Biology subjects

Coleman, J.

Publications and source records attributed to Coleman, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Insights into the molecular systematics of montane voles of the Western Himalayan Mountains

Kashmir voles (Hyperacrius) are poorly studied fossorial arvicolines of the southern Himalayan slopes, with two species recognized. We sequenced Cytb from voles collected in northern Pakistan and combined these data with existing GenBank sequences, yielding 194 tips spanning nearly all arvicoline genera. We analyzed five data sets with maximum likelihood and compared external measurements among species using principal component and linear discriminant analyses. We recovered five well-supported clades of Hyperacrius separated by ~12-14% p-distance, which we treat as distinct species. We recognize clade 1 as H. wynnei, and populations referred to H. w. traubi are genetically indistinguishable from H. w. wynnei. We recognize H. zygomaticus, new rank (clade 2), and tentatively allocate clade 5 to H. brachelix. Clades 3 and 4 likely represent undescribed species. Morphometric analyses of external measurements clearly distinguish H. wynnei but not clades 3 and 4 (overall classification accuracy 70.3%). Phylogenetic analyses including nuclear genes placed Hyperacrius as sister to a clade containing Microtini, Arvicola, Lagurini, Dinaromys, and Ellobiusini, whereas mitochondrial analyses weakly allied it with Ellobiusini. Its traditional placement in Clethrionomyini is thus unsupported, although its exact position remains unresolved. Alticola is nonmonophyletic, with A. macrotis sequences nested within Clethrionomys, likely reflecting mitochondrial capture.

evolutionary biology↗

bioRxiv2026

Structural Determinants of Synaptic Vesicle Protein 2C Ligand Selectivity and Their Impact on Dopamine Release

The synaptic vesicle protein 2 (SV2) family is a highly conserved group of transmembrane glycoproteins sharing approximately 70% sequence identity. SV2A and SV2B are broadly distributed throughout the brain, while SV2C, the evolutionarily oldest member of the family, is primarily found in dopaminergic brain regions in the basal ganglia. Genome-wide association studies have linked SV2C to Parkinson's disease, and SV2C appears to enhance dopamine storage in synaptic vesicles, but the basis for this effect is unknown. SV2s are the target of the racetam class of antiseizure medications, and SV2A-specific ligands are widely used to treat seizures. Recently several SV2C-specific ligands have been developed, but the structural basis for ligand specificity is unclear. A better understanding of SV2C structure, function, and pharmacology could lead to better targeted therapies for epilepsy, Parkinson's disease, and other dopamine-related conditions. Here we present cryo-EM structures of apo SV2C, SV2C bound to the high affinity non-selective SV2 ligand padsevonil, SV2C bound to the SV2C-selective ligand UCB-F, and SV2A bound to the SV2A-selective ligand plosaracetam (also known as ABBV-552/SDI-118). We find that SV2C has a wider luminal opening than SV2A and SV2B, which allows for UCB-F to bind to the primary site and form favorable interactions that are not possible in the narrower primary binding site of SV2A and SV2B. We also demonstrate that UCB-F and padsevonil, but not plosaracetam, reduce dopamine release in striatal sections of mouse brain. Our biochemical experiments and structures provide insights into SV2 ligand specificity and offer a template for the rational development of therapeutics targeting SV2C.

biochemistry↗

bioRxiv2026

Comparative genomics reveals shared accessory regions between members of two Fusarium species complexes virulent on garden pea

The contribution of accessory or conditionally dispensable chromosomes to host-specific virulence was first demonstrated in members of the Fusarium solani species complex (FSSC) that are pathogens of garden pea, Pisum sativum L. The phenomenon has since been shown to exist in many fungal plant pathogens, including the closely related F. oxysporum species complex (FOSC). Genome analysis of members of the FSSC and FOSC pathogenic on pea revealed a diverse size range of the accessory genome of these fungi. Despite the [~]65 million years of diverging time, regions on a chromosome known to carry host-specific virulence factors for pea, including the cytochrome P450 pisatin demethylase (PDA) and other pea pathogenicity (PEP) genes, were present in all genomes of these pea pathogens. Genes directly involved in virulence on pea - PEP2, PDA, and PEP5- were the most frequently clustered together. Transcriptome analysis of fungal mycelia treated with the pea phytoalexin pisatin, identified 1,155 differentially expressed genes where many were involved in cellular stress responses. As wilt pathogens that invade host xylem, members of the FOSC encode more putative effectors, when compared to those in the FSSC, and several FOSC effectors were identified to confer race specificity. The conservation of part of the accessory genomes across two evolutionarily diverged species complexes suggests a common origin. Horizontal transfer of accessory chromosomes containing genetic loci involved in pathogenesis for garden pea offers a parsimonious explanation of the polyphyletic origin of host specificity.

genomics↗

bioRxiv2026

High pathogenicity avian influenza virus H5N1 clade 2.3.4.4b in Antarctica: Multiple Introductions and the First Confirmed Infection of Ice-Dependent Seals

Highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b has expanded rapidly across the Southern Ocean since 2023, causing extensive mortality in sub-Antarctic wildlife. Yet its penetration into Antarctica and impacts on ice-dependent species remain poorly resolved primarily due to surveillance constraints. We report the first confirmed H5N1 infection in an Antarctic ice-dependent seal (crabeater seal; Lobodon carcinophaga) and document mortality of crabeater seals across the northern Weddell Sea during November-December 2024. Combining genomic, serological and observational data across nine species, we detected H5N1 RNA in a crabeater seal and a kelp gull (Larus dominicanus), and recovered complete HA, NA and M2 gene sequences from both. Phylogenetic analyses allowed us to identify at least two independent introductions of HPAI H5N1 clade 2.3.4.4b into the northern Antarctic Peninsula region. Serology provided strong evidence of prior exposure in scavenging birds, but no detectable H5 immunity in penguins or pinnipeds. Together, the results demonstrate ongoing novel viral incursions into Antarctica, likely facilitated by at-sea processes e.g. animal interactions on ice floes, that remain invisible to land-based surveillance. These findings highlight the vulnerability of ice-dependent pinnipeds to HPAI H5N1 clade 2.3.4.4b and the urgent need for expanded integrated Antarctic monitoring frameworks that pair serology, opportunistic carcass sampling and genomic sequencing.

ecology↗

bioRxiv2025

Use of anthropogenic material for extended ornamented phenotype in two fairy-wrens

Birds often advertise their quality to potential mates through sexual displays that complement their colorful plumage. Some species use materials to enhance their attractiveness, such as the use of colorful fruits and anthropogenic materials in the display bowers across bowerbirds. Here we report the first observations of anthropogenic materials in sexual displays by two fairy-wren species. On two separate occasions and sites, we witnessed a White-winged and Red-backed male carrying a piece of plastic as a substitute for a flower petal during a petal display, which are used across Malurus to enhance reproductive fitness. Given increasing plastic pollution globally, the use of anthropogenic materials as part of extended phenotypes in birds and other animals will likely increase and it will be important to understand the effect this has on populations.

ecology↗

bioRxiv2025

The Golgi Rim is a Precise Tetraplex of Golgin Proteins that Can Self-Assemble into Filamentous Bands

Golgin proteins have long been suspected to be organizers of the Golgi stack. Using three-dimensional super-resolution microscopy, we comprehensively localize the human golgin family at the rim of the Golgi apparatus at 10-20 nm resolution in situ. Unexpectedly, we find that the golgins are precisely organized into a tetraplex with four discrete layers, each containing a specific set of rim golgins. We observe no golgins inside the stack between its membrane-bound cisternae. Biochemically characterizing most of the golgins as isolated proteins, we find that they form anti-parallel dimers and further self-assemble into bands of multi-micron-long filaments. Based on our findings, we propose an "outside-in" physical model, the Golgin Organizer Hypothesis, in which the Golgi stack of cisternae and its overall ribbon morphology directly result from bending circumferential bands of rim golgin filaments onto a membrane surface, explaining stack formation without the need for special "stacking proteins."

cell biology↗

bioRxiv2024

A proteome-wide quantitative guide for nanoscale spatially resolved extraction of membrane proteins into native nanodiscs

The intricate molecular environment of the native membrane profoundly influences every aspect of membrane protein (MP) biology. Despite this, the most prevalent method of studying MPs uses detergent-like molecules that disrupt and remove this vital local membrane context. This severely impedes our ability to quantitatively decipher the local molecular context and comprehend its regulatory role in the structure, function, and biogenesis of MPs. Using a library of membrane-active polymers we have developed a platform for the high-throughput analysis of the membrane proteome. The platform enables near-complete spatially resolved extraction of target MPs directly from their endogenous membranes into native nanodiscs that maintain the local membrane context. We accompany this advancement with an open-access database that quantifies the polymer-specific extraction variability for 2065 unique mammalian MPs and provides the most optimized condition for each of them. Our method enables rapid and near-complete extraction and purification of target MPs directly from their endogenous organellar membranes at physiological expression levels while maintaining the nanoscale local membrane environment. Going beyond the plasma membrane proteome, our platform enables extraction from any target organellar membrane including the endoplasmic reticulum, mitochondria, lysosome, Golgi, and even transient organelles such as the autophagosome. To further validate this platform, we took several independent MPs and demonstrated how our resource can enable rapid extraction and purification of target MPs from different organellar membranes with high efficiency and purity. Further, taking two synaptic vesicle MPs, we show how the database can be extended to capture multiprotein complexes between overexpressed MPs. We expect these publicly available resources to empower researchers across disciplines to efficiently capture membrane nano-scoops containing a target MP and interface with structural, functional, and other bioanalytical approaches. We demonstrate an example of this by combining our extraction platform with single-molecule TIRF imaging to demonstrate how it can enable rapid determination of homo-oligomeric states of target MPs in native cell membranes.

biophysics↗

bioRxiv2023

Two successive oligomeric Munc13 assemblies scaffold vesicle docking and SNARE assembly to support neurotransmitter release

The critical presynaptic protein Munc13 serves numerous roles in the process of docking and priming synaptic vesicles. Here we investigate the functional significance of two distinct oligomers of the Munc13 core domain (Munc13C) comprising C1-C2B-MUN-C2C. Oligomer interface point mutations that specifically destabilized either the trimer or lateral hexamer assemblies of Munc13C disrupted vesicle docking, trans-SNARE formation, and Ca2+-triggered vesicle fusion in vitro and impaired neurotransmitter secretion and motor nervous system function in vivo. We suggest that a progression of oligomeric Munc13 complexes couples vesicle docking and assembly of a precise number of SNARE molecules to support rapid and high-fidelity vesicle priming.

neuroscience↗

bioRxiv2023

Synaptophysin Chaperones the Assembly of 12 SNAREpins under each Ready-Release Vesicle

The synaptic vesicle protein Synaptophysin has long been known to form a complex with the v-SNARE VAMP, but a more specific molecular function or mechanism of action in exocytosis has been lacking because gene knockouts have minimal effects. Utilizing fully-defined reconstitution and single-molecule measurements, we now report that Synaptophysin functions as a chaperone that determines the number of SNAREpins assembling between a ready-release vesicle and its target membrane bilayer. Specifically, Synaptophysin directs the assembly of 12 {+/-} 1 SNAREpins under each docked vesicle, even in the face of an excess of SNARE proteins. The SNAREpins assemble in successive waves of 6 {+/-} 1 and 5 {+/-} 2 SNAREpins, respectively, tightly linked to oligomerization of and binding to the vesicle Ca++ sensor Synaptotagmin. Templating of 12 SNAREpins by Synaptophysin is likely the direct result of its hexamer structure and its binding of VAMP2 dimers, both of which we demonstrate in detergent extracts and lipid bilayers. Significance StatementSynaptophysin is the most abundant protein and a unique constituent of synaptic vesicles, yet it has no known function, due to minimal genetic phenotypes and the lack of biochemical assays. Here, we directly establish using two independent methods that the synaptic vesicle protein Synaptophysin forms a hexameric complex containing 12 copies of the v-SNARE VAMP2. These v-SNAREs assemble into SNAREpins as ready-release vesicles are formed in a fully-defined cell-free system, and do so in two equal waves organized by oligomerization of the Ca++ sensor Synaptotagmin. In the absence of Synaptophysin, two waves are also observed, but the number of SNAREpins in each varies widely. We suggest that a single Synaptophysin hexamer in each vesicle symmetrically organizes 6 pairs of peripheral and central SNAREpins, the latter being directly bound to the Synaptotagmin ring. This gives rise to the symmetrical ring-like arrangement of densities observed by cryo-EM tomography under each synaptic vesicle (1, 2).

neuroscience↗

bioRxiv2023

Novel Roles for Diacylglycerol in Synaptic Vesicle Priming and Release Revealed by Complete Reconstitution of Core Protein Machinery

Here we introduce the full functional reconstitution of genetically-validated core protein machinery (SNAREs, Munc13, Munc18, Synaptotagmin, Complexin) for synaptic vesicle priming and release in a geometry that enables detailed characterization of the fate of docked vesicles both before and after release is triggered with Ca2+. Using this novel setup, we discover new roles for diacylglycerol (DAG) in regulating vesicle priming and Ca2+-triggered release involving the SNARE assembly chaperone Munc13. We find that low concentrations of DAG profoundly accelerate the rate of Ca2+-dependent release, and high concentrations reduce clamping and permit extensive spontaneous release. As expected, DAG also increases the number of ready-release vesicles. Dynamic single-molecule imaging of Complexin binding to ready-release vesicles directly establishes that DAG accelerates the rate of SNAREpin assembly mediated by Munc13 and Munc18 chaperones. The selective effects of physiologically validated mutations confirmed that the Munc18-Syntaxin-VAMP2 template complex is a functional intermediate in the production of primed, ready-release vesicles, which requires the coordinated action of Munc13 and Munc18. SIGNIFICANCE STATEMENTMunc13 and Munc18 are SNARE-associated chaperones that act as "priming" factors, facilitating the formation of a pool of docked, release-ready vesicles and regulating Ca2+-evoked neurotransmitter release. Although important insights into Munc18/Munc13 function have been gained, how they assemble and operate together remains enigmatic. To address this, we developed a novel biochemically-defined fusion assay which enabled us to investigate the cooperative action of Munc13 and Munc18 in molecular terms. We find that Munc18 nucleates the SNARE complex, while Munc13 promotes and accelerates the SNARE assembly in a DAG-dependent manner. The concerted action of Munc13 and Munc18 stages the SNARE assembly process to ensure efficient clamping and formation of stably docked vesicles, which can be triggered to fuse rapidly ([~]10 msec) upon Ca2+ influx.

neuroscience↗

bioRxiv2023

Urbanisation generates multiple trait syndromes for terrestrial taxa worldwide

Cities can host significant biological diversity. Yet, urbanisation leads to the loss of habitats and, potentially, to local extinctions. Understanding how multiple taxa respond to urbanisation globally is essential to promote and conserve biodiversity in cities and surrounding landscapes. Using a dataset with site-level occurrence and trait data of 5302 species from six terrestrial fauna taxonomic groups across 379 cities on 6 continents, we show that urbanisation produces taxon-specific changes in trait composition, with traits related to reproductive strategy consistently showing the strongest response. The effect of urbanisation on community trait composition is strongest at the largest spatial scale considered, and more closely linked to landscape composition (% urban) than arrangement (aggregation), although latitude and climatic variables remain a stronger influence. This study did not find evidence in support of a global urban taxa syndrome, but instead we suggest that there are four general urban trait syndromes, with resources associated with reproduction and diet likely to be driving patterns in traits associated with mobility and body size. Functional diversity measures showed a wide range of responses, leading to a shift in trait space that is most likely driven by the distribution and abundance of critical resources, and the urban trait syndrome displayed by individual species within a community. Further research is required to understand the interactions between the four general urban trait syndromes, resource distribution and abundance and changes in functional diversity of taxa at different spatial and temporal scales. Maximising opportunities to support species within taxa groups with different urban trait syndromes should be pivotal in conservation and management programmes within and among cities. This will reduce the likelihood of biotic homogenisation at the taxa level, and helps ensure that urban environments have the ecological capacity to respond to challenges such as climate change, further habitat fragmentation and loss, and other disruptions. These actions are critical if we are to reframe the role of cities in global biodiversity loss.

ecology↗

bioRxiv2023

Rapid Quantification of First and Second Phase Insulin Secretion Dynamics using In vitro Platform for Improving Insulin Therapy

High-throughput quantification of the first- and second-phase insulin secretion dynamics is intractable with current methods. The fact that independent secretion phases play distinct roles in metabolism necessitates partitioning them separately and performing high-throughput compound screening to target them individually. We developed an insulin-nanoluc luciferase reporter system to dissect the molecular and cellular pathways involved in the separate phases of insulin secretion. We validated this method through genetic studies, including knockdown and overexpression, as well as small-molecule screening and their effects on insulin secretion. Furthermore, we demonstrated that the results of this method are well correlated with those of single-vesicle exocytosis experiments conducted on live cells. Thus, we can quantitatively determine the number of vesicles that fuse when a stimulus is applied. We have developed a robust methodology for screening small molecules and cellular pathways that target specific phases of insulin secretion, resulting in a better understanding of insulin secretion, which in turn will result in a more effective insulin therapy through the stimulation of endogenous glucose-stimulated insulin secretion.

cell biology↗

bioRxiv2023

Direct determination of oligomeric organization of integral membrane proteins and lipids from intact customizable bilayer

Hierarchical organization of integral membrane proteins (IMP) and lipids at the membrane is essential for regulating myriad downstream signaling. A quantitative understanding of these processes requires both detections of oligomeric organization of IMPs and lipids directly from intact membranes and determination of key membrane components/properties that regulate them. Addressing this, we have developed a platform that enables native mass spectrometry (nMS) analysis of IMP-lipid complexes directly from intact and customizable lipid membranes. Both the lipid composition and membrane properties (such as curvature, tension, fluidity) of these bilayers can be precisely customized to a target membrane. Subsequent direct nMS analysis of these intact proteo-lipid vesicles can yield the oligomeric states of the embedded IMPs, identify bound lipids, and determine the membrane properties that can regulate the observed IMP-lipid organization. Applying this, we show how lipid binding regulates neurotransmitter release and how membrane composition regulates the functional oligomeric state of a transporter.

biophysics↗

bioRxiv2023

Emotional memories are enhanced when reactivated in slow wave sleep, but impaired when reactivated in REM

Sleep supports memory consolidation. However, it is not completely clear how different sleep stages contribute to this process. While rapid eye movement sleep (REM) has traditionally been implicated in the processing of emotionally charged material, recent studies indicate a role for slow wave sleep (SWS) in strengthening emotional memories. Here, to directly examine which sleep stage is primarily involved in emotional memory consolidation, we used targeted memory reactivation (TMR) in REM and SWS during a daytime nap. Contrary to our hypothesis, reactivation of emotional stimuli during REM led to impaired memory. Consistent with this, REM% was correlated with worse recall in the group that took a nap without TMR. Meanwhile, cueing benefit in SWS was strongly correlated with the product of times spent in REM and SWS (SWS-REM product), and reactivation significantly enhanced memory in those with high SWS-REM product. Surprisingly, SWS-REM product was associated with better memory for reactivated items and poorer memory for non-reactivated items, suggesting that sleep both preserved and eliminated emotional memories, depending on whether they were reactivated. Notably, the emotional valence of cued items modulated both sleep spindles and delta/theta power. Finally, we found that emotional memories benefited from TMR more than did neutral ones. Our results suggest that emotional memories decay during REM, unless they are reactivated during prior SWS. Furthermore, we show that active forgetting complements memory consolidation, and both take place across SWS and REM. In addition, our findings expand upon recent evidence indicating a link between sleep spindles and emotional processing.

neuroscience↗

bioRxiv2022

Jovian enables direct inference of germline haplotypes from short reads via sequence-to-sequence modeling

Detection of germline variants in next-generation sequencing data is an essential component of modern genomics analysis. Variant detection tools typically rely on statistical algorithms such as de Bruijn graphs, Hidden Markov Models and regression models, often coupled with heuristic techniques and thresholds to identify variants. Here we describe a new approach that replaces these handcrafted statistical methods with a single, end-to-end deep learning model that directly infers germline haplotypes from short read pileups. Our model, called Jovian, frames variant detection as a sequence-tosequence modeling task, akin to language translation, and employs a transformer-based architecture to translate alignment columns into two predicted haplotype sequences. After training with 17 whole genome sequences from Genome-in-a-Bottle cell lines, we demonstrate that this method learns to realign complex and ambiguous read mappings to produce accurate haplotype predictions, predicts variant genotypes and phase accurately, and leverages the local read context to inform predictions about a given position. We also demonstrate that a 2-dimensional positional encoding significantly improved precision of the detected variants. Compared to other callers, sensitivity and precision is higher than GATK HaplotypeCaller, but lower than DeepVariant and Strelka2.

bioinformatics↗

bioRxiv2022

Molecular Characterization of the Tumor Microenvironment in Renal Medullary Carcinoma

Renal medullary carcinoma (RMC) is a highly aggressive disease associated with sickle hemoglobinopathies and universal loss of the tumor suppressor gene SMARCB1. RMC has a relatively low rate of incidence compared with other renal cell carcinomas (RCCs) that has hitherto made molecular profiling difficult. To probe this rare disease in detail we performed an in-depth characterization of the RMC tumor microenvironment using a combination of genomic, metabolic and single-cell RNA-sequencing experiments on tissue from a representative untreated RMC patient, complemented by retrospective analyses of archival tissue and existing published data. Our study of the tumor identifies a heterogenous population of malignant cell states originating from the thick ascending limb of the Loop of Henle within the renal medulla, displaying the hallmarks of increased resistance to cell death by ferroptosis and proteotoxic stress driven by MYC-induced proliferative signals. Specifically, genomic characterization of RMC tumors provides substantiating evidence for the recently proposed dependence of SMARCB1-difficient cancers on an intact CDKN2A-p53 pathway and we suggest increased cystine-mTORC-GPX4 signaling also plays a role within transformed RMC cells. We further propose that RMC has an immune landscape comparable to that of untreated RCCs, including heterogenous expression of the immune ligand CD70 within a sub-population of tumor cells, which could provide an immune-modulatory role that serves as a viable candidate for therapeutic targeting.

cancer biology↗

bioRxiv2021

Non-rapid eye movement sleep and wake neurophysiology in schizophrenia

Motivated by the potential of objective neurophysiological markers to index thalamocortical function in patients with severe psychiatric illnesses, we comprehensively characterized key NREM sleep parameters across multiple domains, their interdependencies, and their relationship to waking event-related potentials and symptom severity. In 130 schizophrenia (SCZ) patients and controls, we confirmed a marked reduction in sleep spindle density in SCZ and extended these findings to show that only slow spindles predicted symptom severity, and that fast and slow spindle properties were largely uncorrelated. We also describe a novel measure of slow oscillation and spindle interaction that was attenuated in SCZ. The main sleep findings were replicated in a demographically distinct sample, and a joint model, based on multiple NREM components, predicted disease status in the replication cohort. Although also altered in patients, auditory event-related potentials elicited during wake were unrelated to NREM metrics. Consistent with a growing literature implicating thalamocortical dysfunction in SCZ, our characterization identifies independent NREM and wake EEG biomarkers that may index distinct aspects of SCZ pathophysiology and point to multiple neural mechanisms underlying disease heterogeneity. This study lays the groundwork for evaluating these neurophysiological markers, individually or in combination, to guide efforts at treatment and prevention as well as identifying individuals most likely to benefit from specific interventions.

neuroscience↗

bioRxiv2021

Molecular Determinants of Complexin Clamping in Reconstituted Single-Vesicle Fusion

Previously we reported that Synaptotagmin-1 and Complexin synergistically clamp the SNARE assembly process to generate and maintain a pool of docked vesicles that fuse rapidly and synchronously upon Ca2+ influx (Ramakrishnan et al. 2020). Here using the same in vitro single-vesicle fusion assay, we establish the molecular details of the Complexin clamp and its physiological relevance. We find that a delay in fusion kinetics, likely imparted by Synaptotagmin-1, is needed for Complexin to block fusion. Systematic truncation/mutational analyses reveal that continuous alpha-helical accessory-central domains of Complexin are essential for its inhibitory function and specific interaction of the accessory helix with the SNAREpins, analogous to the trans clamping model, enhances this functionality. The c-terminal domain promotes clamping by locally elevating Complexin concentration through interactions with the membrane. Further, we find that Complexin likely contributes to rapid Ca2+-synchronized vesicular release by preventing un-initiated fusion rather than by directly facilitating vesicle fusion.

biophysics↗