bluuebunny/crossref_metadata_2025_split huggingface dataset:
Support for the deuterostome clade comes from systematic errors
Authors: Silva Ana Serra , Natsidis Paschalis , Piovani Laura , Kapli Paschalia , Telford Maximilian J. 
Published: January 2025

AbstractThere is a long-standing consensus that the animal phyla closest to our own phylum of Chordata are the Echinodermata and Hemichordata. These three phyla constitute the major clade of Deuterostomia. Recent analyses have questioned the support for the monophyly of Deuterostomia, however, showing that the branch leading to deuterostomes is very short and may be influenced by systematic error. Here we use a site-by-site approach to explore multiple sources of error. Under conditions that promote long-branch attraction (LBA) – especially branch-length heterogeneity and sites constrained in their amino acid composition – we find that deuterostome monophyly is strongly supported. When we make efforts to mitigate these sources of error, we cannot distinguish between monophyletic and paraphyletic Deuterostomia. Our findings have implications for the interpretation of putative deuterostome fossils, for the reconstruction of a bilaterian ancestor and, more generally, for how datasets for deep-time phylogenetic analyses are assembled and analyzed.TeaserThe apparently close relationship between Chordata and Ambulacraria (echinoderms and hemichordates) is boosted by a long-branch attraction artefact.
Novel Carbohydrate-substituted Indazole Derivatives Targeting SGLT1 Enhance the Efficacy of Receptor Tyrosine Kinase Inhibitors in Cancer Therapy
Authors: Sun Zhongjie , Qi Hailong 
Published: January 2025

AbstractReceptor tyrosine kinase (RTK) inhibitors have demonstrated significant efficacy in treating malignant tumors. However, the development of drug resistance and limited efficacy in RTK inhibitor-insensitive patients pose challenges to their clinical application. To enhance the efficacy for RTK inhibitors-insensitive patients and overcome the resistance, beyond developing new RTK inhibitors, combination therapy has emerged as a promising approach. In this study, we discovered a novel compound,071, featuring an indazole core flanked by a carbohydrate moiety and two phenyl groups, which exhibits synergistic anti-tumor activity when combined with various RTK inhibitor. Several series of071analogues were synthesized through structure modification and evaluated the synergistic anti-tumor effects and the metabolic stability. Compound10d-02emerged as notably more potent in synergistic anti-tumor activity and demonstrated greater stability than compound071. Notably, the combination of compound10d-02and multiple RTK inhibitors significantly enhanced in vivo efficacy in both RTK inhibitor-sensitive and -insensitive tumor xenograft models without evident toxicity. Furthermore, compound10d-02exhibited an excellent pharmacokinetic profile with nearly 100% oral bioavailability. Using click chemistry technology combined with mass spectrometry analysis, we identified SGLT1 as a potential target for10d-02. SGLT1 has been previously proven to bind and stabilize EGFR, and we further discovered that SGLT1 also binds and stabilizes VEGFR2/3. While compound10d-02could partially block the interaction between SGLT1 and EGFR/VEGFRs, leading to the instability and degradation of EGFR and VEGFRs, potentially elucidating the mechanism of its synergistic effect with RTK inhibitors. Thus, compound10d-02holds substantial promise for use in combination therapies with RTK inhibitors in tumor clinical treatment.
Rare Variant Analyses in Ancestrally Diverse Cohorts Reveal Novel ADHD Risk Genes
Authors: Jung Seulgi , Caballero Madison , Olfson Emily , Newcorn Jeffrey H. , Fernandez Thomas V. , Mahjani Behrang 
Published: January 2025

AbstractAttention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder, but its genetic architecture remains incompletely characterized. Rare coding variants, which can profoundly impact gene function, represent an underexplored dimension of ADHD risk. In this study, we analyzed large-scale DNA sequencing datasets from ancestrally diverse cohorts and observed significant enrichment of rare protein-truncating and deleterious missense variants in highly evolutionarily constrained genes. This analysis identified 15 high-confidence ADHD risk genes, including the previously implicatedKDM5B. Integrating these findings with genome-wide association study (GWAS) data revealed nine enriched pathways, with strong involvement in synapse organization, neuronal development, and chromatin regulation. Protein–protein interaction analyses identified chromatin regulators as central network hubs, and single-cell transcriptomic profiling confirmed their expression in neurons and glial cells, with distinct patterns in oligodendrocyte subtypes. These findings advance our understanding of the genetic architecture of ADHD, uncover core molecular mechanisms, and provide promising directions for future therapeutic development.
Time-resolved immune dynamics in rheumatoid arthritis under methotrexate therapy
Authors: Preglej Teresa , Tosevska Anela , Brinkmann Marie , Schatzlmaier Philipp , Simader Elisabeth , Sieghart Daniela , Hofer Philipp , Krausgruber Thomas , Dobnikar Lina , Bock Christoph , Karonitsch Thomas , Kain Renate , Stockinger Hannes , Ellmeier Wilfried , Aletaha Daniel , Göschl Lisa , Bonelli Michael 
Published: January 2025

AbstractRheumatoid arthritis (RA) is characterized by immune dysregulation, including alterations in peripheral blood mononuclear cell (PBMC) populations and aberrant cytokine signaling. Methotrexate (MTX) is the preferred first-line treatment for RA, yet its precise mechanisms of action remain incompletely understood. This study employed a multi-omics strategy—combining single-cell RNA sequencing (scRNA-seq) and immunophenotyping—to identify key effector peripheral immune cells and their cellular responses in RA patients over 12 weeks of MTX treatment.In our study, MTX was associated with significant immune modulation, including the restoration of naïve T and B cells and reductions in T cell memory subsets with these effects detectable as early as three weeks post-treatment. Plasmablast levels also emerged as a potential biomarker for early therapeutic response, reflecting MTX’s impact on immune homeostasis. Transcriptional analysis revealed modulation of key pathways, including TNF-α signaling, B cell receptor signaling, and T cell receptor-mediated apoptosis. Network analysis identified critical regulatory hubs, such as EGR1, JAK2, and SOCS1, in monocytes and CD4 memory T cells, highlighting these cell types as key mediators of MTX’s effects.In conclusion, these findings advance our understanding of MTX’s effects on immune cell dynamics at different stages of treatment, showing for the first time the early cellular changes leading to immune modulation in RA. Altogether, our results provide the foundation for further mechanistic investigations into MTX.
Psychoacoustic Study of the Rock Art Sites of Cuevas de la Araña (Bicorp, Spain)
Authors: López Samantha , Lokki Tapio , Díaz-Andreu Margarita , Escera Carles 
Published: January 2025

AbstractAcoustics play a crucial role in shaping our perception of sound and its emotional impact. The rock art site ofCuevas de la Arañain Bicorp, Spain, is an archaeological site where pre-historic communities gathered for social and ritual activities.Cuevas de la Arañaexhibits acoustical characteristics that could have enhanced the sensory and emotional impact during ceremonies performed with music. In the present study, a listening test was conducted to assess how the acoustics ofCuevas de la Arañaand other rock art sites influence modern-day listeners’ perception of sound. Listeners were asked to describe, using their own vocabulary, a series of auralizations created with the impulse responses collected inCuevas de la Arañaand other neighboring sites with and without rock art. The words written by participants underwent categorization through a hierarchical clustering approach. Significant results emerged indicating that listeners perceived auralizations from rock art sites as larger, wider, less direct, farther and more reverberant than the auralizations from sites lacking rock art. Notably, the most prominent disparities were observed in the categories of size, distance, and reverberation when contrasting the auralizations fromCuevas de la Arañawith those of non-painted sites. These findings align with the outcomes documented in prior literature that investigated the acoustic characteristics of the sites and offer valuable insights into the auditory experiences at rock art sites, shedding light on their unique acoustic properties.
Uncertainty during visual search: Insights from a computational model and behavioral experiment in natural stimuli
Authors: Bujia Gaston , Ruarte Gonzalo , Sclar Melanie , Solovey Guillermo , Kamienkowski Juan E. 
Published: January 2025

AbstractVisual search, driven by bottom-up and top-down processes, offers a unique framework for investigating decision-making. This study examines individuals’ awareness of their own visual search by combining computational modeling with behavioral experiments. Fifty-seven participants performed a classical visual search task in which the goal was to find an object in a natural scene. Crucially, in some trials, the search was interrupted by clearing the screen before the gaze reached the target object. Participants had to report their best guess of the target’s location and the uncertainty on their response. We show that a modified version of the Entropy-Limit Minimization (ELM) model captures scanpaths and perceived target locations, while also revealing that uncertainty is influenced by scanpath length, the distance between the perceived and true target location, and the entropy of decision maps. These findings highlight the model’s capacity to reflect cognitive processes underlying response selection and uncertainty judgment.
Sequential visual stimuli increase high frequency power in the visual cortex
Authors: Keil Julian , Hernandez-Urbina Victor , Vassiliou Chrystalleni , Dean Camin , Schmitz Dietmar , Kremkow Jens , Sibille Jérémie 
Published: January 2025

ABSTRACTToday, 40 Hz flickering full-field visual stimulation is used to entrain neuronal oscillations for a variety of therapeutic purposes. We here propose spatially organized sequential visual flickering stimulation as a newer tool to entrain the visual system. We show that sequential visual flickering can evoke increased power in high frequencies (100 to 190 Hz) in the visual cortex of mice. Consequently, sequential sensory stimulation should be regarded as a putative new way leading to power increases in high frequency domains.
Specific and redundant roles for Gli2 and Gli3 in establishing cell fate during hair follicle development
Authors: Gozum Gokcen , Wirtz Lisa , Damen Mareike , Reckert Viktoria , Schettina Peter , Nelles Melanie , Bazzi Hisham , Niemann Catherin 
Published: January 2025

ABSTRACTEctodermal appendage formation requires hedgehog (HH) signal reception, its conduction through the primary cilium and activation of Gli transcription factors (TF). How HH signalling induces cell-type-specific responses through Gli TF in stem cells (SCs) and their cilia-dependence remain open questions. Here, we use conditional mouse mutants to genetically dissect the roles of Gli and cilia HH mediators in the skin epithelium. Upon Gli2 depletion, hair follicle (HF) morphogenesis is delayed whereas sebaceous gland (SG) formation is enhanced, suggesting a dual role for Gli2 during appendage formation. By controlling proliferation of SG SCs, Gli2 impacts on the number and size of individual SG lobes. Whereas ablation of Gli3 shows no detectable phenotypes, HF cell fate is blocked in Gli2/3 double knockouts. In addition, loss of cilia phenocopies the loss of Gli2 but not the Gli2/3 mutants. Our study reveals that Gli3 exerts activator and cilia-independent functions in the absence of Gli2.Bullet pointsEpidermal Gli2 and Gli3 together mediate Hedgehog signalling and are essential for proper appendage formationGli3 activator function compensates for the loss of Gli2 during HF morphogenesisGli2 controls HF stem cell sub-compartments and SG formationCilia mediate epidermal Gli2 but not Gli3 signalling in the skin epithelium
An amygdala-cortical circuit for encoding generalized fear memories
Authors: Vincent Carly J. , Aguilar-Alvarez Ricardo , Vanderhoof Samantha O. , Mott David D. , Jasnow Aaron M. 
Published: January 2025

AbstractGeneralized learning is a fundamental process observed across species, contexts, and sensory modalities that enables animals to use past experiences to adapt to changing conditions. Evidence suggests that the prefrontal cortex (PFC) extracts general features of an experience that can be used across multiple situations. The anterior cingulate cortex (ACC), a region of the PFC, is implicated in generalized fear responses to novel contexts. However, the ACC’s role in encoding contextual information is poorly understood, especially under increased threat intensity that promotes generalization. Here, we show that synaptic plasticity within the ACC and signaling from amygdala inputs during fear learning are necessary for generalized fear responses to novel encountered contexts. The ACC did not encode specific fear to the training context, suggesting this region extracts general features of a threatening experience rather than specific contextual information. Together with our previous work, our results demonstrate that generalized learning about threatening contexts is encoded, in part, within an ascending amygdala-cortical circuit, whereas descending ACC projections to the amygdala drive generalized fear responses during exposure to novel contexts. Our results further demonstrate that schematic learning can occur in the PFC after single-trial learning, a process typically attributed to learning over many repeated learning episodes.
GenVarLoader: An accelerated dataloader for applying deep learning to personalized genomics
Authors: Laub David , Ho Aaron , Jaureguy Jeff , Klie Adam , Salem Rany M. , McVicker Graham , Carter Hannah 
Published: January 2025

AbstractDeep learning sequence models trained on personalized genomics can improve variant effect prediction, however, applications of these models are limited by computational requirements for storing and reading large datasets. We address this with GenVarLoader, which stores personalized genomic data in new memory-mapped formats with optimal data locality to achieve ∼1,000x faster throughput and ∼2,000x better compression compared to existing alternatives.
Unified Measures Quantifying Intensity and Similarity of Pain and Somatosensory Percepts
Authors: Earley Eric J. , Ramne Malin , Wessberg Johan 
Published: January 2025

ABSTRACTAcross somatosensory and pain literature, there exist several methods of characterizing the location and extent of perceived sensations, and quantifying how these sensory maps may differ. However, these measures of somatosensory intensity and similarity can give non-unique results, creating challenges in literature review and meta-analysis across different methods. In this paper, we propose novel and unifying measures to quantify the similarity and intensity of pain maps and somatosensory percepts. These measures are generalizable and can be applied to any application of somatosensory maps, and are usable with both discretized and free-hand drawings in both 2D and 3D representations. Somatosensory Percept Intensity (SPI) is inspired by Piper’s Law, which describes the phenomenon of incomplete spatial summation wherein changes in pain area do not yield linearly proportional changes in perceived intensity. Somatosensory Percept Deviation (SPD) is derived from optimal transport theory, which quantifies differences between two probability distributions or somatosensory maps. Mathematical derivations for both measures are provided. The utility of these measures is demonstrated using data from two studies – one characterizing elicited somatosensory percepts, and one investigating neuropathic pain drawings. The proposed measures strongly agree with the validation studies, illustrating their potential as agnostic measures for characterizing somatosensory percepts in studies and meta-analyses. Ultimately, our work yields powerful unified measures for use in the fields of perception and pain, and may aid in improved pain characterization within healthcare, granting a better understanding of the needs and progression of patients experiencing pain.NEW & NOTEWORTHYWe propose novel and unifying measures to quantify the similarity and intensity of pain maps and somatosensory percepts. These measures are generalizable and applicable to any application of somatosensory maps, resulting in improved pain characterization within healthcare and better understanding of the needs and progression of patients experiencing pain.
Activation Metrics for Structural Connectivity Recruitment in Deep Brain Stimulation
Authors: Butenko Konstantin , Roediger Jan , Al-Fatly Bassam , Li Ningfei , Dembek Till A. , Yifei Gan , Guan-Yu Zhu , Jianguo Zhang , Kühn Andrea A. , Horn Andreas 
Published: January 2025

AbstractComparatively high excitability of myelinated fibers suggests that they represent a major mediator of deep brain stimulation effects. Such effects can be modeled using different levels of abstraction, ranging from simple electric field estimates to complex multicompartment axon models. In this study, we explore three approaches to estimate axonal activation: electric field magnitudes, electric field projections and (probabilistic) pathway activation modeling. Our aim is to describe these approaches and also illustrate their relevance. For that, we apply them to a clinical dataset of 15 Parkinson’s disease patients, who were stimulated in the subthalamic nucleus in bipolar mode. To make these approaches accessible for the community, necessary modeling and statistical processing was implemented in the openly available Lead-DBS toolbox.
Acute Respiratory Distress Syndrome in Adults: A Retrospective Analysis of Temperature Trends, Demographic Factors, and Clinical Outcomes from the eICU Collaborative Research Database
Authors: Al Mahrizi Ahmed Dawood , Ezenwanne Charles , Mossolem Fatima , Valladares Carlos , Gill Harman , Boyle Matthew 
Published: January 2025

AbstractBackgroundAcute Respiratory Distress Syndrome is characterized by the sudden onset of hypoxemia, reduced lung compliance, and bilateral pulmonary infiltrates. We investigated patient demographics and clinical predictors of outcomes in adult patients with ARDS.MethodsWe conducted a retrospective multi-center intensive care unit database study using the eICU Collaborative Research Database (eICU-CRD). The Analysis included 304 patients with ARDS who met all inclusion criteria, including key demographic variables. We Assessed associations between these variables and outcomes, including mortality and length of stay (LoS).ResultsFor each year of increased age, odds of mortality decreased by 4.7% (OR = 0.953, p < 0.001). Higher temperatures were associated with reduced mortality (OR=0.470, p=0.003). Gender (p = 0.596) and BMI (p = 0.964) were not significant predictors of mortality. A multiple linear regression model for predicting ICU length of stay was statistically significant at explaining the variance compared to the null model. High temperatures (β = 0.981, p = 0.015) and low temperatures (β = -1.038, p = 0.006) were significant predictors of LoS, while gender and BMI were not. There was significant association between ethnicity and hospital discharge status (χ2(5) = 13.123, p = 0.022), which suggests disparities in outcomes across ethnic groups.ConclusionOur study suggests that increasing age and higher temperatures may serve as protective factors, contrary to the popular belief of age-increasing fragility. Analysis also found that gender and BMI do not affect patient LoS nor mortality. These findings suggest clinicians should consider a patient’s age and core body temperature when assessing risk of mortality and prognosis, placing less emphasis on BMI and gender.
Standardized Measurement of Type 1 Diabetes Polygenic Risk Across Multi-Ancestry Population Cohorts
Authors: Luckett Amber M. , Oram Richard A. , Deutsch Aaron J. , Ortega Hector I , Fraser Diane P. , Ashok Kaavya , Manning Alisa K. , Mercader Josep M. , Rivas Manuel , Udler Miriam S. , Weedon Michael N , Gloyn Anna L. , Sharp Seth A. 
Published: January 2025

AbstractType 1 diabetes (T1D) polygenic risk scores (PRS) are effective tools for discriminating T1D from other diabetes types and predicting T1D risk, with applications in screening and intervention trials. A previously published T1D Genetic Risk Score 2 (GRS2) is widely adopted, but challenges in standardization and accessibility have hindered broader clinical and research utility. To address this, we introduce GRS2x, a standardized and cross- compatible method for accurate T1D PRS calculation, demonstrating genotyping and reference panel independent performance across diverse datasets. GRS2x as a unified approach facilitates accessible and portable measurement of T1D polygenic risk.
Rad5 and Telomere Replication
Authors: Mattarocci Stefano 
Published: January 2025

AbstractThe DNA Damage Tolerance pathway (DDT) is one of the major mechanisms for resolving replication fork blocks. A central factor for DDT is the fork-associated clamp, PCNA, which can undergo to mono- or polyubiquitination, leading to error-free or error-prone modes of repair, respectively. The Rad5 protein in the yeastSaccharomyces cerevisiaeplays important roles in both pathways: promoting the error-free mode by PCNA polyubiquitination and interacting with specialized DNA polymerases involved in the error-prone pathway. Rad5 also associates with telomeres, the repetitive DNA regions present at the ends of chromosomes. Telomeric DNA, tightly bound by tandem proteins arrays, poses unique challenges to replication fork progression. Here, I review the current understanding of the link between Rad5 and telomeres and present evidence that Rad5 is associated with yeast telomeres, with notable enrichment during telomere replication. This data highlights a connection between telomeres and a key DDT factor in unperturbed wild-type cells, raising intriguing possibilities about the functional interplay between telomere replication and DNA damage tolerance mechanisms.