bluuebunny/crossref_metadata_2025_split huggingface dataset:
Indecision and recency-weighted evidence integration in non-clinical and clinical settings
Authors: del Río M , Trudel N , Prabhu G , Hunt LT , Moutoussis M , Dolan RJ , Hauser TU 
Published: November 2024

AbstractBiases in information gathering are common in the general population and can reach pathological extremes in paralysing indecisiveness, as in obsessive-compulsive disorder (OCD). Here, we adopt a new perspective on information gathering and demonstrate an information integration bias where most recent information is over-weighted by means of evidence strength updates (ΔES). In a large, crowd-sourced sample (N=5,237), we find reduced ΔES-weighting drives indecisiveness along an OC spectrum. We replicate the attenuated ΔES- weighting in a second lab-based study (N=105) that includes a transdiagnostic OC spectrum encompassing OCD and generalised anxiety patients. Using magnetoencephalography (MEG), we trace ΔES signals to a late neural signal peaking around 920 ms. Critically, high-OC participants show an attenuated neural ΔES signal in medio-frontal areas while other decision- relevant processes remain intact. Our findings establish biased information-weighting as a key driver of information gathering, where attenuated ΔES can lead to indecisiveness across an OC spectrum.
Glioblastoma-Neuroblastoma co-cultured multicellular spheroid model for anti-cancer drug screening
Authors: Murugappan Sivasubramanian , Mali Ajay , Thorat Nanasaheb 
Published: November 2024

ABSTRACTPreclinical drug screening often relies on 2D mono-cultures and animal models, which fail to replicate the complexity of the human brain tumor microenvironment. This study presents a novel 3D co-culture spheroid model combining glioblastoma (U87-MG) and neuroblastoma (SH-SY5Y) cells to better mimic the cellular and molecular dynamics of brain tumors. Using the liquid overlay technique, reproducible and scalable spheroids were developed and characterized for growth, morphology, and drug sensitivity to temozolomide (TMZ), an FDA-approved brain cancer drug. Our findings demonstrate that glioblastoma spheroids thrive under hypoxic conditions and show significant resistance to TMZ, maintaining ∼88% viability even at 1000 µM. In contrast, neuroblastoma spheroids exhibit marked sensitivity, with viability reducing to ∼67% at the same concentration. Co-cultured spheroids displayed intermediate drug sensitivity (∼68% viability), highlighting the influence of neuroblastoma cells on glioblastoma’s drug response. Notably, neuroblastoma cells in the co-culture model exhibited neurite-like morphologies, suggesting differentiation and enhanced tumor-tumor interactions. This model addresses key limitations of existing preclinical systems by bridging the gap between simplistic 2D cultures and time-intensive organoids. It provides a biologically relevant and time-efficient platform for investigating tumor-stroma interactions, drug responses, and the role of neuron-glia dynamics in glioblastoma progression. Therefore, this co-culture spheroid system represents a critical step forward in developing more effective therapeutic strategies for brain tumors.
Targeting the tomato fruit cuticle by gene overexpression and editing with the fruit epidermis-preferentialnsLTPpromoter
Authors: Alonso Marie , Paulsen Ella , Geneix Nathalie , Pedemay Sandra , D’Orlando Angelina , Marion Didier , Lahaye Marc , Bakan Bénédicte , Rothan Christophe , Petit Johann 
Published: November 2024

AbstractThe thick cuticle covering and embedding epidermal cells of tomato (Solanum lycopersicum) fruit, a model for cuticle studies, plays important roles in fruit protection and quality. To further our understanding of the influence of cuticle components on cuticle architecture and properties, the next step is to engineer cuticle composition. Ideally, to avoid indirect effects at whole-plant level, a fruit-and epidermis-specific promoter should be used. Here, to overexpress and edit target genes in tomato, we selected anon-specific Lipid Transfer Protein 2promoter (pronsLTP) with preferential activity in fruit epidermis, as shown by NLS-GFP fluorescence analysis. Overexpression ofSlMYB75driven bypronsLTPinduced anthocyanin accumulation specifically in the growing fruit epidermis, consistent with the cuticle deposition pattern. In keeping with changes in anthocyanins, the cuticle composition in flavonoids and phenolic acids was altered, as shown by Raman microspectroscopy, as were several cuticle properties. We then edited the carotenoidPSY1gene with apronsLTP–drivenCRISPR/Cas9 system. DifferentPSY1knock-out alleles were detected predominantly in fruit exocarp and mesocarp of color-impairedpronsLTP::Cas9-Psy1mutants, and very little in the leaf. A mutant carrying a heritable knock-out mutation in both fruit and leaf was also detected, indicating that mutants obtained withpronsLTPmay require screening before being studied. Altogether, our results indicate thatpronsLTP2can efficiently result in gene overexpression and editing in fruit epidermis. Implications of these findings are important for the functional analysis and genetic engineering of cuticle-related genes in tomato.
Spatial Transcriptomics Reveals Inflammation and Trans-differentiation States of Acute Myeloid Leukemia in Extramedullary and Medullary Tissues
Authors: Dasdemir Enes , Veletic Ivo , Ly Christopher P. , Quesada Andres E. , Pacheco Christopher D. , Jelloul Fatima Z. , Borges Pamela , Basu Sreyashi , Jindal Sonali , Wang Zhiqiang , Lazar Alexander , Wani Khalida M. , Antunes Dinler A. , Reville Patrick K. , Gunaratne Preethi H. , Tower Robert J. , Sharma Padmanee , Abbas Hussein A. 
Published: November 2024

AbstractAcute myeloid leukemia (AML) is a heterogeneous disease of the bone marrow (medullary) but can also involve extramedullary tissues. While single cell dynamics of AML in suspension are previously explored, a comprehensive spatial transcriptomic assessment in AML remain underexplored. Here, we used Visium spatial transcriptomics to resolve medullary and extramedullary AML environments. We reveal spatial co-localization of monocytes and granulocyte-monocyte progenitors with leukemic populations in the bone marrow, sharing molecular signatures with extramedullary sites. Cell-cell communication via the CXCL12- CXCR4 axis correlated with PI3K/AKT/mTOR signaling in high inflammatory niches. Trans- differentiation states were concentrated in AML-infiltrated regions, with committed-like AML populations present in inflammatory niches and away from the trabeculae, while primitive-like AML cells localized near the endosteal niche. We validated these findings in GeoMx-based Digital Spatial profiling (DSP). Our study applied multimodal spatial transcriptomic approaches to characterize the spatial hierarchy and microenvironmental dynamics of AML differentiation states. We also demonstrated the feasibility of applying Visium-based spatial transcriptomics in decalcified bone tissues.
Differential beta and gamma activity modulation during unimanual and bimanual motor learning
Authors: Wu Min , Schoenfeld Marleen J. , Lindersson Carl , Braeutigam Sven , Zich Catharina , Stagg Charlotte J. 
Published: November 2024

AbstractMovement-related dynamics in the beta and gamma bands have been studied in relation to motor execution and learning during unimanual movements, but their roles in complex bimanual tasks remain largely unexplored. This study aimed to investigate how beta and gamma activity differs between unimanual and bimanual movements, and how these neural signatures evolve during the learning process. Our motor task incorporated varying levels of bimanual interaction: unimanual, bimanual-equal, and bimanual-unequal. Magnetoencephalography data were recorded during task performance, and beta and gamma dynamics were quantified. As expected, increasing task complexity from unimanual to bimanual-equal, and then to bimanual-unequal movements resulted in slower and less accurate performance. Across all conditions, significant beta event-related desynchronization (ERD) and gamma event-related synchronization (ERS) were observed during movement, as well as beta ERS after movement. Bimanual movements exhibited greater beta ERD, beta ERS, and gamma ERS compared to unimanual movements. With practice, participants demonstrated faster and more accurate movements, accompanied by enhanced beta ERS responses. Furthermore, learning-related reductions in errors correlated with increases in beta ERS. These findings suggest the distinct behavioural and neural demands of unimanual versus bimanual movements and highlight the important role of beta dynamics in motor performance and learning.
LOL-EVE: Predicting Promoter Variant Effects from Evolutionary Sequences
Authors: Shearer Courtney A. , Teufel Felix , Orenbuch Rose , Ritter Daniel , Spinner Aviv , Xie Erik , Frazer Jonathan , Dias Mafalda , Notin Pascal , Marks Debora S. 
Published: November 2024

AbstractGenetic studies reveal extensive disease-associated variation across the human genome, predominantly in noncoding regions, such as promoters. Quantifying the impact of these variants on disease risk is crucial to our understanding of the underlying disease mechanisms and advancing personalized medicine. However, current computational methods struggle to capture variant effects, particularly those of insertions and deletions (indels), which can significantly disrupt gene expression. To address this challenge, we present LOL-EVE (Language Of Life across EVolutionary Effects), a conditional autoregressive transformer model trained on 14.6 million diverse mammalian promoter sequences. Leveraging evolutionary information and proximal genetic context, LOL-EVE predicts indel variant effects in human promoter regions. We introduce three new benchmarks for indel variant effect prediction in promoter regions, comprising the identification of causal eQTLs, prioritization of rare variants in the human population, and understanding disruptions of transcription factor binding sites. We find that LOL-EVE achieves state-of-the-art performance on these tasks, demonstrating the potential of region-specific large genomic language models and offering a powerful tool for prioritizing potentially causal non-coding variants in disease studies.
Latent encoding of movement in primary visual cortex
Authors: Cosnier-Horeau Charlie , Germaine Hannah , Van Hooser Stephen , Choi Isaiah , Ribot Jérôme , Touboul Jonathan D. 
Published: November 2024

Neurons in the primary visual cortex (V1) are classically thought to encode spatial features of visual stimuli through simple population codes: each neuron exhibits a preferred orientation and preferred spatial frequency that are invariant to other aspects of the visual stimulus. Here, we show that this simple rule does not apply to the representation of major features of stimulus motion, including stimulus direction and temporal frequency (TF). We collected an extensive dataset of cat V1 responses to stimuli covarying in orientation, direction, spatial frequency, and TF to assess the extent of motion selectivity. In over half of V1, we found that the preferred direction changed with stimulus TF, revealing four distinct map motifs embedded within V1’s functional architecture. Additionally, preferred TF was mostly uniform across the cortical surface. Despite the lack of spatial modulation for the preferred TF map and the lack of invariance for the preferred direction map, we found using convolutional neural networks that direction, TF and stimulus speed can be accurately decoded from V1 responses at all cortical locations. These findings suggest that subtle modulations of V1 activity may convey fine information about stimulus motion, pointing to a novel primary sensory encoding mechanism despite complex co-variation of responses to multiple attributes across V1 neurons.Significance StatementCortical maps are thought to be useful for efficient processing of sensory information. In the primary visual cortex (V1), they are believed to provide uniform coverage across the visual field, ensuring that all orientations, spatial frequencies, and other features are consistently represented at each location in visual space. This organization supports stable visual perception, but it remains unclear how V1 encodes motion, particularly speed. Here, we reveal that cat V1 represents motion speed in a distributed manner without spatially organized temporal frequency maps, and that direction maps vary with stimulus speed. Nonetheless, we show that information on speed and preferred direction is decodable at all cortical locations. These findings challenge the classical uniform coverage hypothesis for motion attributes, and suggest that V1 encodes motion information in a more flexible manner.
Salinity impacted microbial carbonate precipitation mechanisms of modern microbialites in peritidal zone
Authors: Hsieh Yunli Eric , Yang Sung-Yin , Liu Shao-Lun , Wang Shih-Wei , Wang Wei-Lung , Tang Sen-Lin , Yang Shan-Hua 
Published: November 2024

AbstractMicrobialites, ancient records of microbial activity, serve as significant indicators of environmental change. This study examined microbialites from the peritidal zone of three tide pools at Fongchueisha, Hengchun, Taiwan, to investigate the impact of salinity on microbial community composition and carbonate precipitation mechanisms. Microbial samples were collected across varying salinity gradients over multiple timepoints and analyzed using next-generation sequencing of bacterial 16S and eukaryotic 18S rRNA genes. Our findings reveal that the microbial communities in higher salinity environments exhibited significant shifts, with increased relative abundance of ureolytic bacteria and ammonifying microorganisms, such asMyxococcotaandActinobacteriota. This suggests the presence of diverse microbial carbonate precipitation mechanisms beyond photosynthesis, including ureolysis and ammonification. Furthermore, our results show that changes in the composition of cyanobacteria and diatoms were influenced by salinity, with heterocystous cyanobacteria (e.g.,Nostocales) dominating low-salinity environments, and non-heterocystous cyanobacteria (e.g.,Synechococcales) prevailing in higher salinity environments. Functional predictions reveal that microbial communities in high-salinity environments were enriched in anaerobic metabolic pathways, including pyruvate fermentation and the urea cycle. These findings highlight the significant role of salinity in influencing microbial composition and metabolic pathways, shaping carbonate precipitation processes in microbialites.ImportanceThe study focuses on the impact of environmental salinity on microbial community composition and carbonate precipitation mechanisms within modern microbialites, based on an analysis of samples from three tide pools with different salinity levels collected at five time points throughout the year. Using next-generation sequencing of bacterial 16S and eukaryotic 18S rRNA genes, we identified key shifts in microbial communities along salinity gradients and explored diverse microbial processes involved in carbonate precipitation. This work enhances our understanding of microbial ecosystems within modern microbialites and their response to environmental changes. Additionally, our study provides insight into ancient biogeochemical processes, with implications for interpreting microbial metabolism in carbonate precipitation across different salinity regimes.
Structures of vertebrate R2 retrotransposon complexes during target-primed reverse transcription and after second strand nicking
Authors: Thawani Akanksha , Rodríguez-Vargas Anthony , Treeck Briana Van , Hassan Nozhat T , Adelson David L , Nogales Eva , Collins Kathleen 
Published: November 2024

AbstractR2 retrotransposons are model site-specific eukaryotic non-LTR retrotransposons that copy-and-paste into gene loci encoding ribosomal RNAs. Recently we demonstrated that avian A-clade R2 proteins achieve efficient and precise insertion of transgenes into their native safe-harbor loci in human cells. The features of A-clade R2 proteins that support gene insertion are not characterized. Here, we report high resolution cryo-electron microscopy structures of two vertebrate A-clade R2 proteins, avian and testudine, at the initiation of target-primed reverse transcription and one structure after cDNA synthesis and second strand nicking. Using biochemical and cellular assays we discover the basis for high selectivity of template use and unique roles for each of the expanded A-clade zinc-finger domains in nucleic acid recognition. Reverse transcriptase active site architecture is reinforced by an unanticipated insertion motif in vertebrate A-clade R2 proteins. Our work brings first insights to A-clade R2 protein structure during gene insertion and enables further improvement and adaptation of R2-based systems for precise transgene insertion.
Deconstructing evolutionary histories of complex genomic rearrangements in lung malignancies
Authors: Hu Xiaoju , Venkat Vignesh , Riedlinger Gregory , Shen Zhiyuan , Malhotra Jyoti , De Subhajyoti 
Published: November 2024

AbstractSomatic genomic rearrangements are hallmarks of cancer. Complex genomic rearrangements (CGRs) involving multiple intertwined structural alterations are often present in tumor genomes. CGRs frequently harbor oncogenic drivers, but their genomic architectures and etiologies are poorly understood. We used deep-coverage optical mapping technology to profile the genomic landscapes of normal lung tissues, benign pulmonary lesions, carcinoma in situ, and advanced carcinomas to examine the patterns of genome disorganization and instability in different stages of carcinogenesis in lung. Large rearrangements and CGRs were prevalent in the carcinomas. We developed omcplR to resolve the architecture of CGRs and predict their genesis from optical mapping data using genome-graph concept. We found that CGRs often arose from hierarchical combinations of multiple, localized simple structural variations, and harbored allelic heterogeneity at the affected loci. Rearrangement patterns and associated genomic signatures suggested that chromoanasynthesis was a likely prevalent mechanism driving complex genomic rearrangements. The early rearrangement junctions in intra-chromosomal CGRs were usually localized within the same chromatin domains, but the late junctions in advanced tumors had more heterogeneous contexts suggesting progressive organizational heterogeneity. The CGRs, especially the late events therein were under positive selection. A composite signature of genomic alterations including the CGRs captured the trajectory of progressive genomic disorganization and instability with carcinogenesis in lung and underscored the extent of genomic structural heterogeneity among the in-situ tumors.
Sample size estimates for biomarker-based outcome measures in clinical trials in autosomal dominant Alzheimer’s disease
Authors: Cash David M , Morgan Katy E , O’Connor Antoinette , Veale Thomas D , Malone Ian B , Poole Teresa , Benzinger Tammie LS , Gordon Brian A , Ibanez Laura , Li Yan , Llibre-Guerra Jorge J. , McDade Eric , Wang Guoqiao , Chhatwal Jasmeer P , Day Gregory S , Huey Edward , Jucker Mathias , Levin Johannes , Niimi Yoshiki , Noble James M , Roh Jee Hoon , Sánchez-Valle Racquel , Schofield Peter R , Bateman Randall J , Frost Chris , Fox Nick C ,   The Dominantly Inherited Alzheimer Network (DIAN)
Published: November 2024

AbstractINTRODUCTIONAlzheimer disease (AD)-modifying therapies are approved for treatment of early-symptomatic AD. Autosomal dominant AD (ADAD) provides a unique opportunity to test therapies in presymptomatic individuals.METHODSUsing data from the Dominantly Inherited Alzheimer Network (DIAN), sample sizes for clinical trials were estimated for various cognitive, imaging, and CSF outcomes.RESULTSBiomarkers measuring amyloid and tau pathology had required sample sizes below 200 participants per arm (examples CSF Aβ42/40: 22[95%CI 13,46], cortical PIB 32[20,57], CSF p-tau181 58[40,112]) for a four-year trial to have 80% power (5% statistical significance) to detect a 25% reduction in absolute levels of pathology, allowing 40% dropout. For cognitive, MRI, and FDG, it was more appropriate to detect a 50% reduction in rate of change. Sample sizes ranged from 75-250 (examples precuneus volume: 137[80,284], cortical FDG: 256[100,1208], CDR-SB: 161[102,291]).DISCUSSIONDespite the rarity of ADAD, clinical trials with feasible sample sizes given the number of cases appear possible.
Neuroimaging Insights into Brain Mechanisms of Early-onset Restrictive Eating Disorders
Authors: Moreau Clara A. , Ayrolles Anael , Ching Christopher R. K. , Bonicel Robin , Mathieu Alexandre , Stordeur Coline , Bergeret Pierre , Traut Nicolas , Tran Lydie , Germanaud David , Alison Marianne , Elmaleh-Bergès Monique , Ehrlich Stefan , Thompson Paul M. , Bourgeron Thomas , Delorme Richard 
Published: November 2024

AbstractBackgroundEarly-onset restrictive eating disorders (rEO-ED) encompass a heterogeneous group of conditions, including early-onset anorexia nervosa (EO-AN) and avoidant restrictive food intake disorders (ARFID). Almost nothing is known about the consequences of rEO-ED on brain development.MethodsWe performed the largest comparison of MRI-derived brain features in children and early adolescents (<13 years) with EO-AN (n=124), ARFID (n=50), and typically developing individuals (TD, n=112).ResultsDespite similar body mass index (BMI) distributions, EO-AN and ARFID showed divergent structural patterns, suggesting independent brain mechanisms. Half the regional brain measures were correlated with BMI in EO-AN and none in ARFID, indicating a partial mediation of EO-AN signal by BMI. EO-AN was associated with a widespread pattern of thinner cortex, while underweight ARFID patients exhibited smaller surface area and subcortical volumes than TD.ConclusionFuture studies will be required to partition the contribution of low BMIvs.ED mechanisms in neurodevelopmental disorders.
Designing a Structural Equation Model (SEM) for the Relationship between Quality of Working Life and Job Involvement among Nurses, with the Mediating Role of Job Burnout and Job Identity
Authors: Nazari Elham , Roumi Azin , Sabooteh Toomaj 
Published: November 2024

ABSTRACTIntroductionGiven the issue of nursing shortages globally and in Iran, compounded by new global conditions due to the COVID-19 pandemic, the quality of working life (QWL) among nurses and the factors influencing it have become important issues. Therefore, this study aimed to investigate the relationship between QWL and job involvement among nurses, considering the mediating role of job burnout and job identity.MethodologyThis study is a cross-sectional analysis conducted in Khorramabad, Lorestan province, Iran. The statistical population comprised nurses employed in Khorramabad hospitals. The sample size was determined using Cochran’s formula, and simple random sampling was employed. To assess the variables, the Work-Related Quality of Life Scale (WRQOLS), Maslach Burnout Questionnaire, Hao’s Professional Identity Questionnaire, and the Utrecht Work Engagement Scale (UWES-9) were used. Structural Equation Modeling (SEM) was employed to examine the relationships between variables, and Smart-PLS software was used for data analysis.ResultsResults showed a significant negative correlation between job involvement, job identity, and QWL with job burnout. The correlation coefficients were -0.910, -0.878, and -0.900, respectively. Additionally, the results indicated that job identity and job burnout mediate the relationship between QWL and job involvement among nurses.ConclusionAccording to the findings of this study, job identity and job burnout have a mediating effect on the relationship between QWL and employee engagement. Therefore, when nursing managers aim to enhance the job engagement of new nurses, they should consider not only QWL but also the aspects of job identity and job burnout. Enhancing QWL can improve psychological empowerment and reduce nurse burnout. Moreover, professional training and improvement of communication skills among nursing staff can assist them in managing job burnout.