MMS22L in handling histones at the fork and our latest progress in understanding how functional chromatin domains are maintained in dividing cells.
Imaging Mass Spectrometry ‐ The Pyrazinamide Enigma
Authors: Prideaux Brendan , Sarathy Jansy , Via Laura , Gopal Pooja , Barry Clifton , Dick Thomas , Dartois Veronique 
Published: November 2023

Pyrazinamide is a 60‐year old anti‐tuberculosis (TB) drug, the mechanism of which has been the focus of intense research and yet largely remains a mystery. Today, PZA would fall under the category of fragment rather than drug, and would likely be missed because it is not active under standard in vitro conditions despite its remarkable sterilizing activity against human TB. At the time of its introduction, PZA reduced therapy duration from 9 to 6 months, and has been part of the first‐line and most second‐line drug regimens since then. However, resistance to PZA continues to emerge, threatening one of the most valuable drugs in our current arsenal.Given the striking disconnect between PZA's activity in vitro and in vivo, we have developed pharmacological tools to study the pharmacokinetics, tissue distribution, metabolism, and activity of PZA at the site of action, in patients and in animal models. In pulmonary TB, the pathogen is both intracellular and extracellular, and resides in multiple types of lung lesions that essentially comprise layers of immune cells often surrounding necrotic foci. Decades of clinical trials have taught us that the presence of cavities – large necrotic lesions that are connected with an airway – correlates with poor treatment outcome. We also know that the spectrum of lesions seen in human TB is inhabited by multiple bacterial populations with differential susceptibilities to any given drug. We thus asked “which bacterial subpopulations are reached and killed by PZA?”Using MALDI mass spectrometry imaging and classical mass spectrometry, we have discovered that PZA and its active metabolite have the unique ability to distribute rapidly and homogeneously in all lesion types and lesion compartments, including cavities. Lesion‐centric efficacy studies in animal models have been conducted to measure the killing activity of PZA and its active metabolite POA against specific subpopulations, either in vitro or ex vivo. Characterization of resistant mutants isolated in vitro revealed complex metabolic networks affected by PZA's active metabolite. We will discuss what can be learned from these collective results to develop assays and screening strategies that have the potential to capture the “next‐gen PZA” and overcome ramping resistance.
To Stay (At The Bench) Or Go? Determinants Of Career Decision‐Making In Recent Ph.D. Graduates
Authors: Gibbs Kenneth D , Griffin Kimberly 
Published: November 2023

Recent biomedical workforce policy efforts have centered on the challenges of enhancing career preparation for trainees and increasing workforce diversity. While these issues have been addressed separately, little work considers them concurrently. This study addresses two questions: (a) what is the process of career interest formation for recent Ph.D. graduates, and (b) how does this process differ across lines of gender and race‐ethnicity? We report results from a mixed‐methods study, including a survey of 1500 American biomedical Ph.D. graduates (n=276 from underrepresented minority (URM) backgrounds), and interviews with 70 respondents pursuing diverse career pathways. Survey data showed that relative to Ph.D. entry, on average, scientists from all backgrounds reported (i) increased knowledge about career options (ii) significantly decreased interest in faculty careers at research universities, and (iii) significantly increased interest in non‐research careers. There were differences in the overall levels of career pathway interest (at Ph.D. entry, completion, and postdoc), and the magnitude of change in interest in these careers across social identity. Multiple logistic regression showed that when controlling for career pathway interest at Ph.D. entry, first‐author publication rate, faculty support, research self‐efficacy, and graduate training experiences, women and URM men remained 36–54% less likely than White/Asian men to express high interest in faculty careers at research‐intensive universities, and URM women were 93% more likely than all other groups to report high interest in non‐research careers. Qualitative data revealed how vicarious learning experiences during graduate school, systemic dynamics within the biomedical enterprise, and unique personal motivations for pursuing scientific research play determinative roles in the career pathways Ph.D. graduates pursued. Findings point to the need for enhanced career development programs earlier in the training process, and interventions that are sensitive to the distinctive patterns of interest development across social identity groups.Support or Funding InformationThis work was supported, in part, from a generous grant from the Burroughs Wellcome Fund. KG is supported by the NCI Cancer Prevention Fellowship Program.