bluuebunny/crossref_metadata_2025_split huggingface dataset:
Initial data analysis for longitudinal studies to build a solid foundation for reproducible analysis
Authors: Lusa Lara , Proust-Lima Ćecile , Schmidt Carsten O. , Lee Katherine J. , le Cessie Saskia , Baillie Mark , Lawrence Frank , Huebner Marianne 
Published: December 2023

AbstractInitial data analysis (IDA) is the part of the data pipeline that takes place between the end of data retrieval and the beginning of data analysis that addresses the research question. Systematic IDA and clear reporting of the IDA findings is an important step towards reproducible research. A general framework of IDA for observational studies includes data cleaning, data screening, and possible updates of pre-planned statistical analyses. Longitudinal studies, where participants are observed repeatedly over time, pose additional challenges, as they have special features that should be taken into account in the IDA steps before addressing the research question. We propose a systematic approach in longitudinal studies to examine data properties prior to conducting planned statistical analyses.In this paper we focus on the data screening element of IDA, assuming that the research aims are accompanied by an analysis plan, meta-data are well documented, and data cleaning has already been performed. IDA screening domains are participation profiles over time, missing data, and univariate and multivariate descriptions, and longitudinal aspects. Executing the IDA plan will result in an IDA report to inform data analysts about data properties and possible implications for the analysis plan that are other elements of the IDA framework.Our framework is illustrated focusing on hand grip strength outcome data from a data collection across several waves in a complex survey. We provide reproducible R code on a public repository, presenting a detailed data screening plan for the investigation of the average rate of age-associated decline of grip strength.With our checklist and reproducible R code we provide data analysts a framework to work with longitudinal data in an informed way, enhancing the reproducibility and validity of their work.
LEFT ATRIAL APPENDAGE CLOSURE IN PATIENTS WITH MECHANICAL MITRAL VALVE PROSTHESIS: A MULTICENTER ITALIAN PILOT STUDY
Authors: Preda Alberto , Margonato Davide , Gaspardone Carlo , Rizza Vincenzo , Vella Ciro , Rampa Lorenzo , Marzi Alessandra , Guarracini Fabrizio , della Bella Paolo , Agricola Eustachio , Gaspardone Achille , Montorfano Matteo , Mazzone Patrizio 
Published: December 2023

ABSTRACTBackgroundIn patients with atrial fibrillation (AF) on vitamin K antagonist (VKA) therapy and therapeutical INR range the incidence of cardiac thromboembolism is not negligible and the subgroup carrying a mechanical prosthetic mitral valve (PMV) has the highest risk. We aimed to assess the long-term effects of left atrial appendage closure (LAAC) in AF patients carriers of mechanical PMV who experienced a failure of VKA therapy.MethodsIn this retrospective, multicenter study, patients who underwent LAAC because of thrombotic events including TIA/stroke, systemic embolism and evidence of left atrial appendage thrombosis/sludge during VKA therapy were enrolled. Patients with mechanical PMV were included and compared with controls. The primary endpoint was the composite of all-cause death, major cardiovascular events and major bleedings at follow-up. Feasibility and safety of LAAC was also assessed.ResultsA total of 55 patients (42% females; mean age 70 ± 9 years) including 12 carriers of mechanical PMV were enrolled. The most frequent indication to LAAC (71%) was LAA thrombosis or sludge. Procedural success was achieved in 96% of overall cases and in 100% of patients with PMV. In 35 patients a cerebral protection device was used. During a median follow-up of 6.1 ± 4.3 years, 4 patients with PMV and 20 patients without PMV reported adverse events (HR 0.73 [95% CI 0.25 – 2.16, p=0.564]).ConclusionLAAC seems to be a valuable alternative in AF patients with failure of VKA therapy who are carriers of mechanical PMV. This off-label, real-world clinical practice indication deserve validation in further studies.
Association between frequency of rehabilitation therapy and long-term mortality after stroke : a nationwide cohort study
Authors: Nam Je Shik , Heo Seok-Jae , Kim Yong Wook , Lee Sang Chul , Yang Seung Nam , Yoon Seo Yeon 
Published: December 2023

AbstractBackgroundPoststroke rehabilitation reportedly improves functional outcomes and minimizes disability. However, previous studies have demonstrated conflicting results regarding the effects of rehabilitation therapy on post-stroke mortality. Therefore, we aimed to investigate the association between rehabilitation therapy within the first six months after stroke and long-term all-cause mortality in patients with stroke using data from the Korean National Health Insurance System.MethodsA total of 10,974 patients newly diagnosed with stroke using ICD-10 codes (I60-I64) between 2013 and 2019 were enrolled and followed-up for all-cause mortality until 2019. Post-stroke patients were categorized into three groups according to the frequency of rehabilitation therapy: no rehabilitation therapy, ≤ 40 sessions, and > 40 sessions. Cox proportional hazard models were used to assess the mortality risk according to rehabilitation therapy stratified by disability severity.ResultsHigher frequency of rehabilitation therapy was associated with significantly lower post-stroke mortality in comparison to no rehabilitation therapy (HR=0.88, 95% CI 0.79-0.9 9), especially among individuals with severe disability after stroke (HR=0.74, 95% CI 0.62-0.87). An inverse association between number of rehabilitation therapy sessions and mortality was identified in a multivariate Cox regression model with restricted cubic splines. In the context of stroke type, higher frequency of rehabilitation therapy was associated with reduced mortality rates compared to no rehabilitation therapy only in patients with hemorrhagic stroke (HR=0.60, 95% CI 0.49-0.74). While socioeconomic factors were not associated with mortality, older age, male sex, and pneumonia were associated with increased mortality risk, regardless of disability severity.ConclusionsPost-stroke rehabilitation therapy within six months of stroke onset seems to play a substantial role in reducing long-term mortality after stroke. A higher frequency of rehabilitation therapy is recommended for post-stroke patients, particularly among those with severe disability.
Normative Values of Echocardiographic Chamber Size and Function in Older Healthy Adults: The Multi-Ethnic Study of Atherosclerosis
Authors: Mukherjee Monica , Strom Jordan B. , Afilalo Jonathan , Hu Mo , Beussink-Nelson Lauren , Kim Jiwon , Addetia Karima , Bertoni Alain , Gottdiener John , Michos Erin D. , Gardin Julius M. , Shah Sanjiv J. , Freed Benjamin H. 
Published: December 2023

ABSTRACTBackgroundEchocardiographic (2DE) thresholds indicating disease or impaired functional status compared to normal physiologic aging in individuals ≥ 65 years are not clearly defined. In the present study, we sought to establish standard values for 2DE parameters related to chamber size and function in older adults without cardiopulmonary or cardiometabolic conditions.MethodsIn this cross-sectional study of 3032 individuals who underwent 2DE at Exam 6 in the Multi-Ethnic Study of Atherosclerosis (MESA), 608 participants fulfilled our inclusion criteria, with normative values defined as the mean value ± 1.96 standard deviations and compared across sex and race/ethnicity. Functional status measures included NT-proBNP, 6-minute walk distance [6MWD], and Kansas City Cardiomyopathy Questionnaire [KCCQ]. Prognostic performance using MESA cutoffs was compared to established guideline cutoffs using time-to-event analysis.ResultsParticipants meeting our inclusion criteria (69.5 ± 7.0 years, 46.2% male, 47.5% White) had lower NT-proBNP, higher 6MWD, and higher (better) KCCQ summary values. Women had significantly smaller chamber sizes and better biventricular systolic function. White participants had the largest chamber dimensions, while Chinese participants had the smallest, even after adjustment for body size. Current guidelines identified 81.6% of healthy older adults in MESA as having cardiac abnormalities.ConclusionsAmong a large, diverse group of healthy older adults, we found significant differences in cardiac structure and function across sexes and races/ethnicities, which may signal sex-specific cardiac remodeling with advancing age. It is crucial for existing guidelines to consider the observed and clinically significant differences in cardiac structure and function associated with healthy aging. Our study highlights that existing guidelines, which grade abnormalities in echocardiographic cardiac chamber size and function based on younger individuals, may not adequately address the anticipated changes associated with normal aging.
Detecting and understanding meaningful cancerous mutations based on computational models of mRNA splicing
Authors: Lynn Nicolas , Tuller Tamir 
Published: December 2023

ABSTRACTCancer research has long relied on non-silent mutations. Yet, it has become overwhelmingly clear that silent mutations can affect gene expression and cancer cell fitness. One fundamental mechanism that apparently silent mutations can severely disrupt is alternative splicing. Here we introduceOncosplice, a tool that scores mutations based on models of proteomes generated using aberrant splicing predictions.Oncospliceleverages a highly accurate neural network that predicts splice sites within arbitrary mRNA sequences, a greedy transcript constructor that considers alternate arrangements of splicing blueprints, and an algorithm that grades the functional divergence between proteins based on evolutionary conservation. By applying this tool to 12M somatic mutations we identify 8K deleterious variants that are significantly depleted within the healthy population; we demonstrate the tool’s ability to identify clinically validated pathogenic variants with a positive predictive value of 94%; we show strong enrichment of predicted deleterious mutations across pan-cancer drivers. We also achieve improved patient survival estimation using a proposed set of novel cancer-involved genes. Ultimately, this pipeline enables accelerated insight-gathering of sequence-specific consequences for a class of understudied mutations and provides an efficient way of filtering through massive variant datasets – functionalities with immediate experimental and clinical applications.
Unravelling effects of fine-scale changes within wild-bird flocks on sociality
Authors: Troisi C.A. , Firth J.A. , Crofts S.J. , Davidson G.L. , Reichert M.S. , Quinn J.L. 
Published: December 2023

AbstractSocial structure and individual sociality impact a wide variety of behavioural and ecological processes. Although it is well known that changes in the physical and social environment shape sociality, how perturbations govern sociality at a fine spatial scale remains poorly understood. By applying automated experimental treatments to RFID-tracked wild great tits (Parus major) in a field experiment, we examined how individual social network metrics changed when food resources and social stability were experimentally manipulated at the within-group spatial scale.First, we examined how individual sociality responds when food resources changed from a dispersed distribution (50m apart) to a clustered distribution (1m apart). Second, we tested how sociality changed when individuals were restricted to feeding in a manner that mimics assortative behaviour within flocks. Third, we tested the effects of experimentally manipulating the stability of these social groupings. Finally, we returned the feeders to the original dispersed distribution to test whether effects carried over.Repeatability analyses showed consistent differences among individuals in their social phenotypes across the various manipulations; dyadic association preferences also showed consistency. Nevertheless, average flock size and social centrality measures increased after the food was clustered. Some of these metrics changed further when birds were then forced to feed from only one of the five clustered feeders. There was some support for group stability at individual feeders also impacting individual social network metrics: increase in flock size was more pronounced in the stable than the unstable group. Most of the differences in sociality were maintained when the food distribution returned to the dispersed pattern, and this was caused primarily by the change in resource distribution rather than the social manipulation.Our results show that perturbations in the access to resources and social group stability can change sociality at a surprisingly fine spatial scale. These small-scale changes could arise through a variety of mechanisms, including assortative positioning within groups due to, for instance, similarity among individuals in their preferences for different resource patches. Our results suggest that small-scale effects could lead to social processes at larger scales and yet are typically overlooked in social groups.
Leaf- and diverged shoot meristem programs shape the stem in rice
Authors: Tsuda Katsutoshi , Maeno Akiteru , Otake Ayako , Kato Kae , Tanaka Wakana , Hibara Ken-Ichiro , Nonomura Ken-Ichi 
Published: December 2023

AbstractThe stem is the shoot axis in seed plants and has been a primary target in breeding to regulate crop height. However, early processes of stem development remain elusive. Here we show that regulators for shoot meristems and leaves determine the node-internode pattern in rice. Mutants ofKNOX1genesOSH15andOSH1, known to maintain shoot meristem indeterminacy1,2, showed dwarfism due to enlarged nodes and diminished internodes. These genes confine node differentiation by repressing leaf developmental regulatorYABBYgenes in internodal vasculatures.YABBYexpression, which normally extends from leaves to nodes along vasculatures, promotes nodal vascular differentiation and limits stem elongation. It expands inknox1mutants, and the loss ofYABBYgenes reverts their dwarfism.OSH15also represses node-specificKNOX1subclade genesOSH6andOSH71to allow internode elongation. Importantly, bothYABBYand node-specificKNOX1genes are required for pulvinus formation at the leaf base, further elaborating the nodal structure for gravitropism. Thus, intersections between leaf and sub-functionalized shoot meristem programs shape nodes and internodes along the stem. Phylogenetic analysis showed thatKNOX1sub-functionalization likely occurred in the progenitor of gymnosperms and angiosperms. Given that seed plants acquired their leaves independently from other vascular plant lineages3,4, the emergence of the node-internode pattern andKNOX1-YABBYregulatory module may be linked to seed plant leaf evolution.
CHARACTERIZATION OF EARLY-MATURING COWPEA (Vigna unguiculata(L.) WALP.) GERMPLASMS THROUGH ASSOCIATION ANALYSIS
Authors: Ogbeche Iduh Michael , Ekeruo Godspower Chibuike , Vange T , Omoigui Lucky , Ogbu Odang Emmanuel , Oyinkansola Koletowo Faruq , Olalekan Ayeni 
Published: December 2023

ABSTRACTEarly maturing cowpea is a valuable crop for sub-Saharan Africa that offers a number of benefits, including a short growing season, drought tolerance, and the potential to improve food security. This study was conducted to analyze character associations in genetically diverse cowpea (Vigna unguiculata(L.) Walp.) germplasm, employing ten distinct accessions within a randomized complete block design with four replicates. Parameters such as days to first flowering, days to fifty percent flowering, number of branches per plant, days to ninety-five percent maturity, number of pods per plant, hundred-seed weight, total pod weight, and total seed weight were subjected to analysis of variance (ANOVA), Correlation, and Path Coefficient Analysis. Results revealed significant positive correlations between “branches per plant and pods per plant (r = 0.317, p ≤ 0,001),” “pods per plant and pod weight (r = 0.136, p < ≤ 0,001),” and “pod weight and seed weight (r =0.567, p ≤ 0,001).” Path coefficient analysis identified pod weight (0.840938) as the most influential direct contributor to yield, while the number of pods (-0.04268) indirectly influenced yield through pod weight. High grain yield selection can be achieved through indirect manipulation of pod weight. Accession IT99K-573-1-1, IT10K-863-11 and IT08K-125-24 exhibited the highest yield characters (pod weight and seed weight) and therefore further studies is recommended to consolidate this work, to enhance adoption by farmers.
TGF-β2 regulates neuronal Ankyrin-G and promotes its interaction with KCC2
Authors: Rigkou Anastasia , Pethe Abhishek , Roussa Eleni 
Published: December 2023

ABSTRACTThe neuronal K+/Cl-cotransporter 2 (KCC2) is the major Cl-extruder in CNS neurons and responsible for fast hyperpolarizing postsynaptic inhibition in mature neurons. Impaired KCC2 function has been associated with several brain pathologies. KCC2 forms immunocomplexes with several proteins that may regulate KCC2 membrane trafficking, stability and function, thus, tuning important cellular processes, including chloride homeostasis and dendritic spine development. In the brain, the scaffold protein Ankyrin-G, encoded by theAnk3gene, is expressed in several isoforms with distinct spatial and temporal expression patterns, is regulated by TGF-β signalling and is proposed as a KCC2 interaction partner. Moreover,Ank3gene has been implicated in several neuropsychiatric disorders.Here, we investigated a putative impact of transforming growth factor beta 2 (TGF-β2) on KCC2/Ankyrin-G interaction using quantitative RT-PCR, immunoblotting, immunoprecipitation and immunofluorescence in mouse immature and differentiated hippocampal neurons and in forebrain and brainstem tissue fromTgf-β2deficient mice. The results show TGF-β2-dependent downregulation ofAnk3transcripts, as well as KCC2/Ankyrin-G interaction in mouse brainstem tissue at embryonic day (E) 17.5.In vitro, loss ofTgf-β2resulted in significantly reduced axonal and somatic Ankyrin-G in immature neurons and significantly reduced somatic Ankyrin-G abundance in differentiated mouse hippocampal neurons. Membrane abundance of Ankyrin-G was downregulated inTgf-β2mutants as well, a phenotype rescued by application of exogenous TGF-β2. Moreover, the results suggest the presence of a Golgi-associated Ankyrin-G isoform in neurons and significantly impaired membrane KCC2 abundance following knock down ofAnk3. Thus, the present study provides new insights into Ankyrin-G regulation by TGF-β2 in neurons and first evidence of a TGF-β2-regulated interaction of KCC2 with Ankyrin-G. Moreover, these results strengthen the notion for TGF-β2 as pivotal regulator of KCC2 abundance and function.
Sexual Dimorphism, Altered Hippocampal Glutamatergic Neurotransmission and Cognitive Impairment in APP Knock-In Mice
Authors: Findley Caleigh A. , McFadden Samuel .A. , Hill Tiarra , Peck Mackenzie R. , Quinn Kathleen , Hascup Kevin N. , Hascup Erin R. 
Published: December 2023

AbstractBackgroundIt is well established that glutamatergic neurotransmission plays an essential role in learning and memory. Previous studies indicate that glutamate dynamics shift with Alzheimer’s disease (AD) progression, contributing to negative cognitive outcomes.ObjectiveIn this study, we characterized hippocampal glutamatergic signaling with age and disease progression in a knock-in mouse model of AD (APPNL-F/NL-F).MethodsAt 2-4 and 18+ months old, male and female APPNL/NL, APPNL-F/NL-F, and C57BL/6 mice underwent cognitive assessment using Morris water maze (MWM) and Novel Object Recognition (NOR). Then, basal and 70 mM KCl stimulus-evoked glutamate release was measured in the dentate gyrus (DG), CA3, and CA1 regions of the hippocampus using a glutamate-selective microelectrode in anesthetized mice.ResultsGlutamate recordings support elevated stimulus-evoked glutamate release in the DG and CA3 of young APPNL-F/NL-Fmale mice that declined with age compared to age-matched control mice. Young female APPNL-F/NL-Fmice exhibited increased glutamate clearance in the CA1 that slowed with age compared to age-matched control mice. Male and female APPNL-F/NL-Fmice exhibited decreased CA1 basal glutamate levels, while males also showed depletion in the CA3. Cognitive assessment demonstrated impaired spatial cognition in aged male and female APPNL-F/NL-Fmice, but only aged females displayed recognition memory deficits compared to age-matched control mice.ConclusionsThese findings confirm a sex-dependent hyper-to-hypoactivation glutamatergic paradigm in APPNL-F/NL-Fmice. Further, data illustrate a sexually dimorphic biological aging process resulting in a more severe cognitive phenotype for female APPNL-F/NL-Fmice than their male counterparts. Research outcomes mirror that of human AD pathology and provide further evidence of divergent AD pathogenesis between sexes.
Intracellular defensive symbiont is culturable and capable of transovarial, vertical transmission
Authors: Maeda Gerald P. , Kelly Mary Katherine , Sundar Aadhunik , Moran Nancy A. 
Published: December 2023

ABSTRACTInsects frequently form heritable associations with beneficial bacteria that are vertically transmitted from parent to offspring. Long term vertical transmission has repeatedly resulted in genome reduction and gene loss rendering many such bacteria incapable of independent culture. Among aphids, heritable endosymbionts often provide a wide range of context-specific benefits to their hosts. Although these associations have large impacts on host phenotypes, experimental approaches are often limited by an inability to independently cultivate these microbes. Here, we report the axenic culture ofCandidatusFukatsuia symbiotica strain WIR, a heritable bacterial endosymbiont of the pea aphid,Acyrthosiphon pisum. Whole genome sequencing revealed similar genomic features and high sequence similarity to previously described strains, suggesting the cultivation techniques used here may be applicable toCa. F. symbiotica strains from distantly related aphids. Microinjection of the isolated strain into uninfected aphids revealed that it can reinfect developing embryos, and is maintained in subsequent generations via transovarial maternal transmission. Artificially infected aphids exhibit similar phenotypic and life history traits compared to native infections, including protective effects against an entomopathogenicFusariumspecies. Overall, our results show thatCa. F. symbiotica may be a useful tool for experimentally probing the molecular mechanisms underlying heritable symbioses and antifungal defense in the pea aphid system.IMPORTANCEDiverse eukaryotic organisms form stable, symbiotic relationships with bacteria that provide benefits to their hosts. While these associations are often biologically important, they can be difficult to probe experimentally, because intimately host-associated bacteria are difficult to access within host tissues, and most cannot be cultured. This is especially true of the intracellular, maternally inherited bacteria associated with many insects, including aphids. Here, we demonstrate that a pea aphid-associated strain of the heritable endosymbiont,CandidatusFukatsuia symbiotica, can be grown outside of its host using standard microbiology techniques, and can readily re-establish infection that is maintained across host generations. These artificial infections recapitulate the effects of native infections making this host-symbiont pair a useful experimental system. Using this system, we demonstrate thatCa. F. symbiotica infection reduces host fitness under benign conditions, but protects against a previously unreported fungal pathogen.