bluuebunny/crossref_metadata_2025_split huggingface dataset:
INFLAMMATORY MARKERS AND BODY MASS INDEX AMOUNG HISPANIC CHILDREN
Authors: Lang Henry , Loudermilk Elaine N. , Clark W. Andrew , Marrs Jo-Ann , Joyner T. Andrew , Wang Liang , Gerber Kathryn S. , Alamian Arsham 
Published: July 2023

AbstractBackground and ObjectivesBody mass index (BMI) is inversely proportional with adiponectin levels among adults, while insulin, C-reactive protein (CRP), interleukin 6 (IL-6), resistin, and tumor necrosis factor-alpha (TNF-α) have been linked with elevated BMI. The role and relation of these biomarkers with BMI among Hispanic pediatric populations are less known. Thus, the objective of this cross-sectional study was to examine the association of inflammatory markers with the odds of overweight/obesity while controlling for several sociodemographic factors among a Hispanic youth population of Northeast Tennessee.MethodsHeight, weight, demographic information, and blood samples were collected from 107 Hispanic children aged 2 to 10 years recruited at a large community health center in 2015-2016 in Northeast Tennessee. Data for this research were accessed and analyzed in 2022. Multivariable logistic regression was conducted to assess the relations between adiponectin, insulin, resistin, CRP, TNF-α, and IL-6, and overweight/obesity vs. having a healthy (normal) weight.ResultsAdiponectin levels were significantly lower among overweight/obese Hispanic children (p = 0.0048) compared to healthy weight children. The odds of overweight/obesity decreased by 4% for every one-unit increase in serum adiponectin. Insulin levels were significantly higher among overweight/obese Hispanic children (p = 0.0048) compared to healthy weight children (p=0.0008). The odds of overweight/obesity increased by 7% for every one-unit increase in serum insulin. Resistin, IL-6, TNF-α, and CRP were not significantly associated with overweight/obesity in this population.ConclusionAdiponectin behaves similarly in Hispanic youth as it does in other pediatric populations, possibly making it a valuable marker when examining metabolic health status in this population.
The RNA binding proteins ZFP36L1 and ZFP36L2 are dysregulated in airway epithelium in human and a murine model of asthma
Authors: Rynne Jennifer , Ortiz-Zapater Elena , Bagley Dustin C. , Doherty George , Kanabar Varsha , Jackson David , Parsons Maddy , Rosenblatt Jody , Adcock Ian , Martinez-Nunez Rocio T 
Published: July 2023

AbstractAsthma is the most common chronic inflammatory disease of the airways. The airway epithelium is a key driver of the disease, and numerous studies have established genome-wide differences in mRNA expression between health and asthma. However, the underlying molecular mechanisms for such differences remain poorly understood. We investigated the expression and possible role of the tristetraprolin (TTP) family of RNA binding proteins (RBPs), which are poorly understood in asthma. The human TTP family is comprised ofZFP36,ZFP36L1andZFP36L2,and has essential roles in immune regulation by determining the stability and translation of myriad mRNAs encoding for inflammatory mediators. We foundZFP36L1andZFP36L2mRNA levels significantly downregulated in the airway epithelium of patients with very severe asthma in different cohorts (5 healthy vs 8 severe asthma; 36 moderate asthma vs 37 severe asthma on inhaled steroids vs 26 severe asthma on oral corticoids). Integrating several datasets allowed us to infer that mRNAs potentially targeted by these RBPs are increased in severe asthma.Zfp36l1was downregulated in the lung of a mouse model of asthma, and immunostaining ofex vivolung slices with a dual antibody demonstrated that Zfp36l1/l2 nuclear localization is increased in the airway epithelium of an acute asthma mouse model. Immunostaining of human bronchial biopsies showed that airway epithelial cell staining of ZFP36L1 was decreased in severe asthma as compared with mild, while ZFP36L2 was upregulated. We propose that the dysregulation of ZFP36L1/L2 levels as well as their subcellular mislocalization contributes to changes in mRNA expression and cytoplasmic fate in asthma.
A Parkinson’s disease genetic risk score associates with blood DNAm on chromosome 17
Authors: Casazza William , Schaffner Samantha L. , Artaud Fanny , Domenighetti Cloé , Baglietto Laura , Schulze-Hentrich Julia M. , Lesage Suzanne , Brice Alexis , Corvol Jean-Christophe , Mostafavi Sara , Kobor Michael S. , Elbaz Alexis , Dennis Jessica K. ,   DIG-PD Study Group
Published: July 2023

AbstractAlthough Parkinson’s disease (PD) coincides with altered immune functioning, there are few reproducible associations between blood DNA methylation (DNAm) and PD case-control status. Integrative analyses of genotype and blood DNAm can address this gap and can help us characterize the biological function of PD genetic risk loci. First, we tested for associations between a PD genetic risk score (GRS) and DNAm. Our GRS included 36 independent genome-wide significant variants from the largest GWAS of PD to date. Our discovery sample was TERRE, consisting of French agricultural workers (71 PD cases and 147 controls). The GRS associated with DNAm at 85 CpG sites, with 19 associations replicated in an independent sample (DIG-PD). The majority of CpG sites (73) are within a 1.5 Mb window on chromosome 17, and 36 CpG sites annotate toMAPTandKANSL1, neighboring genes that affect neurodegeneration. All associations were invariant to non-genetic factors, including exposure to commercial-grade pesticides, and omitting chromosome 17 variants from the GRS had little effect on association. Second, we compared our findings to the relationship between individual PD risk loci and blood DNAm using blood mQTL from a large independent meta-analysis (GoDMC). We found 79 CpG sites that colocalized with PD loci, and via summary Mendelian randomization analysis, we show 25/79 CpG sites where DNAm causally affects PD risk. The nine largest causal effects are within chromosome 17, including an effect withinMAPT. Thus, all integrative analyses prioritized DNAm on chromosome 17, drawing from multiple independent data sets, meriting further study of this region.
Urinary Cortisol and Cardiovascular Events in Women vs. Men: The Multi-Ethnic Study of Atherosclerosis
Authors: Flynn Spencer , Srikanthan Preethi , Ravellette Keeley , Inoue Kosuke , Watson Karol , Horwich Tamara 
Published: July 2023

BackgroundResearch suggests that women experience greater cardiovascular ischemic effects from stress than men. Visceral adiposity is an endocrine tissue that differs by sex and interacts with stress hormones. We hypothesized that urinary cortisol would be associated with increased cardiovascular events and change in coronary artery calcium score (CAC) in women, and these relationships would vary by central obesity.MethodsIn the Multi-Ethnic Study of Atherosclerosis Stress Ancillary study, cortisol was quantified by 12-hour overnight urine collection. Central obesity was estimated by waist-hip ratio (WHR). Multivariable Cox models estimated the relationship between cortisol and cardiovascular events and assessed for moderation by WHR. The relationship between cortisol and change in CAC Agatston score was assessed by Tobit regression models.Results918 patients were analyzed with median follow up of 11 years. There was no association between urinary cortisol and cardiovascular events in the cohort. However, in individuals with below median WHR, higher urinary cortisol levels (upper tertile) were associated with higher cardiovascular event rates in the full cohort, women, and men, but not in groups with above median WHR. There was significant moderation by WHR in women, but not men, whereby the association between elevated cortisol and increased cardiovascular events diminished as WHR increased. Urinary cortisol was associated with increased change in CAC in women (P=0.003) but not men, without moderation by WHR.ConclusionsOur study highlights associations between cortisol and subclinical atherosclerosis in women, and moderation of the relationship between cortisol and cardiovascular events by central obesity in both genders.
Neuronal DAMPs exacerbate neurodegeneration via astrocytic RIPK3 signaling
Authors: Chang Nydia P. , DaPrano Evan M. , Evans Wesley R. , Nissenbaum Marialaina , McCourt Micheal , Alzate Diego , Lindman Marissa , Chou Tsui-Wen , Atkins Colm , Kusnecov Alexander W. , Huda Rafiq , Daniels Brian P. 
Published: July 2023

AbstractAstrocyte activation is a common feature of neurodegenerative diseases. However, the ways in which dying neurons influence the activity of astrocytes is poorly understood. RIPK3 signaling has recently been described as a key regulator of neuroinflammation, but whether this kinase mediates astrocytic responsiveness to neuronal death has not yet been studied. Here, we used the MPTP model of Parkinson’s disease to show that activation of astrocytic RIPK3 drives dopaminergic cell death and axon damage. Transcriptomic profiling revealed that astrocytic RIPK3 promoted gene expression associated with neuroinflammation and movement disorders, and this coincided with significant engagement of DAMP signaling. Using human cell culture systems, we show that factors released from dying neurons signal through RAGE to induce RIPK3-dependent astrocyte activation. These findings highlight a mechanism of neuron-glia crosstalk in which neuronal death perpetuates further neurodegeneration by engaging inflammatory astrocyte activation via RIPK3.
Characterization of a novel temperate phage facilitatingin vitrodispersal of multicellular bacteria
Authors: Jaffal Hoda , Kortebi Mounia , Misson Pauline , Tavares Paulo , Ouldali Malika , Leh Hervé , Lautru Sylvie , Lioy Virginia S. , Lecointe François , Bury-Moné Stéphanie 
Published: July 2023

ABSTRACTStreptomycesare renowned for their prolific production of specialized metabolites with applications in medicine and agriculture. These multicellular bacteria present a sophisticated developmental cycle, and play a key role in soil ecology. Little is known aboutStreptomyces-phage interactions and the impact of phages onStreptomycesphysiology. In this study, we investigated the conditions governing the expression and production of ‘Samy’, a prophage found inStreptomyces ambofaciensATCC 23877. This siphoprophage is produced simultaneously with the activation of other mobile genetic elements. We show that Samy production increases bacterial dispersal underin vitrostress conditions. Altogether, we unveiled a new property of a bacteriophage infection that it is closely linked to the multicellular community life ofStreptomycesbacteria.Graphical summaryIMPORTANCEStreptomycesare multicellular bacteria producing valuable metabolites, including antibiotics, with applications in medicine and agriculture. In this study, we characterized a novel temperate phage, named Samy, and its impact on bacteria physiology. Remarkably, the presence and production of Samy increases bacterial dispersal underin vitrostress conditions. This constitutes an emerging property associated with bacteriophage infection that might enhance the spread of the species. Our study reveals a new aspect of bacteriophage infection in the context of multicellular aggregate dynamics.
Long-lived coherences for magnetic interactions in proteins
Authors: Teleanu Florin , Ciumeica Andrei , Ianc Octavian , Lupulescu Adonis , Sadet Aude , Vasos Paul R. 
Published: July 2023

AbstractLiving systems rely on molecular building blocks of low symmetry such as amino-acids and nucleotides, which generally yield short-lived magnetic transitions in response to electromagnetic radiation. This is the first demonstration that in proteins of relatively large size local magnetic symmetry can be induced to enable the detection of interactions based on long-lived coherent transitions of nuclear spins. Long-lived coherences (LLC’s) are superpositions of quantum states with singlet and triplet spin-permutation symmetries that feature significantly longer relaxation time constants compared to those of standard nuclear spin coherences. We report in this study that glycine residues in Lysozyme, a 14.3 kDa protein, feature Gly-Hα2,3LLC’s with relaxation time constants twice as long as the classical counterparts. Using a new excitation method for LLC’s in glycines 4, 49, 54, 67, 117, and 126, Lysozyme Gly-Hαdipolar interactions with neighboring hydrogen spins were mapped in a high magnetic field – at 950 MHz1H Larmor frequency. As predicted by theory, the positions of nearby atoms in the protein structure on one side or the other of Gly molecular symmetry planes reflecting protons Hα2,3determines the signs of LLC magnetic interaction signals. LLC-based transfers therefore yield stereospecific signals from glycine residues to1H neighboring atoms. The symmetry-encoded sign of the detected signals provides angle constraints, in addition to the distance information. LLC probes based on naturally-abundant1H spins can be useful for in-cell spectroscopy, circumventing the introduction of heterogenous spin labels for following protein-ligand or protein-protein interactions in the natural environment.This is the first demonstration that magnetisation transfer through space from long-lived coherences can be obtained in proteins. Applications of LLC’s were believed to be limited to systems featuring fast rotational motion in solution, mainly small molecules. This new LLC-based method yields stereospecific distance constraints and has the potential to extend the protein-size domain for the study of intra- and intermolecular interactions.
Kitacrispants for systematic image-based genetic screens of complex traits in zebrafish larvae
Authors: Mazzaferro Eugenia , Metzendorf Christoph , Zhang Hanqing , Mujica Endrina , Höijer Ida , Alavioon Ghazal , Campos Costa Joao , Cook Naomi L. , Gry Vienberg Sara , Djordjevic Djordje , Larsson Anders , Ameur Adam , Emmanouilidou Anastasia , Allalou Amin , den Hoed Marcel 
Published: July 2023

AbstractWith thousands of loci identified by genome-wide association studies for complex traits, there is a need forin vivomodel systems that can reliably and quickly infer the role of large numbers of candidate genes. CRISPR/Cas9-based functional screens in F0zebrafish represent such a system. However, negative controls used so far – including scrambled guide RNAs (gRNAs), inactivated Cas9, and sham injections – do not elicit the same cellular and organismal responses as mutagenesis by CRISPR/Cas9, and may fuel biased conclusions. Here, we show that targetingkitafacilitates efficient optical pre-screening for successful mutagenesis, higher quality imaging data, and efficient classification of cases and controls. We identified and tested two gRNAs that targetkitawith similarly high mutagenic efficiency and effects on pigmentation, and are free from off-target effects or major effects on cardiometabolic traits. We propose several approaches that will result in valid, unbiased conclusions.
Regulation of mitochondrial calcium uniporter expression and calcium signalling by lncRNATug1in cardiomyocytes
Authors: Trewin Adam J. , Weeks Kate L. , Wadley Glenn. D. , Lamon Séverine 
Published: July 2023

AbstractCardiomyocyte calcium homeostasis is a tightly regulated process. The mitochondrial calcium uniporter (MCU) complex can buffer elevated cytosolic Ca2+levels and consists of pore-forming proteins including MCU, and various regulatory proteins such as mitochondrial calcium uptake proteins 1 and 2 (MICU1/2). The stoichiometry of these proteins influences the sensitivity to Ca2+and activity of the complex. However, the factors that regulate their gene expression remain incompletely understood. Long non-coding RNAs (lncRNAs) regulate gene expression through various mechanisms, and we recently found that the lncRNATug1increased the expression ofMcuand associated genes. To further explore this, we performed antisense LNA knockdown ofTug1(Tug1KD) in H9c2 rat cardiomyocytes.Tug1KD increased MCU protein expression, yet pyruvate dehydrogenase dephosphorylation, which is indicative of mitochondrial Ca2+uptake was not enhanced. However, RNA-seq revealed thatTug1KD increasedMcualong with differential expression of >1000 genes including many related to Ca2+regulation pathways in the heart. To understand the effect of this on Ca2+signalling, we measured phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and its downstream target cAMP Response Element-Binding protein (CREB), a transcription factor known to driveMcugene expression. In response a Ca2+stimulus, the increase in CaMKII and CREB phosphorylation was attenuated byTug1KD. Inhibition of CaMKII, but not CREB, partially prevented theTug1KD- mediated increase inMcu. Together, these data suggest thatTug1modulates MCU expression via a mechanism involving CaMKII and regulates cardiomyocyte Ca2+signalling which could have important implications for cardiac function.
Metabolomic rearrangement controls the intrinsic microbial response to temperature changes
Authors: Knapp Benjamin D. , Willis Lisa , Gonzalez Carlos , Vashistha Harsh , Touma Joanna Jammal , Tikhonov Mikhail , Ram Jeffrey , Salman Hanna , Elias Josh E. , Huang Kerwyn Casey 
Published: July 2023

AbstractTemperature is one of the key determinants of microbial behavior and survival, whose impact is typically studied under heat- or cold-shock conditions that elicit specific regulation to combat lethal stress. At intermediate temperatures, cellular growth rate varies according to the Arrhenius law of thermodynamics without stress responses, a behavior whose origins have not yet been elucidated. Using single-cell microscopy during temperature perturbations, we show that bacteria exhibit a highly conserved, gradual response to temperature upshifts with a time scale of ∼1.5 doublings at the higher temperature, regardless of initial/final temperature or nutrient source. We find that this behavior is coupled to a temperature memory, which we rule out as being neither transcriptional, translational, nor membrane dependent. Instead, we demonstrate that an autocatalytic enzyme network incorporating temperature-sensitive Michaelis-Menten kinetics recapitulates all temperature-shift dynamics through metabolome rearrangement, which encodes a temperature memory and successfully predicts alterations in the upshift response observed under simple-sugar, low-nutrient conditions, and in fungi. This model also provides a mechanistic framework for both Arrhenius-dependent growth and the classical Monod Equation through temperature-dependent metabolite flux.
Multiplex, quantitative, high-resolution imaging of protein:protein complexes via hybridization chain reaction
Authors: Schulte Samuel J. , Shin Boyoung , Rothenberg Ellen V. , Pierce Niles A. 
Published: July 2023

ABSTRACTSignal amplification based on the mechanism of hybridization chain reaction (HCR) facilitates spatial exploration of gene regulatory networks by enabling multiplex, quantitative, high-resolution imaging of RNA and protein targets. Here, we extend these capabilities to the imaging of protein:protein complexes, using proximity-dependent cooperative probes to conditionally generate a single amplified signal if and only if two target proteins are colocalized within the sample. HCR probes and amplifiers combine to provide automatic background suppression throughout the protocol, ensuring that even if reagents bind nonspecifically in the sample, they will not generate amplified background. We demonstrate protein:protein imaging with high signal-to-background in human cells, mouse proT cells, and highly autofluorescent formalin-fixed paraffin-embedded (FFPE) human breast tissue sections. Further, we demonstrate multiplex imaging of 3 different protein:protein complexes simultaneously and validate that HCR enables accurate and precise relative quantitation of protein:protein complexes with subcellular resolution in an anatomical context. Moreover, we establish a unified framework for simultaneous multiplex, quantitative, high-resolution imaging of RNA, protein, and protein:protein targets, with 1-step, isothermal, enzyme-free HCR signal amplification performed for all target classes simultaneously.Abstract Figure
Recombinant Ranpirnase enhances the expression of co-transfected mRNA by modulating cellular metabolic activity
Authors: Wu Xiujin , Chen Liang , Lei Yingxue , Peng Xu , Zhang Yaoyi , Yang Guang , Yin Hailin , Xu Kai 
Published: July 2023

AbstractAs the world’s first approved prophylactic mRNA vaccine, the development of the Covid-19 mRNA vaccine marks a milestone in mRNA therapeutics. However, achieving efficient transgene expression in therapeutic applications such as protein replacement and cancer therapeutical vaccines remains challenging. This study explores the use of recombinant Ranpirnase, a small ribonuclease, as a novel expression-enhancing tool for mRNA-based therapeutics. In Balb/c mice, co-expression of Ranpirnase significantly increased transgene expression levels by 3-to 6-fold and prolonged expression duration by more than 85%, regardless of mRNA nucleoside modification status. Recombinant Ranpirnase induces a cytostatic state in host cells, stabilizing mRNA and protein transcripts, thereby enhancing transgene expression. Importantly, co-expression of Ranpirnase recombinants did not cause detectable cytotoxicity or alter the tissue distribution of transgene expression, ensuring safety and tolerability at higher translation levels. The compact size of the recombinant Ranpirnase gene allows for seamless fusion with the target gene or co-transfection with existing delivery technologies. Altogether, recombinant Ranpirnase shows promise as an expression-enhancing element in mRNA-based therapeutics, including veterinary applications.
Evaluating AI-Assistance for Pathologists in Diagnosing and Grading Laryngeal Lesions
Authors: Bellahsen-Harrar Yaëlle , Lubrano Mélanie , Lépine Charles , Beaufrère Aurélie , Bocciarelli Claire , Brunet Anaïs , Decroix Elise , El-Sissy Franck Neil , Fabiani Bettina , Morini Aurélien , Tilmant Cyprien , Walter Thomas , Badoual Cécile 
Published: July 2023

AbstractImportanceDiagnosis of head and neck squamous dysplasias and carcinomas is challenging, with a moderate inter-rater agreement. Nowadays, new artificial intelligence (AI) models are developed to automatically detect and grade lesions, but their contribution to the performance of pathologists hasn’t been assessed.ObjectiveTo evaluate the contribution of our AI tool in assisting pathologists in diagnosing squamous dysplasia and carcinoma in the head and neck region.Design, Setting, and ParticipantsWe evaluated the effectiveness of our previously described AI model, which combines an automatic classification of laryngeal and pharyngeal squamous lesions with a confidence score, on a panel of eight pathologists coming from different backgrounds and with different levels of experience on a subset of 115 slides.Main Outcomes and MeasuresThe main outcome was the inter-rater agreement, measured by the weighted linear kappa. Other outcomes on diagnostic efficiency were assessed using pairedttests.ResultsAI-Assistance significantly improved the inter-rater agreement (linear kappa 0.73, 95%CI [0.711-0.748] with assistance versus 0.675, 95%CI [0.579-0.765] without assistance, p < 0.001). The agreement was even better on high confidence predictions (mean linear kappa 0.809, 95%CI [0.784-0.834] for assisted review, versus 0.731, 95%CI [0.681-0.781] non-assisted, p = 0.018). These improvements were particularly strong for non-specialized and younger pathologists. Hence, the AI-Assistance enabled the panel to perform on par with the expert panel described in the literature.Conclusions and RelevanceOur AI-Assistance is of great value for helping pathologists in the difficult task of diagnosing squamous dysplasias and carcinomas, improving for the first time the inter-rater agreement. It demonstrates the possibility of a truly Augmented Pathology in complex tasks such as the classification of head and neck squamous lesions.