bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutant EZH2 alters the epigenetic network and increases epigenetic heterogeneity in B cell lymphoma
Authors: Griess Ofir , Furth Noa , Harpaz Nofar , Bernardo Nicoletta Di , Salame Tomer-Meir , Dassa Bareket , Karagiannidis Ioannis , Isshiki Yusuke , Gross Menachem , Melnick Ari M. , Béguelin Wendy , Ron Guy , Shema Efrat 
Published: August 2024

AbstractDiffuse large B cell lymphomas and follicular lymphomas show recurrent mutations in epigenetic regulators; among these are loss-of-function mutations in KMT2D and gain-of-function mutations in EZH2. To systematically explore the effects of these mutations on the wiring of the epigenetic network, we applied a single-cell approach to probe a wide array of histone modifications. We show that mutant-EZH2 elicits extensive effects on the epigenome of lymphomas, beyond alterations to H3K27 methylations, and is dominant over KMT2D mutations. Utilizing the single-cell data, we present computational methods to measure epigenetic heterogeneity. We identify an unexpected characteristic of mutant-EZH2, but not KMT2D, in increasing heterogeneity, shedding light on a novel oncogenic mechanism mediated by this mutation. Finally, we present tools to reconstruct known interactions within the epigenetic network, as well as reveal potential novel cross talk between various modifications, validated by functional perturbations. Our work highlights novel roles for mutant-EZH2 in lymphomagenesis and establishes new concepts for measuring epigenetic heterogeneity and intra-chromatin connectivity in cancer cells.
A small regulatory RNA controls antibiotic tolerance inStaphylococcus aureusby modulating efflux pump expression
Authors: Ha Kam Pou , Bouloc Philippe 
Published: August 2024

AbstractStaphylococcus aureusis an opportunistic pathogen that poses a considerable burden to healthcare settings worldwide, aided by its ability to thrive in different environmental growth conditions and survive exposure to antibiotics. Small regulatory RNAs (sRNAs) are crucial in enhancing bacterial fitness by modulating gene expression in response to changing environmental conditions. We investigated the role of sRNAs inS. aureusantibiotic resistance and tolerance. By assessing the fitness of a library of sRNA mutants, we identified that RsaA sRNA is required for bacterial growth when exposed to low concentrations of fluoroquinolone, a class of antibiotics targeting DNA replication. We also found that in the absence of RsaA,S. aureusis less susceptible to β-lactam antibiotics, which act on the cell wall. RsaA has been reported to prevent the expression of MgrA, a master regulatory protein controlling the expression of efflux pumps. Here, we show that RsaA affects the sensitivity ofS. aureusto fluoroquinolone and β-lactam antibiotics through MgrA. RsaA has two forms, a short one that is commonly referred to in RsaA studies, and a long form about twice the length, of which not much is known. Interestingly, our phenotype was restored only when complemented with the long form of the gene. This work demonstrates the role of regulatory RNAs in the adaptation ofS. aureusto antibiotic resistance and highlights their value as potential therapeutic targets for manipulating individual sRNA responses to promote the efficacy of existing antibiotics.
Human Vascularized Macrophage-Islet Organoids to Model Immune-Mediated Pancreatic β cell Pyroptosis upon Viral Infection
Authors: Yang Liuliu , Han Yuling , Zhang Tuo , Dong Xue , Ge Jian , Roy Aadita , Zhu Jiajun , Lu Tiankun , Vandana J. Jeya , de Silva Neranjan , Robertson Catherine C. , Xiang Jenny Z , Pan Chendong , Sun Yanjie , Que Jianwen , Evans Todd , Liu Chengyang , Wang Wei , Naji Ali , Parker Stephen C.J. , Schwartz Robert E. , Chen Shuibing 
Published: August 2024

SUMMARYThere is a paucity of human models to study immune-mediated host damage. Here, we utilized the GeoMx spatial multi-omics platform to analyze immune cell changes in COVID-19 pancreatic autopsy samples, revealing an accumulation of proinflammatory macrophages. Single cell RNA-seq analysis of human islets exposed to SARS-CoV-2 or Coxsackievirus B4 (CVB4) viruses identified activation of proinflammatory macrophages and β cell pyroptosis. To distinguish viral versus proinflammatory macrophage-mediated β cell pyroptosis, we developed human pluripotent stem cell (hPSC)-derived vascularized macrophage-islet (VMI) organoids. VMI organoids exhibited enhanced marker expression and function in both β cells and endothelial cells compared to separately cultured cells. Notably, proinflammatory macrophages within VMI organoids induced β cell pyroptosis. Mechanistic investigations highlighted TNFSF12-TNFRSF12A involvement in proinflammatory macrophage-mediated β cell pyroptosis. This study established hPSC- derived VMI organoids as a valuable tool for studying immune cell-mediated host damage and uncovered mechanism of β cell damage during viral exposure.
Impact of clinical severity on plasma p-tau performance in predementia Alzheimer’s disease
Authors: Gonzalez-Ortiz Fernando , Kirsebom Bjørn-Eivind , Yakoub Yara , Gundersen Julia K. , Pålhaugen Lene , Waterloo Knut , Selnes Per , Jarholm Jonas Alexander , Gísladóttir Berglind , Rongve Arvid , Skogseth Ragnhild Eide , Bråthen Geir , Aarsland Dag , Turton Michael , Harrison Peter , Zetterberg Henrik , Villeneuve Sylvia ,   PREVENT AD research group, Fladby Tormod , Blennow Kaj 
Published: August 2024

AbstractBackground and objectivesDetecting Alzheimer’s disease (AD) biological and clinical changes is crucial for early diagnostic and therapeutic interventions. Here we investigate the relationship between clinical severity and levels of phosphorylated tau, focusing on plasma biomarkers, in preclinical and prodromal AD.MethodsIn this study (n=621), we examined two independent cohorts consisting of preclinical and prodromal AD. Cohort-1 included 431 participants classified as either cognitively normal (CN) or mild cognitive impaired (MCI) with normal or abnormal cerebrospinal fluid (CSF) Aβ42/40 ratio (A) and p-tau181 (T) [CN A-/T-, n=169; A+/T-, CN=26; MCI=24; A+/T+, CN=40; MCI=105; CN=34; MCI=33]. A total of n=418 of the participants had longitudinal assessments of verbal memory up to 9.67 years from baseline. Cohort-2 included 190 participants in whom amyloid status was determined using Aβ positron emission tomography (PET) [Aβ- CN= 118; Aβ+ CN= 49; Aβ+ MCI= 21].ResultsIn cohort-1, plasma p-tau217 showed a moderate correlation with its corresponding CSF biomarker (rho=0.65, p<.001) and high accuracy identifying Aβ+ participants (AUC: 0.85). Diagnostic accuracy of plasma p-tau217 was significantly greater for MCI Aβ+ (AUC: 0.89) versus CN Aβ+ (AUC: 0.79, p<.05) and for A+/T+ (AUC: 0.88) versus A+/T- (AUC: 0.78, p<.05). P-tau181 and p-tau231 showed significantly weaker CSF-plasma correlations (rho= 0.47, and rho=0.32, p<.001, respectively) and levels were not as tightly associated with cognitive status in the Aβ+ group. While all the CSF p-tau markers were associated to future cognitive deterioration, p-tau217 was the only plasma biomarker associated with future memory decline (β=0.05, p<0.05). In cohort 1 and 2, plasma p-tau217 showed significantly higher concentrations in MCI Aβ+ as compared to CN Aβ+. Furthermore, plasma p-tau217 demonstrates similar biomarker elevations when compared to CN Aβ- controls in both cohorts.DiscussionOur findings indicate that, unlike p-tau181 and p-tau231, plasma p-tau217 consistently aligns with cognitive status in Aβ+ individuals and more closely reflects CSF biomarker abnormalities, potentially reducing discrepancies between clinical and biochemical findings. The associations of plasma p-tau217 with baseline and future cognitive decline make it a valuable complement to clinical evaluations in preclinical and prodromal AD, especially when CSF analysis or PET are not feasible.
Prevalence of early neonatal mortality and its predictors in sub-Saharan Africa: A Systematic review and Meta-Analysis
Authors: Zulu Teebeny , Jacobs Choolwe , Biemba Godfrey , Musonda Patrick 
Published: August 2024

AbstractBackgroundAlthough early neonatal mortality (ENM) has been reported to have a greater contribution to the overall neonatal mortality compared to late neonatal mortality, no meta-analysis has studied this phenomenon in isolation. The prevalence of ENM and its predictors in sub-Saharan Africa (SSA) remains unknown. Therefore, this meta-analysis is aimed at pooling the prevalence of ENM and its predictors in SSA.MethodsGoogle Scholar, PubMed, Scopus, CINAHL, and Google were searched for studies conducted in SSA that reported the prevalence and predictors of ENM. The data were extracted using a Microsoft Excel spreadsheet and imported into R version 4.4.1 for further analysis. Publication bias, heterogeneity, sensitivity analysis, and subgroup analysis were performed. Prevalence and odds ratios were pooled using the random effects model if significant heterogeneity existed; otherwise, the fixed effects model was used.ResultsA total of 26 studies were included in this systematic review and meta-analysis. The overall pooled prevalence of ENM in SSA was 11% (95% CI: 7-15;I2=100%). Birth asphyxia (OR=3.85; 95% CI: 1.12-13.21; P = 0.0388;I2= 86.6%), home delivery (OR=2.46; 95% CI: 1.79-3.38; p<0.001;I2= 0.0%), prematurity (OR=4.69; 95% CI: 3.57-6.16; p<0.001;I2= 36.8%), male gender (OR= 1.37; 95% CI: 1.28-1.46; P < 0.001;I2= 30.7%), delivery through caesarean section (OR=1.74; 95% CI: 1.49-2.02; P < 0.001;I2= 31.5%) and low birth weight (OR=3.00; 95% CI: 1.01-8.91; P = 0.0482;I2= 94.4%) were associated with a significant increase in pooled odds of ENM in SSA.ConclusionThe prevalence of ENM in SSA in significantly high and it contributes greatly to the overall neonatal mortality. Therefore, tailor-made interventions that target the reduction of birth asphyxia, prematurity, home delivery, and low birth weight should be implemented in order to reduce the burden of ENM in SSA.
Personalized Fluid Management in Patients with Sepsis and AKI: A Policy Tree Approach
Authors: Oh Wonsuk , Takkavatakarn Kullaya , Kittrell Hannah , Shawwa Khaled , Gomez Hernando , Sawant Ashwin S. , Tandon Pranai , Kumar Gagan , Sterling Michael , Hofer Ira , Chan Lili , Oropello John , Kohli-Seth Roopa , Charney Alexander W , Kraft Monica , Kovatch Patricia , Kellum John A. , Nadkarni Girish N. , Sakhuja Ankit 
Published: August 2024

ABSTRACTRationaleIntravenous fluids are mainstay of management of acute kidney injury (AKI) after sepsis but can cause fluid overload. Recent literature shows that restrictive fluid strategy may be beneficial in some patients with AKI, however, identifying these patients is challenging.ObjectivesWe aimed to develop and validate a machine learning algorithm to identify patients who would benefit from a restrictive fluid strategy.MethodsWe included patients with sepsis who developed AKI within 48 hours of ICU admission and defined restrictive fluid strategy as receiving <500mL fluids within 24 hours after AKI. Our primary outcome was early AKI reversal at 24 hours of AKI onset, and secondary outcomes included sustained AKI reversal and major adverse kidney events by 30 days (MAKE30). We used a causal forest, a machine learning algorithm to estimate individual treatment effects and policy tree algorithm to identify patients who would benefit by restrictive fluid strategy. We developed the algorithm in MIMIC-IV and validated it in SICdb databases.Measurements and Main ResultsAmong 2,044 patients in the external validation cohort, policy tree recommended restrictive fluids for 66.7%. Among these, patients who received restrictive fluids demonstrated significantly higher rate of early AKI reversal (47.1% vs 31.7%,p=0.004), sustained AKI reversal (28.7% vs 17.5%, p=0.013) and lower rates of MAKE30 (23.0% vs 37.1%, p=0.011). These results were consistent in adjusted analysis.ConclusionPolicy tree based on causal machine learning can identify septic patients with AKI who benefit from a restrictive fluid strategy. This approach needs to be validated in prospective trials.
Comparative Effectiveness of the Bivalent (Original/Omicron BA.4/BA.5) mRNA COVID-19 Vaccines mRNA-1273.222 and BNT162b2 Bivalent in Adults With Underlying Medical Conditions in the United States
Authors: Kopel Hagit , Nguyen Van Hung , Bogdanov Alina , Winer Isabelle , Boileau Catherine , Ducruet Thierry , Zeng Ni , Winer-Jones Jessamine , Esposito Daina B. , Bausch-Jurken Mary , Beck Ekkehard , Bonafede Mac , Mansi James A. 
Published: August 2024

AbstractThis retrospective cohort study evaluated the relative vaccine effectiveness (rVE) of two bivalent (Original/Omicron BA.4/BA.5) vaccines mRNA-1273.222 versus BNT162b2 Bivalent in preventing COVID-19-related outcomes in adults with underlying medical conditions associated with increased risk for severe COVID-19.In a linked EHR-claims dataset, US adults (≥18 years) with ≥1 underlying medical condition of interest who received either bivalent vaccine between August 31, 2022, and February 28, 2023, were identified. Inverse probability of treatment weighting was used to adjust for cohort differences. Cohorts were followed up for COVID-19-related hospitalizations and outpatient encounters until May 31, 2023. Hazard ratios and rVEs were estimated using Cox regression. Subgroup analyses were performed on individuals with pre-specified comorbid conditions.757,572 mRNA-1273.222 and 1,204,975 BNT162b2 Bivalent recipients were identified. The adjusted rVE over a median follow-up of 198 days was 10.9% (6.2%-15.2%) against COVID-19-related hospitalization and 3.2% (1.7%-4.7%) against COVID-19-related outpatient encounters. rVE estimates for COVID-19 hospitalizations among subgroups with comorbid conditions were: diabetes 15.1% (8.7%–21.0%), cardiovascular disease 14.7% (9.0%–20.1%), chronic lung disease 11.9% (5.1%–18.2%), immunocompromised 15.0% (7.2%–22.2%), chronic kidney disease 8.4% (0.5%–15.7%).Overall, among adults with underlying medical conditions, mRNA-1273.222 was more effective than BNT162b2 Bivalent, especially in preventing COVID-19-related hospitalizations.
Prevalence of blindness and vision impairment among people 50 years and older in Nepal: a national Rapid Assessment of Avoidable Blindness survey
Authors: Mishra Sailesh Kumar , Shah Ranjan , Gogate Parikshit , Sapkota Yuddha Dhoj , Gurung Reeta , Shrestha Mohan Krishna , Mactaggart Islay , McCormick Ian , Shahi Brish Bahadur , Khandekar Rajiv , Burton Matthew 
Published: August 2024

ABSTRACTPurposeTo determine the prevalence and causes of blindness and vision impairment among people 50 years and older in Nepal.MethodsWe conducted seven provincial-level Rapid Assessment of Avoidable Blindness (RAAB) cross-sectional, population-based surveys between 2018-2021. Provincial prevalence estimates were weighted to give nationally representative estimates. Sampling, enumeration, and examination of the population 50 years and older were done at the province level following standard RAAB protocol.ResultsAcross seven surveys, we enrolled 33,228 individuals, of whom 32,565 were examined (response rate 98%). Females (n=17,935) made up 55% of the sample. The age-sex-province weighted national prevalence of blindness (better eye presenting visual acuity <3/60) was 1.1% (95% confidence interval [CI] 1.0-1.2%), and any vision impairment <6/12 was 20.7% (95% CI 19.9-21.5%). The prevalence of blindness and any vision impairment were both higher in women than men (1.3% [95% CI 1.1-1.5%] vs 0.9% [95% CI 0.7-1.0%]). Age-sex weighted blindness prevalence was highest in Lumbini Province (1.8% [95% CI 1.3-2.2%]) and lowest in Bagmati Province (0.7% [95% CI 0.4-0.9%]) and Sudurpaschim Province (0.7% [95% CI 0.4-0.9%]). Cataract (65.2%) was the leading cause of blindness in our sample, followed by corneal opacity (6.4%), glaucoma (5.8%) and age-related macular degeneration (5.3%). Other posterior segment diseases accounted for 8.4% of cases.ConclusionThe prevalence of blindness was higher among women than men and varied by province. The Lumbini and Madesh Provinces in the Terai (plains) region had higher prevalence of blindness than elsewhere. Cataract was the leading cause of blindness, severe vision impairment and moderate vision impairment while refractive error was the leading cause of mild vision impairment.
Inside Out: the physiology ofBrucellaVegetative and Intracellular Growth
Authors: Wade Nazarena , Comerci Diego J. , Soler-Bistué Alfonso , Marchesini María Inés 
Published: August 2024

AbstractGrowth rate is a key prokaryotic trait that allows estimating fitness and understanding cell metabolism. While in some clades it has been well studied in model organisms, there is little data on slow-growing bacteria. In particular, there is a lack of quantitative studies on the species of theBrucellagenus. This is an important microorganism since it is the causative agent of brucellosis, one of the most widespread bacterial zoonoses affecting several species of animals, including humans.Brucellaspecies exhibit approximately 97% genomic similarity. Despite this,Brucellaspecies show different host preferences, zoonotic risks, and pathogenicity. After more than one hundred years of research, numerous aspects ofBrucellabiology, such asin vivoandin vitrogrowth remain poorly characterized. In this work, we analyzed vegetative and intracellular growth of the classicalBrucellaspecies (B. abortus2308,B. melitensis16M.B. suis1330,B. ovis, andB. canis). Strikingly, each species displayed particular growth parameters in culture. Doubling time (DT) spanned from 2.7 hs-1inB. suisto 18h-1forB. ovis. In the context of intracellular infection of J774A.1 phagocytic cells, DT was higher, but it widely varied across species, closely correlating to the growth observedin vitro. Overall, despite high similarity of the genomes, we found species-specific growth parameters in the intracellular cell cycle.
Complex impact of stimulus envelope on motor synchronization to sound
Authors: Sun Yue , Michalareas Georgios , Ghitza Oded , Poeppel David 
Published: August 2024

AbstractThe human brain tracks temporal regularities in acoustic signals faithfully. Recent neuroimaging studies have shown complex modulations of synchronized neural activities to the shape of stimulus envelopes. How to connect neural responses to different envelope shapes with listeners’ perceptual ability to synchronize to acoustic rhythms requires further characterization. Here we examine participants’ motor and sensory synchronization to noise stimuli with periodic amplitude modulations (AM). We used three envelope shapes that varied in the sharpness of amplitude onset. In a synchronous motor finger-tapping task, we show that participants more consistently align their taps to the same phase of stimulus envelope when listening to stimuli with sharp onsets than to those with gradual onsets. This effect is replicated in a sensory synchronization task, suggesting a sensory basis for the facilitated phase alignment to sharp-onset stimuli. Surprisingly, despite less consistent tap alignments to the envelope of gradual-onset stimuli, participants are equally effective in extracting the rate of amplitude modulation from both sharp and gradual-onset stimuli, and they tapped consistently at that rate alongside the acoustic input. This result demonstrates that robust tracking of the rate of acoustic periodicity is achievable without the presence of sharp acoustic edges or consistent phase alignment to stimulus envelope. Our findings are consistent with assuming distinct processes for phase and rate tracking during sensorimotor synchronization. These processes may be underpinned by different neural mechanisms whose relative strengths are modulated by specific temporal dynamics of stimulus envelope characteristics.
RIPK4 driven by TP53 mutations promotes resistance to redox stress of CRC by phosphorylating MTHFD1
Authors: Yu Long , Zhou Sha , Xu Yan-Bo , Zhang Zhong-Jin , Cheng Xiao-Man , Zhou Chi , Li Wei-Hao , He Jia-Hua , Ou Qing-Jian , Qin Jia-Yi , Fang Yu-Jing , Peng Jian-Hong , Lin Jun-Zhong , Lin Bo , Hou Zhen-Lin , Pan Zhi-Zhong 
Published: August 2024

AbstractThis study investigates advanced colorectal cancer (CRC), focusing on its tendency for distant metastasis and chemotherapy resistance. It highlights the importance of PANoptosis, a cell death pathway, and the role of the Receptor-interacting serine/threonine-protein kinase (RIPK) family in tumor progression. RIPK4’s tissue-specific functions in cancer cell behavior are emphasized, including its influence on invasion, migration, and oxidative stress resistance. The study reveals the critical balance of reactive oxygen species (ROS) in cancer cells, linked to antioxidant defenses and NADPH production for survival. A key finding is the connection between TP53 mutations in CRC and increased RIPK4 expression, which enhances MTHFD1 phosphorylation, boosts NADPH production, reduces ROS, and promotes resistance to PANoptosis, leading to metastasis. The research identifies the molecular basis of CRC metastasis, showing how RIPK4 regulates MTHFD1 to resist PANoptosis, offering new therapeutic targets for metastatic CRC and potential improvements in patient outcomes.
Temporal misexpression ofEn1during limb development causes distinct phenotypes
Authors: Ringel Alessa R. , Magg Andreas , Benetti Natalia , Schöpflin Robert , Kühnlein Mira , Stiege Asita Carola , Fischer Ute , Wittler Lars , Lorenz Stephan , Mundlos Stefan , Allou Lila 
Published: August 2024

AbstractThe precise spatiotemporal regulation of developmental genes is required for proper organogenesis.Engrailed-1(En1) is essential for dorsal-ventral patterning during mouse limb development from embryonic day E9.5 to E11.5. Previously, we identified the long non-coding RNA locusMaenli, which drives limb-specificEn1expression at E9.5. In this study, we investigated the regulatory mechanisms sustainingEn1expression at later developmental stages whenMaenlitranscriptional activity is drastically reduced. Usingin vivoCRISPR editing, we identified two intergenic enhancer elements, LSEE1 and LSEE2, that maintainEn1expression at E10.5 and E11.5. Mice lacking these enhancers exhibit only a subset of the limb malformations observed inEn1andMaenlimutants, indicating that the timing ofEn1misexpression causes distinct phenotypes. These findings underscore the role of temporally restricted activities ofcis-regulatory elements, including lncRNA loci and enhancers, in modulating gene expression and explaining subtle differences in complex disease phenotypes.
Sphingosine-1-phosphate signaling regulates the ability of Müller glia to become neurogenic, proliferating progenitor-like cells
Authors: Taylor Olivia , DeGroff Nick , El-Hodiri Heithem , Gao Chengyu , Fischer Andy J. 
Published: August 2024

AbstractThe purpose of these studies is to investigate how Sphingosine-1-phosphate (S1P) signaling regulates glial phenotype, dedifferentiation of Müller glia (MG), reprogramming into proliferating MG-derived progenitor cells (MGPCs), and neuronal differentiation of the progeny of MGPCs in the chick retina. We found that S1P-related genes are highly expressed by retinal neurons and glia, and levels of expression were dynamically regulated following retinal damage. Drug treatments that activate S1P receptor 1 (S1PR1) or increase levels of S1P suppressed the formation of MGPCs. Conversely, treatments that inhibit S1PR1 or decrease levels of S1P stimulated the formation of MGPCs. Inhibition of S1P receptors or S1P synthesis significantly enhanced the neuronal differentiation of the progeny of MGPCs. We report that S1P-related gene expression in MG is modulated by microglia and inhibition of S1P receptors or S1P synthesis partially rescues the loss of MGPC formation in damaged retinas missing microglia. Finally, we show that TGFβ/Smad3 signaling in the resting retina maintains S1PR1 expression in MG. We conclude that the S1P signaling is dynamically regulated in MG and MGPCs in the chick retina, and activation of S1P signaling depends, in part, on signals produced by reactive microglia.