Biology subjects

White, H.

Publications and source records attributed to White, H..

11 recordsLinked to original sources

bioRxiv2026

Whole genome sequencing of endometrial cancer identifies novel subgroups, drivers, and actionable alterations

Endometrial cancer (EC) is the most common gynaecological malignancy in high income countries, and is increasing in incidence. While molecular stratification has improved its management, precision care is hampered by incomplete characterization of the EC genome. We address this by analysis of whole genome sequencing (WGS) of 665 ECs generated by the UK Genomics England 100,000 Genome Project (100kGP). 5% of cases were associated with germline pathogenic variants in cancer genes, including BRCA1 which we confirmed predisposes to EC. We identified 107 putative coding driver genes, 35% of which had no prior established role in EC. Novel structural variants included gains of MYCN and loss of its negative regulator NEDD4.1 which were significantly mutually exclusive in copy number (CN) high tumours. Immunogenomic analysis confirmed selection for driver alterations of low immunogenicity based on patient HLA haplotype, and pervasive immune escape through multiple mechanisms. Unsupervised clustering of mutational signatures and genomic alterations identified known and novel molecular subgroups, including a CN-high subset with mutational signatures of homologous recombination deficiency (HRD) and favourable outcome. Independent prognostic value of single nucleotide variant (SNV) burden, CN burden and multiple coding drivers, along with the identification of targetable molecular alterations in over one-third of cases, underscores the promise of WGS for precision medicine in EC.

genomics↗

bioRxiv2026

Neuronal Dynamics During Isoflurane Induction in Caenorhabditis elegans

BackgroundHow does neuronal activity change as an animal transitions from being awake to a state of general anesthesia? Previous studies used C. elegans to investigate awake and anesthetized states, emergence from anesthesia, and to establish metrics characterizing how system-wide neuronal dynamics differ under these conditions. This study employs a new technique to image pan-neuronal activity in C. elegans continuously during induction of anesthesia with isoflurane. MethodsC. elegans worms expressing pan-neuronal nuclear RFP and cytosolic GCaMP6s were imaged with light sheet microscopy to measure single cell activity in the majority of neurons in the animals head during induction via isoflurane exposure. Stable concentrations of isoflurane were maintained throughout the experiment by measured flow vaporization of isoflurane into a specially designed gas enclosure compatible with the imaging system. Building on our previous work investigating emergence from anesthesia, we analyzed ensemble neuronal activity, spectrograms of frequency over time, and metrics of information flow between neurons. ResultsInduction of isoflurane anesthesia caused a progressive reduction in neuronal activity over the course of 40 minutes. Spectrograms indicated a loss of bulk signal power across all frequencies, notably in low frequencies too. State Decoupling and Internal Predictability were among the most useful metrics for discriminating the anesthetized state, demonstrating induction kinetics that are the inverse of emergence. However, each animal does not arrive at the anesthetized state at the same time; response times are highly individualized. ConclusionsInformation metrics of neurodynamic activity demonstrate that isoflurane induction results in a gradual increase in neuronal disconnection and disorganization. Thus, at the level of individual neuron connectivity and system dynamics, the induction of anesthesia in C. elegans nematodes is in essence the reverse of emergence. Induction however occurs more rapidly and shows marked variability between individuals. Future genetic studies will show which molecular targets define sensitivity to volatile anesthetics like isoflurane. Summary StatementIsoflurane-induced unconsciousness is a common phenomenon across species. Does the induction of anesthesia arise by distinct state transitions, or through gradual changes in system dynamics when activity is measured at the level of individual neurons?

neuroscience↗

bioRxiv2026

Identification of novel inhibitors of Mycobacterium smegmatis growth through genome-wide overexpression of Cluster P3 mycobacteriophage Xavia genes

We examined whether genes encoded by the mycobacteriophage Xavia disrupt growth of Mycobacterium smegmatis, a widely used mycobacterial model. Seventy-one Xavia genes were individually expressed using an inducible plasmid system and assessed for effects on colony formation. Two genes were lethal even without induction, indicating toxicity under basal expression. Induction of sixteen additional genes reduced bacterial growth, spanning structural proteins, lysogeny regulators, DNA-associated enzymes, a lysis protein, and several genes with no known function. These findings expand functional insights into mycobacteriophage gene repertoires and identify candidates for future mechanistic studies. AbstractBacteriophage genomes encode large numbers of genes with no known function, and many of these genes affect essential host processes when expressed in a heterologous system. For mycobacteriophages, genome-wide overexpression in Mycobacterium smegmatis provides a direct way to identify proteins that impair growth and to determine which mycobacterial pathways are sensitive to phage gene products. To evaluate the cytotoxic potential of the Cluster P3 phage Xavia, a lineage that has not undergone functional screening, we constructed an arrayed pExTra library containing 71 predicted Xavia genes under control of the anhydrotetracycline inducible promoter pTet. All constructs were sequence-verified and transformed into M. smegmatis, and induction allowed measurement of gene-specific effects on growth. Two genes prevented recovery of transformants, suggesting toxicity under basal promoter leakiness. Inducible expression of 16 additional genes impaired growth, and these inhibitory proteins include structural components, regulators of lysogeny, enzymes of DNA metabolism, a lysis factor, and several proteins with no known function. Four of the strongest inhibitors were genes with no known function. These results extend functional screening into the previously untested P3 branch of Actinobacteriophages and identify new proteins that require mechanistic analysis.

microbiology↗

bioRxiv2025

Short-term sensory memory mediates adaptation, habituation, and a paradoxical neural-behavioral transformation in C. elegans

Repeated exposure to stimuli elicits decreasing sensory neural responses over time (adaptation). However, resulting behavioral responses can either weaken over time (habituation) or remain invariant, indicating that the neural-behavioral link is not fixed. To investigate neural adaptation and its flexible translation into behavioral decision making, we created a mathematical framework hypothesizing (1) that sensory networks optimize the speed and accuracy of encoding exogenous stimuli, and (2) that representations form along two time scales, one embedding immediate information and the other stimulus history. Using experimental recordings of the nematode C. elegans, we validated normative model predictions of this optimal encoding strategy, specifically how neural dynamics and adaptation levels vary with stimulus timing. A parametric Bayesian decoder architecture predicted conditions leading to behavioral habituation or invariance, but also paradoxical inversion, whereby appetitive stimuli elicit aversive responses. Experiments with food odors validated that inversion behavior occurred after several repetitions with a long stimulation time and low odor concentrations. Mechanistically, during sensory neural adaptation, weaker immediate stimulus representations can be compensated by secondary processes through memory effects, with biological origins that remain to be studied.

neuroscience↗

bioRxiv2025

Global excitatory synchrony: Ketamine induces global common-mode excitatory network oscillation by decoupling key interneurons

Ketamine is a dissociative anesthetic used in subanesthetic doses with analgesic and anti-depressive properties. However, its mechanistic effects on neuronal signaling and circuit function remain underexplored. We address this shortcoming by employing multi-neuronal imaging in the simple nematode C. elegans that allows measurement of neuron activity across the animals entire head with single-cell resolution. Neuronal imaging during low dose ketamine induction reveals two distinct phases: an early/low dose state of hyperactive synchronized dynamics and late/higher dose state of system disorganization and spastic microscale motion. Specifically examining the activity of the NMDA-receptive interneuron AVA, we find it decouples from the system under low dose ketamine. These results are consistent with the clinical hypothesis that ketamine causes neuronal disinhibition through suppression of key inhibitory interneurons. We identify functional differences between low and high dose activity dynamics and elucidate a mechanism of action of ketamine in a complete, intact nervous system.

biophysics↗

bioRxiv2024

Hydrophobins from Aspergillus mediate fungal interactions with microplastics

Microplastics present myriad ecological and human health risks including serving as a vector for pathogens in human and animal food chains. However, the specific mechanisms by which pathogenic fungi colonize these microplastics have yet to be explored. In this work, we examine the opportunistic fungal pathogen, Aspergillus fumigatus, and other common soil and marine Aspergilli, which we found bind microplastics tightly. Up to 3.85+/-1.48 g microplastic plastic/g fungi were bound and flocculated for polypropylene (PP), polyethylene (PE), and polyethylene terephthalate (PET) powders and particles ranging in size from 0.05 - 5 mm. Gene knockouts revealed hydrophobins as a key biomolecule driving microplastic-fungi binding. Moreover, purified hydrophobins were still able to flocculate microplastics independent of the fungus. Our work elucidates a role for hydrophobins in fungal colonization of microplastics and highlights a potential target for mitigating the harm of microplastics through engineered fungal-microplastic interactions. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/622132v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@13eb679org.highwire.dtl.DTLVardef@3dc9c0org.highwire.dtl.DTLVardef@888c96org.highwire.dtl.DTLVardef@c5e1aa_HPS_FORMAT_FIGEXP M_FIG C_FIG Significance StatementMicroplastics pose serious ecological and human health effects by introducing pathogens and toxins into animal and human food chains. Many pathogenic microorganisms preferentially form biofilms on microplastic particles that are then ingested. Here, we demonstrate that hydrophobins, highly hydrophobic, cell surface proteins, enable microplastic binding and colonization by the opportunistic pathogen Aspergillus fumigatus and other fungi within the Aspergillus genus. Our work recognizes a novel role for hydrophobin proteins, identifying potential strategies for pathogen control and protein-based microplastics recovery.

molecular biology↗

bioRxiv2023

A TrkB and TrkC partial agonist restores deficits in synaptic function and promotes activity-dependent synaptic and microglial transcriptomic changes in a late-stage Alzheimer's mouse model

IntroductionTrkB and TrkC receptor signaling promotes synaptic plasticity and interacts with pathways affected by amyloid-{beta} (A{beta})-toxicity. Upregulating TrkB/C signaling could reduce Alzheimers disease (AD)-related degenerative signaling, memory loss, and synaptic dysfunction. MethodsPTX-BD10-2 (BD10-2), a small molecule TrkB/C receptor partial agonist, was orally administered to aged London/Swedish-APP mutant mice (APPL/S) and wild-type controls (WT). Effects on memory and hippocampal long-term potentiation (LTP) were assessed using electrophysiology, behavioral studies, immunoblotting, immunofluorescence staining, and RNA-sequencing. ResultsMemory and LTP deficits in APPL/S mice were attenuated by treatment with BD10-2. BD10-2 prevented aberrant AKT, CaMKII, and GLUA1 phosphorylation, and enhanced activity-dependent recruitment of synaptic proteins. BD10-2 also had potentially favorable effects on LTP-dependent complement pathway and synaptic gene transcription. ConclusionsBD10-2 prevented APPL/S/A{beta}-associated memory and LTP deficits, reduced abnormalities in synapse-related signaling and activity-dependent transcription of synaptic genes, and bolstered transcriptional changes associated with microglial immune response.

neuroscience↗

bioRxiv2022

LabGym: A versatile computational tool for automatic quantification of user-defined animal behaviors

Quantifying animal behavior is important for many branches of biological research. Current computational tools for behavioral quantification typically rely on a few pre-defined, simplified features to identify a behavior. However, such an approach restricts the information used and the tools applicability to a limited range of behavior types or species. Here we report a new tool, LabGym, for quantifying animal behaviors without such limitations. Combining a novel approach for effective evaluation of animal motion with customizable convolutional recurrent networks for capturing spatiotemporal details, LabGym provides holistic behavioral assessment and accurately identify user-defined animal behaviors without restrictions on behavior types or animal species. It then provides quantitative measurements of each behavior, which quantify the behavior intensity and the body kinematics during the behavior. LabGym requires neither any intermediate step for processing features that causes information loss nor programming knowledge from users for post-hoc analysis. It tracks multiple animals simultaneously in various experimental settings for high-throughput and versatile analysis. It also provides users a way to generate visualizable behavioral datasets that are valuable resources for the research community. We demonstrate its efficacy in capturing subtle behavioral changes in animals ranging from soft-bodied invertebrates to mammals.

animal behavior and cognition↗

bioRxiv2021

Morphological Metrics of Magnetic Resonance Imaging of Glioblastoma as Biomarkers of Prognosis

Morphological characteristics have been linked to outcomes across a variety of cancers. Lacunarity is a quantitative morphological measure of how shapes fill space while fractal dimension is a morphological measure of the complexity of pixel arrangement. Glioblastoma is the most aggressive primary brain tumor with a short expected survival given the current standard-of-care treatment. Due to the sensitive location of the tumor, there is a heavy reliance on imaging to assess the state of the disease in the clinic. In this project, we computed lacunarity and fractal dimension values for glioblastoma-induced abnormalities on gadolinium-enhanced T1-weighted magnetic resonance imaging (T1Gd MRI) as well as T2-weighted (T2) and fluid-attenuated inversion recovery (FLAIR) MRIs. In our patient cohort (n=402), we aim to connect these morphological metrics calculated on pretreatment MRI with the survival of patients with GBM. We calculated lacunarity and fractal dimension across all MRI slices on necrotic regions (n=390) and abnormalities on T1Gd MRI (n=402), as well as on enhancing abnormalities present on T2/FLAIR MRI (n=257). We also explored the relationship between these metrics and age at diagnosis, as well as abnormality volume. We found statistically significant relationships to outcome across all three imaging subtypes, with the shape of T2/FLAIR abnormalities showing the strongest relationship with overall survival. The link between morphological and survival metrics could be driven by underlying biological phenomena, tumor location or microenvironmental factors that should be further explored.

bioinformatics↗

bioRxiv2020

A polymer gel index-matched to water enables diverse applications in fluorescence microscopy

We demonstrate diffraction-limited and super-resolution imaging through thick layers (tens-hundreds of microns) of BIO-133, a biocompatible, UV-curable, commercially available polymer with a refractive index (RI) matched to water. We show that cells can be directly grown on BIO-133 substrates without the need for surface passivation and use this capability to perform extended time-lapse volumetric imaging of cellular dynamics 1) at isotropic resolution using dual-view light-sheet microscopy, and 2) at super-resolution using instant structured illumination microscopy. BIO-133 also enables immobilization of 1) Drosophila tissue, allowing us to track membrane puncta in pioneer neurons, and 2) Caenorhabditis elegans, which allows us to image and inspect fine neural structure and to track pan-neuronal calcium activity over hundreds of volumes. Finally, BIO-133 is compatible with other microfluidic materials, enabling optical and chemical perturbation of immobilized samples, as we demonstrate by performing drug and optogenetic stimulation on cells and C. elegans.

bioengineering↗

bioRxiv2019

Image-based metric of invasiveness predicts response to adjuvant temozolomide for primary glioblastoma

Temozolomide (TMZ) has been the standard-of-care chemotherapy for glioblastoma (GBM) patients for more than a decade. Despite this long time in use, significant questions remain regarding how best to optimize TMZ therapy for individual patients. Understanding the relationship between TMZ response and factors such as number of adjuvant TMZ cycles, patient age, patient sex, and image-based tumor features, might help predict which GBM patients would benefit most from TMZ, particularly for those whose tumors are not MGMT methylated. Using a cohort of 90 newly-diagnosed GBM patients treated according to the Stupp protocol, we examined the relationships between several patient and tumor characteristics and volumetric and survival outcomes during adjuvant chemotherapy. Volumetric changes in MR imaging abnormalities during adjuvant therapy were used to assess TMZ response. T1Gd volumetric response is associated with younger patient age, increased number of TMZ cycles, longer time to nadir volume, and decreased tumor invasiveness. Moreover, increased adjuvant TMZ cycles corresponded with improved volumetric response only among more nodular tumors, and this volumetric response was associated with improved survival outcomes. Finally, in a subcohort of patients with known MGMT methylation status, MGMT methylated tumors were more diffusely invasive than unmethylated tumors, suggesting that the improved response in nodular tumors is not driven by a preponderance of MGMT methylated tumors. Our finding that less diffusely invasive tumors are associated with greater volumetric response to TMZ suggests that patients with these tumors may benefit from additional cycles of adjuvant TMZ, even for those without MGMT methylation.

cell biology↗