bluuebunny/crossref_metadata_2025_split huggingface dataset:
Excessive monitoring for Hydroxychloroquine retinal toxicity in a trial to delay clinical type 1 diabetes created burden without benefit
Authors: Lord Sandra M , Libman Ingrid M , Buckner Jane H , Dansingani Kunal K , Nischal Ken K , Bingley Polly J , Speake Cate , You Lu , Greenbaum Carla J 
Published: January 2025

AbstractBackground/AimsType 1 Diabetes TrialNet (TrialNet) conducted a placebo randomized trial in children and adults with pre-clinical type 1 diabetes (T1D) to test whether hydroxychloroquine (HCQ) could delay or prevent progression to clinical T1D. Study regulators required more frequent monitoring for retinal toxicity than is recommended by clinical guidelines and we evaluated the impact of this monitoring.MethodsWe obtained the outcome of all eye exams from TrialNet and focused on exams that were recommended for follow up outside the protocol or for repeat testing within the trial.ResultsNo HCQ related retinal toxicity was found, but increased frequency of monitoring led to additional testing due to incomplete exams or technical difficulties, and incidental findings prompted the need for follow up outside the study.ConclusionOur analysis suggests that increased frequency of retinal monitoring provided no benefit, created additional burdens, and that future trials testing HCQ in a pre-clinical T1D population could safely follow standard clinical guidelines for retinal surveillance.
Sparse Polygenic Risk Score Inference with the Spike-and-Slab LASSO
Authors: Song Junyi , Zabad Shadi , Yang Archer , Li Yue 
Published: January 2025

AbstractLarge-scale biobanks, with comprehensive phenotypic and genomic data across hundreds of thousands of samples, provide amble opportunities to elucidate the genetics of complex traits and diseases. Consequently, there is a growing demand for robust and scalable methods for disease risk prediction from genotype data. Performing inference in this setting is challenging due to the high-dimensionality of genomic data, especially when coupled with relatively smaller sample sizes. Popular Polygenic Risk Score (PRS) inference methods address this challenge by adopting sparse Bayesian priors or penalized regression techniques, such as the Least Absolute Shrinkage and Selection Operator (LASSO). However, the former class of methods are not as scalable and do not produce exact sparsity, while the latter may over-shrink large coefficients. In this study, we presentSSLPRS, a novel PRS method based on the Spike-and-Slab LASSO (SSL) prior, which offers a theoretical bridge between the two frameworks. We extend previous work to derive a coordinate-ascent inference algorithm for theSSLPRSmodel that operates on GWAS summary statistics. The software implementation, which uses state-of-the-art techniques to scale PRS inference to millions of genetic variants, has an average runtime of three minutes. To illustrate the statistical properties of the new model, we conducted experiments on nine quantitative phenotypes in the UK Biobank, which showed thatSSLPRSis competitive with state-of-the-art methods in terms of prediction accuracy. The method also produces highly sparse effect size estimates without excessive shrinkage and, on average, selects 5% fewer variants than theLASSO.
Hydrological Connectivity Enhances Fish Biodiversity in Amazonian Mining Ponds: Insights from eDNA and Traditional Sampling
Authors: Timana-Mendoza Camila , Reyes-Calderón Alonso , Venail Patrick , Britzke Ricardo , Santa-Maria Monica C. , Araújo-Flores Julio M. , Silman Miles , Fernandez Luis E. 
Published: January 2025

AbstractThe expansion of artisanal and small-scale gold mining (ASGM) in the Madre de Dios region of the Peruvian Amazon has transformed primary forests into a novel wetland complex of thousands of abandoned mining ponds. Despite their ecological relevance, post-mining recovery of these systems remains understudied, particularly regarding fish biodiversity and recolonization. In this study, we evaluate fish community richness and composition in mining ponds of different dimensions, years post abandonment, and degree of pulse flood connectivity using traditional collection-based methods and environmental DNA (eDNA) with the 12S and COI markers. We compared these two methods of biodiversity inventory and contrasted results from ASGM waterbodies with those obtained from nearby pristine oxbow lakes. Overall, we registered more fish richness at all sites using eDNA vs traditional methods, especially with the 12S marker. We identified 14 and 13 unique genera using traditional methods and eDNA, respectively, with 40 genera detected by both approaches, evidencing their complementarity. Notably, we found that the degree of pulse flooding connectivity was the main predictor of species richness among the abandoned mining ponds (p-value < 0.05). We registered 11 to 22, 23 to 71, and 56 morphospecies in non-flooded mining ponds, pulse flooded mining ponds and nearby oxbow lakes, respectively. Furthermore, the fish community composition of mining ponds most influenced by pulse flooding were similar to that of pristine lakes. Our findings highlight the role of hydrological connectivity in ecological recovery within mining-impacted wetlands. Future restoration efforts should enhance aquatic connectivity to accelerate recovery in post-mining environments.
The genusBoecheraas a model for apomixis research
Authors: Mandakova Terezie 
Published: January 2025

AbstractThe genusBoechera, a prominent member of the tribe Boechereae within the family Brassicaceae, has emerged as an exceptional model for apomixis research, owing to its unique evolutionary, reproductive, and genomic characteristics. With over 480 genetically distinct taxa and a distribution spanning North America, Greenland, and parts of Asia,Boecheraexemplifies remarkable ecological and genetic diversity. A hallmark of the genus is its high frequency of gametophytic apomixis, including diplospory and apospory, which, combined with hybridization, drive genetic innovation and environmental adaptability. Moreover,Boecherais notable for its diploid expression of apomixis, independent of polyploidy, providing an unparalleled system for dissecting asexual reproduction. Genomic adaptations, such as heterochromatic supernumerary chromosomes, further highlight its evolutionary complexity. Recent advances, including the discovery of critical regulatory genes likeAPOLLOandUPGRADE2, have deepened our understanding of the genetic basis of apomixis. These insights positionBoecheraas a cornerstone for elucidating apomictic pathways and leveraging these mechanisms for crop improvement. The genus not only enhances our understanding of apomixis but also offers transformative potential for agriculture.
Histone Variant H2A.Z Cooperates with EBNA1 to Maintain Epstein-Barr Virus Latent Epigenome
Authors: Castro-Muñoz Josue Leonardo , Maestri Davide , Yoon Leena , Karisetty Bhanu Chandra , Tempera Italo , Lieberman Paul 
Published: January 2025

AbstractChromatin structure plays a central role in the regulation of Epstein-Barr Virus (EBV) latency. The histone variant H2A.Z.1 has been implicated in chromatin structures associated with initiation of transcription and DNA replication. Here, we investigate the functional role of H2AZ.1 in the regulation of EBV chromatin, gene expression and copy number during latent infection. We found that H2A.Z.1 is highly enriched with EBNA1 binding sites atoriPand Qp, and to a lesser extent with transcriptionally active CTCF binding sites on the EBV genomes in both Mutu I Burkitt lymphoma (BL) and SNU719 EBV-associated gastric carcinoma (EBVaGC) cell lines. RNA-interference depletion of H2A.Z.1 resulted in the reactivation of viral lytic genes (ZTA and EAD) and increases viral DNA copy numbers in both MutuI and SNU719 cells. H2A.Z depletion also led to a decrease in EBNA1 binding tooriPandQp, on the viral episome as well as on oriP plasmids independently of other viral genes and genomes. H2A.Z.1 depletion also reduced peaks of H3K27ac and H4K20me3 at regulatory elements in the EBV genome. In the cellular genome, H2A.Z.1 colocalized with only a subset of EBNA1 binding sites and H2A.Z.1 depletion altered transcription of genes associated withmyc targetsandmTORC1 signaling. Taken together, these findings indicate that H2A.Z.1 cooperates with EBNA1 to regulate chromatin structures important for epigenetic programming of the latent episome.ImportanceCellular factors the restrict latent viral reactivation are of fundamental importance. We have found that the cellular histone variant H2A.Z functions in cooperation with the Epstein-Barr Virus (EBV) latency maintenance protein EBNA1 to establish a stable epigenome and restrict lytic cycle reactivation during latency. We show that H2A.Z co-occupies EBNA1 binding sites on the EBV and host genome, and that depletion of H2A.Z leads to robust reactivation of EBV from latency. H2A.Z is important for the function of EBNA1 at the origin of plasmid (oriP) replication and establishing EBV epigenetic marks. H2A.Z binds with EBNA1 at cellular binding sites and controls the expression of cellular genes in the cMyc and mTORC1 pathways that are also implicated in control of EBV latency.
Molecular evolution of silver nanoparticle resistance in a bacterial pathogen and a unique adaptation response to ionic silver
Authors: McNeilly Oliver , Mediati Daniel G. , Pittorino Matthew J. , Mann Riti , Söderström Bill , Hamidian Mehrad , Gunawan Cindy 
Published: January 2025

AbstractThis research explores the adaptive defense mechanisms of a nanosilver-resistant pathogen (NAgR) to protect and fight off the complex antimicrobial targeting of silver nanoparticles. The Gram-negative bacteriumAcinetobacter baumanniiupregulated expression of outer membrane proteins for cell surface defense, as well as membrane and capsule synthesis genes. Increased abundance of surface-attached biofilm colonies in NAgRwas linked to the phenotypically indicated increase in membrane integrity, with the bacterium also forming more EPS, the biopolymer matrix that protects the residing colony. In response to the known reactive oxygen species (ROS) toxicity characteristics of the nanoparticle, NAgRupregulated its oxidative stress management system, specifically involving ROS scavenger enzymes and opportunistic metal efflux pumps. Many of these evolved defense mechanisms only manifested in the resistant bacterium, while they were absent in the wild-type strain. This study also details the unique defenses of an ionic silver-adaptedA. baumanniivariant, having evolved from the same wild-type parental strain as NAgR. Despite similarities in cell surface and biofilm defense trends, the slower-to-kill tolerant strain (AgT) exclusively upregulated multidrug efflux systems and respiratory chain enzymes, thought to maintain enhanced respiration activity, a known tolerant characteristic. Identification of these stable defense mechanisms can recommend strategies for molecular targeting to overcome the adaptation phenomena.
Electrophysiological and network dynamics disruption of hippocampal CA1 neurons after NMDAr blockade by MK-801
Authors: Abad-Perez P. , Molina-Payá F. J. , Rigamonti G. , Tirado M , Cabrales G. , Montesinos Antonio Falcó , Martínez-Otero L. , Borrell V. , Sánchez-Mut J. , Redondo R. , Brotons-Mas J. R. 
Published: January 2025

AbstractThe N-methyl-D-aspartate receptor (NMDAr) hypofunction hypothesis suggests that excitatory-inhibitory (E-I) imbalance underlies cognitive deficits associated with neuropsychiatric disorders, such as schizophrenia (SCZ). In this study, we investigated the impact of NMDAr blockade on pyramidal neurons and interneurons in the CA1 region of the hippocampus using in vivo electrophysiological recordings during both spontaneous and exploratory behaviors. Through the administration of MK-801, an NMDAr antagonist, we assessed changes in spike train dynamics, network synchrony, and neuronal modulation by oscillatory activity, with particular emphasis on theta, gamma, and sharp-wave ripple (SWR) oscillations. We found that NMDAr blockade significantly disrupted the E-I balance, leading to altered spike train properties, reduced bursting propensity, and impaired neuronal synchronization. These changes were accompanied by decreased modulation of pyramidal neurons and interneurons by theta and gamma oscillations, as well as diminished recruitment of pyramidal neurons during SWR events. Additionally, the correlation between firing rates and movement speed was reduced, reflecting deficits in spatial coding and memory processing. Moreover, MK-801 administration disrupted place cell stability and spatial information processing. These effects likely contribute to functional disconnection between the hippocampus and other brain regions, such as the prefrontal cortex, and may underlie SCZ-associated cognitive impairments. Our findings provide valuable insights into the cellular and network-level mechanisms affected by NMDAr dysfunction, highlighting the role of oscillatory activity and spike timing in cognitive deficits. This work advances our understanding of how NMDAr hypofunction impacts hippocampal circuits and identifies potential targets for therapeutic interventions aimed at restoring cognitive function in neuropsychiatric disorders.
A recombinant hybrid provides insights into gene regulation, pathogenesis and tumorigenesis of phytopathogenic smut fungi
Authors: Werner Janina , Zuo Weiliang , Winkler Tom , Doehlemann Gunther 
Published: January 2025

AbstractThe maize smut fungiUstilago maydisandSporisorium reilianumare closely related and have similar genomes in terms of size and synteny. WhileU. maydisinduces tumors locally at sites of infection,S. reilianumsystemically colonizes the host and causes symptoms in the inflorescences. To investigate the genetic basis of these differences, an interspecific recombinant hybrid (rUSH) with the mating type system ofS. reilianumwas generated. rUSH exhibited extensivein-plantaproliferation, showing aS. reilianum-like phenotype at all developmental stages except teliospore formation. Transcriptome profiling revealed that expression of pathogenicity-related effector gene orthologs was induced in rUSH, but not in a wild-type hybrid control. Multiple transcriptome comparisons identified 253 differentially expressed one-to-one effector orthologs with distinct regulatory patterns, including cis-, trans-, and rUSH-specific regulation. Functional analysis via CRISPR/Cas9 mutagenesis uncovered three novel virulence factors among the rUSH-specific regulated effectors. Ultimately, rUSH facilitated to identify the transcription factor UmHdp2 as key regulator ofU. maydis-induced tumorigenesis. Together, these findings highlight the utility of a recombinant, interspecific hybrid in unraveling the molecular mechanisms underlying pathogenic differences in closely related fungal pathogens.
Advancing (-)-Premarineosin A as a Potent Antimalarial Therapeutic via Metabolic Engineering and Late-Stage Derivatization
Authors: McBride Christina M. , McCauley Morgan , Harris Natalia R. , Amin Sahar , Verhey-Henke Linnea , Teklemichael Awet A. , Oliphant Erin N. , Dranchak Patricia , Curtis Brian J. , Lev Katherine L. , Qu Fengrui , Snodgrass Harrison M. , Lewis Jared C. , Inglese James , Su Xin-zhuan , Pereira Filipa , Sherman David H. 
Published: January 2025

AbstractDespite modern preventative and curative efforts, malaria has remained a major global health crisis. In 2023 alone, malaria was responsible for an estimated 263 million cases and 597,000 deaths. To complicate this issue, the causativePlasmodiumparasites are becoming more resistant to available therapeutics, making it difficult to treat and prevent disease progression. Hence, the discovery of new antimalarial drugs is crucial to mitigating this crisis. One promising contender is the natural product premarineosin A, an intermediate of the marineosin biosynthetic pathway that exhibits potent and selective antimalarial activity against both chloroquine-sensitive and multi-drug-resistantPlasmodiumstrains. However, its complex chemical structure and low production titers have prevented further exploration. To improve access to this promising metabolite, we identified a biosynthetic gene cluster for (-)-premarineosin A production inStreptomyces eitanensis.Metabolic engineering approaches increased production from trace levels to nearly 35 mg/L, which enabled semi-synthetic and biocatalytic derivatization of the (-)-premarineosin A scaffold. Late-stage C-H bromination of the B-ring resulted in a highly potent (EC50< 5 nM) antimalarial compound with low cytotoxicity. These findings report progress toward the sustainable access of (-)-premarineosin A and the first structure-activity relationship study for this unique scaffold in the search for improved antimalarial therapeutics.
Differential endopeptidase requirements during adaptation to changing growth conditions inVibrio cholerae
Authors: Rosch Kelly , Lei Samantha , Zheng Jennifer , Dörr Tobias 
Published: January 2025

AbstractThe bacterial cell wall is a covalently linked meshwork of peptidoglycan (PG) that establishes cell shape and prevents osmotic lysis. This structure must be flexible enough to accommodate transenvelope protein complexes, but strong enough to withstand high intracellular pressure. In order to elongate and divide, cells must remodel the cell wall through the concerted action of PG synthesis and degradation. Endopeptidases, a class of PG degrading enzymes, facilitate cell growth by hydrolyzing PG crosslinks.Vibrio choleraeencodes several functionally redundant endopeptidases, two of which are nearly identical: ShyA and ShyC. To investigate differential roles of these enzymes, we assessed growth and morphology of ShyA and ShyC mutants. We found that ShyA, but not ShyC, is required for normal adaptation to low osmolarity medium. Cells lacking ShyA exhibited longer lag phase and aberrant morphology during adaptation, and reduced survival in the presence of a beta-lactam antibiotic. Lastly, our experiments revealed that cells lacking ShyA’s LysM domain exhibited more severe defects than cells lacking ShyA altogether, implicating the LysM domain in proper regulation of ShyA activity.
RNA promotes synapsin coacervation and modulates local translation
Authors: Rankovic Branislava , Geisterfer Zachary M , Chhabra Akshita , Jovanovic Vladimir M , Seim Ian , Hoffmann Christian , Condric Antonela , Pérez Gerard Aguilar , Freitag Kiara , Nowick Katja , Jendrach Marina , Heppner Frank , Reshetniak Sofiia , Gladfelter Amy S , Milovanovic Dragomir 
Published: January 2025

AbstractCondensates are found at synapses where they support the clustering of synaptic vesicles (SVs) and neurotransmitter release. The possibility of RNA promoting the formation or function of these condensates is not known. Here, we set out to assess whether RNA affects molecular condensates in the synapse or could be regulated at these sites, focusing on synapsin-1, which is essential for synapse condensates. Usingin vitroreconstitution systems, cell lines and neurons, we show that RNA drives synapsin-1 coacervation, with some bias toward structured RNAs being more effective at promoting demixing. The importance of RNA was confirmed in living synapses, where acute disruption of native RNA induces a dispersion of SVs and synapsin. Conversely, ectopically expressed SV-like condensates have the ability to recruit RNA species and the translational machinery, which accumulates within condensate-microdomains, resulting in increased translation efficacy. Our work indicates a novel role of RNAs in modulating SV condensates, as well as translation, at the synapse.Key ConclusionsRNA forms coacervates with synapsin-1 that readily sequester SVs.Acute disruption of RNA affects the organization of the presynapse.RNA secondary structure tunes the assembly of synapsin-SV condensates.RNA competes with α-synuclein for partitioning at the condensates.Synapsin-1/RNA condensates are hubs for local translation.
An updated inventory of genes essential for oxidative phosphorylation identifies a mitochondrial origin in familial Ménière’s disease
Authors: Harhai Marcell , Foged Mads M. , Recazens Emeline , Lisci Miriam , Chollet Sylvain , Landoni Juan C. , Laban Nora , Manley Suliana , Lopez-Escamez Jose Antonio , Lysakowski Anna , Jourdain Alexis A. 
Published: January 2025

SummaryMitochondrial disorders (MDs) are among the most common inborn errors of metabolism and primarily arise from defects in oxidative phosphorylation (OXPHOS). Their complex mode of inheritance and diverse clinical presentations render the diagnosis of MDs challenging and, to date, most lack a cure. Here, we build on previous efforts to discover genes necessary for OXPHOS and report a highly complementary galactose-sensitized CRISPR-Cas9 “growth” screen, presenting an updated inventory now with 481 OXPHOS genes, including 157 linked to MDs. We further focus onFAM136A, a gene associated with Ménière’s disease, and show that it supports inter-membrane space protein homeostasis and OXPHOS in cell lines, mice, and patients. Our study identifies a mitochondrial basis in a familial form of Ménière’s disease (fMD), provides a comprehensive resource of OXPHOS-related genes, and sheds light on the pathways involved in mitochondrial disorders, with the potential to guide future diagnostics and treatments for MDs.Graphical abstractBullet pointsGenome-wide CRISPR-Cas9 growth screening complements death screening481 genes essential for OXPHOS, including 157 mitochondrial disease genesFAM136Asupports mitochondrial intermembrane space protein homeostasisDepletion ofFAM136Ain Ménière’s disease models causes OXPHOS defects
Local olfactory nerve stimulation triggers patchy activation of columns across rat olfactory bulb
Authors: Jahan Israt , Kindler Lisa , Reichardt Nicolas , Suyama Hajime , Egger Veronica 
Published: January 2025

AbstractColumnar organization is a hallmark of neocortical sensory areas, most prominently in primary somatosensory and visual cortex. In the olfactory bulb, the existence of a vertical columnar organization of circuits associated with glomerular input channels has been implicated by various approaches. Here, based on activity-dependent labelling and tissue clearing, we provide direct evidence for functional bulbar columns formed by mitral cells and granule cells that display a uniform morphology.