Biology subjects

White, O.

Publications and source records attributed to White, O..

At least 19 recordsLinked to original sources

bioRxiv2026

Cytokine-induced nuclear translocation of STAT1 via a non-transferable NLS

The targeting function of nuclear localization signals (NLSs) is generally considered independent of a protein's native sequence or fold and is readily transferable to heterologous cargos. Contrary to this paradigm, rapid nuclear translocation of phosphorylated STAT1 (pSTAT1) following cytokine stimulation requires importin {beta}, Ran-GTP, and the importin 5 isoform, which recognizes a non-transferable NLS. Here, we present cryo-EM structures of pSTAT1 bound to importin 5, revealing an asymmetric 2:1 complex that diverges from canonical NLS-mediated cargo recognition. Importin 5 occupies the DNA-binding groove of the pSTAT1 dimer, with a single STAT1 N-terminal domain positioning the C-terminal Armadillo repeats 9-10 (S1B domain) orthogonal to the DNA-binding interface. This interface is also targeted by the Ebola virus protein VP24, an antagonist of interferon signaling. We further show that Ran-GTP alone is insufficient to trigger nuclear release of pSTAT1, which additionally requires the exportin CAS. A cryo-EM reconstruction of the CAS-Ran-GTP-5 complex, supported by in vitro competition assays, demonstrates that CAS and pSTAT1 are mutually exclusive ligands for importin 5. Together, these findings define the molecular choreography of cytokine-induced STAT1 nuclear translocation and release, establishing a general paradigm for STAT family signaling.

biochemistry↗

bioRxiv2026

Grip Force Complexity Under Constraint: Evidence from Fractal and Entropy Analyses

The present study investigates how grip force (GF) and load force (LF) dynamics reorganize under varying task constraints, focusing on the fractal and entropic properties of motor output. Twenty healthy adults performed precision grip tasks across five force conditions: two spontaneous conditions (pre, post) without visual feedback and three target-driven conditions (natural, -10%, +10% of natural). The temporal and informational structure of GF and LF signals were quantified using the Hurst exponent (H) and Sample Entropy (SampEn), capturing long-range temporal organization and local irregularity. Constrained conditions reduced GF coefficient of variation but increased both H and SampEn relative to spontaneous pre-trials, while LF indices remained largely unchanged. Thus, grip control under constraint became more temporally persistent and locally irregular, suggesting a more structured temporal organization rather than a simple loss of complexity. Intra-trial analyses further revealed an increase in H from the first to the second half of spontaneous trials, consistent with progressive self-organization in the absence of explicit constraints. Across conditions, H and SampEn were positively correlated for both GF and LF, suggesting that predictability and complexity are not necessarily inversely related in this context. Overall, these findings suggest that the human motor system adapts to force constraints not by suppressing variability, but by reorganizing it across scales, combining temporal persistence with local flexibility. This multidimensional characterization of variability may help refine theoretical models of optimal movement variability and may inform clinical or training approaches aimed at assessing or enhancing neuromotor adaptability.

neuroscience↗

bioRxiv2026

A layered standards framework for integrating single-cell and spatial omics data into brain cell atlases

The BRAIN Initiative Cell Atlas Network (BICAN) is generating large-scale multimodal datasets to profile cell types in the human, non-human primate, and mouse brain. The diversity of single-cell and spatial transcriptomic and epigenomic assays, combined with varied experimental contexts, multiple data-generating laboratories and distributed infrastructure, poses substantial challenges for data integration and reuse in BICAN. To address this, we implemented a standards framework that enables layered integration of these data into knowledge-ready products for interoperable brain cell atlases. This framework organizes data based on three progressively structured layers. First, we introduced an assay-agnostic modeling layer that unifies the representation of single-cell and spatial omics data using a common set of biological entities and processes assessed by diverse experimental techniques. Second, we implemented harmonized metadata standards that capture key experimental features linked to biospecimen provenance across heterogeneous tissue sources, species, and preparations, supporting integration and validation while minimizing burden on data contributors. Third, we present an extensible representation for data-driven cell type taxonomies that integrates molecular data with annotations, ontology mappings, and evidence. Together, these contributions represent an end-to-end framework that transforms heterogeneous datasets into structured, interoperable resources that support broad community reuse via mapping algorithms, annotation systems, and visualization platforms. This approach links biospecimen provenance with cell-level outputs and embeds these in a standardized taxonomy format, enabling downstream applications such as cross-dataset integration, reference mapping, and knowledge-driven analysis. More broadly, our work demonstrates a generalizable strategy for enabling an efficient data-to-knowledge pipeline in a large-scale consortium setting.

genomics↗

bioRxiv2026

A Community Standard Multispecies Cell Atlas of the Basal Ganglia

The NIH BRAIN Initiative Cell Atlas Network (BICAN) aims to generate a standardized, integrated cell atlas of the human, macaque, marmoset, and mouse brain that serves as a foundational community reference for the classification and study of brain cell types. Here we present the first major component of this effort: a cross-species, multimodal atlas of the basal ganglia, a group of subcortical nuclei central to motor control and implicated in a broad range of neurological disorders. Grounded in large-scale single-cell transcriptomic classification and integrated with epigenomic and spatial genomic modalities, this resource is enabled by coordinated cross-species sampling and harmonized analytical frameworks. It provides extensive phenotypic characterization of cell types, incorporates community-informed annotation, and establishes a highly curated, data-driven taxonomy with standardized nomenclature. The atlas is anchored to species-specific anatomical reference frameworks and linked across species through unified structural ontologies, enabling consistent cross-species comparisons. Multiple complementary datasets are mapped to this reference, including multiomic profiles and developmental trajectories aligned to adult cell states. Realization of this resource has required coordinated standards for tissue processing across human and model organisms, harmonization of donor metadata across brain banks, and the development of unified anatomical reference systems. To support these advances, BICAN has established an integrated ecosystem comprising standardized sequencing pipelines, neuroanatomically grounded data infrastructure, scalable visualization and mapping tools, and interoperable metadata standards. Analogous to the standardization achieved in genome science, this ecosystem provides a FAIR (findable, accessible, interoperable, and reusable) framework that enables researchers to map, compare, and interpret diverse datasets against a shared reference and associated knowledge base. The BICAN reference system is now being extended to the whole brain, with principles that are readily generalizable to other organ systems.

neuroscience↗

bioRxiv2025

Integrative analysis of genomic and transcriptomic data informs precancer progression in the pancreas

Pancreatic ductal adenocarcinoma (PDAC) arises from heterogeneous precursor lesions, including intraductal papillary mucinous neoplasms (IPMNs), but the features distinguishing indolent from progressive lesions remain unclear. We performed an integrative analysis of transcriptomic, genomic, and microenvironmental profiles of IPMNs to define multi-omic phenotypes. Using transfer learning, we projected IPMN-derived transcriptional programs onto spatial transcriptomic datasets from IPMNs and pancreatic intraepithelial neoplasias (PanINs). We identified two major phenotypes: one associated with cancer-associated fibroblasts and epithelial-to-mesenchymal transition, shared across IPMN, PanIN, and PDAC; and a second, glycolysis-enriched phenotype with a unique somatic mutation profile specific to IPMN. Spatial mapping further revealed grade-specific enrichment of transcriptional programs and distinct interactions with stromal and immune subtypes, underscoring the role of the precancer microenvironment in progression. These findings establish multi-omic phenotypes that unify genetic, transcriptional, and microenvironmental heterogeneity, providing a framework for distinguishing progressive from indolent precancers and a web-based public atlas for future exploration of these data and transcriptional phenotypes.

bioinformatics↗

bioRxiv2025

Endothelial lipase facilitates low-density lipoprotein (LDL) uptake in LDL receptor deficiency by a heparan sulfate proteoglycan-dependent mechanism.

Current lipid-lowering drugs are relatively ineffective in reducing low-density lipoprotein (LDL) cholesterol in patients with Familial Hypercholesterolemia (FH) due to a dysfunctional LDL receptor (LDLR). However, LDL cholesterol reductions have been achieved in FH patients using angiopoietin-like 3 (ANGPTL3) inhibitors, which act through an uncharacterized, LDLR-independent pathway that requires endothelial lipase (EL). Here, we aim to investigate ELs direct role in LDLR-independent uptake of LDL in hepatocytes. Control and LDLR-KO HepG2 cells were transfected with an empty plasmid or a plasmid encoding the human LIPG gene, and the cellular uptake of fluorescent human LDL was measured by FACS. To test the contribution of heparan sulfate proteoglycans (HSPG), LDL uptake was assessed with and without the pre-incubation with heparin or a heparinase cocktail. Finally, tetrahydrolipstatin was used to inhibit EL enzymatic activity in uptake studies. Unsurprisingly, LDLR-KO HepG2 cells showed an 80% reduction in LDL uptake compared to controls (p<0.001). Remarkably, EL overexpression almost fully rescued LDL uptake in LDLR-KO cells (p<0.001), without effects in control cells. EL-mediated LDL uptake was completely blocked by heparinases and heparin in LDLR-KO cells, suggesting a crucial role of HSPG in EL-mediated LDL uptake. Notably, treatment with tetrahydrolipstatin reduced LDL uptake in EL-overexpressing LDLR-KO cells (p=0.0015). Our data reveals that EL facilitates the uptake of LDL in hepatocytes through an LDLR-independent, HSPG-dependent pathway that involves ELs enzymatic activity. This pathway provides an additional mechanism to explain the reduction of LDL cholesterol induced by ANGPTL3 inhibitors and represents a potential druggable target to treat FH.

physiology↗

bioRxiv2023

Metabolism-focused CRISPR screen unveils Mitochondrial Pyruvate Carrier 1 as a critical driver for PARP inhibitor resistance in lung cancer

Homologous recombination (HR) and poly ADP-ribosylation are partially redundant pathways for repair of DNA damage in normal and cancer cells. In cell lines that are deficient in HR, inhibition of poly (ADP-ribose) polymerase (PARP1/2) is a proven target with several PARP inhibitors (PARPi) currently in clinical use. Resistance to PARP inhibitors often develops, usually involving genetic alterations in DNA repair signaling cascades, but also metabolic rewiring particularly in HR-proficient cells. PARP1/2 utilize NAD+ (nicotinamide adenine dinucleotide), an essential substrate not only for PARPs but also for multiple pathways in cellular metabolism, TCA cycle and mitochondrial functions. Thus, NAD+ is central to many key cellular functions. Both activation of PARPs by DNA damage and their inhibition by drugs such as olaparib affect NAD+ consumption. We surmised that alterations in NAD+ metabolism by cancer drugs such as Olaparib might be involved in the development of resistance to drug therapy. To test this hypothesis, we conducted a metabolism-focused CRISPR knockout (KO) screen to identify genes which undergo alterations during treatment of tumor cells with PARP inhibitors. Of about 3000 genes in the screen, our data revealed that mitochondrial pyruvate carrier 1 (MPC1) is an essential factor in desensitizing NSCLC lung cancer lines to PARP inhibition. In contrast to NSCLC lung cancer cells, triple negative breast cancer cells do not exhibit such desensitization following MPC1 loss and reprogram the TCA cycle and oxidative phosphorylation pathways to overcome PARP inhibitor treatment. Our findings unveil a previously unknown synergistic response between MPC1 loss and PARP inhibition in lung cancer cells.

cancer biology↗

bioRxiv2023

go_batch: A snakemake pipeline to assemble mitochondrial and ribosomal sequences from genome skims

Low coverage "genome-skims" are often used to assemble organelle genomes and ribosomal gene sequences for cost effective phylogenetic and barcoding studies. Natural history collections hold invaluable biological information, yet poor preservation resulting in degraded DNA often hinders PCR based analyses. However, with improvements to molecular techniques and sequencing technology, it is possible to use methods developed for working with ancient DNA to generate libraries and sequence the short fragments typical of degraded DNA to generate genome skims from museum collections. Here we introduce a snakemake toolkit comprised of three pipelines skim2mt, skim2rrna and gene2phylo, designed to unlock the genomic potential of historical museum specimens using genome skimming. Specifically, skim2mt and skim2rrna perform the batch assembly, annotation and phylogenetic analysis of mitochondrial genomes and nuclear ribosomal genes, respectively, from low-coverage genome skims. The third pipeline gene2phylo takes a set of gene alignments and performs phylogenetic analysis of individual genes, partitioned analysis of concatenated alignments and a phylogenetic analysis based on gene trees. We benchmark our pipelines with simulated data, followed by testing with a novel genome skimming dataset from both recent and historical solariellid gastropod samples. We show that the toolkit can recover mitochondrial and ribosomal genes from poorly preserved museum specimens of the gastropod family Solariellidae. In addition, the phylogenetic analysis of multiple gene sequences is consistent with our current understanding of taxonomic relationships. The generation of bioinformatic pipelines that facilitate processing large quantities of sequence data from the vast repository of specimens held in natural history museum collections will greatly aid species discovery and exploration of biodiversity over time, ultimately aiding conservation efforts in the face of a changing planet.

bioinformatics↗

bioRxiv2023

Exome capture of Antarctic krill (Euphausia superba) for cost effective population genetics of historical collections

Antarctic Krill (Euphausia superba) is a pivotal keystone species in the Southern Ocean ecosystem, with immense ecological and commercial significance. However, its vulnerability to climate change necessitates urgent investigation of its population genetics and adaptive responses. Historical spirit collections of Antarctic krill from the early 20th century represent an ideal opportunity for genomic research, to investigate how krill have changed over time and been impacted by predation, fishing and climate change. In this study, we assessed the utility of shotgun sequencing and exome capture for genomic analyses with historical spirit collections of Antarctic krill. Because the krill genome is very large (48Gb) two full-length transcriptomes were generated and used to identify putative targets for targeted resequencing. Skim genome sequencing allowed sample and library quality control. By comparing genome to exome resequencing of the same libraries we calculate enrichment and variant calling metrics. Full-length mitochondrial and nuclear ribosomal sequences were successfully assembled from genomic data demonstrating that endogenous DNA sequences could be assembled from historical collections. We find that exome capture provided enrichment of on-target sequence data, with increased depth and higher variant quality for targeted loci. Our findings demonstrate the feasibility of extracting genomic information from historical krill samples, despite the challenges of fragmented DNA and huge genome size unlocking such collections to provide valuable insights into past and present krill diversity, resilience, and adaptability to climate change. This approach unlocks the potential for broader genomic studies in similar samples, and for enhancing conservation efforts and fisheries management in the Southern Ocean ecosystem.

genomics↗

bioRxiv2022

The BRAIN Initiative Cell Census Data Ecosystem: A User's Guide

Characterizing cellular diversity at different levels of biological organization across data modalities is a prerequisite to understanding the function of cell types in the brain. Classification of neurons is also required to manipulate cell types in controlled ways, and to understand their variation and vulnerability in brain disorders. The BRAIN Initiative Cell Census Network (BICCN) is an integrated network of data generating centers, data archives and data standards developers, with the goal of systematic multimodal brain cell type profiling and characterization. Emphasis of the BICCN is on the whole mouse brain and demonstration of prototypes for human and non-human primate (NHP) brains. Here, we provide a guide to the cellular and spatial approaches employed, and to accessing and using the BICCN data and its extensive resources, including the BRAIN Cell Data Center (BCDC) which serves to manage and integrate data across the ecosystem. We illustrate the power of the BICCN data ecosystem through vignettes highlighting several BICCN analysis and visualization tools. Finally, we present emerging standards that have been developed or adopted by the BICCN toward FAIR (Wilkinson et al. 2016a) neuroscience. The combined BICCN ecosystem provides a comprehensive resource for the exploration and analysis of cell types in the brain.

bioinformatics↗

bioRxiv2022

Time-of-day effects on motor learning

While the time-of-day significantly impacts motor performance, its effect on motor learning has not yet been elucidated. Here, we investigated the influence of the time-of-day on skill acquisition (i.e., skill improvement immediately after a training-session) and consolidation (i.e., skill retention after a time interval). Three groups were trained at 10 a.m. (G10am), 3 p.m. (G3pm), or 8 p.m. (G8pm) on a finger-tapping task. We recorded the skill (i.e. the ratio between movement duration and accuracy), before and immediately after the training to evaluate skill acquisition, and after 24 hours, to measure skill consolidation. We did not observe any difference in acquisition according to the time of the day. However, we found an improvement in performance 24 hours after the evening training (G8pm) while the morning (G10am) and the afternoon (G3pm) groups deteriorated and stabilized their performance, respectively. Furthermore, two control experiments (G8wake and G8sleep) supported the idea that a night of sleep contributes to the skill consolidation of the evening group. These results show an influence of time-of-day on the consolidation process, with better consolidation when the training is carried out in the evening. This finding may have an important impact on the planning of training programs in sports, clinical, or experimental domains.

neuroscience↗

bioRxiv2021

Making Common Fund data more Findable: Catalyzing a Data Ecosystem

The Common Fund Data Ecosystem (CFDE) has created a flexible system of data federation that enables users to discover datasets from across the U.S. National Institutes of Health Common Fund without requiring that data owners move, reformat, or rehost those data. The CFDEs federation system is centered on a catalog that ingests metadata from individual Common Fund Programs Data Coordination Centers (DCCs) into a uniform metadata model that can then be indexed and searched from a centralized portal. This uniform Crosscut Metadata Model (C2M2) supports the wide variety of data types and metadata terms used by the individual DCCs and is designed to enable easy expansion to accommodate new data types. We describe its use to ingest and index data from ten DCCs.

bioinformatics↗

bioRxiv2020

gEAR: gene Expression Analysis Resource portal for community-driven, multi-omic data exploration

The gEAR portal (gene Expression Analysis Resource, umgear.org) is an open access community-driven tool for multi-omic and multi-species data visualization, analysis and sharing. The gEAR supports visualization of multiple RNA-seq data types (bulk, sorted, single cell/nucleus) and epigenomics data, from multiple species, time points and tissues in a single-page, user-friendly browsable format. An integrated scRNA-seq workbench provides access to raw data of scRNA-seq datasets for de novo analysis, as well as marker-gene and cluster comparisons of pre-assigned clusters. Users can upload, view, analyze and privately share their own data in the context of previously published datasets. Short, permanent URLs can be generated for dissemination of individual or collections of datasets in published manuscripts. While the gEAR is currently curated for auditory research with over 90 high-value datasets organized in thematic profiles, the gEAR also supports the BRAIN initiative (via nemoanalytics.org) and is easily adaptable for other research domains.

bioinformatics↗

bioRxiv2020

The Distribution of Enset Pests and Pathogens and a Genomic Survey of Enset Xanthomonas Wilt

Mapping the distribution of crop pests and pathogens is essential to safeguard food security and sustainable livelihoods. However, these data are unavailable for many neglected and underutilised crops, particularly in developing countries. In Ethiopia, the worlds largest historic recipient of food aid, the indigenous banana relative enset (Ensete ventricosum) is threatened by multiple pests and pathogens whilst providing the staple starch source for 20 million people. Foremost among these is Xanthomonas Wilt of enset (EXW), caused by Xanthomonas vasicola pv. musacearum (Xvm), a globally important disease of bananas (Musa sp.) that likely originated in enset. Here we collate 1069 farm surveys to map the distribution and relative prevalence of enset pests and pathogens across the entire enset growing region. We find that EXW is the most frequently encountered pathogen, and that farmers consistently ranked EXW as the most significant constraint on enset agriculture. Our surveys also showed that corm rot, and the pests root mealybug, mole rat and porcupine are all virtually ubiquitous. Finally, we apply genotyping-by-sequencing to the detection of Xvm and demonstrate that it is present even in asymptomatic domesticated and wild enset samples, suggesting that management of plants displaying symptoms alone may not be sufficient to reduce disease transmission. Holistic understanding of pests and pathogen distributions in enset may have significant benefits for both food security in Ethiopia, and preventing proliferation in related crops such as banana across central and east Africa.

ecology↗

bioRxiv2020

Germination ecology of wild and domesticated Ensete ventricosum: Evidence for maintenance of sexual reproductive capacity in a vegetatively propagated perennial crop

O_LILoss of sexual reproductive capacity has been proposed as a syndrome of domestication in vegetatively propagated crops, but there are relatively few examples from agricultural systems. In this study we compare sexual reproductive capacity in wild (sexual) and domesticated (vegetative) populations of enset (Ensete ventricosum (Welw.) Cheesman), a tropical banana relative and Ethiopian food security crop. C_LIO_LIWe examined floral and seed morphology and germination ecology across 35 wild and domesticated enset. We surveyed variation in floral and seed traits, including seed weight, viability and internal morphology, and germinated seeds across a range of constant and alternating temperature regimes to characterise optimum germination requirements. C_LIO_LIWe report highly consistent floral allometry, seed viability, internal morphology and days to germination in wild and domesticated enset. However, seeds from domesticated plants responded to cooler temperatures with greater diurnal range. Shifts in germination behaviour appear concordant with a climatic envelope shift in the domesticated distribution. C_LIO_LIOur findings provide evidence that sexual reproductive capacity has been maintained despite long-term near-exclusive vegetative propagation in domesticated enset. Furthermore, certain traits such as germination behaviour and floral morphology, may be under continued selection, presumably through rare sexually reproductive events. Compared to sexually propagated crops banked as seeds, vegetative crop diversity is typically conserved in living collections that are more costly and insecure. Improved understanding of sexual propagation in vegetative crops may have applications in germplasm conservation and plant breeding. C_LI

ecology↗

bioRxiv2020

Visuo-motor rotation influences representational acuity but not space representation

Prism adaptation is a well-known experimental procedure to study sensorimotor plasticity. It has been shown that following prism exposure, after-effects are not only restricted to the sensorimotor level but extend as well to spatial cognition. In the present study, we used a visuo-motor rotation task which approaches the perturbations induced by prism exposure. We induced either leftward or rightward 15-degree rotations and we presented the perturbation either abruptly (from one trial to the next) or gradually (over a 34-trial transition). First, we found that none of the conditions produced cognitive after-effects in perceptive line bisection task. This result has a strong methodological impact for prospective investigations focusing on sensorimotor plasticity while sparing space cognition; it is particularly relevant when investigating sensorimotor plasticity in patients with specific representational feature to preserve from aggravation. Second, another interesting result was the increase of the sensitivity with which we discriminate the center of the line, that we propose to call representational acuity. It improved following the perturbation more particularly after gradual exposure and persisted for some time after the sensorimotor adaptation. These innovative results are discussed in terms of sensorimotor processes underpinning the transfer of visuomotor plasticity to spatial cognition.

neuroscience↗

bioRxiv2019

Adiabatic invariants drive rhythmic human motion in variable gravity

Natural human movements are stereotyped. They minimise cost functions that include energy, a natural candidate from mechanical and physiological points of view. In time-changing environments, however, motor strategies are modified since energy is no longer conserved. Adiabatic invariants are relevant observables in such cases, although they have not been investigated in human motor control so far. We fill this gap and show that the theory of adiabatic invariants explains how humans move when gravity varies.

biophysics↗

bioRxiv2019

Gravity highlights a dual role of the insula in internal models

Movements rely on a mixture of predictive and reactive mechanisms. With experience, the brain builds internal representations of actions in different contexts. Many factors are taken into account in this process among which the immutable presence of gravity. Any displacement of a massive body in the gravitational field generates forces and torques that must be predicted and compensated by appropriate motor commands. Studies have shown that the insular cortex is a key brain area for graviception. However, none attempted to address whether the same internal representation of gravity is shared between reactive and predictive mechanisms. Here, participants either mentally simulated (only predictive) or performed (predictive and reactive) vertical movements of the hand. We found that the posterior part of the insular cortex was engaged when feedback was processed. The anterior insula, however, was activated only in mental simulation of the action. A psychophysical experiment shows participants ability to integrate the effects of gravity. Our results demonstrate a dual internal representation of gravity within the insula and discuss how they can conceptually be linked.

neuroscience↗