bluuebunny/crossref_metadata_2025_split huggingface dataset:
A personalized multi-platform assessment of somatic mosaicism in the human frontal cortex
Authors: Zhou Weichen , Mumm Camille , Gan Yanming , Switzenberg Jessica A. , Wang Jinhao , De Oliveira Paulo , Kathuria Kunal , Losh Steven J. , McDonald Torrin L. , Bessell Brandt , Van Deynze Kinsey , McConnell Michael J. , Boyle Alan P. , Mills Ryan E. 
Published: December 2024

AbstractSomatic mutations in individual cells lead to genomic mosaicism, contributing to the intricate regulatory landscape of genetic disorders and cancers. To evaluate and refine the detection of somatic mosaicism across different technologies with personalized donor-specific assembly (DSA), we obtained tissue from the dorsolateral prefrontal cortex (DLPFC) of a post-mortem neurotypical 31-year-old individual.We sequenced bulk DLPFC tissue using Oxford Nanopore Technologies (∼60X), NovaSeq (∼30X), and linked-read sequencing (∼28X). Additionally, we applied Cas9 capture methodology coupled with long-read sequencing (TEnCATS), targeting active transposable elements. We also isolated and amplified DNA from flow-sorted single DLPFC neurons using MALBAC, sequencing 115 of these MALBAC libraries on Nanopore and 94 on NovaSeq.We constructed a haplotype-resolved assembly with a total length of 5.77 Gb and a phase block length of 2.67 Mb (N50) to facilitate cross-platform analysis of somatic genetic variations. We observed an increase in the phasing rate from 11.6% to 38.0% between short-read and long-read technologies. By generating a catalog of phased germline SNVs, CNVs, and TEs from the assembled genome, we applied standard approaches to recall these variants across sequencing technologies. We achieved aggregated recall rates from 97.3% to 99.4% based on long-read bulk tissue data, setting an upper bound for detection limits.Moreover, utilizing haplotype-based analysis from DSA, we achieved a remarkable reduction in false positive somatic calls in bulk tissue, ranging from 14.9% to 72.4%. We developed pipelines leveraging DSA information to enhance somatic large genetic variant calling in long-read single cells. By examining somatic variation using long-reads in 115 individual neurons, we identified 468 candidate somatic heterozygous large deletions (1.5Mb - 20Mb), 137 of which intersected with short-read single-cell data. Additionally, we identified 61 putative somatic TEs (60Alus, one LINE-1) in the single-cell data.Collectively, our analysis spans personalized assembly to single-cell somatic variant calling, providing a comprehensiveab initio ad finemapproach and resource in real human tissue.
Transfusion Probability as a Novel Measure for Lab-Guided Medical Decision-Making
Authors: Risk Malcolm , Callum Jeannie , Trentino Kevin , Murray Kevin , Zhao Lili , Shi Xu , Verma Amol , Razak Fahad , Raza Sheharyar 
Published: December 2024

ABSTRACTThe clinical decision to transfuse is strongly influenced by laboratory results. Analysis of transfusion decision-making based on pre-transfusion laboratory results (e.g. pre-transfusion hemoglobin) is a common yet misleading approach to study lab-guided transfusion practice. We introduce “Transfusion Probability” as a novel method which overcomes many limitations of pre-transfusion lab result analyses. Under this approach, we estimate the probability of transfusion after results at a specific value (e.g. hemoglobin 7.4 g/dL) or in a range of values (e.g. 7.0-7.9 g/dL) using the proportion of tests followed by transfusion. We provide statistical methodology for causal inference on the effect of patient conditions and apply our method to a large multi-center dataset. Analyses using pre-transfusion and transfusion probability were compared using data from a large longitudinal cohort of hospitalized patients (N=525,032 patients). We found red blood cell transfusion probabilities of 76.2% in the 6.0-6.9 g/dL, 18.9% in the 7.0-7.9 g/dL, and 4.5% in the 8.0-8.9 g/dL hemoglobin range. After confounder adjustment, patients with gastrointestinal bleeding patients were more likely to be transfused across all ranges, with risk differences ranging from 6.6% in the 8.0-8.9 g/dL range to 13.8% in the 6.0-6.9 g/dL range. Pre-transfusion hemoglobin results showed minimal differences between gastrointestinal bleeding patients and other patients in unadjusted (0.00 g/dL) and adjusted analyses (-0.20 g/dL). In contrast to pre-transfusion result analysis, transfusion probability offers a nuanced account of transfusion practice and allows for natural comparisons between patient groups. Wider adoption of transfusion probability analysis may provide direct and actionable insights for clinical decision-making.KEY POINTSPre-transfusion lab results are a widely used method for studying lab-guided transfusion but subject to many limitationsTransfusion probability analysis is a novel and superior approach
Secondary analysis of the Game of Stones trial of text messages with financial incentives for men with obesity
Authors: Dombrowski Stephan U , Hoddinott Pat , Macaulay Lisa , O’Dolan Catriona , Swingler James , Cotton Seonaidh , Avenell Alison , Getaneh Abraham M , Gray Cindy , Hunt Kate , Kee Frank , MacLean Alice , McKinley Michelle C , Torrens Claire , Turner Katrina , Marjon van der Pol , MacLennan Graeme 
Published: December 2024

AbstractObjectiveTo explore whether socio-economic, health and behavioural characteristics moderate effectiveness of a text message intervention with or without financial incentives versus a control group, and to examine differences in exploratory outcomes.MethodsThree-group randomized trial including 585 men with obesity comparing daily automated behavioural text messages for 12-months alongside financial incentives; text messages alone; or a waiting list control. Moderator analyses examined percent weight change after 12 months for 9 socio-economic and 11 health factors. Exploratory outcomes included: self-reported physical activity, sedentary behaviour, smoking and alcohol behaviours, engagement in 15 weight management strategies, and weight-management related confidence.ResultsNo moderator effects were found by any factors for either comparison versus control. There were no differences between groups for health behaviours. The texts with incentives group had higher levels of engagement in six strategies including weight goals, food changes and self-weighing, and higher levels of confidence compared to the control group.ConclusionNo evidence of differential intervention effectiveness was found across socio-economic, health or wellbeing status. The texts and financial incentives group showed greater engagement in weight management and favourable changes in weight management confidence compared to the control group.
Social Determinants of Sepsis Mortality in the United States: A Retrospective, Epidemiologic Analysis
Authors: Ardabili Ahad Khaleghi , Sadr Alireza Vafaei , Abedi Vida , Bonavia Anthony S 
Published: December 2024

AbstractObjectiveTo determine whether neighborhood-level social determinants of health (SDoH) influence mortality following sepsis in the United States.Study Setting and DesignRetrospective analysis of data from 4.4 million hospitalized patients diagnosed with sepsis, identified using International Classification of Diseases-10 codes, across the United States.Data Sources and Analytic SampleDe-identified, aggregated data were sourced from the TriNetX Diamond Network. SDoH variables included income, housing cost burden, broadband access, park proximity, racial/ethnic diversity, and the Area Deprivation Index (ADI). The primary outcome was mortality, assessed using univariate and multivariate binomial generalized linear models. Predictors with high multicollinearity (Variance Inflation Factor > 5) were excluded to enhance model stability.Principal FindingsLower median income, higher ADI scores, limited park access, and lack of broadband connectivity were strongly associated with increased sepsis mortality. Unexpectedly, greater racial/ethnic diversity was negatively associated with mortality, possibly reflecting regional disparities in healthcare access and socioeconomic conditions. Multivariate analyses revealed that the inclusion of SDoH variables attenuated some effects observed in univariate models, highlighting their complex interplay. Random Forest analysis identified park access as the most important predictor of sepsis mortality, emphasizing its role as a potential proxy for broader neighborhood resources.ConclusionsNeighborhood-level SDoH are critical for risk stratification in sepsis prognostic models and should be systematically integrated into predictive frameworks. These findings highlight the need for targeted public health interventions to address social vulnerabilities, enhance access to green spaces, and reduce disparities in sepsis outcomes across diverse populations.Callout BoxWhat is known on this topicSocial determinants of health (SDoH) influence a variety of health outcomes although their impact on sepsis mortality has been under-explored.Sepsis is a leading cause of mortality in the United States, with over 350,000 deaths annually.What this study addsNeighborhood-level, SDoH such as park access and Area Deprivation Index (ADI) are associated with mortality in sepsis.Incorporation of these variables may assist in patient risk stratification, potentially improving public health initiatives or allowing them to be more targeted to at-risk populations.
Marsupial limb patterning redefines the necessity of lateral plate mesoderm subdivision for limb formation
Authors: Newton Axel H , Leggatt Alexandra , Farley Ella R , Sears Karen E , Couzens Aidan MC , Ord Sara , Pask Andrew J 
Published: December 2024

AbstractThe tetrapod limb has long served as a model for elucidating molecular and cellular mechanisms driving tissue patterning, development and evolution. While significant advances have been made in understanding the drivers of limb initiation, outgrowth, and patterning, the early morphogenetic processes that transform the lateral plate mesoderm (LPM) into limb fields remain less resolved. Marsupial mammals provide a unique opportunity to investigate these foundational processes due to their accelerated forelimb development, driven by the functional demands of altricial neonates to crawl into the pouch at birth. Heterochronic formation of the forelimbs occurs prior to development of other surrounding structures, offering unparalleled insights into the plasticity of limb field specification. Here, we reveal that marsupial limb initiation and outgrowth bypasses physical subdivision of the LPM, a process previously considered critical for tetrapod limb formation. Instead, limb development proceeds through early activation of LPM-associated genes and proliferation before coelom formation, demonstrating remarkable morphogenetic plasticity. This evolutionary adaptation enables heterochronic limb development, redefining conserved processes to meet extreme functional constraints. These findings challenge previous models of tetrapod limb specification, highlighting the evolutionary plasticity of limb patterning mechanisms and reshaping our understanding of how selective pressures influence foundational developmental events.
Recurrent cancer-associated ERBB4 mutations are transforming and confer resistance to targeted therapies
Authors: Ojala Veera K. , Ahonen Sini , Tuohisto-Kokko Aura , Esparta Olaya , Suominen Peppi , Jokilammi Anne , Farahani Iman , Chakroborty Deepankar , Dibus Nikol , Boettcher Steffen , Airenne Tomi T. , Johnson Mark S. , Eli Lisa D. , Elenius Klaus , Kurppa Kari J. 
Published: December 2024

ABSTRACTReceptor tyrosine kinase ERBB4 (HER4) is frequently mutated in human cancer, andERBB4mutations have been identified in patients relapsing on targeted therapy. Here, we addressed the functional consequences of recurrent cancer-associatedERBB4mutations that are located at regions important for dimer interactions and/or are paralogous to known oncogenic hotspot mutations in otherERBBgenes. Eleven out of 18 analyzed mutations were transforming in cell models, thus suggesting oncogenic potential for more than half of the recurrent ERBB4 mutations. More detailed analyses of the most potent mutations, S303F, E452K and L798R, showed that they are activating, can co-operate with other ERBB receptors and are targetable with clinically available second-generation pan-ERBB inhibitors neratinib, afatinib and dacomitinib. Furthermore, the S303F mutation, together with a previously identified activating ERBB4 mutation, E715K, promoted resistance to third-generation EGFR inhibitor osimertinib in EGFR-mutant lung cancer modelin vitroandin vivo. Together, these results are expected to facilitate clinical interpretation of the most recurrent cancer-associatedERBB4mutations. The findings provide rationale for testing the efficacy of clinically used pan-ERBB inhibitors in patients harboring driverERBB4mutations both in the treatment-naïve setting, and upon development of resistance to targeted agents.
Common and distinct neural correlates of social interaction perception and theory of mind
Authors: Miao Zizhuang , Jung Heejung , Kragel Philip A. , Sadil Patrick , Lindquist Martin A. , Wager Tor D. 
Published: December 2024

AbstractSocial cognition spans from perceiving agents and their interactions to making inferences based on theory of mind (ToM). Despite their frequent co-occurrence in real life, the commonality and distinction between social interaction perception and ToM at behavioral and neural levels remain unclear. Here, participants (N= 231) provided moment-by-moment ratings of four text and four audio narratives on social interactions and ToM engagement. Social interaction and ToM ratings were reliable (split-halfr= .98 and .92, respectively) but only modestly correlated across time (r= .32). In a second sample (N= 90), we analyzed co-variation between normative social interaction and ToM ratings and functional magnetic resonance (fMRI) activity during narrative reading (text) and listening (audio). Social interaction perception and ToM activity maps generalized across text and audio presentation (r= .83 and .57 between unthresholdedtmaps, respectively). When ToM was held constant, merely perceiving social interactions activated all regions canonically associated with ToM under both modalities (FDRq< .01), including temporoparietal junction, superior temporal sulcus, medial prefrontal cortex, and precuneus. ToM activated these regions as well, indicating a shared, modality-general system for social interaction perception and ToM. Furthermore, ToM uniquely engaged lateral occipitotemporal cortex, left anterior intraparietal sulcus, and right premotor cortex. These results imply that perceiving social interactions automatically engages regions implicated in mental state inferences. In addition, ToM is distinct from social interaction perception in its recruitment of regions associated with higher- level cognitive processes, including action understanding and executive functions.Author NoteThanks to Bogdan Petre, Yaroslav O. Halchenko, David M. Gantz, Sydney L. Shohan, Xinming Xu, Maryam Amini, Bethany J. Hunt, and Eilis I. Murphy for data collection and management. This project was supported by grants NIBIB R01EB026549. Matlab code for analyses is available at:https://github.com/canlab, with documentation and examples athttps://canlab.github.io.
A non-canonical glucose metabolic rewiring enables resistance to cancer targeted therapy
Authors: Lei Huimin , Xia Ruixue , Tang Yabin , Lu Jun , Xiang Chan , Li Yujing , Liu Hongyu , Zou Peichen , Aihemaiti Ayinazhaer , Zhang Wei , Shen Ying , Han Baohui , Han Yuchen , Zhong Hua , Chen Hongzhuan , Zhu Liang 
Published: December 2024

AbstractTargeting glucose metabolism for cancer therapy is a long-lasting pursuit but with disappointing translational success. Revelation of actionable distinctions between the malignancy traits to achieve selectivity is a prerequisite for fulfilling a therapeutic window. We discover a non-canonical glucose transporter GLUT6-facilitated, lactate-independent, glucose metabolic rewiring that selectively enables resistance to targeted therapy in lung cancer. Downstream, GLUT6 facilitated glucose influx and straying to methylglyoxal which dimerized KEAP1 and upregulated NRF2 pathway to confer resistance. Upstream, GLUT6 was transcriptionally upregulated by therapy-induced MAZ activation. Targeting GLUT6 prevented and overcame resistance to EGFR and KRAS inhibitors and the MAZ-GLUT6-NRF2 signaling correlated with clinical therapy response and relapse. Our findings uncover an unrecognized non-genetic, metabolic mechanism for drug resistance and a scenario specifically determined by a distinct glucose metabolic rewiring in cancer. The preferential dependance of the non-canonical, general-homeostasis-less-perturbing transporter GLUT6 implies a promise for resistance overcoming and for glucose metabolism-targeting strategy, two long and urgent quests.
The conserved global regulator H-NS has a strain-specific impact on biofilm formation inVibrio fischerisymbionts
Authors: Zarate Dani , Isenberg Ruth Y. , Pavelsky Morgan , Speare Lauren , Jackson Aundre , Mandel Mark J. , Septer Alecia N. 
Published: December 2024

AbstractStrain-level variation among host-associated bacteria often determines host range and the extent to which colonization is beneficial, benign, or pathogenic.Vibrio fischeriis a beneficial symbiont of the light organs of fish and squid with known strain-specific differences that impact host specificity, colonization efficiency, and interbacterial competition. Here, we describe how the conserved global regulator, H-NS, has a strain-specific impact on a critical colonization behavior: biofilm formation. We isolated a mutant of the fish symbiontV. fischeriMJ11 with a transposon insertion in thehnsgene. This mutant formed sticky, moderately wrinkled colonies on LBS plates, a condition not known to induce biofilm in this species. A reconstructedhnsmutant displayed the same wrinkled colony, which became smooth whenhnswas complementedin trans, indicating thehnsdisruption is causal for biofilm formation in MJ11. Transcriptomes revealed differential expression for thesypbiofilm locus in thehnsmutant, relative to the parent, suggesting biofilm may in part involve SYP polysaccharide. However, enhanced biofilm in the MJ11hnsmutant was not sufficient to allow colonization of a non-native squid host. Finally, moving thehnsmutation into otherV. fischeristrains, including the squid symbionts ES114 and ES401, and seawater isolate PP3, revealed strain-specific biofilm phenotypes: ES114 and ES401hnsmutants displayed minimal biofilm phenotypes while PP3hnsmutant colonies were more wrinkled than the MJ11hnsmutant. These findings together define H-NS as a novel regulator ofV. fischerisymbiotic biofilm and demonstrate key strain specificity in that role.ImportanceThis work, which shows how H-NS has strain-specific impacts on biofilm inVibrio fischeri, underscores the importance of studying multiple strains, even when examining highly conserved genes and functions. Our observation that knocking out a conserved regulator can result in a wide range of biofilm phenotypes, depending on the isolate, serves as a powerful reminder that strain-level variation is common and worthy of exploration. Indeed, uncovering the mechanisms of strain-specific phenotypic differences is essential to understand drivers of niche differentiation and bacterial evolution. Thus, it is important to carefully match the number and type of strains used in a study with the research question to accurately interpret and extrapolate the results beyond a single genotype. The additional work required for multi-strain studies is often worth the investment of time and resources, as it provides a broader view of the complexity of within-species diversity in microbial systems.
Time restricted feeding with or without ketosis influences metabolism-related gene expression in a tissue-specific manner in aged rats
Authors: Ding Sarah , Banerjee Anisha , Burke Sara N. , Hernandez Abbi R. 
Published: December 2024

AbstractMany of the ‘hallmarks of aging’ involve alterations in cellular and organismal metabolism. One pathway with the potential to impact several traditional markers of impaired function with aging is the PI3K/AKT metabolic pathway. Regulation of this pathway includes many aspects of cellular function, including protein synthesis, proliferation and survival, as well as many downstream targets, including mTOR and FOXOs. Importantly, this pathway is pivotal to the function of every organ system in the human body. Thus, we investigated the expression of several genes along this pathway in multiple organs, including the brain, liver and skeletal muscle, in aged subjects that had been on different experimental diets to regulate metabolic function since mid-life. Specifically, rats were fed a control ad lib diet (AL), a time restricted feeding diet (cTRF), or a time restricted feeding diet with ketogenic macronutrients (kTRF) for the majority of their adult lives (from 8-25 months). We previously reported that regardless of macronutrient ratio, TRF-fed rats in both macronutrient groups required significantly less training to acquire a biconditional association task than their ad lib fed counterparts. The current experiments expand on this work by quantifying metabolism-related gene expression across tissues and interrogating for potential relationships with cognitive performance. AKT expression was significantly reduced in kTRF fed rats within liver and muscle tissue. However, AKT expression within the perirhinal cortex (PER) was higher in kTRF rats with the best cognitive performance. Within CA3, higher levels of FOXO1 gene expression correlated with poorer cognitive performance in ad libitum fed rats. Together, these data demonstrate diet- and tissue-specific alterations in metabolism-related gene expression and their correlation with cognitive status.
Female Olfactory Sensitivity Is Temporally Asynchronous with Male Courtship in a Butterfly
Authors: Murphy Matthew J. , Ter Yi Ting , Riddington Ian M. , Joshi Neelendra K. , Westerman Erica L. 
Published: December 2024

AbstractSignal efficacy is crucial to communicative behaviours. To be effective, a signal once broadcast must be capable of being received and interpreted by a receiver or receivers. In addition to maximizing the amount that a signal stimulates receptive organs, optimally the timing of when a signal is broadcast would synchronize with a receiver’s peak receptivity. Here, we investigated whether peak timing of male courtship, which includes release of a pheromone required for copulation to occur, is synchronized with female pheromone sensitivity in the butterflyBicyclus anynana(Lepidoptera: Nymphalidae). To do this, we performed behavioural and electrophysiological assays at dawn, noon, and dusk. We also investigated the circadian rhythmicity of antennae gene expression by performing RNA-Sequencing on antennal tissues collected at dawn, noon and dusk. We found that although males court most often near dusk, females are more sensitive to odorants in the morning. Furthermore, antennae exhibited differential and diurnally rhythmic expression of odorant receptors and genes associated with learning and sexual receptivity, as well as gene ontology (GO) terms related to fatty acid metabolism and trehalose biosynthesis, supporting our circadian electrophysiological results. Previous literature indicates females form both positive and negative mate preference associations with male pheromones in the morning, regardless of whether males court females. Thus, this asynchrony may enable femaleB. anynanato learn mate preferences before they are courted by conspecific (or potentially heterospecific) males.SummaryMaleBicyclus anynanabutterflies court more at dusk while females are more sensitive to odorants in the morning. Patterns of antenna gene expression also suggest circadian rhythmicity of odorant sensitivity.