bluuebunny/crossref_metadata_2025_split huggingface dataset:
Non-endoscopic screening for Barrett’s esophagus and Esophageal Adenocarcinoma in at risk Veterans
Authors: Greer Katarina B. , Blum Andrew E. , Faulx Ashley L. , Deming Erica M. , Hricik Lauren L. , Siddiqui Hinnah , Wilson Brigid M. , Chak Amitabh 
Published: March 2024

AbstractBackgroundWhile rates of Esophageal Adenocarcinoma (EAC) in the US continue to rise, many patients at risk of disease are not screened. EsoCheck (EC), a non-endoscopic esophageal balloon sampling device coupled with EsoGuard (EG), a DNA based screening assay, is an FDA-approved minimally invasive alternative to the traditional screening method of upper endoscopy.AimAim To prospectively determine the diagnostic accuracy, tolerance, and acceptability of the EC/EG test in a screening population.MethodsWe recruited Veterans who met the American College of Gastroenterology (ACG) Guideline criteria for endoscopic Barrett’s Esophagus (BE) and EAC screening at Louis Stokes Cleveland Veteran Affairs Medical Center. All study participants completed unsedated EC guided distal esophageal sampling followed by a sedated esophagogastroduodenoscopy (EGD). Diagnostic yield of the EG assay and EGD was recorded and used in calculation of sensitivity and specificity of EC/EG in prospective screening. The abbreviated Spielberger State-Trait Anxiety Inventory (STAI-6) questionnaire was administered before and after completion of EC. Overall tolerance of EC sampling was evaluated on a 10-point Likert scale.ResultsResults Esophageal cancer screening was accepted by 130/782 (16.6%) eligible veterans and we analyzed results of those who completed both screening tests (N = 124). Prevalence of BE/EAC among studied veterans was 12.9% (16/124), based on EGD. Sensitivity and specificity of EC/EG for EGD-detected BE/EAC were 92.9% (95% CI 66.1, 99.8) and 72.2% (95% CI 62.1, 80.8), respectively. Positive and negative predictive values were 32.5% (95% CI 18.6, 49.1) and 98.6% (95% CI 92.4, 100), respectively. Baseline STAI-6 scores were reflective of notable levels of anxiety among veterans in the peri-procedural setting. Mean post-procedure acceptability score for Esocheck test was 7.23 (SD 2.45).ConclusionsConclusions Our data suggest excellent sensitivity and negative predictive value of EC/EG in a screening population of veterans, making this modality a powerful screening tool for BE and EAC.
Retention and the Intersection of Structural Inequities in a Breastfeeding Intervention Study
Authors: LaPlant Helen Wilde , Francis-Edoziuno Confidence , Guan Zhe , Aderibigbe Tumilara , Chang Xiaolin , Alhabodal Ashwag Saad , Delaney Kristen , Scott Dana , Marshall-Crim Mary , Freytes Idelisa , Henderson Wendy A. , Walsh Stephen , Lucas Ruth F. 
Published: March 2024

AbstractIntroductionWomen below the poverty threshold have lower representation and retention in breastfeeding studies.MethodsA secondary analysis of a longitudinal randomized controlled self-management for breast and nipple pain during breastfeeding study. Participants completed online surveys at discharge, weeks 1, 2, 3, 6, 9, 12, 18, and 24, with face-to-face interviews at 6 and 24 weeks. Text messages were sent to participants when modules and surveys were due. Retention was assessed in R with descriptive statistics, Mann-Whitney, Pearson’s chi-square, and Cox Proportional Hazard Regression.ResultsTwo hundred and forty-four women (89 ≤$50,000 and 155 >$50,000) were recruited. Retention rates at 1 (93%), 2 (87%), 6 (82%), 9 (77%) and 24 (72%) weeks. For women of low income compared to those of high income there was a hazard ratio (HR) of 2.5 (p=0.0001) for retention. For non-Hispanic Black and Hispanic women compared to the combined non-Hispanic White and Other group, HRs for retention were 3.3 and 2.6 respectively (p=0.0001). Adjustment for age in the final hazard regression model of income, age, race and ethnicity decreased the HR for women of low income to 1.6 and HRs for non-Hispanic Black and Hispanic women to 2.1 and 1.9, respectively (p=.0001). However, none of the individual factors in the model achieved statistical significance.DiscussionRetention in breastfeeding studies impacts breastfeeding duration, a key lifelong preventative health behavior. Despite accessible study design, retention of women desiring to breastfeed was adversely affected by the intersection of income, race and ethnicity, and age.
Molecular dissection of HERV-W dependent microglial- and astroglial cell polarization
Authors: Gruchot Joel , Reiche Laura , Werner Luisa , Herrero Felisa , Schira Jessica , Meyer Urs , Küry Patrick 
Published: March 2024

Abstract/SubjectThe endogenous retrovirus type W (HERV-W) is a human-specific entity, which was initially discovered in multiple sclerosis (MS) patient derived cells. We initially found that the HERV-W envelope (ENV) protein negatively affects oligodendrogenesis and controls microglial cell polarization towards a myelinated axon associated and damaging phenotype. Such first functional assessments were conductedex vivo, given the human-specific origin of HERV-W. Recent experimental evidence gathered on a novel transgenic mouse model, mimicking activation and expression of the HERV-W ENV protein, revealed that all glial cell types are impacted and that cellular fates, differentiation, and functions were changed. In order to identify HERV-W-specific signatures in glial cells, the current study analyzed the transcriptome of ENV protein stimulated microglial- and astroglial cells and compared the transcriptomic signatures to lipopolysaccharide (LPS) stimulated cells, owing to the fact that both ligands can activate toll-like receptor-4 (TLR-4). Additionally, a comparison between published disease associated glial signatures and the transcriptome of HERV-W ENV stimulated glial cells was conducted. We, therefore, provide here for the first time a detailed molecular description of specific HERV-W ENV evoked effects on those glial cell populations that are involved in smoldering neuroinflammatory processes relevant for progression of neurodegenerative diseases.
Dendritic Cell – Fibroblast Crosstalk via TLR9 and AHR Signaling Drives Lung Fibrogenesis
Authors: Carter Hannah , Costa Rita Medina , Adams Taylor S. , Gilchrist Talon , Emch Claire E. , Bame Monica , Oldham Justin M. , Linderholm Angela L. , Noth Imre , Kaminski Naftali , Moore Bethany B. , Gurczynski Stephen J. 
Published: March 2024

AbstractIdiopathic pulmonary fibrosis (IPF) is characterized by progressive scarring and loss of lung function. With limited treatment options, patients succumb to the disease within 2-5 years. The molecular pathogenesis of IPF regarding the immunologic changes that occur is poorly understood. We characterize a role for non-canonical aryl-hydrocarbon receptor signaling (ncAHR) in dendritic cells (DCs) that leads to production of IL-6 and IL-17, promoting fibrosis. TLR9 signaling in myofibroblasts is shown to regulate production of TDO2 which converts tryptophan into the endogenous AHR ligand kynurenine. Mice with augmented ncAHR signaling were created by crossing floxed AHR exon-2 deletion mice (AHRΔex2) with mice harboring a CD11c-Cre. Bleomycin was used to study fibrotic pathogenesis. Isolated CD11c+ cells and primary fibroblasts were treated ex-vivo with relevant TLR agonists and AHR modulating compounds to study how AHR signaling influenced inflammatory cytokine production. Human datasets were also interrogated. Inhibition of all AHR signaling rescued fibrosis, however, AHRΔex2mice treated with bleomycin developed more fibrosis and DCs from these mice were hyperinflammatory and profibrotic upon adoptive transfer. Treatment of fibrotic fibroblasts with TLR9 agonist increased expression of TDO2. Study of human samples corroborate the relevance of these findings in IPF patients. We also, for the first time, identify that AHR exon-2 floxed mice retain capacity for ncAHR signaling.
Synchrony between midbrain gene transcription and dopamine terminal regulation is modulated by chronic alcohol drinking
Authors: Farahbakhsh Zahra Z. , Holleran Katherine M. , Sens Jonathon P. , Fordahl Steve C. , Mauterer Madelyn I. , López Alberto J. , Cuzon Carlson Verginia C. , Kiraly Drew D. , Grant Kathleen A. , Jones Sara R. , Siciliano Cody A. 
Published: March 2024

AbstractAlcohol use disorder is marked by disrupted behavioral and emotional states which persist into abstinence. The enduring synaptic alterations that remain despite the absence of alcohol are of interest for interventions to prevent relapse. Here, 28 male rhesus macaques underwent over 20 months of alcohol drinking interspersed with three 30-day forced abstinence periods. After the last abstinence period, we paired direct sub-second dopamine monitoring viaex vivovoltammetry in nucleus accumbens slices with RNA-sequencing of the ventral tegmental area. We found persistent augmentation of dopamine transporter function, kappa opioid receptor sensitivity, and dynorphin release – all inhibitory regulators which act to decrease extracellular dopamine. Surprisingly, though transcript expression was not altered, the relationship between gene expression and functional readouts of these encoded proteins was highly dynamic and altered by drinking history. These results outline the long-lasting synaptic impact of alcohol use and suggest that assessment of transcript-function relationships is critical for the rational design of precision therapeutics.
A matter of food and substrain: obesogenic diets induce differential severity of cardiac remodeling and diastolic dysfunction in C57Bl/6J and C57Bl/6N substrains
Authors: Cascarano Lorena , Esfahani Hrag , Michel Pierre , Bouzin Caroline , Dessy Chantal , Balligand Jean-Luc , Michel Lauriane Y.M. 
Published: March 2024

ABSTRACTThe prevalence of metabolic syndrome in cardiac diseases such as heart failure with preserved ejection fraction (HFpEF) prompts the scientific community to investigate its adverse effects on cardiac function and remodeling and its associated mechanisms. However, the choice of a preclinical model of obesity-induced cardiac remodeling has proven more challenging with inconsistencies often found in very similar mouse models. Here, we invesgated the implication of both genetic background of mouse substrains as well as diet composition to identify a suitable model of diet-induced cardiac alterations. C57Bl/6J and C57Bl/6N male mice were subjected to distinct obesogenic diets consisting of high-fat and moderate-sucrose content (HF-S) or High-Sucrose and moderate lipid content (F-HS) versus matching control diets. 5-month dietary intervention with obesogenic diets induced weight gain, adipocyte hypertrophy and increased visceral and subcutaneous fat mass in both substrains. Obese mice showed similar impairment of glucose disposition and insulin tolerance among genotypes, both strains developing insulin resistance within two months. However, echocardiographic follow-up and histological analysis confirmed that HF-S diet increases cardiac hypertrophy, interstitial fibrosis as well as le atrial area in the C57Bl/6J strain only. On the contrary C57Bl/6N exhibit cardiac eccentric remodeling under control diets, possibly owing to a genetic mutation in the myosin light chain kinase 3 (Mylk3)gene, specific to this substrain, which was not further enhanced under obesogenic diets. Altogether, the present results highlight the importance of carefully selecting the suitable mouse strain and diets to model diet-induced cardiac remodeling. In this regard, C57Bl/6J mice develop significant cardiac remodeling in response to HF-S, and seem a suitable model for cardiometabolic disease.
Transcriptional modulation unique to vulnerable motor neurons predicts ALS across species and SOD1 mutations
Authors: Mei Irene , Nichterwitz Susanne , Leboeuf Melanie , Nijssen Jik , Lenoel Isadora , Repsilber Dirk , Lobsiger Christian S. , Hedlund Eva 
Published: March 2024

AbstractAmyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of somatic motor neurons (MNs), which innervate skeletal muscles. However, certain MN groups including ocular MNs that regulate eye movement are relatively resilient to ALS. To reveal mechanisms of differential susceptibility, we investigate the transcriptional dynamics of two vulnerable and two resilient MN populations in SOD1G93A ALS mice. Analysis of differentially expressed genes (DEGs) shows that each neuron type displays a largely unique spatial and temporal response to disease. Baseline gene expression of resilient MNs is clearly divergent from vulnerable MNs and their response to mutant SOD1 is minor, with regulation of few genes, some with known neuroprotective properties, including e.g.Ucn,CckandPostn. EASE, fGSEA and ANUBIX enrichment analysis demonstrate that vulnerable MN groups share pathway activation, including regulation of neuronal death, inflammatory response, ERK and MAPK cascades, cell adhesion and synaptic signaling. These pathways are largely driven by 11 upregulated genes, includingAtf3, Nupr1, Cd44, Gadd45a, Ngfr, Ccl2, Ccl7, Gal, Timp1, Serpinb1aandChl1, and indicate that cell death occurs through similar mechanisms across vulnerable MNs albeit with distinct timing. Machine learning using DEGs upregulated in our SOD1G93A spinal MNs predict disease in human stem cell-derived MNs harboring theSOD1E100Gmutation, and show that dysregulation ofVGF,INA, PENKandNTSare strong disease-predictors across SOD1 mutations and species. Meta-analysis across SOD1 transcriptome datasets identifies a shared vulnerability code of 32 genes including e.gAtf3,Nupr1,Vgf,Ina,Sprr1a, Fgf21, C1qb, Gap43, Adcyap1,andMt1. In conclusion our study reveals cell-type-specific gene expression and dynamic disease-induced regulation that may act to preserve neurons and can be used to predict disease.
Functional regimes define the response of the soil microbiome to environmental change
Authors: Lee Kiseok Keith , Liu Siqi , Crocker Kyle , Huggins David R. , Tikhonov Mikhail , Mani Madhav , Kuehn Seppe 
Published: March 2024

AbstractThe metabolic activity of soil microbiomes plays a central role in carbon and nitrogen cycling. Given the changing climate, it is important to understand how the metabolism of natural communities responds to environmental change. However, the ecological, spatial, and chemical complexity of soils makes understanding the mechanisms governing the response of these communities to perturbations challenging. Here, we overcome this complexity by using dynamic measurements of metabolism in microcosms and modeling to reveal regimes where a few key mechanisms govern the response of soils to environmental change. We sample soils along a natural pH gradient, construct >1500 microcosms to perturb the pH, and quantify the dynamics of respiratory nitrate utilization, a key process in the nitrogen cycle. Despite the complexity of the soil microbiome, a minimal mathematical model with two variables, the quantity of active biomass in the community and the availability of a growth-limiting nutrient, quantifies observed nitrate utilization dynamics across soils and pH perturbations. Across environmental perturbations, changes in these two variables give rise to three functional regimes each with qualitatively distinct dynamics of nitrate utilization over time: a regime where acidic perturbations induce cell death that limits metabolic activity, a nutrientlimiting regime where nitrate uptake is performed by dominant taxa that utilize nutrients released from the soil matrix, and a resurgent growth regime in basic conditions, where excess nutrients enable growth of initially rare taxa. The underlying mechanism of each regime is predicted by our interpretable model and tested via amendment experiments, nutrient measurements, and sequencing. Further, our data suggest that the long-term history of environmental variation in the wild influences the transitions between functional regimes. Therefore, quantitative measurements and a mathematical model reveal the existence of qualitative regimes that capture the mechanisms and dynamics of a community responding to environmental change.
Correspondence of fentanyl brain pharmacokinetics and behavior measured via engineering opioids biosensors and computational ethology
Authors: Muthusamy Anand K. , Rosenberg Matthew H. , Kim Charlene H. , Wang Alex Z. , Ebisu Haruka , Chin Theodore M. , Koranne Ashil , Marvin Jonathan S. , Cohen Bruce N. , Looger Loren L. , Oka Yuki , Meister Markus , Lester Henry A. 
Published: March 2024

AbstractDespite the ongoing epidemic of opioid use disorder and death by fentanyl overdose, opioids remain the gold standard for analgesics. Pharmacokinetics (PK) dictates the individual’s experience and utility of drugs; however, PK and behavioral outcomes have been conventionally studied in separate groups, even in preclinical models. To bridge this gap, we developed the first class of sensitive, selective, and genetically encodable fluorescent opioid biosensors, iOpioidSnFRs, including the fentanyl sensor, iFentanylSnFR. We expressed iFentanylSnFR in the ventral tegmental area of mice and recorded [fentanyl] alongside videos of behaviors before and after administration. We developed a machine vision routine to quantify the effects of the behavior on locomotor activity. We found that mice receiving fentanyl exhibited a repetitive locomotor pattern that paralleled the [fentanyl] time course. In a separate experiment, mice navigating a complex maze for water showed a dose-dependent impairment in navigation, in which animals repeated incorrect paths to the exclusion of most of the unexplored maze for the duration of the average fentanyl time course. This approach complements classical operant conditioning experiments and introduces a key feature of human addiction, the ability to carry out an ethologically relevant survival task, only now quantified in rodents. Finally, we demonstrate the utility of iFentanylSnFR in detecting fentanyl spiked into human biofluids and the generalizability of engineering methods to evolve selective biosensors of other opioids, such as tapentadol and levorphanol. These results encourage diagnostic and continuous monitoring approaches to personalizing opioid regimens for humans.
Cohesin regulates promoter-proximal pausing of RNA Polymerase II by limiting recruitment of super elongation complex
Authors: Tei Shoin , Sakata Toyonori , Yoshimura Atsunori , Natsume Toyoaki , Kanemaki Masato T , Bando Masashige , Shirahige Katsuhiko 
Published: March 2024

AbstractCohesin is a ring-shaped complex, responsible for establishing sister chromatid cohesion and forming topologically associating domains (TADs) and chromatin loops. Loss-of-function mutations in cohesin subunits and its regulatory factors can cause Cornelia de Lange syndrome (CdLS). Because dysregulated gene expression was observed in CdLS, it has long been thought that cohesin plays a regulatory role in transcription. Here, we investigated the effect of acute cohesin depletion on transcription and observed that a small number of genes exhibited differential expression. Analysis of RNA polymerase II (Pol II) distribution revealed that the depletion reduced Pol II promoter binding and pausing simultaneously at the majority of genes. This implies that at most genes, the two decreases counterbalance each other, resulting in unchanged gene expression. Additionally, we find that cohesin loss increased promoter binding of super elongation complex (SEC), which mediates the release of Pol II from paused state. Moreover, the reduction in pausing caused by cohesin depletion was no longer observed when SEC was inhibited. These observations suggest that cohesin regulates Pol II pausing by restricting SEC recruitment to promoters. Together, our study demonstrates the involvement of cohesin in transcriptional regulation, particularly in Pol II pause and release.
C1q/MASP complexes – hybrid complexes of classical and lectin pathway proteins are found in the circulation
Authors: Rosbjerg Anne , Plchová Tereza Alica , Bayarri-Olmos Rafael , Holm Bettina Eide , Pedersen Ida Sandau , Skjoedt Mikkel-Ole , Garred Peter 
Published: March 2024

AbstractComplement pathways, traditionally regarded as separate entities in vitro, are increasingly noted for cross-communication and bypass mechanisms. Among these, the MBL/Ficolin/CL associated serine protease-3 (MASP-3) — a component of lectin pathway pattern recognition receptors (PRMs) — has shown the ability to process critical substrates like pro-factor D and insulin growth factor binding protein-5 (IGFBP-5). Given shared features between lectin pathway PRMs and C1q from the classical pathway, we hypothesized that C1q might be a viable in vivo binding partner for the MASPs.We used microscale thermophoresis, ELISA and immunoprecipitation assays to detect C1q/MASP complexes and functionally assessed the complexes through enzymatic cleavage assays.C1q/MASP-3 complexes were detected in human serum and correlated well with MASP-3 serum levels in healthy individuals. The binding affinity between MASP-3 and C1q in vitro was in the nanomolar range, and the interaction was calcium-dependent, as demonstrated by their dissociation in the presence of EDTA. Furthermore, most of the circulating C1q-bound MASP-3 was activated. Based on immunoprecipitatin, also C1q/MASP-2 complexes appereared to be present in serum. Finally, C1q/MASP-2 and C1q/MASP-3 in vitro complexes were able to cleave C4 and pro-factor D, respectively.Our study reveals the existence of C1q/MASP complexes in the circulation of healthy individuals and both C1q/MASP-2 and C1q/MASP-3 complexes display proteolytic activity. Hence, this study uncovers a crosstalk route between complement pathways not previously described.
RNA 3’end tailing safeguards cells against products of pervasive transcription termination
Authors: Wu Guifen , Rouvière Jérôme O. , Schmid Manfred , Jensen Torben Heick 
Published: March 2024

SummaryPremature transcription termination yields a wealth of unadenylated (pA-) RNA. Although this can be targeted for degradation by the Nuclear EXosome Targeting (NEXT) complex, possible back-up pathways remain poorly understood. Here, we find RNA 3’end uridylation and adenylation upon NEXT inactivation. U-tailed RNAs are generally short and modified by the cytoplasmic tailing enzymes, TUT4/7, following their PHAX-dependent nuclear export and prior to their degradation by the cytoplasmic exosome or the exoribonuclease DIS3L2. Longer RNAs are instead adenylated redundantly by enzymes TENT2, PAPOLA and PAPOLG. These transcripts are either degraded via the nuclear Poly(A) tail eXosome Targeting (PAXT) connection or exported by conventional factors and removed by the cytoplasmic exosome in a translation-dependent manner. Failure to do so decreases global translation and induces cell death. We conclude that post-transcriptional 3’end modification and removal of excess pA-RNA is achieved by tailing enzymes and export factors shared with productive RNA pathways.
Stereochemically-aware bioactivity descriptors for uncharacterized chemical compounds
Authors: Comajuncosa-Creus Arnau , Lenes Aksel , Sánchez-Palomino Miguel , Aloy Patrick 
Published: March 2024

SummaryWe recently presented a set of deep neural networks to generate bioactivity descriptors associated to small molecules (i.e.Signaturizers), capturing their effects at increasing levels of biological complexity (i.e. from protein targets to clinical outcomes)1. However, such models were trained on 2D representations of molecules and are thus unable to capture key differences in the activity of stereoisomers. Now, we systematically assess the relationship between stereoisomerism and bioactivity on over 1M compounds, finding that a very significant fraction (∼40%) of spatial isomer pairs show, to some extent, distinct bioactivities. We then used these data to train a second generation of Signaturizers, which are now stereochemically-aware, and provide an even more faithful description of complex small molecule bioactivity properties.