bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of a Single Case-Finding Questionnaire to Simultaneously Target Multiple Related Diseases Allows Enhanced Disease Detection
Authors: Aaron Shawn D. , Huynh Chau , Whitmore George Alex 
Published: December 2023

AbstractObjectiveTo develop a research methodology to apply a single case-finding tool to multiple related diseases and to evaluate the ability of a single tool to detect two or more related chronic diseases.MethodsAdults in the community with no prior history of physician-diagnosed lung disease who self-reported respiratory symptoms were contacted via random-digit dialing. Multiple risk scores, one for asthma and one for COPD, were developed using data from a single case-finding questionnaire administered to the study population. Each score was statistically optimized for targeted detection of cases having one disease in the class. External validation of tandem risk scores was prospectively conducted in an independent sample and predictive performance re-evaluated.ResultsSensitivity for detection of asthma improved from 87% using single risk scores to 96% using tandem risk scores, and sensitivity for detection of COPD similarly improved from 87% to 99%. In the independent validation cohort, case-finding sensitivities increased from 64% and 59% using single risk scores to 95% and 96% using tandem risk scores for asthma and for COPD, respectively.ConclusionsUse of a single questionnaire which incorporates risk scores for multiple diseases considered in tandem, rather than individually, enhances the yield of cases detected when compared with one-at-a-time application of risk scores for case discovery. Benefits include greater efficiency in case-finding and improved sensitivities for detection of each disease.What is New?We describe case finding in a population of undiagnosed, symptomatic subjects who have one disease from a class of related chronic diseases.Multiple risk scores are developed using data from a single case-finding instrument administered to a representative sample from the study population. Each score is statistically optimized for targeted detection of cases having one disease in the class.Use of multiple risk scores, when considered in tandem, enhances the yield of cases detected when compared with one-at-a-time application of risk scores for case discovery.
LOW LEVELS OF DIRECT ORAL ANTICOAGULANTS AT STEADY STATE IN ATRIAL FIBRILLATION PATIENTS WHO LATER DEVELOP THROMBOTIC COMPLICATIONS; THE PROSPECTIVE MAS (MEASURE AND SEE) STUDY
Authors: Testa Sophie , Palareti Gualtiero , Legnani Cristina , Dellanoce Claudia , Cini Michela , Paoletti Oriana , Ciampa Antonio , Antonucci Emilia , Poli Daniela , Morandini Rossella , Tala Maurizio , Chiarugi Paolo , Santoro Rita Carlotta , Iannone Angela Maria , Candia Erica De , Pignatelli Pasquale , Faioni Elena Maria , Chistolini Antonio , Esteban Maria del Pilar , Marietta Marco , Tripodi Armando , Tosetto Alberto ,   MAS Study group
Published: December 2023

ABSTRACTBackgroundThough effective and safe, treatment with direct oral anticoagulants (DOAC) in atrial fibrillation (AF) is still associated with thrombotic complications. Whether the measurement of DOAC levels may improve the efficacy of treatment is an open issue.MethodsWe carried out the observational, prospective, multicenter study [“Measure and See” Study (MAS) (NCT03803579)]. Blood was collected 15-30 days after starting DOAC treatment in AF patients, who were then followed for one year. Plasma samples were centralized, for DOAC levels measurement. Patients’ DOAC levels were converted into drug/dosage standardized values to allow a pooled analysis in a time-dependent, competitive-risk model. The measured values were transformed into standardized values by subtracting from the original values the overall mean value of each DOAC and divided by the standard deviation. Standardized values represent the distance of each value from the overall mean.ResultsTrough and peak DOAC levels were assessed in 1657 and 1303 patients, respectively. Twenty-one thrombotic complications were recorded during 1606 years of follow-up (incidence of 1.31% patient/years). 17/21 thrombotic events occurred in patients whose standardized activity levels were below the mean of each DOAC (zero); the incidence was the highest (4.08% patient/years) in patients whose standardized values were in the lowest class (below zero, σ; - 1.00).ConclusionsEarly measurement of DOAC levels in AF patients allowed us to identify most of the subjects who, having low baseline DOAC levels, subsequently developed thrombotic complications. Further studies are warranted to assess whether thrombotic complications may be reduced by measuring baseline DOAC levels and modifying treatment when indicated.
Somatic mutation as an explanation for epigenetic aging
Authors: Koch Zane , Li Adam , Evans Daniel S. , Cummings Steven , Ideker Trey 
Published: December 2023

AbstractDNA methylation marks have recently been used to build models known as “epigenetic clocks” which predict calendar age. As methylation of cytosine promotes C-to-T mutations, we hypothesized that the methylation changes observed with age should reflect the accrual of somatic mutations, and the two should yield analogous aging estimates. In analysis of multimodal data from 9,331 human individuals, we find that CpG mutations indeed coincide with changes in methylation, not only at the mutated site but also with pervasive remodeling of the methylome out to ±10 kilobases. This one-to-many mapping enables mutation-based predictions of age that agree with epigenetic clocks, including which individuals are aging faster or slower than expected. Moreover, genomic loci where mutations accumulate with age also tend to have methylation patterns that are especially predictive of age. These results suggest a close coupling between the accumulation of sporadic somatic mutations and the widespread changes in methylation observed over the course of life.
Exploring white matter dynamics and morphology through interactive numerical phantoms: The White Matter Generator
Authors: Winther S. , Peulicke O. , Andersson M. , Kjer H. M. , Bærentzen J. A. , Dyrby T. B. 
Published: December 2023

AbstractBrain white matter is a dynamic environment that continuously adapts and reorganizes in response to stimuli and pathological changes. Glial cells, especially, play a key role in tissue repair, inflammation modulation, and neural recovery. The movements of glial cells and changes in their concentrations can influence the surrounding axon morphology. We introduce the White Matter Generator (WMG) tool to enable the study of how axon morphology is influenced through such dynamical processes, and how this, in turn, influences the diffusion-weighted MRI signal. This is made possible by allowing interactive changes to the configuration of the phantom generation throughout the optimisation process. The phantoms can consist of axons, myelinated axons, and cell clusters, separated by extra-cellular space. Due to morphological flexibility and computational advantages during the optimisation, the tool uses ellipsoids as building blocks for all structures; chains of ellipsoids for axons, and individual ellipsoids for cell clusters. After optimisation, the ellipsoid representation can be converted to a mesh representation which can be employed in Monte-Carlo diffusion simulations. This offers an effective method for evaluating tissue microstructure models for diffusion-weighted MRI in controlled realistic white matter environments. Hence, the WMG offers valuable insights into white matter’s adaptive nature and implications for diffusion-weighted MRI microstructure models, and thereby holds the potential to advance clinical diagnosis, treatment, and rehabilitation strategies for various neurological disorders and injuries.
Virological characteristics of the SARS-CoV-2 JN.1 variant
Authors: Kaku Yu , Okumura Kaho , Padilla-Blanco Miguel , Kosugi Yusuke , Uriu Keiya , Hinay Alfredo A , Chen Luo , Plianchaisuk Arnon , Kobiyama Kouji , Ishii Ken J ,   The Genotype to Phenotype Japan (G2P-Japan) Consortium, Zahradnik Jiri , Ito Jumpei , Sato Kei 
Published: December 2023

AbstractThe SARS-CoV-2 BA.2.86 lineage, first identified in August 2023, is phylogenetically distinct from the currently circulating SARS-CoV-2 Omicron XBB lineages, including EG.5.1 and HK.3. Comparing to XBB and BA.2, BA.2.86 carries more than 30 mutations in the spike (S) protein, indicating a high potential for immune evasion. BA.2.86 has evolved and its descendant, JN.1 (BA.2.86.1.1), emerged in late 2023. JN.1 harbors S:L455S and three mutations in non-S proteins. S:L455S is a hallmark mutation of JN.1: we have recently shown that HK.3 and other “FLip” variants carry S:L455F, which contributes to increased transmissibility and immune escape ability compared to the parental EG.5.1 variant. Here, we investigated the virological properties of JN.1.
Effects of urbanisation, habitat characteristics, and management on garden pond biodiversity: findings from a large-scale citizen science survey
Authors: Márton Zsuzsanna , Barta Barbara , Vad Csaba F. , Szabó Beáta , Hamer Andrew J. , Kardos Vivien , Laskai Csilla , Fierpasz Ádám , Horváth Zsófia 
Published: December 2023

AbstractThe rapid expansion of urban areas often leads to degradation, fragmentation, and loss of natural habitats, threatening biodiversity. While urban ponds might contribute substantially to the biodiversity of urban blue-green infrastructure, the role of garden ponds is still largely unkown. We lack a comprehensive understanding of how local habitat features, different forms of management, and urbanisation might impact the biodiversity of these habitats. This study aimed to reveal the importance of garden ponds via a country-wide online citizen science survey in Hungary, Central Europe. Data from over 800 pond owners revealed the occurrence and local frequency of various native animal taxa (amphibians, odonates, and birds), and introduced animals (e.g., fish). We collected data about pond features and management practices. We tested the effect of pond features, pond management, and landscape-level drivers (urbanisation, surrounding wetland coverage) on the presence of conspicuous animal taxa (adult amphibians and tadpoles, birds, odonates) to identify the potential drivers of the biodiversity of garden ponds. Key pond features including pond age, area, aquatic and shoreline vegetation were the most important factors, while algaecide addition was the most influential management practice negatively affecting amphibian presence. Urbanisation negatively affected the presence of adult amphibians and their tadpoles, but it was not associated negatively with the presence of odonates and birds. Our results indicate the high potential to utilise garden ponds as urban habitats surveyed with the help of the public. Developing effective urban biodiversity monitoring and conservation strategies are necessary for a better functioning blue-green infrastructure. The high level of engagement of pond owners, as in our survey, can create valuable data for achieving these aims.
Antagonistic effects of arginine methylation of LSM4 on alternative splicing during plant stress responses
Authors: Agrofoglio Yamila Carla , Iglesias María José , Perez-Santángelo Soledad , José de Leone María , Koester Tino , Catalá Rafael , Salinas Julio , Yanovsky Marcelo J. , Staiger Dorothee , Mateos Julieta L. 
Published: December 2023

AbstractArabidopsis PROTEIN ARGININE METHYLTRANSFERASE 5 (PRMT5) post-translationally modifies RNA-binding proteins by arginine (R) methylation. The impact of this modification on the regulation of RNA processing is largely unknown. Here we use LSM4, a component of the spliceosome, as a paradigm to study the impact of R-methylation on its function in RNA processing. We identify in vivo targets of LSM4 and show that LSM4 regulates alternative splicing of a suite of them. Furthermore, LSM4 affects mRNA levels of some of the targets, showing for the first time its role in both AS and steady-state abundance. Thelsm4andprmt5mutants show a considerable overlap of genes with altered splicing patterns, suggesting that these might be regulated by PRMT5-dependent LSM4 methylation. Wild-type LSM4 and an unmethylable version complement thelsm4-1growth and circadian rhythms defects, suggesting that methylation is not critical for growth in normal environments. However, LSM4 methylation increases with ABA and is necessary for plants to respond properly to salt stress. In contrast, LSM4 methylation is reduced by bacterial infection, and plants expressing unmethylable LSM4 are more resistant than plants expressing wild-type LSM4. This tolerance correlates with decreased intron retention of immune-response genes upon infection, augmenting the functional isoform. Taken together, this provides the first direct evidence that R methylation adjusts LSM4 function on pre-mRNA splicing in an antagonistic manner in response to biotic and abiotic stress.HighlightPlease provide a statement that, in fewer than 30 words, highlights the novelty of the paper for the non-expert.Arginine methylation of the LSM4 spliceosome component by PROTEIN ARGININE METHYLTRANSFERASE 5 fine-tunes alternative splicing of a set of stress-related genes to antagonistically control biotic and abiotic responses in Arabidopsis.
Concurrent threats and extinction risk in a long-lived, highly fecund vertebrate with parental care
Authors: Brooks George C. , Hopkins William A. , Kindsvater Holly K. 
Published: December 2023

ABSTRACTDetecting declines and quantifying extinction risk of long-lived, highly fecund vertebrates including fishes, reptiles, and amphibians, can be challenging. In addition to the false notion that large clutches always buffer against population declines, the imperiled status of long-lived species can often be masked by extinction debt, wherein adults persist on the landscape for several years after populations cease to be viable. Here we develop a demographic model for the Eastern Hellbender (Cryptobranchus alleganiensis), an imperiled aquatic salamander with paternal care. We examined the individual and interactive effects of three of the leading threats hypothesized to contribute to the species’ demise: habitat loss due to siltation, high rates of nest failure, and excess adult mortality caused by fishing and harvest. We parameterized the model using data on their life history and reproductive ecology to model the fates of individual nests and address multiple sources of density-dependent mortality under both deterministic and stochastic environmental conditions. Our model suggests that high rates of nest failure observed in the field are sufficient to drive hellbender populations towards a geriatric age distribution and eventually to localized extinction, but that this process takes decades. Moreover, the combination of limited nest site availability due to siltation, nest failure, and stochastic adult mortality can interact to increase the likelihood and pace of extinction, which was particularly evident under stochastic scenarios. Density-dependence in larval survival and recruitment can severely hamper a population’s ability to recover from declines. Our model helps to identify tipping points beyond which extinction becomes certain and management interventions become necessary. Our approach can be generalized to understand the interactive effects of various threats to the extinction risk of other long-lived vertebrates. As we face unprecedented rates of environmental change, holistic approaches incorporating multiple concurrent threats and their impacts on different aspects of life history will be necessary to proactively conserve long-lived species.
High-resolution awake mouse fMRI at 14 Tesla
Authors: Hike David , Liu Xiaochen , Xie Zeping , Zhang Bei , Choi Sangcheon , Zhou Xiaoqing Alice , Liu Andy , Murstein Alyssa , Jiang Yuanyuan , Devor Anna , Yu Xin 
Published: December 2023

AbstractHigh-resolution awake mouse fMRI remains challenging despite extensive efforts to address motion-induced artifacts and stress. This study introduces an implantable radiofrequency (RF) surface coil design that minimizes image distortion caused by the air/tissue interface of mouse brains while simultaneously serving as a headpost for fixation during scanning. Furthermore, this study provides a thorough acclimation method used to accustom animals to the MRI environment minimizing motion induced artifacts. Using a 14T scanner, high-resolution fMRI enabled brain- wide functional mapping of visual and vibrissa stimulation at 100x100x200µm resolution with a 2s per frame sampling rate. Besides activated ascending visual and vibrissa pathways, robust BOLD responses were detected in the anterior cingulate cortex upon visual stimulation and spread through the ventral retrosplenial area (VRA) with vibrissa air-puff stimulation, demonstrating higher-order sensory processing in association cortices of awake mice. In particular, the rapid hemodynamic responses in VRA upon vibrissa stimulation showed a strong correlation with the hippocampus, thalamus, and prefrontal cortical areas. Cross-correlation analysis with designated VRA responses revealed early positive BOLD signals at the contralateral barrel cortex (BC) occurring 2 seconds prior to the air-puff in awake mice with repetitive stimulation, which was not detected using a randomized stimulation paradigm. This early BC activation indicated a learned anticipation through the vibrissa system and association cortices in awake mice under continuous training of repetitive air-puff stimulation. This work establishes a high-resolution awake mouse fMRI platform, enabling brain-wide functional mapping of sensory signal processing in higher association cortical areas.Significance StatementThis awake mouse fMRI platform was developed by implementing an advanced implantable radiofrequency (RF) coil scheme, which simultaneously served as a headpost to secure the mouse head during scanning. A thorough acclimation method was used to accustom animals to the MRI environment minimizing motion induced artifacts. The ultra-high spatial resolution (100x100x200µm) BOLD fMRI enabled the brain-wide mapping of activated visual and vibrissa systems during sensory stimulation in awake mice, including association cortices, e.g. anterior cingulate cortex and retrosplenial cortex, for high order sensory processing. Also, the activation of barrel cortex at 2 s prior to the air-puff indicated a learned anticipation of awake mice under continuous training of the repetitive vibrissa stimulation.
VviWRKY10andVviWRKY30co-regulate powdery mildew resistance through modulating SA and ET-based defenses in grapevine
Authors: Zhou Min , Wang Hongyan , Yu Xuena , Cui Kaicheng , Hu Yang , Xiao Shunyuan , Wen Ying-Qiang 
Published: December 2023

ABSRACTGrapevine is one of the most important economic fruit crops in the world. The widely cultivated grapevine (Vitis vinifera,Vvi) is susceptible to powdery mildew caused byErysiphe necator. In this study, CRISPR-Cas9 was used to simultaneously knock outVviWRKY10andVviWRKY30encoding two transcription factors reported to be implicated in defense regulation. Fifty-threewrky10(Vviwrky10single mutant) transgenic plants and fifteenwrky10wrky30(Vviwrky10Vviwrky30double mutant) transgenic plants were generated. In a 2-year field evaluation of resistance to powdery mildew, thewrky10showed strong resistance, while thewrky10wrky30showed moderate resistance. Further analyses revealed that salicylic acid (SA) and reactive oxygen species (ROS) contents in the leaves ofwrky10andwrky10wrky30were significantly increased, so did the ethylene (ET) content in the leaves ofwrky10. The results from dual luciferase (DLUC) reporter assays, electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation (ChIP)-qPCR assays demonstrated that VviWRKY10 could directly bind to the W-boxes in the promoter ofVviEDS5-2,VviPR1,VviPR5andVviRBOHD2and inhibit their transcription, supporting its role as a negative regulator of SA-dependent defense. By contrast, VviWRKY30 could directly bind to the W-boxes in the promoter ofVviACS3andVviACS3Land promote their transcription, playing a positive role in ET production and ET-dependent defense. Moreover, VviWRKY10 and VviWRKY30 can bind to each other’s promoters and mutually inhibit each other’s transcription. Taken together, our results have revealed a complex mechanism of regulation by VviWRKY10 and VviWRKY30 for activation of measured and balanced defense responses against powdery mildew in grapevine.One-sentence summaryVviWRKY10andVviWRKY30play different roles in powdery mildew resistance through the salicylic acid and ethylene, respectively, and there is mutual inhibition betweenVviWRKY10andVviWRKY30.
StrengtheningBordetella pertussisgenomic surveillance by direct sequencing of residual positive specimens
Authors: Peng Yanhui , Williams Margaret M. , Xiaoli Lingzi , Simon Ashley , Fueston Heather , Tondella M. Lucia , Weigand Michael R. 
Published: December 2023

AbstractWhole-genome sequencing (WGS) of microbial pathogens recovered from patients with infectious disease facilitates high-resolution strain characterization and molecular epidemiology. However, increasing reliance on culture-independent methods to diagnose infectious diseases has resulted in few isolates available for WGS. Here we report a novel culture-independent approach to genome characterization ofBordetella pertussis, the causative agent of pertussis and a paradigm for insufficient genomic surveillance due to limited culture of clinical isolates. Sequencing libraries constructed directly from residual pertussis-positive diagnostic nasopharyngeal specimens were hybridized with biotinylated RNA “baits” targetingB. pertussisfragments within complex mixtures that contained high concentrations of host and microbial background DNA. Recovery ofB. pertussisgenome sequence data was evaluated with mock and pooled negative clinical specimens spiked with reducing concentrations of either purified DNA or inactivated cells. Targeted enrichment increased yield ofB. pertussissequencing reads up to 90% while simultaneously decreasing host reads to less than 10%. Filtered sequencing reads provided sufficient genome coverage to perform characterization via whole-genome single nucleotide polymorphisms (wgSNP) and whole-genome multilocus sequencing typing (wgMLST). Moreover, these data were concordant with sequenced isolates recovered from the same specimens such that phylogenetic reconstructions from either consistently clustered the same putatively linked cases. The optimized protocol is suitable for nasopharyngeal specimens with IS481Ct < 35 and > 10 ng DNA. Routine implementation of these methods could strengthen surveillance and study of pertussis resurgence by capturing additional cases with genomic characterization.