bluuebunny/crossref_metadata_2025_split huggingface dataset:
A protocol for high-dose quadrivalent influenza vaccine effectiveness in the community and long-term care facilities using electronic health records
Authors: Soares Patrícia , Gomez Verónica , Gaio Vânia , Santos João Almeida , Rodrigues Ana Paula , Machado Ausenda 
Published: November 2024

AbstractSince the 2022-2023 season in Portugal, a high-dose quadrivalent influenza vaccine is freely available for individuals living in long-term care facilities (LTCF). In 2024-2025, vaccination was extended to community-dwelling individuals aged ≥85 years. Given the scarcity of reported high-dose influenza vaccine effectiveness (IVE) estimates for this population, this study aims to estimate the high-dose relative and absolute IVE.A retrospective cohort study using data from electronic health records databases (EHR) will be implemented, using two cohorts, one of individuals vaccinated with influenza vaccine (to estimate relative IVE) and another of individuals eligible for the high-dose quadrivalent influenza vaccine (to estimate absolute IVE). We will consider two subgroups for both cohorts: individuals living in LTCF and community-dwelling individuals aged ≥85. We will use a fixed cohort approach, defining the eligible population by age at the vaccination campaign(s) start and living status. The outcomes are based on the primary cause of hospital admission. The reference population database will be defined by linking EHR on vaccination, comorbidities, and hospitalisations using a unique identifier through a deterministic data linkage procedure, and influenza vaccination status will be assessed retrospectively. We will use Cox proportional hazards regression models to estimate the hazard ratio (HR), considering as event the first hospitalisation due to influenza-like-illness and as exposure the vaccination status. IVE will be estimated as one minus the confounder-adjusted HR of vaccinated with the high-dose quadrivalent influenza vaccine vs vaccinated with standard dose (to estimate relative IVE) or unvaccinated (to estimate absolute IVE).While challenges such as EHR constraints and potential reporting bias pose limitations, using routinely collected data has successfully estimated COVID-19 VE and enables precise monitoring of VE with higher representativeness. The results of this study will inform the Health Ministry on the future influenza vaccine programme in Portugal.
A comprehensive representation of selection at loci with multiple alleles that allows complex forms of genotypic fitness
Authors: Vellnow Nikolas , Gossmann Toni I. , Waxman David 
Published: November 2024

AbstractGenetic diversity is central to the process of evolution. Both natural selection and random genetic drift are influenced by the level of genetic diversity of a population; selection acts on diversity while drift samples from it. At a given locus in a diploid population, each individual carries only two alleles, but the population as a whole can possess a much larger number of alleles, with the upper limit constrained by twice the population size. This allows for many possible types of homozygotes and heterozygotes. Moreover, there are biologically important loci, for example those related to the MHC complex, the ABO blood types, and cystic fibrosis, that exhibit a large number of alleles. Despite this, much of population genetic theory, and data analysis, are limited to considering biallelic loci. However, to the present, what is lacking is a flexible expression for the force of selection that allows an arbitrary number of alleles (and hence an arbitrary number of heterozygotes), along with a variety of forms of fitness. In this work, we remedy this absence by giving an analytical representation of the force of selection that emphasises the very different roles played by the diversity of the population, and the fitnesses of different genotypes. The result presented facilitates our understanding and applies in a variety of different situations involving multiple alleles. This includes situations where fitnesses are: additive, multiplicative, randomly fluctuating, frequency-dependent, and it allows fitnesses which involve explicit gene interactions, such as heterozygote advantage.Significance statementGenetic diversity is a cornerstone of evolutionary processes, influencing both natural selection and genetic drift. While many biologically significant loci, like those associated with the MHC complex, ABO blood types, and cystic fibrosis, contain a large number of alleles, population genetics often simplifies analysis to biallelic loci. This study provides a new, flexible framework to quantify the force of selection in populations with an arbitrary number of alleles. This approach broadens our understanding of complex genetic scenarios, including those involving additive, multiplicative, and frequency-dependent fitness, as well as heterozygote advantage. This advancement enables more nuanced modeling of real-world evolutionary dynamics across diverse biological contexts.
Long-Read RNA-sequencing reveals transcript-specific regulation in human-derived cortical neurons
Authors: Xu Jishu , Hörner Michaela , Atienza Elena Buena , Manibarathi Kalaivani , Nagel Maike , Hauser Stefan , Admard Jakob , Casadei Nicolas , Ossowski Stephan , Schüle Rebecca 
Published: November 2024

AbstractLong-read RNA sequencing has transformed transcriptome analysis by enabling comprehensive mapping of full-length transcripts, providing an unprecedented resolution of transcript diversity, alternative splicing, and transcript-specific regulation. In this study, we employed nanopore long-read RNA sequencing to profile the transcriptomes of human fibroblasts, induced pluripotent stem cells, and stem cell-derived cortical neurons, identifying extensive transcript diversity with 15,072 transcripts in stem cell-derived cortical neurons, 13,048 in fibroblasts, and 12,759 in induced pluripotent stem cells. Our analyses uncovered 35,519 differential transcript expression events and 5,135 differential transcript usage events, underscoring the complexity of transcriptomic regulation across these cell types. Importantly, by integrating differential transcript expression and usage analyses, we gained deeper insights into transcript dynamics that are not captured by gene-level expression analysis alone. Notably, differential transcript usage analysis highlighted transcript-specific changes in disease-relevant genes such asAPP, KIF2A, andBSCL2, associated with Alzheimer’s disease, neuronal migration disorders, and degenerative axonopathies, respectively. This added resolution emphasizes the significance of transcript- level variations that often remain hidden in traditional differential gene expression analyses.Overall, our work provides a framework for understanding transcript diversity in both pluripotent and specialized cell types, which can be used to investigate transcriptomic changes in disease states. Additionally, this study underscores the utility of differential transcript usage analysis in advancing our understanding of neurodevelopmental and neurodegenerative diseases, paving the way for identifying transcript-specific therapeutic targets.
Cellular moonlighting function of Hsp20 directs morphological and pathogenic development inUstilago maydis
Authors: Mitra Aroni , Kar Ankita , Bhakta Koustav , Roy Anisha , Mukherjee Dibya , Ghosh Abhrajyoti , Ghosh Anupama 
Published: November 2024

SummaryUstilago maydisHsp20 is involved in the pathogenicity of the fungus. In this study we have investigated the molecular basis of contribution of Hsp20 toU. maydispathogenicity. Through biochemical studies we have demonstrated environment-dependent oligomeric plasticity associated with Hsp20. Hsp20 was also found to form higher order oligomers that undergo phase separation in vitro. Within cells Hsp20 was found to form distinct punctate structures that we believe play a pivotal role in its function. These punctate structures were demonstrated to sequester proteins such as actin and septin within it. Absence of Hsp20 was found to significantly affect key cellular processes like endocytosis, budding, cell polarity determination and mating inU. maydiscells. The deletion mutant failed to sporulate and complete pathogenic life cycle. This study presents a comprehensive understanding of the pathogenic development ofU. maydisin reference to the moonlighting function of Hsp20 within the cell.
Adducins regulate morphology and fate of neural progenitors during neocortical neurogenesis
Authors: Ossola Chiara , Cokorac Nikola , Faletti Stefania , Capra Emanuele , Bertani Ilaria , Ambrosini Chiara , Faga Giovanni , Kalebic Nereo 
Published: November 2024

SummaryThe evolutionary expansion of the mammalian neocortex is mediated by an increase in the proliferative capacity of neural progenitor cells. However, the molecular machinery controlling the proliferation of apical and basal progenitors during neocortical development is still poorly understood. Here we show that the three actin-associated morpho-regulatory adducins (ADD1-3), underlie abundance of basal progenitors in developing mouse and ferret neocortexin vivoand in human cortical organoids. Over expression of adducins in embryonic mouse neocortex increases the number of protrusions of basal progenitors, leading to an increase in their proliferative capacity and neuronal output. Conversely, knock-out of ADD1 in human cortical organoids, which also leads to down-regulation of other adducins, results in reduced proliferation of progenitors and aberrant neurogenesis. Hence, we show that adducins underlie proliferation and fate of neural progenitors, which are key cellular features underlying progression of mammalian neurogenesis.
An environment-responsive SCLA-type GRAS protein controls reproductive strategy inMarchantia polymorpha
Authors: Hoey David J. , Carella Philip , Yang Weibing , Schornack Sebastian 
Published: November 2024

AbstractBy controlling their reproductive strategies, plants strike a balance between generating genetic diversity or maintaining stability, promoting long-term survival in a range of environmental conditions. The liverwortMarchantia polymorphapropagates clonally through vegetative gemmae or via sexually generated spores, but our understanding of the genetic pathways underpinning reproductive decision-making is limited. GRAS transcriptional regulators are highly conserved proteins across land plants, with diverse functionality in stress and development. Here, we discover a central role for the SCLA-type transcription regulator MpGRAS7in both stress signalling and reproduction in Marchantia. MpGRAS7is highly expressed in gemma cups and gametangiophores and is activated in response to Far Red (FR) light and abscisic acid (ABA) environmental cues. Genetic dissection further suggests MpGRAS7is required to maintain gemma dormancy, gemma cup frequency, and FR-induced gametangiophore development. The sequence conservation and expression patterns of MpGRAS7orthologs in flowering plants hints towards the broader function of SCLA-type GRAS proteins in stress-regulated developmental transitions in plants.
The landscape of structural variation in aye-ayes (Daubentonia madagascariensis)
Authors: Versoza Cyril J. , Jensen Jeffrey D. , Pfeifer Susanne P. 
Published: November 2024

ABSTRACTAye-ayes (Daubentonia madagascariensis) are one of the 25 most critically endangered primate species in the world. Endemic to Madagascar, their small and highly fragmented populations make them particularly vulnerable to both genetic disease and anthropogenic environmental changes. Over the past decade, conservation genomic efforts have largely focused on inferring and monitoring population structure based on single nucleotide variants to identify and protect critical areas of genetic diversity. However, the recent release of a highly contiguous genome assembly allows, for the first time, for the study of structural genomic variation (deletions, duplications, insertions, and inversions) which are likely to impact a substantial proportion of the species’ genome. Based on whole-genome, short-read sequencing data from 14 individuals, >1,000 high-confidence autosomal structural variants were detected, affecting ∼240 kb of the aye-aye genome. The majority of these variants (>85%) were deletions shorter than 200 bp, consistent with the notion that longer structural mutations are often associated with strongly deleterious fitness effects. For example, two deletions longer than 850 bp located within disease-linked genes were predicted to impose substantial fitness deficits owing to a resulting frameshift and gene fusion, respectively; whereas several other major effect variants outside of coding regions are likely to impact gene regulatory landscapes. Taken together, this first glimpse into the landscape of structural variation in aye-ayes will enable future opportunities to advance our understanding of the traits impacting the fitness of this endangered species, as well as allow for enhanced evolutionary comparisons across the full primate clade.
Ccp1 depletion disrupts network integration of hippocampal parvalbumin interneurons
Authors: Le Bail Romain , Lakaye Bernard , Espuny-Camacho Ira , Janke Carsten , Magiera Maria M. , Engel Dominique , Silva Carla G. , Nguyen Laurent 
Published: November 2024

AbstractPost-translational modifications (PTMs) of microtubules (MTs) endow them with specific properties that are essential for key cellular functions, such as axonal transport. Polyglutamylation, a PTM that accumulates in long-lived MTs, has been linked to neurodegeneration in the cerebellum when in excess. While hyperglutamylation of MTs leads to neurodegeneration and disrupts the function of specific neuronal subtypes like Purkinje cells, cortical neurons, and hippocampal excitatory neurons, little is known about its impact on inhibitory interneurons and their functional integration into local networks. In this study, we generated a conditional knockout mouse model to deplete cytosolic carboxypeptidase 1 (Ccp1) in GABAergic neurons, a key MT deglutamylase expressed by hippocampal interneurons. Our findings reveal that the loss of Ccp1 has a profound effect on hippocampal parvalbumin (PV)-expressing interneurons, impairing their axonal transport and reducing their perisomatic inhibition of pyramidal cells (PCs) in the CA2 region of the hippocampus.Research TopicsMolecular Neuroscience, Cell BiologyHighlightsDifferent subtypes of hippocampal interneurons express unique sets of (de)glutamylases and show varying levels of protein posttranslational glutamylation.Parvalbumin interneurons become hyperglutamylated when Ccp1 activity is lost.The loss of Ccp1 disrupts axonal transport in interneurons and is associated with decreased perisomatic inhibition of hippocampal pyramidal cells in the CA2 region.
Development of a New N-Terminomic Method to Study the Pathodegradome of theStaphylococcus aureusV8 Protease in Human Neutrophils
Authors: Mustor Emilee M. , Frey Andrew M. , Jobson Mary-Elizabeth , Chaput Dale , Shaw Lindsey Neil 
Published: November 2024

ABSTRACTStaphylococcus aureusis a notorious human pathogen that relies on an array of virulence factors to engender infection and evade the host-immune system. Among these are the secreted proteases, which promote pathogenesis by degrading host proteins and modulating host-defenses. Human neutrophils play a pivotal role in these defenses, acting as the first responders against invading bacteria. While manyS. aureuseffectors of virulence have been shown to target leukocytes, there is limited knowledge on how the extracellular proteases modulate neutrophil fate. Typically, protease substrates have been identified in isolated settings using one at a time approaches; with neutrophil targets few and far between. Herein, we have developed a novel N-terminomic methodology termed TAGS-CR that can facilitate global substrate characterization in streamlined manner. We thus present the application of TAGS-CR to unravelling the human neutrophil pathodegradome of theS. aureusV8 protease. In so doing, we captured ∼350 V8 targets, revealing critical insight into how this virulence factor can modulate neutrophil functionality on various levels relevant toS. aureusdisease progression. We recorded cleavage of proteins necessary for neutrophil adhesion and migration, a fundamental process necessary for pathogen clearance. Furthermore, we highlight V8 cleavage of proteins involved in important neutrophil defense tactics, such as degranulation and reactive oxygen species production. This protease may also facilitate bacterial dissemination via the intentional activation of neutrophil apoptosis. Collectively, this work deepens our understanding of host-pathogen interaction and begins to unravel howS. aureusproteases can induce immune dysregulation through the targeting of leukocytes.ImportanceDuring infectionStaphylococcus aureusmust engage and evade the host immune system in order to successfully cause disease. As neutrophils represent the frontline of defense against invadingS. aureuscells, it becomes increasingly important to decode how this bacterium subverts their host-defense tactics. While the contributing role to neutrophil engagement for manyS. aureusvirulence factors have been elucidated, the effects of their proteases remain largely unclear. Here, we present a novel method for global protease substrate identification, TAGS-CR, and use it to identifyS. aureusV8 protease targets in human neutrophils. These include factors that not only govern general neutrophil function but moreover, their defense mechanisms, such as migration, degranulation, oxidative defense, phagocytosis and apoptosis.
Inferring Cell-Type-Specific Co-Expressed Genes from Single Cell Data
Authors: Shan Xinning , Zhao Hongyu 
Published: November 2024

AbstractBackgroundCell-type-specific gene co-expression networks are widely used to characterize gene relationships. Although many methods have been developed to infer such co-expression networks from single-cell data, the lack of consideration of false positive control in many evaluations may lead to incorrect conclusions because higher reproducibility, higher functional coherence, and a larger overlap with known biological networks may not imply better performance if the false positives are not well controlled.ResultsIn this study, we have developed an efficient and effective simulation tool to derive empirical p-values in co-expression inference to appropriately control false positives in assessing method performance. We studied the power of the p-value-based approach in inferring cell-type-specific co-expressions from single-cell data using both simulated and real data. We also highlight the need to adjust for random overlaps between the inferred and known networks when the number of selected correlated gene pairs varies substantially across different methods. We further illustrate the expression level bias in known biological networks and the impact of such bias in method assessment.ConclusionOur study indicates the importance of controlling false positives in the inference of co-expressed genes to achieve more reliable results and proposes a simulation-based p-value method to achieve this.
Structure of the TXNL1-bound proteasome
Authors: Gao Jingjing , Nardone Christopher , Yip Matthew C.J. , Chino Haruka , Gu Xin , Mirman Zachary , Rale Michael J. , Paulo Joao A. , Elledge Stephen J. , Shao Sichen 
Published: November 2024

AbstractProteasomes degrade diverse proteins in different cellular contexts through incompletely defined regulatory mechanisms. Here, we report the cryo-EM structure of thioredoxin-like protein 1 (TXNL1) bound to the 19S regulatory particle of proteasomes via interactions with PSMD1/Rpn2, PSMD4/Rpn10, and PSMD14/Rpn11. These interactions are necessary for the ubiquitin-independent degradation of TXNL1 upon cellular exposure to metal- or metalloid-containing oxidative agents, thereby establishing a structural basis for the stress-induced degradation of TXNL1.
FREQUENCY SPECIFICITY OF NARROWBAND CHIRPS AND 2-1-2 STIMULI: SPECTRAL ANALYSES
Authors: Adjekum Ronald , Small Susan A. , Chan Sylvia , Stapells David R. 
Published: November 2024

AbstractObjectiveThe current study examined the frequency specificity of NB chirps by comparing the spectral characteristics of 500-, 1000-, 2000- and 4000-Hz NB CE-Chirp®LS stimuli with those of 2-1-2 tones.DesignSpectral characteristics including the center frequency, main lobe bandwidth, and stimulus energy changes after stopband filtering were compared. The bandwidth was computed as the difference between the upper and lower frequencies at -20 dB cutoff points of the main lobe; the centre frequency was determined as the geometric mean of the upper and lower frequencies at the -20 dB cutoff points.ResultsAt 100 dB peSPL, the mainlobe bandwidths of the 500, 1000, and 2000 Hz NB CE-Chirp®LS acoustic spectra were 1.8-1.9 times wider than the acoustic spectra for the 2-1-2 tones; the 4000 Hz NB CE-Chirp®LS bandwidths were 1.4-1.5 times wider than those of the 2-1-2 tones. The energy of NB CE-Chirp® LS stimuli was concentrated within ±0.75 octave of the center frequency, compared to ±0.5 octave for 2-1-2 tones.ConclusionNB CE-Chirp®LS stimuli demonstrated poorer frequency specificity compared with 2-1-2 tones. Further studies are needed to investigate the place specificity of the ABRs to NB CE-Chirp®LS before implementing them clinically.
Targeting IL-1/IRAK1/4 signaling in Acute Myeloid Leukemia Stem Cells Following Treatment and Relapse
Authors: Ho Tzu-Chieh , LaMere Mark W. , Kawano Hiroki , Byun Daniel K. , LaMere Elizabeth A. , Chiu Yu-Chiao , Chen Chunmo , Wang Jian , Dokholyan Nikolay V. , Calvi Laura M. , Liesveld Jane L. , Jordan Craig T. , Kapur Reuben , Singh Rakesh K. , Becker Michael W. 
Published: November 2024

AbstractTherapies for acute myeloid leukemia (AML) face formidable challenges due to relapse, often driven by leukemia stem cells (LSCs). Strategies targeting LSCs hold promise for enhancing outcomes, yet paired comparisons of functionally defined LSCs at diagnosis and relapse remain underexplored. We present transcriptome analyses of functionally defined LSC populations at diagnosis and relapse, revealing significant alterations in IL-1 signaling. Interleukin-1 receptor type I (IL1R1) and interleukin-1 receptor accessory protein (IL1RAP) were notably upregulated in leukemia stem and progenitor cells at both diagnosis and relapse. Knockdown ofIL1R1andIL1RAPreduced the clonogenicity and/or engraftment of primary human AML cells. In leukemic MLL-AF9 mice,Il1r1knockout reduced LSC frequency and extended survival. To target IL-1 signaling at both diagnosis and relapse, we developed UR241-2, a novel interleukin-1 receptor-associated kinase 1 and 4 (IRAK1/4) inhibitor. UR241-2 robustly suppressed IL-1/IRAK1/4 signaling, including NF-κB activation and phosphorylation of p65 and p38, following IL-1 stimulation. UR241-2 selectively inhibited LSC clonogenicity in primary human AML cells at both diagnosis and relapse, while sparing normal hematopoietic stem and progenitor cells. It also reduced AML engraftment in leukemic mice. Our findings highlight the therapeutic potential of UR241-2 in targeting IL-1/IRAK1/4 signaling to eradicate LSCs and improve AML outcomes.