Biology subjects

White, T.

Publications and source records attributed to White, T..

At least 19 recordsLinked to original sources

bioRxiv2026

Developmental Convergence Across Diverse Genetic Architectures in Childhood Apraxia of Speech

Childhood apraxia of speech (CAS) is a neurodevelopmental disorder of speech-motor planning and programming, associated with literacy, academic, and psychosocial difficulties. We performed whole-exome sequencing in 11 families comprising 21 affected and 15 unaffected individuals with phenotyping spanning speech, language, cognition, literacy, and motor function. We identified 60 prioritized variant observations representing 22 unique variants across 20 genes with family-based segregation analysis assessed in informative relatives; 5 arose de novo. Our cohort included multiple affected siblings and extended relatives, with several families carrying multiple prioritized variants, suggesting cumulative or oligogenic susceptibility. Speech and literacy impairment co-occurred with oral-motor, feeding, and fine-motor difficulties. BrainSpan co-expression analysis identified MECP2 and ANK2 as the genes with the highest observed connectivity in the sampled postnatal network. Exploratory analysis of the KOLF2.1J perturbation atlas in undifferentiated human induced pluripotent stem cells identified a positive LMO3 expression-response score following NIPBL repression and opposing LMO3 and ANK2 response directions within a cohesin-associated perturbation cluster. These observations motivate testing in human neural cells. Functional enrichment, protein-association, and developmental-expression analyses supported shared biological themes involving chromatin regulation, neuronal signaling, and extracellular-matrix organization. Among six families, multiple affected relatives shared prioritized variants across a unique set of several genes, demonstrating multilocus candidate profiles whose individual and combined effects may contribute to CAS susceptibility. We propose four novel CAS candidate genes: LMO3 and PCDH10, previously linked to human accelerated regions, as well as MYCBP2 and PTPRS. Our work provides multiple testable hypotheses for future variant-specific functional validation in speech-motor development.

genetics↗

bioRxiv2026

The Vagus Nerve conducts viable translocation of gut flora to the lungs that impacts interstitial lung disease severity in mice

Communication between gut microbiota and extraintestinal organs is increasingly recognized, yet elucidation of relevant translocation mechanism(s) remains enigmatic. Vagus neuroanatomy and reports of vagal protein transfer to extraintestinal organs suggest that this "superhighway" could translocate bacteria. Here we explore whether the vagus superhighway can translocate bacteria to extraintestinal organs. Gavage of green fluorescent protein-expressing Escherichia coli (GFP-E. coli) into germ-free (GF) or specific-pathogen free (SPF) C57BL/6 mice yielded high bacillary loads in the stomach and lungs, followed by the heart, stool and peripheral muscles, despite negative blood cultures. Notably, confocal microscopy and culture revealed GFP-E. coli within the vagus nerve within five minutes of gavage suggesting rapid translocation. Metagenomic analysis of stool, lung, heart, vagus nerve, and muscle from non-gavaged SPF mice demonstrated significant microbial overlap, supporting that bacterial translocation occurs despite the presence of endogenous microflora. Remarkably, subdiaphragmatic vagotomy performed prior to GFP-E. coli gavage resulted in marked reductions of bacterial transduction in the lungs and other extraintestinal organs, except muscle. Furthermore, vagotomy significantly reduced lung fibrosis in SPF mice following intranasal bleomycin administration. In lung cancer patients undergoing lobectomy, vagotomy inhibited postsurgical reductions in forced vital capacity. These findings identify the vagus nerve as a literal gut-lung axis, facilitating viable bacterial translocation and influencing lung severity.

microbiology↗

bioRxiv2025

A biphasic metabolism-β-lactamase production landscape governs the inoculum effect in β-lactamase-expressing Escherichia coli.

The inoculum effect (IE) reduces antibiotic efficacy in vitro and in clinical settings, yet remains difficult to predict. IE limits antibiotic efficacy but remains unpredictable, particularly in resistant bacteria, where resistance mechanisms and bacterial physiology interact in poorly understood ways. Using Escherichia coli expressing the NDM-1 {beta}-lactamase and clinical isolates, we quantified metabolism, growth rate, {beta}-lactamase expression, and IE across diverse growth environments. Across enzyme classes, antibiotics, and clinical isolates, we find that IE is governed by a conserved, biphasic dependence on metabolism normalized by growth rate. Mathematical modeling shows that this behavior reflects a tradeoff between {beta}lactamasemediated protection and metabolismpotentiated antibiotic lethality. These findings establish a predictive, physiology-based framework for IE in resistant bacteria and explain why resistance determinants alone fail to predict treatment outcomes across environments, including the clinic. Significance StatementAntibiotic efficacy depends on both bacterial resistance and physiology, yet these factors are rarely integrated when predicting treatment outcomes. One important consequence of their interaction is the inoculum effect (IE), in which antibiotic efficacy depends on the density of a resistant bacterial population. Here, we show that IE in {beta}lactamase-expressing bacteria is governed by a conserved physiological tradeoff between metabolism and growth. Across growth environments, antibiotics, inocula, and clinical isolates, IE is strongest at intermediate metabolic states, reflecting a balance between resistancemediated protection and metabolismpotentiated antibiotic lethality. This framework helps explain why resistance determinants alone are insufficient to account for IE and underscores the role of bacterial physiology in shaping antibiotic responses.

microbiology↗

bioRxiv2025

A Novel Rotation-Mitigation Technology for Cycling HelmetsTested Across Helmet Types, Impact Locations and Headforms

Head rotation is the leading cause of diffuse brain injuries from cycling accidents, with severe, long-term or even fatal consequences. Here, we present a novel helmet safety technology, the Release Layer System (RLS), designed to enhance conventional helmets and reduce the likelihood of such injuries. RLS is located on the outer side of the helmet and thus gets impacted first. The force of the impact activates a rolling mechanism triggering the release of an outer polycarbonate panel, thereby dispersing and transforming a substantial portion of the incident rotational energy. To evaluate the effectiveness of the technology, we conducted oblique impact tests on three popular helmet types, in conventional and RLS-equipped configurations, at three impact locations. RLS-equipped helmets reduced Peak Angular Velocity (PAV) by 57-66%, averaged across impact locations, compared to their conventional counterparts. This corresponds to a 68-86% reduction in the probability of an AIS2+ brain injury, as estimated by the Brain Injury Criterion. The most notable improvement was observed at the pYrot location (front impacts, mid-sagittal plane) with up to 85% PAV reduction. Testing across headforms further demonstrated the effectiveness of the technology in mitigating head rotation irrespective of variations in evaluation setups. This work introduces a novel mechanism for rotational impact mitigation and provides evidence of its potential benefits compared with conventional helmets. As an outer-layer approach, RLS may offer an alternative pathway for managing rotational kinematics in future helmet designs.

bioengineering↗

bioRxiv2025

Poldip2 deficiency attenuates disease severity in a mouse model of COVID-19

The lungs are the primary target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2), with the infection resulting in lung inflammation, pulmonary vascular leakage and diffuse alveolar damage. Polymerase delta-interacting protein-2 (Poldip2) mediates lung inflammation and vascular permeability after lipopolysaccharide-induced acute respiratory distress syndrome; however, its role in regulating lung permeability, vascular inflammation and tissue damage following SARS-CoV-2 infection is completely unknown. Here, we assessed the role of Poldip2 in inflammation, immune cell infiltration and lung tissue damage in response to SARS-CoV-2 infection. Our data shows that while deletion of Poldip2 does not affect the susceptibility to SARS- CoV-2 infection, mice heterozygous for Poldip2 exhibit reduced lung tissue damage, reduced cytokine and chemokine induction and decreased infiltration of myeloperoxidase (MPO)-positive neutrophils into inflamed lung tissue. These data reveal that Poldip2 depletion mitigates inflammation and immune cell infiltration following SARS-CoV-2 infection, highlighting the therapeutic potential of Poldip2 inhibition to attenuate severe lung injury.

pathology↗

bioRxiv2024

Unique cuticular morphology of a truly marine insect, Echinophthirius horridus von Olfers, 1816 (Phthiraptera: Echinophthiriidae)

Echinophthiriidae is a family of aquatic lice parasitizing aquatic carnivorans, each member distinguished by their uniquely modified, curved setae. Echinophthirius horridus is known to parasitize a wide range of phocid (earless) seals as opposed to exhibiting the more species-specific parasitism of other echinophthiriid lice. In this study, we use a combination of bright field microscopy, confocal laser scanning microscopy (CLSM), and line drawings to provide a detailed description of the general body setae of E. horridus and discuss its possible significance as an adaptation to a marine lifestyle.

physiology↗

bioRxiv2024

Cell-derived matrices mechanics as a functional read-out in Collagen VI-related Congenital Muscular Dystrophies

Atomic force microscopy-force spectroscopy (AFM-FS) applied to biological samples can provide information on the micro- and nanoscale mechanical properties of tissues, which are a determinant of cellular behavior. Mechanical properties are largely determined by the structure and composition of the extracellular matrix (ECM), for which several in vitro models have been developed, including cell-derived matrices (CDMs). CDMs are decellularized natural ECMs assembled by cells, that closely mimic the in vivo stromal fiber organization and molecular content. Here we applied AFM-FS to evaluate the nanomechanical properties of CDMs obtained from primary skin fibroblast cultures of patients affected by collagen VI-related congenital muscular dystrophies (COL6-RDs). COL6-RDs are a set of neuromuscular conditions caused by pathogenic variants in any of the three major COL6 genes, which result in deficiency or dysfunction of the COL6 incorporated into the ECM of connective tissues. Current diagnosis includes the genetic confirmation of the disease and categorization of the phenotype based on maximum motor ability, as no direct correlation exists between genotype and phenotype of COL6-RDs. The development of new tools able to identify phenotype traits can significantly contribute to the diagnosis and prognosis of COL6-RDs. We describe differences in the elastic modulus (E) among CDMs deriving from patients with different clinical phenotypes, as well as the restoration of E in CDMs obtained from genetically edited cells. Results anticipate the potential of the nanomechanical analysis of CDMs as a complementary clinical tool, providing phenotypic information about COL6-RDs and their response to gene therapies.

biophysics↗

bioRxiv2024

In vivo antibody labeling route and fluorophore dictate labeling efficiency, sensitivity, and longevity

Leukocytes migrate through the blood and extravasate into organs to surveil the host for infection or cancer. Recently, we demonstrated that intravenous (IV) anti-CD45.2 antibody labeling allowed for precise tracking of leukocyte migration. However, the narrow labeling window can make this approach challenging for tracking rare migration events. Here, we show that altering antibody administration route and fluorophore can significantly extend the antibody active labeling time. We found that while both IV and intraperitoneal (IP) anti-CD45.2 antibody labeled circulating leukocytes after injection, they had different kinetic properties that impacted labeling time and intensity. Quantification of circulating antibody revealed that while unbound IV anti-CD45.2 antibody rapidly decreased, unbound IP anti-CD45.2 antibody increased over one hour. Using in vitro and in vivo serial dilution assays, we found that Alexa Fluor 647 (AF647) and Brilliant Blue 700 (BB700) dyes had the greatest labeling sensitivity compared to other fluorophores. However, IP antibody injection with anti-CD45.2 BB700, but not AF647, resulted in continuous blood leukocyte labeling for over 6 hours. Finally, we leveraged IP anti-CD45.2 BB700 antibody to track slower migrating leukocytes into tumors. We found that IP anti-CD45.2 antibody injection allowed for the identification of [~]seven times as many tumor-specific CD8+ T cells that had recently migrated from blood into tumors. Our results demonstrate how different injection routes and fluorophores affect anti-CD45.2 antibody leukocyte labeling and highlight the utility of this approach for defining leukocyte migration in the context of homeostasis and cancer.

immunology↗

bioRxiv2024

Molecular basis of FIGNL1 in dissociating RAD51 from DNA and chromatin

Maintaining genome integrity is an essential and challenging process. RAD51 recombinase, the central player of several crucial processes in repairing and protecting genome integrity, forms filaments on DNA. RAD51 filaments are tightly regulated. One of these regulators is FIGNL1, that prevents persistent RAD51 foci post-damage and genotoxic chromatin association in cells. The cryogenic electron microscopy structure of FIGNL1 in complex with RAD51 reveals that the FIGNL1 forms a non-planar hexamer and RAD51 N-terminus is enclosed in the FIGNL1 hexamer pore. Mutations in pore loop or catalytic residues of FIGNL1 render it defective in filament disassembly and are lethal in mouse embryonic stem cells. Our study reveals a unique mechanism for removing RAD51 from DNA and provides the molecular basis for FIGNL1 in maintaining genome stability.

biochemistry↗

bioRxiv2024

Multiplexed screen identifies a Pseudomonas aeruginosa-specific small molecule targeting the outer membrane protein OprH and its interaction with LPS

SUMMARYThe surge of antimicrobial resistance threatens efficacy of current antibiotics, particularly against Pseudomonas aeruginosa, a highly resistant gram-negative pathogen. The asymmetric outer membrane (OM) of P. aeruginosa combined with its array of efflux pumps provide a barrier to xenobiotic accumulation, thus making antibiotic discovery challenging. We adapted PROSPECT1, a target-based, whole-cell screening strategy, to discover small molecule probes that kill P. aeruginosa mutants depleted for essential proteins localized at the OM. We identified BRD1401, a small molecule that has specific activity against a P. aeruginosa mutant depleted for the essential lipoprotein, OprL. Genetic and chemical biological studies identified that BRD1401 acts by targeting the OM {beta}-barrel protein OprH to disrupt its interaction with LPS and increase membrane fluidity. Studies with BRD1401 also revealed an interaction between OprL and OprH, directly linking the OM with peptidoglycan. Thus, a whole-cell, multiplexed screen can identify species-specific chemical probes to reveal novel pathogen biology.

microbiology↗

bioRxiv2022

Genomic expression responses in sensu stricto Saccharomyces yeast to DNA damage induced by methyl methanesulfonate

BackgroundOne way single-celled eukaryotes respond to DNA damage stress is by modifying their gene expression, facilitating genomic repair. Gene expression responses to DNA damage induced by methyl methanesulfonate (MMS) have been studied in the model organism Saccharomyces cerevisiae. However, lacking are investigations of the MMS stress responses in evolutionarily-related sensu stricto Saccharomyces species, including Saccharomyces cerevisiae. MethodsNext-generation Illumina RNA-sequencing was to characterize the entire transcriptomes of four evolutionarily-related species of yeast, S. cerevisiae, S. paradoxus, S. mikatae, and S. bayanus, under control and experimental (MMS) conditions. Subsequent genomic studies included gene set enrichment analysis, promoter analysis, and concentration gradient studies. ResultsS. mikitae and S. paradoxus grew well in light of MMS while S. bayanus showed no growth. While there was fair overlap in induced and repressed genes, overall each species had unique expression responses. S. paradoxus and S. bayanus showed the most distinct changes with the former greatly inhibiting a large segment of its genome while the latter induced such segments. Gene set enrichment analysis revealed significantly modulated biologic, cellular, and molecular processes in each species. Promoter analysis revealed sets of induced/repressed transcription factors for genes highly modulated in the stress response. Concentration gradient studies of S. cerevisiae showed linear increase in gene expression of RAD54, DIN7, and IRC19 in response to increasing concentrations of MMS. ConclusionOverall, we depict the transcriptome changes of four evolutionarily-related sensu stricto yeast species and several functional genomic analyses to provide a novel understanding of their responses to MMS.

genomics↗

bioRxiv2021

The C. albicans virulence factor Candidalysin polymerizes in solution to form membrane pores and damage epithelial cells.

The pathogenic fungus Candida albicans causes severe invasive candidiasis. C. albicans infection requires the action of the virulence factor Candidalysin (CL), which damages the plasma membrane of the target human cells. However, the molecular mechanism that CL uses to permeabilize membranes is poorly understood. We employed complementary biophysical, modeling, microscopy, and cell biology methods to reveal that CL forms membrane pores using a unique molecular mechanism. Unexpectedly, it was observed that CL readily assembles into linear polymers in solution. The basic structural unit in polymer formation is a CL 8-mer, which is sequentially added into a string configuration. Finally, the linear polymers can close into a loop. Our data indicate that CL loops spontaneously insert into the membrane to become membrane pores. We identified a CL mutation (G4W) that inhibited the formation of polymers in solution and prevented formation of pores in different synthetic lipid membranes systems. Studies in epithelial cells showed that G4W CL failed to activate the danger response signaling pathway, a hallmark of the pathogenic effect of CL. These results indicate that CL polymerization in solution is a necessary step for the damage of cellular membranes. Analysis of thousands of CL pores by atomic force microscopy revealed the co-existence of simple depressions and complex pores decorated with protrusions. Imaging and modeling indicate that the two types of pores are formed by CL molecules assembled into alternate orientations. We propose that this structural rearrangement represents a maturation mechanism that might stabilize pore formation to achieve more robust cellular damage. Taken together, the data show that CL uses a previously unknown mechanism to damage membranes, whereby pre-assembly of CL loops in solution directly leads to formation of membrane pores. Our investigation not only unravels a new paradigm for the formation of membrane pores, but additionally identifies CL polymerization as a novel therapeutic target to treat candidiasis.

biophysics↗

bioRxiv2020

Selection for Decreased BRCA2 Functional Activity in Homo sapiens After Divergence from the Chimpanzee-Human Last Common Ancestor

Humans have an increased incidence of epithelial neoplasia compared to non-human primates. We performed a comparative analysis of 21 non-human primate genomes and 54 ancient human genomes to identify variations in known cancer genes that may explain this difference. We identified 299 human-specific fixed non-silent single nucleotide polymorphisms. Bioinformatics analyses for functional consequences identified a number of variants predicted to have altered protein function, one of which was located at the most evolutionarily conserved domain of human BRCA2. This variant, in which a polar threonine residue replaces a hydrophobic methionine residue to codon 2662 within the DSS1 binding domain, decreases the interactions of BRCA2 with other proteins, specifically the binding of BRCA2 and RAD51, as well as the repairing ability of cells for DNA double-strand breaks. We conclude that a 20% reduction in BRCA2 DNA repair ability was positively selected for in the course of human evolution. One Sentence SummaryReduction of BRCA2 functional activity has been selected for during human evolution since the chimpanzee-human last common ancestor.

evolutionary biology↗

bioRxiv2020

Massive X-ray screening reveals two allosteric drug binding sites of SARS-CoV-2 main protease

The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous health problems and economical challenges for mankind. To date, no effective drug is available to directly treat the disease and prevent virus spreading. In a search for a drug against COVID-19, we have performed a massive X-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (Mpro), which is essential for the virus replication and, thus, a potent drug target. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds binding to Mpro. In subsequent cell-based viral reduction assays, one peptidomimetic and five non-peptidic compounds showed antiviral activity at non-toxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2.

biophysics↗

bioRxiv2020

Test Agreement Between Roche Cobas 6800 and Cepheid GeneXpert Xpress SARS-CoV-2 Assays at High Cycle Threshold Ranges

The SARS-CoV-2 pandemic has changed the face of the globe and upended the daily lives of billions. In an effort to bring mass-testing to as many as possible, multiple diagnostic tests including molecular, antigen detection and serological assays have been rapidly developed. However, there is very little information on positive test agreement across modalities, especially for lower viral loads. Thirty-five nasopharyngeal samples that had cycle threshold (Ct) values greater than 30.0 from the Roche cobas 6800 assay were run on the Cepheid GeneXpert Xpress SARS-CoV-2 assay. Ct values ranged from 30.1 to 37.9 (mean 36.7 {+/-} 1.9) on the Roche cobas 6800 assay and 24.6 to 42.4 (mean 32.8{+/-}4.1) on the Cepheid assay. There was a bias of 0.33 {+/-} 3.21, (mean difference -1.59, 95% limits of agreement -5.97, 6.63) signifying close agreement between the 2 instruments with a high standard deviation. The close test agreement between the cobas 6800 and GeneXpert at high Ct values allows for utilization of both assays interchangeable in accordance with testing algorithms.

microbiology↗

bioRxiv2019

The visual lures of spiders exploit insect preferences for flower-like colour and symmetry

Sensory systems can capture only a fraction of available information, which creates opportunities for deceptive signalling. The sensory traps and sensory bias models have proven valuable for explaining how visual systems and environments shape the design of sexual signals, but their application to deceptive signals is largely untapped. Here we use the jewelled orb-web spider Gasteracantha fornicata to experimentally test two longstanding hypotheses for the function of deceptive visual lures. Namely, that they: (1) exploit generalised preferences for conspicuous colouration (sensory bias), or (2) co-opt the otherwise-adaptive foraging response of prey toward flowers (sensory traps). In a field-based study we manipulated the conspicuous dorsal signal of female spiders along two axes --- colour pattern and symmetry -- to generate a gradient of floral resemblance, and monitored the per-individual consequences for prey interception. As predicted by the traps model, the most attractive phenotypes were those with flower-like radial symmetry and solid colour patterns, and their attractiveness equaled that of wild-type models. These results demonstrate that deceptive orb-web spider lures function, in part, as inter-kingdom sensory traps via floral mimicry, and support the broader extension of sensory-based models to deceptive signalling contexts.

animal behavior and cognition↗

bioRxiv2019

Diurnal profiles of physical activity and postures derived from wrist-worn accelerometry in UK adults

BackgroundWrist-worn accelerometry is the commonest objective method for measuring physical activity in large-scale epidemiological studies. Research-grade devices capture raw triaxial acceleration which, in addition to quantifying movement, facilitates assessment of orientation relative to gravity. No population-based study has yet described the interrelationship and variation of these features by time and personal characteristics. Methods2043 UK adults (35-65years) wore an accelerometer on the non-dominant wrist and a chest-mounted combined heart-rate-and-movement sensor for 7days free-living. From raw (60Hz) wrist acceleration, we derived movement (non-gravity acceleration) and pitch and roll (arm) angles relative to gravity. We inferred physical activity energy expenditure (PAEE) from combined sensing and sedentary time from approximate horizontal arm-angle coupled with low movement. ResultsMovement differences by time-of-day and day-of-week were associated with arm-angles; more movement in downward arm-positions. Mean(SD) movement was similar between sexes [~]31(42)mg, despite higher PAEE in men, 53(22) vs 48(19)J{middle dot}min-1{middle dot}kg-1. Women spent longer with the arm pitched >0{degrees} (53% vs 36%) and less time at <0{degrees} (37% vs 53%). Diurnal pitch was 2.5-5{degrees} above and 0-7.5{degrees} below horizontal during night and daytime, respectively; corresponding roll angles were [~]0{degrees} and [~]20{degrees} (thumb-up). Differences were more pronounced in younger participants. All diurnal profiles indicated later wake-times on weekends. Daytime pitch was closer to horizontal on weekdays; roll was similar. Sedentary time was higher (17 vs 15hours/day) in obese vs normal-weight individuals. ConclusionsMore movement occurred in arm positions below horizontal, commensurate with activities including walking. Findings suggest time-specific population differences in behaviours by age, sex, and BMI.

epidemiology↗

bioRxiv2018

Beyond Bonferroni Revisited: Concerns over inflated false positives in conservation genetics, genetics, and neuroscience

In 2006, Narum published a paper in Conservation Genetics that was motivated by the stringent nature of the Bonferroni approach for family wise error correction. That work suggested that the approach of Benjamini and Yekutieli in 2001 provided adequate correction and was more biologically relevant. However, there are crucial differences between the original Benjamini and Yekutieli procedure and that described by Narum. After carefully reviewing both papers, we believe that the Narum procedure is both different than the Benjamini and Yekutieli procedure and does not adequately control for family wise error. We provide an overview of approaches for FWE correction as well as evidence for the faulty implementation of the Benjamini and Yekutieli procedure by Narum using the equations from the respective papers, data from both papers, and the results of simulation.

genetics↗