Biology subjects

Green, M.

Publications and source records attributed to Green, M..

30 records · Page 2Linked to original sources

bioRxiv2022

Genome-wide association and genomic prediction of growth traits in the European flat oyster (Ostrea edulis)

The European flat oyster (Ostrea edulis) is a bivalve mollusc that was once widely distributed in Europe and represented an important food resource for humans for centuries. Populations of O. edulis experienced a severe decline across their biogeographic range mainly due to anthropogenic activities and disease outbreaks. To restore the economic and ecological benefits of European flat oyster populations, extensive protection and restoration efforts are in place within Europe. In line with the increasing interest in supporting restoration and oyster farming through the breeding of stocks with enhanced performance, the present study aimed to evaluate the potential of genomic selection for improving growth traits in a European flat oyster population obtained from successive mass-spawning events. Four growth-related traits were evaluated: total weight (TW), shell height (SH), shell width (SW) and shell length (SL). The heritability of the growth traits was moderate-low, with estimates of 0.45, 0.37, 0.22, and 0.32 for TW, SH, SW and SL, respectively. A genome-wide association analysis revealed a largely polygenic genetic architecture for the four growth traits, with two distinct QTLs detected on chromosome 4. To investigate whether genomic selection can be implemented in flat oyster breeding at a reduced cost, the utility of low-density SNP panels (down to 100 SNPs) was assessed. Genomic prediction accuracies using the full density panel were high (>0.83 for all traits). The evaluation of the effect of reducing the number of markers used to predict genomic breeding values revealed that similar selection accuracies could be achieved for all traits with 2K SNPs as for a full panel containing 4,577 SNPs. Only slight reductions in accuracies were observed at the lowest SNP density tested (i.e. 100 SNPs), likely due to a high relatedness between individuals being included in the training and validation sets during cross-validation. Overall, our results suggest that the genetic improvement of growth traits in oysters is feasible. Nevertheless, and although low-density SNP panels appear as a promising strategy for applying GS at a reduced cost, additional populations with different degrees of genetic relationship should be assessed to derive estimates of prediction accuracies to be expected in practical breeding programmes.

genetics↗

bioRxiv2022

Microenvironmental Ammonia Enhances T cell Exhaustion in Colorectal Cancer

Effective therapies are lacking for patients with advanced colorectal cancer (CRC). The CRC tumor microenvironment has elevated metabolic waste products due to altered metabolism and proximity to the microbiota. The role of metabolite waste in tumor development, progression, and treatment resistance is unclear. We generated an autochthonous metastatic mouse model of CRC and unbiased multi-omic analyses in this model reveals a robust accumulation of tumoral ammonia. The high ammonia levels induce T cell metabolic reprogramming, increase exhaustion and decrease proliferation. CRC patients have increased serum ammonia, and our ammonia-related gene signature correlates with altered T cell response, adverse patient outcomes, and lack of response to immune checkpoint blockade. We demonstrate that enhancing ammonia clearance reactivates T cells, decreases tumor growth, and extends survival. Moreover, decreasing tumor-associated ammonia enhances anti-PD-L1 efficacy. Our findings indicate that ammonia detoxification can reactivate T cells, highlighting a new approach to enhance the efficacy of immunotherapies. Statement of SignificanceWe demonstrate that ammonia accumulates in the microenvironment of colorectal cancer. Ammonia alters T-cells redox singling leading to a decrease in T cell proliferation and an increase in T cell exhaustion. Enhancing ammonia clearance reduces tumor size, increases survival, and increases the efficacy to immunotherapies.

cancer biology↗

bioRxiv2021

Organizing Principles of Astrocytic Nanoarchitecture in the Mouse Cerebral Cortex

Astrocytes have complex roles in central nervous system (CNS) health and disease. Underlying these roles is an elaborate architecture based on frequent, extremely fine, but seemingly haphazard branches, as well as prominent features including tripartite synaptic complexes and perivascular endfeet. While broad categories of structures in astrocytes are known, the fundamental building blocks that compose them and their organizing principles have yet to be adequately defined. This is largely due to the absence of high-resolution datasets that can reveal nanoscopic features of astrocytes (i.e. 10-20nm diameter in x, y, and z) and a lack of computational approaches that can effectively interrogate astrocyte shape, organization, and nanoarchitecture. Here, we produced and analyzed multiple, high-resolution datasets of layer 2/3 mouse somatosensory cortex using focused ion beam scanning electron microscopy (8nm intervals) and computer vision approaches to provide a principled, quantitative analysis of astrocytic nanoarchitecture. A decomposition of astrocytes into fundamental parts led to the discovery of unique structural components, recurring structural motifs, and assembly of parts into an organized hierarchy. New relationships were also discerned between astrocytic processes and other CNS microanatomy including mitochondria, tripartite synapses, and cerebrovasculature. By deploying computational resources to quantitatively understand the organizing principles and nanoarchitecture of astrocytes, this study reveals the specialized anatomical adaptations of these complex cells within the CNS. One Sentence SummaryUsing high-resolution serial electron microscopy datasets and computer vision, this study provides a systematic analysis of astrocytic nanoarchitecture from multiple samples of layer 2/3 of adult mouse neocortex, and presents quantitative evidence that astrocytes organize their morphology into purposeful, classifiable assemblies with unique structural and subcellular organelle adaptations related to their physiological functions.

neuroscience↗

bioRxiv2020

The life-history fitness of F1 hybrids of the microcrustacean Daphnia pulex and D. pulicaria (Crustacea, Anomopoda)

Negative interaction between alleles that arise independently in diverging populations (i.e., Dobzhansky-Muller incompatibilities) can cause reduction of fitness in their hybrids. However, heterosis in hybrids can emerge if hybridization breaks down detrimental epistatic interaction within parental lineages. In this study, we examined the life-history fitness of the inter-specific F1 hybrids of two recently diverged microcrustacean species Daphnia pulex and D. pulicaria as well as intra-specific F1 hybrids of D. pulex. We identified heterosis in four out of five life-history traits in the inter-specific F1 hybrids. The observation of heterosis in these life-history traits suggests that there are no major genetic incompatibilities between these two species affecting these traits. This also suggests that D. pulex and D. pulicaria are at the early stage of speciation where heterosis can still occur.

evolutionary biology↗

bioRxiv2019

Structure of the Glutamate-Like Receptor GLR3.2 ligand-binding domain

Glutamate-like receptors (GLRs) in plants play an important role in a number of physiological processes, including wound response, stomatal aperture control, seed germination, root development, innate immune responses, pollen tube growth and morphogenesis. GLRs share amino acid sequence similarity with ionotropic glutamate receptors (iGluRs) that mediate neurotransmission in the nervous system of vertebrates. In contrast to iGluRs, however, for which numerous full-length structures are available, the structural information about the plant GLRs has been missing. Here we determine crystal structures of Arabidopsis thaliana GLR3.2 ligand-binding domain (LBD) in complex with glycine and methionine to 1.57 and 1.86 [A] resolution, respectively. Our structures show a fold similar to iGluRs, with several secondary structure elements either missing or different. The closed clamshell conformation of GLR3.2 LBD suggests that both glycine and methionine act as agonists. The structures reveal molecular determinants of ligand binding and explain the promiscuity of GLRs ligand activation compared to iGluRs. Structural similarities of LBDs confirm an evolutionary relationship between GLRs and iGluRs and predict common molecular principles of their gating mechanisms that are driven by the bilobed clamshell-like LBDs.

biophysics↗

bioRxiv2019

Pathognomonic and epistatic genetic alterations in B-cell non-Hodgkin lymphoma

B-cell non-Hodgkins lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common subtypes of B-NHL such as diffuse large B-cell lymphoma (DLBCL) have been comprehensively interrogated at the genomic level. But rarer subtypes such as mantle cell lymphoma (MCL) remain sparsely characterized. Furthermore, multiple B-NHL subtypes have thus far not been comprehensively compared using the same methodology to identify conserved or subtype-specific patterns of genomic alterations. Here, we employed a large targeted hybrid-capture sequencing approach encompassing 380 genes to interrogate the genomic landscapes of 685 B-NHL tumors at high depth; including DLBCL, MCL, follicular lymphoma (FL), and Burkitt lymphoma (BL). We identified conserved hallmarks of B-NHL that were deregulated in the majority of tumor from each subtype, including the frequent genetic deregulation of the ubiquitin proteasome system (UPS). In addition, we identified subtype-specific patterns of genetic alterations, including clusters of co-occurring mutations and DNA copy number alterations. The cumulative burden of mutations within a single cluster were more discriminatory of B-NHL subtypes than individual mutations, implicating likely patterns of genetic cooperation that contribute to disease etiology. We therefore provide the first cross-sectional analysis of mutations and DNA copy number alterations across major B-NHL subtypes and a framework of co-occurring genetic alterations that deregulate genetic hallmarks and likely cooperate in lymphomagenesis.

genomics↗

bioRxiv2019

An adult brain atlas reveals broad neuroanatomical changes in independently evolved populations of Mexican cavefish

A shift in environmental conditions impacts the evolution of complex developmental and behavioral traits. The Mexican cavefish, Astyanax mexicanus, is a powerful model for examining the evolution of development, physiology, and behavior because multiple cavefish populations can be compared to an extant and ancestral-like surface population of the same species. Many behaviors have diverged in cave populations of A. mexicanus, and previous studies have shown that cavefish have a loss of sleep, reduced stress, an absence of social behaviors, and hyperphagia. Despite these findings, surprisingly little is known about the changes in neuroanatomy that underlie these behavioral phenotypes. Here, we use serial sectioning to generate a brain atlas of surface fish and three independent cavefish populations. Volumetric reconstruction of serial-sectioned brains confirms convergent evolution on reduced optic tectum volume in all cavefish populations tested. In addition, we quantified volumes of specific neuroanatomical loci within several brain regions, which have previously been implicated in behavioral regulation, including the hypothalamus, thalamus, and habenula. These analyses reveal an expansion of the hypothalamus across all three cavefish populations relative to surface fish, as well as subnuclei-specific differences within the thalamus and habenulae. Taken together, these analyses support the notion that changes in environmental conditions are accompanied by neuroanatomical changes in brain structures associated with behavior. This atlas provides a resource for comparative neuroanatomy of additional brain regions and the opportunity to associate brain anatomy with evolved changes in behavior.

neuroscience↗

bioRxiv2019

Selective inhibition of HDAC3 targets synthetic vulnerabilities and activates immune surveillance in lymphoma

CREBBP mutations are highly recurrent in B-cell lymphomas and either inactivate its histone acetyltransferase (HAT) domain or truncate the protein. Herein, we show that these two classes of mutations yield different degrees of disruption of the epigenome, with HAT mutations being more severe and associated with inferior clinical outcome. Genes perturbed by CREBBP mutation are direct targets of the BCL6/HDAC3 onco-repressor complex. Accordingly, we show that HDAC3 selective inhibitors fully reverse CREBBP mutant aberrant epigenetic programming resulting in: a) growth inhibition of lymphoma cells through induction of BCL6 target genes such as CDKN1A and b) restoration of immune surveillance due to induction of BCL6 repressed IFN pathway and antigen presentation genes. By reactivating these genes, exposure to HDAC3-i restored the ability of tumor infiltrating lymphocytes to kill DLBCL cells in an MHC II and MHC I dependent manner. Hence HDAC3-i represent a novel mechanism-based immune-epigenetic therapy for CREBBP mutant lymphomas. STATEMENT OF SIGNIFICANCEWe have leveraged the molecular characterization of different types of CREBBP mutations to define a rational approach for targeting these mutations through selective inhibition of HDAC3. This represents an attractive therapeutic avenue for targeting synthetic vulnerabilities in CREBBP mutant cells in tandem with promoting anti-tumor immunity.

cancer biology↗

bioRxiv2018

Sensitive information leakage from functional genomics data: Theoretical quantifications & practical file formats for privacy preservation

The generation of functional genomics datasets is surging, as they provide insight into gene regulation and organismal phenotypes (e.g., genes upregulated in cancer). The intention of functional genomics experiments is not necessarily to study genetic variants, yet they pose privacy concerns due to their use of next-generation sequencing. Moreover, there is a great incentive to share raw reads for better analyses and general research reproducibility. Thus, we need new modes of sharing beyond traditional controlled-access models. Here, we develop a data-sanitization procedure allowing raw functional genomics reads to be shared while minimizing privacy leakage, thus enabling principled privacy-utility trade-offs. It works with traditional Illumina-based assays and newer technologies such as 10x single-cell RNA-sequencing. The procedure depends on quantifying the privacy leakage in reads by statistically linking study participants to known individuals. We carried out these linkages using data from highly accurate reference genomes and more realistic environmental samples.

bioinformatics↗

bioRxiv2018

Risk Factors for Fouling Biomass: Evidence from Small Vessels in Australia

Invasive marine non-indigenous species are a major threat to marine biodiversity and marine related industries. Recreational vessels are recognised as an important vector of non-indigenous species translocation, particularly the secondary translocation of species domestically.\n\nThis paper reports on a novel application of multilevel modelling and multiple imputation to biomass samples gathered from the hull and other external surfaces of recreational yachts and fishing vessels in order to quantify the relationship between the wet biomass of biofouling and vessel-level characteristics. Unsurprisingly, we find that the number of days since the vessel was last cleaned was strongly related to the wet weight of biomass. The number of days since the vessel was last used was also related to the wet weight of biomass, yet differed depending on the vessel type. Similarly, the median number of trips undertaken by the vessel was related to the wet weight of biomass, and varied according to the type of antifouling paint used by the vessel. The relationship between vessel size, as measured by hull surface area, and wet weight biomass per sample unit area was not significant.\n\nIn order to reduce the international and domestic spread of invasive species, small vessel owners should use an appropriate type of antifouling paint that suits their vessels operational profile, and be encouraged to maintain a maintenance

ecology↗

bioRxiv2017

A 30-minute nucleic acid amplification point-of-care test for genital Chlamydia trachomatis infection in women: a prospective, multi-centre study of diagnostic accuracy

BackgroundRapid Point-Of-Care Tests (POCTs) for Chlamydia trachomatis (CT) may reduce onward transmission and reproductive sexual health (RSH) sequelae by reducing turnaround times between diagnosis and treatment. The io(R) single module system (Atlas Genetics Ltd) runs clinical samples through a microfluidic CT cartridge, delivering results in 30 minutes. We evaluated its performance on female genital samples in four UK Genito-Urinary Medicine (GUM)/RSH clinics.\n\nMethodsProspective diagnostic accuracy study, using BD ProbeTec CT/GC assay as the routine clinic nucleic acid amplification test (NAAT) as the initial comparator test, and the QIAgen Artus CT assay to resolve discrepancies. In these instances, the reference standard was defined as the resolved result when two out of three assay results concurred. Female participants aged [≥]16 provided additional-to-routine self-collected vulvovaginal swabs. Samples were tested fresh with the io(R) CT assay within 7 days of collection, or were frozen at -80{degrees}C for later testing. Participant clinical, demographic and behavioural characteristics were collected to assess risk factors associated with CT infection.\n\nResultsOf 785 participants recruited, final analyses were conducted on 709 (90.3%). CT prevalence was 7.2% (51/709) overall. Sensitivity, specificity, positive and negative predictive values of the io(R) CT assay were, respectively, 96.1% (95% Confidence Interval (CI): 86.5-99.5), 97.7% (95%CI: 96.3-98.7), 76.6% (95%CI: 64.3-86.2) and 99.7% (95%CI: 98.9-100). There was no significant difference in performance measures between fresh and frozen samples, or between symptomatic and asymptomatic participants (p>0.05). The only risk factor associated with CT infection was being a sexual contact of an individual with CT.\n\nConclusionsThe io(R) CT-assay is the only 30-minute, fully automated, high-performing NAAT currently CE-marked for CT diagnosis in women, making it a highly promising diagnostic to enable specific treatment, initiation of partner notification and appropriately intensive health promotion at the point of care. Future research is required to evaluate acceptability by clinicians and patients in GUM/RSH clinics, impact on clinical pathways and patient management, and cost-effectiveness.

epidemiology↗

bioRxiv2017

DNA copy number gains of TCF4 (E2-2) are associated with poor outcome and the activated B-cell-like subtype of diffuse large B-cell lymphoma

The activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) is characterized by the chronic activation of signaling initiated by immunoglobulin- (IgM). By analyzing DNA copy profiles of 1,000 DLBCLs, we identified gains of 18q21.2 as the most frequent genetic alteration in ABC-like DLBCL. We show that these alterations target the TCF4 (E2-2) transcription factor, and that over-expression of TCF4 leads to its occupancy on immunoglobulin gene enhancers and increased expression of IgM at the transcript and protein level. The TCF4 gene is one of the top BRD4-regulated genes in DLBCL. Using a BET proteolysis-targeting chimera (PROTAC) we show that TCF4 and IgM expression can be extinguished, and ABC-like DLBCL cells can be killed in vitro and in vivo. This highlights a novel genetic mechanism for promoting immunoglobulin signaling in ABC-like DLBCL and provides a functional rationale for the use of BET inhibitors in this disease.

genomics↗