bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association ofESR1germline variants withTP53somatic variants in breast tumors in a genome-wide study
Authors: Tjader Nijole P. , Beer Abigail J. , Ramroop Johnny , Tai Mei-Chee , Ping Jie , Gandhi Tanish , Dauch Cara , Neuhausen Susan L. , Ziv Elad , Sotelo Nereida , Ghanekar Shreya , Meadows Owen , Paredes Monica , Gillespie Jessica , Aeilts Amber , Hampel Heather , Zheng Wei , Jia Guochong , Hu Qiang , Wei Lei , Liu Song , Ambrosone Christine B. , Palmer Julie R. , Carpten John D. , Yao Song , Stevens Patrick , Ho Weang-Kee , Pan Jia Wern , Fadda Paolo , Huo Dezheng , Teo Soo-Hwang , McElroy Joseph Paul , Toland Amanda Ewart 
Published: December 2023

ABSTRACTBackgroundIn breast tumors, somatic mutation frequencies inTP53andPIK3CAvary by tumor subtype and ancestry. HER2 positive and triple negative breast cancers (TNBC) have a higher frequency ofTP53somatic mutations than other subtypes.PIK3CAmutations are more frequently observed in hormone receptor positive tumors. Emerging data suggest tumor mutation status is associated with germline variants and genetic ancestry. We aimed to identify germline variants that are associated with somaticTP53orPIK3CAmutation status in breast tumors.MethodsA genome-wide association study was conducted using breast cancer mutation status ofTP53andPIK3CAand functional mutation categories includingTP53gain of function (GOF) and loss of function mutations andPIK3CAactivating/hotspot mutations. The discovery analysis consisted of 2850 European ancestry women from three datasets. Germline variants showing evidence of association with somatic mutations were selected for validation analyses based on predicted function, allele frequency, and proximity to known cancer genes or risk loci. Candidate variants were assessed for association with mutation status in a multi-ancestry validation study, a Malaysian study, and a study of African American/Black women with TNBC.ResultsThe discovery Germline x Mutation (GxM) association study found five variants associated with one or moreTP53phenotypes withPvalues <1×10-6, 33 variants associated with one or moreTP53phenotypes withPvalues <1×10-5, and 44 variants associated with one or morePIK3CAphenotypes withPvalues <1×10-5. In the multi-ancestry and Malaysian validation studies, germlineESR1locus variant, rs9383938, was associated with the presence ofTP53mutations overall (Pvalues 6.8×10-5and 9.8×10-8, respectively) andTP53GOF mutations (Pvalue 8.4×10-6). Multiple variants showed suggestive evidence of association withPIK3CAmutation status in the validation studies, but none were significant after correction for multiple comparisons.ConclusionsWe found evidence that germline variants were associated withTP53andPIK3CAmutation status in breast cancers. Variants near the estrogen receptor alpha gene,ESR1,were significantly associated with overallTP53mutations and GOF mutations. Larger multi-ancestry studies are needed to confirm these findings and determine if these variants contribute to ancestry-specific differences in mutation frequency.
Development and Evaluation of a Digital Scribe: Conversation Summarization Pipeline for Emergency Department Counseling Sessions towards Reducing Documentation Burden
Authors: Sezgin Emre , Sirrianni Joseph , Kranz Kelly 
Published: December 2023

AbstractObjectiveWe present a proof-of-concept digital scribe system as an ED clinical conversation summarization pipeline and report its performance.Materials and MethodsWe use four pre-trained large language models to establish the digital scribe system: T5-small, T5-base, PEGASUS-PubMed, and BART-Large-CNN via zero-shot and fine-tuning approaches. Our dataset includes 100 referral conversations among ED clinicians and medical records. We report the ROUGE-1, ROUGE-2, and ROUGE-L to compare model performance. In addition, we annotated transcriptions to assess the quality of generated summaries.ResultsThe fine-tuned BART-Large-CNN model demonstrates greater performance in summarization tasks with the highest ROUGE scores (F1ROUGE-1=0.49, F1ROUGE-2=0.23, F1ROUGE-L=0.35) scores. In contrast, PEGASUS-PubMed lags notably (F1ROUGE-1=0.28, F1ROUGE-2=0.11, F1ROUGE-L=0.22). BART-Large-CNN’s performance decreases by more than 50% with the zero-shot approach. Annotations show that BART-Large-CNN performs 71.4% recall in identifying key information and a 67.7% accuracy rate.DiscussionThe BART-Large-CNN model demonstrates a high level of understanding of clinical dialogue structure, indicated by its performance with and without fine-tuning. Despite some instances of high recall, there is variability in the model’s performance, particularly in achieving consistent correctness, suggesting room for refinement. The model’s recall ability varies across different information categories.ConclusionThe study provides evidence towards the potential of AI-assisted tools in reducing clinical documentation burden. Future work is suggested on expanding the research scope with larger language models, and comparative analysis to measure documentation efforts and time.
Navigating the Molecular Maze of Alzheimer’s Disease: Developing A Human Hippocampal Atlas to Bridge Discovery and Clinical Practice
Authors: Wang Pan , Wang Lifang , Tao Quyuan , Guo Zhen , Luo Ting , Xu Zhi , He Youzhe , Yu Jiayi , Liu Yuyang , Wu Zihan , Xu Bin , Jin Bufan , Yang Ying , Cheng Mengnan , Jiang Yujia , Tian Chen , Zheng Huiwen , Fan Zhongqin , Jiang Peiran , Gao Yue , Wu Juanli , Wang Shengpeng , Sun Bing , Wei Yanrong , Fang Zheng , Lei Junjie , Luo Benyan , Wen Huiying , Peng Guoping , Tang Yuanchun , Su Xinhui , Pan Catherine , Zhu Keqing , Shen Yi , Liu Shiping , Bao Aimin , Yao Jianhua , Wang Jian , Xu Xun , Li Xiaoming , Liu Longqi , Duan Shumin , Han Lei , Zhang Jing 
Published: December 2023

AbstractAlzheimer’s disease (AD), the primary cause of dementia worldwide, persists as an enigma, with the specific molecular and cellular mechanisms driving cognitive decline still eluding understanding. To aid in unraveling this enigma, we generated a spatial transcriptomic atlas of the human hippocampus with single-cell resolution, leveraging integration of spatial mapping with single-cell transcriptomic profiles from six individuals with or without AD. Utilizing this complex and multi-dimensional data, the atlas pinpoints AD-associated transcriptomic changes with spatial specificity, such as a pronounced elevation of inflammatory responses and energy metabolism in fimbria and CA4, respectively. AD also caused alterations of the cellular composition in hippocampal subregions, even around the amyloid-beta (Aβ) plaques. Finally, our investigation uncovered pathways intricately linked to synthesis and secretion of extracellular vesicles (EVs). Within these altered pathways, we identified several corresponding proteins, including CCK and PMP2, that are readily detectable in human blood, holding promise for aiding AD diagnosis in clinical settings.
A single dose of lamotrigine induces a positive memory bias in healthy volunteers
Authors: Zghoul Tarek , Hortelano Pilar Artiach , Kaltenboeck Alexander , Wright Lucy , Goodwin Guy , Capitão Liliana , Harmer Catherine 
Published: December 2023

AbstractBackgroundLamotrigine has been shown to be effective in the long-term treatment and relapse prevention of depression in bipolar disorder. However, the neuropsychological mechanisms underlying these effects are unclear. We investigated the effects of lamotrigine on a battery of emotional processing tasks, previously shown to be sensitive to antidepressant drug action in healthy volunteers.MethodsHealthy volunteers (n=36) were randomised in a double blind design to receive a single dose of placebo or 300mg lamotrigine. Mood and subjective effects were monitored throughout the study period and emotional processing was assessed using the Oxford Emotional Test Battery (ETB) 3 hours post administration.ResultsParticipants receiving lamotrigine showed increased accuracy for the recall of positive vs. negative self-descriptors, compared to those in the placebo group. There were no other signficant effects on emotional processing in the ETB, and lamotrigine did not affect ratings of mood or subjective experience.ConclusionsLamotrigine induced a positive bias in emotional memory, similar to the effects of other antidepressants as reported in previous studies. Further work is needed to assess whether similar effects are seen in the clinical treatment of patients with bipolar disorder and the extent to which this is associated with its clinical action in relapse prevention.
Impact of COVID-19 on mental illness in vaccinated and unvaccinated people: a population-based cohort study in OpenSAFELY
Authors: Walker Venexia M , Patalay Praveetha , Cuitun Coronado Jose Ignacio , Denholm Rachel , Forbes Harriet , Stafford Jean , Moltrecht Bettina , Palmer Tom , Walker Alex , Thompson Ellen J. , Taylor Kurt , Cezard Genevieve , Horne Elsie M F , Wei Yinghui , Al Arab Marwa , Knight Rochelle , Fisher Louis , Massey Jon , Davy Simon , Mehrkar Amir , Bacon Seb , Goldacre Ben , Wood Angela , Chaturvedi Nishi , Macleod John , John Ann , Sterne Jonathan A C 
Published: December 2023

ABSTRACTBackgroundCOVID-19 is associated with subsequent mental illness in both hospital- and population-based studies. Evidence regarding effects of COVID-19 vaccination on mental health consequences of COVID-19 is limited.MethodsWith the approval of NHS England, we used linked electronic health records (OpenSAFELY-TPP) to conduct analyses in a ‘pre-vaccination’ cohort (17,619,987 people) followed during the wild-type/Alpha variant eras (January 2020-June 2021), and ‘vaccinated’ and ‘unvaccinated’ cohorts (13,716,225 and 3,130,581 people respectively) during the Delta variant era (June-December 2021). We estimated adjusted hazard ratios (aHRs) comparing the incidence of mental illness after diagnosis of COVID-19 with the incidence before or without COVID-19.OutcomesWe considered eight outcomes: depression, serious mental illness, general anxiety, post-traumatic stress disorder, eating disorders, addiction, self-harm, and suicide. Incidence of most outcomes was elevated during weeks 1-4 after COVID-19 diagnosis, compared with before or without COVID-19, in each cohort. Vaccination mitigated the adverse effects of COVID-19 on mental health: aHRs (95% CIs) for depression and for serious mental illness during weeks 1-4 after COVID-19 were 1.93 (1.88-1.98) and 1.42 (1.24-1.61) respectively in the pre-vaccination cohort and 1.79 (1.68-1.91) and 2.21 (1.99-2.45) respectively in the unvaccinated cohort, compared with 1.16 (1.12-1.20) and 0.91 (0.84-0.98) respectively in the vaccinated cohort. Elevation in incidence was higher, and persisted for longer, after hospitalised than non-hospitalised COVID-19.InterpretationIncidence of mental illness is elevated for up to a year following severe COVID-19 in unvaccinated people. Vaccination mitigates the adverse effect of COVID-19 on mental health.FundingMedical Research Council (MC_PC_20059) and NIHR (COV-LT-0009).
Integrative proteogenomics study identifies the indirect effect of circulating proteins on 8 diseases via telomere length
Authors: Li Shifang , Gong Meijiao 
Published: December 2023

AbstractGrowing evidence has revealed the associations between telomere length and diseases; however, the mechanisms behind these links are not fully understood. In this study, by applying proteome-wide Mendelian randomisation (MR), multiple sensitivity analyses, colocalization, single-cell RNA-sequencing, and mediation analysis, the potential mechanisms that link 4,907 plasma proteins, telomere length, and 8 diseases were identified. Following MR analysis for the effects of plasma protein levels on telomere length, 34 proteins were found to be causally related to telomere length. Among these, 8 proteins (PSMB4, PARP1, GDI2, MAX, GMPR2, ARPC1B, ATOX1, and NUDT5) were found to be well colocalized with telomere length (posterior probability >80%). 21 mediation pairs were revealed for the indirect effect of circulating proteins on 8 diseases via telomere length. Furthermore, 35 proteins, including CD8A, were found to be influenced by telomere length among 4,907 proteins. No significant mediation pairs for circulating proteins that mediate the effects of telomere length on disease have been identified. Overall, our study provided insights into understanding the biology of telomeres and prioritized the identified proteins as prospective intervention targets for the disease.
Does Zipf’s law of abbreviation shape birdsong?
Authors: Gilman R. Tucker , Durrant CD , Malpas Lucy , Lewis Rebecca N. 
Published: December 2023

AbstractZipf’s law of abbreviation predicts that in human languages, words that are used more frequently will be shorter than words that are used less frequently. This has been attributed to the principle of least effort – communication is more efficient when words that are used more frequently are easier to produce. Zipf’s law of abbreviation appears to hold for all human languages, and recently attention has turned to whether it also holds for animal communication. In birdsong, which has been used as a model for human language learning and development, researchers have focused on whether more frequently used notes or phrases are shorter than those that are less frequently used. Because birdsong can be highly stereotyped, have high interindividual variation, and have phrase repertoires that are small relative to human language lexicons, studying Zipf’s law of abbreviation in birdsong presents challenges that do not arise when studying human languages. In this paper, we describe a new method for assessing evidence for Zipf’s law of abbreviation in birdsong, and we introduce the R package ZLAvian to implement this analysis. We used ZLAvian to study Zipf’s law of abbreviation in the songs of 11 bird populations archived in the open-access repository Bird-DB. We did not find strong evidence for Zipf’s law of abbreviation in any population when studied alone, but we found weak trends consistent with Zipf’s law of abbreviation in 10 of the 11 populations. Across all populations, the negative correlation between phrase length and frequency of use was several times weaker than the negative correlation between word length and frequency of use in human languages. This suggests that the mechanisms that underlie this correlation may be different in birdsong and human language.
Evolution of individual variation in a competitive trait: a theoretical analysis
Authors: Reinhold Klaus , Eigentler Lukas , Kikuchi David W. 
Published: December 2023

AbstractWhen competitive traits are costly, negative frequency-dependence can maintain genetic variance. Most theoretical studies examining this question assume binary polymorphisms, yet most trait variation in wild populations is continuous. We propose that continuous trait variation can result from continuous variation in resource quality and that the shape of the resource distribution determines trait maintenance. We used an individual-based model to test which conditions favour the stable maintenance of variation and which cause temporal fluctuations in trait values. This approach, inspired by contrasting outcomes of previous studies, clearly showed the decisive role played by the shape of resource distributions. Under extreme conditions, like the absence of resource variation or with very scarce resources for weak competitors, traits evolved to a single non-competitive or highly competitive strategy, respectively. Some distributions led to strong temporal fluctuations on trait values, whereas others led to the maintenance of large standing variation in competitive traits together with stable mean trait values. Our results thus explain the contradicting outcomes of previous theoretical studies and at the same time provide hypotheses to explain the maintenance of genetic variation and individual differences. We also suggest how the proposed effects of resource variation on trait maintenance can be tested empirically.
Dilated cardiomyopathy-associated RNA Binding Motif Protein 20 regulates long pre-mRNAs in neurons
Authors: Di Bartolomei Giulia , Ortiz Raul , Schreiner Dietmar , Falkner Susanne , Creemers Esther E. , Scheiffele Peter 
Published: December 2023

AbstractPrecise coordination of molecular programs and neuronal growth govern the formation, maintenance, and adaptation of neuronal circuits. RNA metabolism has emerged as a key regulatory node of neural development and nervous system pathologies. To uncover cell-type-specific RNA regulators, we systematically investigated expression of RNA recognition motif-containing proteins in the mouse neocortex. Surprisingly, we found RBM20, an alternative splicing regulator associated with dilated cardiomyopathy, to be expressed in cortical parvalbumin interneurons and mitral cells of the olfactory bulb. Genome-wide mapping of RBM20 target mRNAs revealed that neuronal RBM20 binds pre-mRNAs in distal intronic regions. Loss of neuronal RBM20 has only modest impact on alternative splice isoforms but results in a significant reduction in an array of mature mRNAs in the neuronal cytoplasm. This phenotype is particularly pronounced for genes with long introns that encode synaptic proteins. We hypothesize that RBM20 ensures fidelity of pre-mRNA splicing by suppressing non-productive splicing events in long neuronal genes. This work highlights a common requirement for RBM20-dependent transcriptome regulation in cardiomyocytes and neurons and demonstrates that a major genetic risk factor of heart disease impacts neuronal gene expression.
Root hydraulic properties: an exploration of their variability across scales
Authors: Cabrera Juan C. Baca , Vanderborght Jan , Couvreur Valentin , Behrend Dominik , Gaiser Thomas , Nguyen Thuy Huu , Lobet Guillaume 
Published: December 2023

AbstractRoot hydraulic properties are key physiological traits that determine the capacity of root systems to take up water, at a specific evaporative demand. They can strongly vary among species, cultivars or even within the same genotype, but a systematic analysis of their variation across plant functional types (PFTs) is still missing. Here, we reviewed published empirical studies on root hydraulic properties at the segment-, individual root-, or root system scale and determined its variability and the main factors contributing to it.We observed an extremely large range of variation (of orders of magnitude) in root hydraulic properties, but this was not caused by systematic differences among PFTs. Rather, the (combined) effect of factors such as root system age, driving force used for measurement, or stress treatments shaped the results. We found a significant decrease in root hydraulic properties under stress conditions (drought and aquaporin inhibition) and a significant effect of the driving force used for measurement (hydrostatic or osmotic gradients). Furthermore, whole root system conductance increased significantly with root system age across several crop species, causing very large variation in the data (> 2 orders of magnitude). Interestingly, this relationship showed an asymptotic shape, with a steep increase during the first days of growth and a flattening out at later stages of development. This behaviour was also observed in simulations with computational plant models, suggesting common patterns across studies and species.These findings provide better understanding of the main causes of root hydraulic properties variations observed across empirical studies. They also open the door to better representation of hydraulic processes across multiple plant functional types and at large scales. All data collected in our analysis has been aggregated into an open access database (https://roothydraulic-properties.shinyapps.io/database/), fostering scientific exchange.
Enhancer cooperativity can compensate for loss of activity over large genomic distances
Authors: Thomas Henry , Feng Songjie , Huber Marie , Loubiere Vincent , Vanina Daria , Pitasi Mattia , Stark Alexander , Buecker Christa 
Published: December 2023

AbstractEnhancers are short DNA sequences that activate their target promoter from a distance; however, increasing the genomic distance between the enhancer and the promoter decreases expression levels. Many genes are controlled by combinations of multiple enhancers, yet the interaction and cooperation of individual enhancer elements is not well understood. Here, we developed a novel synthetic platform that allows building complex regulatory landscapes from the bottom up. We tested the system by integrating individual enhancers at different distances and revealed that the strength of an enhancer determines how strongly it is affected by increased genomic distance. Furthermore, synergy between two enhancer elements depends on the distance at which the two elements are integrated: introducing a weak enhancer between a strong enhancer and the promoter strongly increases reporter gene expression, allowing enhancers to activate from increased genomic distances.
RERconverge Expansion: Using Relative Evolutionary Rates to Study Complex Categorical Trait Evolution
Authors: Redlich Ruby , Kowalczyk Amanda , Tene Michael , Sestili Heather H. , Foley Kathleen , Saputra Elysia , Clark Nathan , Chikina Maria , Meyer Wynn K. , Pfenning Andreas 
Published: December 2023

AbstractComparative genomics approaches seek to associate evolutionary genetic changes with the evolution of phenotypes across a phylogeny. Many of these methods, including our evolutionary rates based method, RERconverge, lack the capability of analyzing non-ordinal, multicategorical traits. To address this limitation, we introduce an expansion to RERconverge that associates shifts in evolutionary rates with the convergent evolution of multi-categorical traits. The categorical RERconverge expansion includes methods for performing categorical ancestral state reconstruction, statistical tests for associating relative evolutionary rates with categorical variables, and a new method for performing phylogenetic permulations on multi-categorical traits. In addition to demonstrating our new method on a three-category diet phenotype, we compare its performance to naive pairwise binary RERconverge analyses and two existing methods for comparative genomic analyses of categorical traits: phylogenetic simulations and a phylogenetic signal based method. We also present a diagnostic analysis of the new permulations approach demonstrating how the method scales with the number of species and the number of categories included in the analysis. Our results show that our new categorical method outperforms phylogenetic simulations at identifying genes and enriched pathways significantly associated with the diet phenotype and that the new ancestral reconstruction drives an improvement in our ability to capture diet-related enriched pathways. Our categorical permulations were able to account for non-uniform null distributions and correct for non-independence in gene rank during pathway enrichment analysis. The categorical expansion to RERconverge will provide a strong foundation for applying the comparative method to categorical traits on larger data sets with more species and more complex trait evolution.