Biology subjects

Oliver, B.

Publications and source records attributed to Oliver, B..

At least 19 recordsLinked to original sources

bioRxiv2026

A brain-tumour axis links chronic stress to gastric cancer progression through NPY signalling

Chronic stress promotes gastric tumour growth, but the central neural pathways remain largely enigmatic. Here, we identify a brain-tumour axis, implicating the central amygdala (CeA) activity in promoting gastric cancer growth through sympathetic neuropeptide Y (NPY) signalling occurring within the tumour. Using clinical datasets, patient samples, pathway tracing, electrophysiology and chemogenetic manipulation, we demonstrate that stress selectively increases NPY Y1 receptor (NPY1R) synthesis in the patients gastric cancer tissue; moreover, the NPY1R density correlates with advanced cancer stage and poor prognosis. In mice, daily constraint chronic stress enhances CeA excitability and promotes sympathetic neurotransmitter norepinephrine release within the tumour microenvironment. Norepinephrine, in turn, increases tumour endogenous NPY/NPY1R production and the activation of downstream MAPK/Erk1/2 signalling pathway, which drives cancer cell proliferation and invasion. Manipulating CeA neuronal activity alone can regulate tumour growth, whereas selectively blocking tumour NPY1R prevents stress-induced tumour progression in vivo and cancer cell migration in vitro. This study identifies a central-to-peripheral circuit linking chronic stress to gastric cancer growth, and highlights NPY1R as a potential therapeutic target.

Cancer Biology↗

bioRxiv2026

Conserved Molecular Responses to Arsenite Exposure in Drosophila melanogaster

Arsenic exposure is a pervasive global health threat strongly associated with increased risk of morbidities such as diabetes, cardiovascular disease, and cancer. Despite extensive studies describing the dangers of arsenic exposure, the molecular initiating events that link arsenic to chronic disease onset and progression remain poorly defined. To address this knowledge gap, we combined time-resolved transcriptomic and metabolomic profiling of adult Drosophila melanogaster exposed to sodium (meta) arsenite (NaAsO2). We uncovered coordinated, dose-dependent shifts in gene expression and metabolite abundance that activate canonical detoxification pathways and mirror arsenic-associated disease signatures in humans. Notably, flies rapidly upregulated heatshock and xenobiotic response gene networks, followed by biomarkers characteristic of diabetic states (elevated glucose, lactate, and methylglyoxal, for example). These findings reveal conserved molecular pathways that couple arsenic exposure to metabolic dysfunction and establish Drosophila as a powerful whole-organism model for identifying early biomarkers and mechanistic drivers of arsenic-induced disease phenotypes.

pharmacology and toxicology↗

bioRxiv2024

Diverse somatic Transformer and sex chromosome karyotype pathways regulate gene expression in Drosophila gonad development

The somatic sex determination gene transformer (tra) is required for the highly sexually dimorphic development of most somatic cells, including those of the gonads. In addition, somatic tra is required for the germline development even though it is not required for sex determination within germ cells. Germ cell autonomous gene expression is also necessary for their sex determination. To understand the interplay between these signals, we compared the phenotype and gene expression of larval wild-type gonads and the sex-transformed tra gonads. XX larval ovaries transformed into testes were dramatically smaller than wild-type, with significant reductions in germ cell number, likely due to altered geometry of the stem cell niche. Additionally, there was a defect in progression into spermatocyte stages. XY larval testes transformed into ovaries had excessive germ cells, possibly due to the earlier onset of cell division. We suggest that germ cells are neither fully female nor male following somatic sex transformation, with certain pathways characteristic of each sex expressed in tra mutants. We found multiple patterns of somatic and germline gene expression control exclusively due to tra, exclusively due to sex chromosome karyotype, but usually due to a combination of these factors showing tra and sex chromosome karyotype pathways regulate gene expression during Drosophila gonad development.

developmental biology↗

bioRxiv2023

OVO Positively Regulates Essential Maternal Pathways by Binding Near the Transcriptional Start Sites in the Drosophila Female Germline

Differentiation of female germline stem cells into a mature oocyte includes the expression of RNAs and proteins that drive early embryonic development in Drosophila. We have little insight into what activates the expression of these maternal factors. One candidate is the zinc-finger protein OVO. OVO is required for female germline viability and has been shown to positively regulate its own expression, as well as a downstream target, ovarian tumor, by binding to the transcriptional start site (TSS). To find additional OVO targets in the female germline and further elucidate OVOs role in oocyte development, we performed ChIP-seq to determine genome-wide OVO occupancy, as well as RNA-seq comparing hypomorphic and wild type rescue ovo alleles. OVO preferentially binds in close proximity to target TSSs genome-wide, is associated with open chromatin, transcriptionally active histone marks, and OVO-dependent expression. Motif enrichment analysis on OVO ChIP peaks identified a 5'-TAACNGT-3' OVO DNA binding motif spatially enriched near TSSs. However, the OVO DNA binding motif does not exhibit precise motif spacing relative to the TSS characteristic of RNA Polymerase II complex binding core promoter elements. Integrated genomics analysis showed that 525 genes that are bound and increase in expression downstream of OVO are known to be essential maternally expressed genes. These include genes involved in anterior/posterior/germ plasm specification (bcd, exu, swa, osk, nos, aub, pgc, gcl), egg activation (png, plu, gnu, wisp, C(3)g, mtrm), translational regulation (cup, orb, bru1, me31B), and vitelline membrane formation (fs(1)N, fs(1)M3, clos). This suggests that OVO is a master transcriptional regulator of oocyte development and is responsible for the expression of structural components of the egg as well as maternally provided RNAs that are required for early embryonic development.

developmental biology↗

bioRxiv2023

Female germline expression of OVO transcription factor bridges Drosophila generations

OVO is required for karyotypically female germ cell viability but has no known function in the male germline in Drosophila. ovo is autoregulated by two antagonistic isoforms, OVO-A and OVO-B. All ovo- alleles were created as partial revertants of the antimorphic ovoD1allele. Creation of new targeted alleles in an ovo+ background indicated that disrupting the germline-specific exon extension of ovo-B leads to an arrested egg chamber phenotype, rather than germ cell death. RNA-seq analysis, including >1K full length cDNAs, indicates that ovo utilizes a number of unannotated splice variations in the extended exon and a minor population of ovo-B transcripts utilizes an alternative splice. This indicates that classical ovo alleles such as ovoD1rv23, are not truly null for ovo, and are likely to be weak antimorphs. To generate bonafide nulls, we deleted the ovo-A and ovo-B promoters showing that only ovo-B is required for female germ cell viability and there is an early and polyphasic developmental requirement for ovo-B in the female germline. To visualize OVO expression and localization, we endogenously tagged ovo and found nuclear OVO in all differentiating female germ cells throughout oogenesis in adults. We also found that OVO is maternally deposited into the embryo, where it showed nuclear localization in newly formed pole cells. Maternal OVO persisted in embryonic germ cells until zygotic OVO expression was detectable, suggesting that there is continuous nuclear OVO expression in the female germline in the transition from one generation to the next. Article Summaryovo has long been considered to be at the top of the female germline sex determination pathway. We utilized updated genetic methods to determine OVO expression, localization, and requirement in the embryonic and adult germline. Our results indicate that OVO is always present, and likely required, in the Drosophila female germline.

genetics↗

bioRxiv2022

Emergent dynamics of adult stem cell lineages from single nucleus and single cell RNA-Seq of Drosophila testes

Proper differentiation of sperm from germline stem cells, essential for production of the next generation, requires dramatic changes in gene expression that drive remodeling of almost all cellular components, from chromatin to organelles to cell shape itself. Here we provide a single nucleus and single cell RNA-seq resource covering all of spermatogenesis in Drosophila starting from in-depth analysis of adult testis single nucleus RNA-seq (snRNA-seq) data from the Fly Cell Atlas (FCA) study (Li et al., 2022). With over 44,000 nuclei and 6,000 cells analyzed, the data provide identification of rare cell types, mapping of intermediate steps in differentiation, and the potential to identify new factors impacting fertility or controlling differentiation of germline and supporting somatic cells. We justify assignment of key germline and somatic cell types using combinations of known markers, in situ hybridization, and analysis of extant protein traps. Comparison of single cell and single nucleus datasets proved particularly revealing of dynamic developmental transitions in germline differentiation. To complement the web-based portals for data analysis hosted by the FCA, we provide datasets compatible with commonly used software such as Seurat and Monocle. The foundation provided here will enable communities studying spermatogenesis to interrogate the datasets to identify candidate genes to test for function in vivo.

developmental biology↗

bioRxiv2021

A meta-analysis of task-based differences in bilingual L1 and L2 language networks

The functional organization of first (L1) and second (L2) language processing in bilinguals remains a topic of great interest to the neurolinguistics community. Functional magnetic resonance imaging (fMRI) studies report meaningful differences in the location and extent of hemodynamic changes between tasks performed in the L1 and L2, yet there is no consensus on whether these networks can be considered truly distinct. In part, this may be due to the multiplicity of task designs implemented in such studies, which complicates the interpretation of their findings. This paper compares the results of previous bilingual meta-analyses to a new ALE meta-analysis that categorizes neuroimaging studies by task design. Factors such as the age of L2 acquisition (AoA) and the L2 language proficiency level of participants are also considered. The findings support previous accounts of the effect of participant characteristics on linguistic processing, while at the same time revealing dissociable differences in fMRI activation for L1 and L2 networks within and across tasks that appear independent of these external factors.

neuroscience↗

bioRxiv2021

Fly Cell Atlas: a single-cell transcriptomic atlas of the adult fruit fly

The ability to obtain single cell transcriptomes for stable cell types and dynamic cell states is ushering in a new era for biology. We created the Tabula Drosophilae, a single cell atlas of the adult fruit fly which includes 580k cells from 15 individually dissected sexed tissues as well as the entire head and body. Over 100 researchers from the fly community contributed annotations to >250 distinct cell types across all tissues. We provide an in-depth analysis of cell type-related gene signatures and transcription factor markers, as well as sexual dimorphism, across the whole animal. Analysis of common cell types that are shared between tissues, such as blood and muscle cells, allowed the discovery of rare cell types and tissue-specific subtypes. This atlas provides a valuable resource for the entire Drosophila community and serves as a comprehensive reference to study genetic perturbations and disease models at single cell resolution.

genomics↗

bioRxiv2020

Dynamic Sex Chromosome Expression in Drosophila Male Germ Cells

Sex chromosome gene content and expression is unusual. In many organisms the X and Y chromosomes are inactivated in spermatocytes, possibly as a defense mechanism against insertions into unpaired chromatin. In addition to current sex chromosomes, Drosophila has a small gene-poor X-chromosome relic (4th) that re-acquired autosomal status. Using single cell RNA-Seq, we demonstrate that the single X and pair of 4th chromosomes are specifically inactivated in primary spermatocytes. In contrast, genes on the single Y chromosome become maximally active in primary spermatocytes. Reduced X steady-state transcript levels are due to failed activation of RNA-Polymerase-II by phosphorylation of Serine 2 and 5. One Sentence SummarySex chromosome expression during spermatogenesis at the single cell level

developmental biology↗

bioRxiv2020

Glycolytic metabolism of pathogenic T cells enables early detection of GvHD by 13C-MRI

Graft-versus-host disease (GvHD) is a prominent barrier to allogeneic hematopoietic stem cell transplantation (HSCT). Definitive diagnosis of GvHD is invasive and biopsies of involved tissues pose a high risk of bleeding and infection. Our previous studies in a chronic GvHD mouse model demonstrated that alloreactive CD4+ T cells are distributed to target organs ahead of overt symptoms, meanwhile CD4+ T cell activation is tied to increased glycolysis. Thus, we hypothesized that metabolic imaging of glycolysis would allow non-invasive detection of insipient GvHD in target organs infiltrated by glycolytic effector memory CD4+ T cells. We metabolically characterized CD4+ T cell subsets on day 14 post-transplant before the onset of chronic GvHD in a pre-clinical mouse model and performed 13C hyperpolarized magnetic resonance imaging (MRI) to quantify glycolytic activity in the liver of mice over the course of the disease. Intracellular metabolic screening and ex vivo metabolic profiling of CD4+ T cell subsets at day 14 confirmed that activated CD4+ T cells were highly glycolytic. Concurrently, hyperpolarized 13C-pyruvate MRI of the liver showed high conversion of pyruvate to lactate, indicative of increased glycolytic activity, that distinguished allogeneic from syngeneic HSCT recipients prior to the development of overt chronic GvHD. Furthermore, single cell sequencing of T cells in patients undergoing allogeneic HSCT indicated that similar metabolic changes may play a role in acute GvHD, providing a rationale for testing this imaging approach in the clinical post-HSCT setting. Our imaging approach is amenable to clinical translation and may allow early, non-invasive diagnosis of GvHD.

immunology↗

bioRxiv2020

Reconstruction of Gene Regulatory Networks by integrating biological model and a recommendation system

Gene Regulatory Networks (GRNs) control many aspects of cellular processes including cell differentiation, maintenance of cell type specific states, signal transduction, and response to stress. Since GRNs provide information that is essential for understanding cell function, the inference of these networks is one of the key challenges in systems biology. Leading algorithms to reconstruct GRN utilize, in addition to gene expression data, prior knowledge such as Transcription Factor (TF) DNA binding motifs or results of DNA binding experiments. However, such prior knowledge is typically incomplete hence resulting in missing values. Therefore, the integration of such incomplete prior knowledge with gene expression to elucidate the underlying GRNs remains difficult. To address this challenge we introduce NetREX-CF - Regulatory Network Reconstruction using EXpression and Collaborative Filtering - a GRN reconstruction approach that brings together a modern machine learning strategy (Collaborative Filtering model) and a biologically justified model of gene expression (sparse Network Component Analysis based model). The Collaborative Filtering (CF) model is able to overcome the incompleteness of the prior knowledge and make edge recommends for building the GRN. Complementing CF, the sparse Network Component Analysis (NCA) model can use gene expression data to validate the recommended edges. Here we combine these two approaches using a novel data integration method and show that the new approach outperforms the currently leading GRN reconstruction methods. Furthermore, our mathematical formalization of the model has lead to a complex optimization problem of a type that has not been attempted before. Specifically, the formulation contains{ell} 0 norm that can not be separated from other variables. To fill this gap, we introduce here a new method Generalized PALM (GPALM) that allows us to solve a broad class of non-convex optimization problems and prove its convergence.

bioinformatics↗

bioRxiv2020

Modeling gene expression evolution with EvoGeneX uncovers differences in evolution of species, organs and sexes

While DNA sequence evolution has been well studied, the expression of genes is also subject to evolution, yet the evolution of gene expression is currently not well understood. Recently, new tissue/organ-specific gene expression datasets spanning several organisms across the tree of life, have become available, providing the opportunity to study gene expression evolution in more detail. While a theoretical model to study the evolution of continuous traits exists, in practice computational methods often cannot confidently distinguish between alternative evolutionary scenarios. This lack of power has been attributed to modest numbers of species considered in these studies. We hypothesised that biological replicates can be used to increase predictive power of these models. With this in mind, we introduce EvoGeneX, a computationally efficient method to uncover the mode of gene expression evolution based on the Ornstein-Uhlenbeck process. Importantly, in addition to modelling expression variations between species, EvoGeneX models within-species variation. Furthermore, to facilitate comparative analysis of gene expression evolution, we introduce a formal approach, based on Michaelis-Menten equation, to measure the dynamics of evolutionary divergence of a group of genes in terms of groups asymptotic divergence level and rate. Finally, we used these tools to preform the first analysis the evolution of gene expression across different body parts, species, and sexes of the Drosophila genus. Our analysis revealed that neutral expression evolution can be confidently rejected in favor of purifying selection in nearly half of the genes. In addition, we quantified differences in the evolutionary dynamics of male and female gonads and uncovered interesting examples of adaptive gene expression evolution.

evolutionary biology↗

bioRxiv2019

IRBIT Directs Differentiation of Intestinal Stem Cell Progeny to Maintain Tissue Homeostasis

The maintenance of the intestinal epithelium is ensured by the controlled proliferation of intestinal stem cells (ISCs) and differentiation of their progeny into various cell types, including enterocytes (ECs) that both mediate nutrient absorption and provide a barrier against pathogens. The signals that regulate transition of proliferative ISCs into differentiated ECs are not fully understood. IRBIT is an evolutionarily conserved protein that regulates ribonucleotide reductase (RNR), an enzyme critical for the generation of DNA precursors. Here, we show that IRBIT expression in ISC progeny within the Drosophila midgut epithelium cells is essential for their differentiation via suppression of RNR activity. Disruption of this IRBIT-RNR regulatory circuit causes a rapid, premature loss of intestinal tissue integrity as flies age. This age-related dysplasia can be reversed by suppression of RNR activity in ISC progeny. Collectively, our findings demonstrate an unexpected and novel role of the IRBIT-RNR pathway in gut homeostasis.

developmental biology↗

bioRxiv2018

Non-canonical Drosophila X chromosome dosage compensation and repressive topologically-associated domains

BackgroundIn animals with XY sex chromosomes, X-linked genes from a single X chromosome in males are imbalanced relative to autosomal genes. To minimize the impact of genic imbalance in male Drosophila, there is a dosage compensation complex (MSL), that equilibrates X-linked gene expression with the autosomes. There are other potential contributions to dosage compensation. Hemizygous autosomal genes located in repressive chromatin domains are often de-repressed. If this homolog-dependent repression occurs on the X, which has no pairing partner, then de-repression could contribute to male dosage compensation.\n\nResultsWe asked whether different chromatin states or topological associations correlate with X chromosome dosage compensation, especially in regions with little MSL occupancy. Our analyses demonstrated that male X chromosome genes that are located in repressive chromatin states are depleted of MSL occupancy, however they show dosage compensation. The genes in these repressive regions were also less sensitive to knockdown of MSL components.\n\nConclusionsOur results suggest that this non-canonical dosage compensation is due to the same trans-acting de-repression that occurs on autosomes. This mechanism would facilitate immediate compensation during the evolution of sex chromosomes from autosomes. This mechanism is similar to that of C. elegans, where enhanced recruitment of X chromosomes to the nuclear lamina dampens X chromosome expression as part of the dosage compensation response in XX individuals.

genomics↗

bioRxiv2018

The High-throughput WAFFL System for Treating and Monitoring Individual Drosophila melanogaster Adults

Non-mammalian model organisms have been essential for our understanding of the mechanisms and control of development, disease, and physiology, but are underutilized in pharmacological phenotypic screening assays due to low throughput compared to cell-based systems. To increase the utility of using Drosophila melanogaster in screening, we have designed the whole animal feeding flat (WAFFL), a novel, flexible, and complete system for feeding, monitoring, and assaying flies in a high throughput format. Our system was conceived keeping in mind the use of off-the-shelf, commercial, 96-well consumables and equipment in order to be amenable to experimental needs. Here we provide an overview of the design and 3-D printing manufacture specifications.

pharmacology and toxicology↗

bioRxiv2018

Rapid development of an infant-derived HIV-1 broadly neutralizing antibody lineage

HIV-infected infants develop broadly neutralizing plasma responses with more rapid kinetics than adults, suggesting the ontogeny of infant responses could better inform a path to achievable vaccine targets. We developed computational methods to reconstruct the developmental lineage of BF520.1, the first example of a HIV-specific broadly neutralizing antibody (bnAb) from an infant. The BF520.1 inferred naive precursor binds HIV Env and a bnAb evolved within six months of infection and required only 3% mutation. Mutagenesis and structural analyses revealed that for this infant bnAb, substitutions in the kappa chain were critical for activity, particularly in CDRL1. Overall, the developmental pathway of this infant antibody includes features distinct from adult antibodies, including several that may be amenable to better vaccine responses.

immunology↗

bioRxiv2018

Whole genome screen reveals a novel relationship between Wolbachia and Drosophila host translation

Wolbachia is an intracellular bacterium that infects a remarkable range of insect hosts. Insects such as mosquitos act as vectors for many devastating human viruses such as Dengue, West Nile, and Zika. Remarkably, Wolbachia infection provides insect hosts with resistance to many arboviruses thereby rendering the insects ineffective as vectors. To utilize Wolbachia effectively as a tool against vector-borne viruses a better understanding of the host-Wolbachia relationship is needed. To investigate Wolbachia-insect interactions we used the Wolbachia/Drosophila model that provides a genetically tractable system for studying host-pathogen interactions. We coupled genome-wide RNAi screening with a novel high-throughput fluorescence in situ hybridization (FISH) assay to detect changes in Wolbachia levels in a Wolbachia-infected Drosophila cell line JW18. 1117 genes altered Wolbachia levels when knocked down by RNAi of which 329 genes increased and 788 genes decreased the level of Wolbachia. Validation of hits included in depth secondary screening using in vitro RNAi, Drosophila mutants, and Wolbachia-detection by DNA qPCR. A diverse set of host gene networks was identified to regulate Wolbachia levels and unexpectedly revealed that perturbations of host translation components such as the ribosome and translation initiation factors results in increased Wolbachia levels both in vitro using RNAi and in vivo using mutants and a chemical-based translation inhibition assay. This work provides evidence for Wolbachia-host translation interaction and strengthens our general understanding of the Wolbachia-host intracellular relationship.\n\nAuthor summaryInsects such as mosquitos act as vectors to spread devastating human diseases such as Dengue, West Nile, and Zika. It is critical to develop control strategies to prevent the transmission of these diseases to human populations. A novel strategy takes advantage of an endosymbiotic bacterium Wolbachia pipientis. The presence of this bacterium in insect vectors prevents successful transmission of RNA viruses. The degree to which viruses are blocked by Wolbachia is dependent on the levels of the bacteria present in the host such that higher Wolbachia levels induce a stronger antiviral effect. In order to use Wolbachia as a tool against vector-borne virus transmission a better understanding of host influences on Wolbachia levels is needed. Here we performed a genome-wide RNAi screen in a model host system Drosophila melanogaster infected with Wolbachia to identify host systems that affect Wolbachia levels. We found that host translation can influence Wolbachia levels in the host.

microbiology↗

bioRxiv2018

Drosophila small ovary encodes a zinc-finger repressor required for ovarian differentiation

Repression is essential for coordinated cell type-specific gene regulation and controlling the expression of transposons. In the Drosophila ovary, stem cell regeneration and differentiation requires controlled gene expression, with derepression leading to tissue degeneration and ovarian tumors. Likewise, the ovary is acutely sensitive to deleterious consequences of transposon derepression. The small ovary (sov) locus was identified in a female sterile screen, and mutants show dramatic ovarian morphogenesis defects. We mapped the locus to the uncharacterized gene CG14438, which encodes a zinc-finger protein that colocalizes with the essential Heterochromatin Protein 1 (HP1a). We demonstrate that Sov functions to repress inappropriate cell signaling, silence transposons, and suppress position-effect variegation in the eye, suggesting a central role in heterochromatin stabilization.

developmental biology↗