Biology subjects

Richardson, B.

Publications and source records attributed to Richardson, B..

9 recordsLinked to original sources

bioRxiv2026

Restoration of Keratinocyte Homeostasis Drives Resolution of Skin Inflammation

Chronic skin inflammation is sustained by reciprocal interactions between epidermal dysfunction and immune activation, yet whether epithelial state actively governs restoration of tissue homeostasis remains unclear. Using a murine model of inflammatory skin disease, we modulated epidermal lipid metabolism and examined its effects on tissue organization. Transcriptomic profiling revealed coordinated reversal of inflammatory, metabolic, and structural gene programs accompanied by normalization of epidermal architecture. Single-cell RNA sequencing showed that this remodeling was concentrated in differentiated keratinocytes, with suppression of IL-17 and neutrophil-associated responses and restoration of barrier and mitochondrial-lipid programs, while stromal and myeloid compartments displayed secondary adaptation. Cross-species analysis demonstrated that resolution-associated gene networks are inversely regulated in human psoriasis. Integrated proteomic and transcriptomic analyses further identified a conserved epithelial regulatory triad whose concordant regulation in psoriasis and atopic dermatitis, and whose in vivo silencing, establish mechanistic control of disease severity. Together, these findings indicate that inflammatory resolution reflects reorganization of epidermal transcriptional networks and position epithelial state as a determinant of inflammatory persistence.

cell biology↗

bioRxiv2024

Aggregation promoting sequences rather than phosphorylation are essential for Tau-mediated toxicity in Drosophila

BackgroundDisease-modifying therapies for tauopathies like Alzheimers disease have targeted Tau hyperphosphorylation and aggregation, as both pathological manifestations are implicated in Tau-mediated toxicity. However, the relative contributions of these pathology-linked changes to Tau neurotoxicity remain unclear. MethodsLeveraging the genetic tractability of Drosophila, we generated multiple inducible human Tau transgenes with altered phosphorylation status and/or aggregation propensity. Their individual and combined impact was tested in vivo by quantifying Tau accumulation and neurodegenerative phenotypes in the aging fly nervous system. ResultsWe report that phospho-mimicking Tau (hTau2N4RE14) induced profound neurodegeneration, supporting a neurotoxic role for phosphorylation. However, when we rendered hTau2N4RE14 aggregation incompetent, by deleting the 306VQIVYK311 motif in the microtubule-binding region, neurotoxicity was abolished. Moreover, a peptide inhibitor targeting this motif efficaciously reduced Tau toxicity in aging Drosophila. ConclusionNeurodegeneration mediated by Tau hyperphosphorylation is gated via at least one aggregation-mediating motif on the protein. This highlights the primacy of blocking Tau aggregation in therapy, perhaps without the need to clear phosphorylated species.

neuroscience↗

bioRxiv2022

Global analysis of the yeast knock-out phenome

Genome-wide phenotypic screens in the budding yeast Saccharomyces cerevisiae have produced the largest, richest and most systematic phenotypic description of any organism. Such an achievement was enabled by the development of highly scalable phenotypic assays and construction of the yeast knock-out (YKO) collection, comprising ~5,000 isogenic strains each deleted for exactly one open reading frame. Systematic screening of the YKO collection led to ~500 publications describing ~14,500 phenotypes capturing nearly every aspect of yeast biology. Yet, integrative analyses of this rich data source have been virtually impossible due to the lack of a central repository and consistent meta-data annotations. Here, we describe the aggregation, harmonization and analysis of all published phenotypic screens of the YKO collection, which we refer to as the Yeast Phenome (www.yeastphenome.org). To demonstrate the power of data integration and illustrate how much it facilitates the generation of testable hypotheses, we present three discoveries uniquely enabled by Yeast Phenome. First, we use the variation in the number of phenotypes per gene to identify tryptophan homeostasis as a central point of vulnerability to a wide range of chemical compounds, including FDA-approved drugs. Second, using phenotypic profiles as a tool for predicting gene function, we identify and validate the role of YHR045W as a novel regulator of ergosterol biosynthesis and DNA damage response, and YGL117W as a new member of the aromatic amino acid biosynthesis pathway. Finally, we describe a surprising exponential relationship between phenotypic similarity and intergenic distance in both yeast and human genomes. This relationship, which stretches as far as 380 kb in yeast and 100 Mb in humans, suggests that gene positions are optimized for function to a much greater extent than appreciated previously. Overall, we show that Yeast Phenome enables systematic enquiries into the nature of gene-gene and gene-phenotype relationships and is an important new resource for systems biology.

systems biology↗

bioRxiv2022

Sex-specific niche signaling contributes to sexual dimorphism following stem cell transplantation

Hematopoietic stem cell (HSC) transplantation (HST) is a curative treatment for many hematopoietic cancers and bone marrow (BM) disorders but is currently limited by numerous complications including a lengthy recovery period, prolonged neutropenia resulting in severe infections and bleeding, and a high incidence of graft vs. host disease (GVHD). While clinical studies have demonstrated that sex mismatch, notably male recipients with female donor cells, results in increased risk of GVHD (likely due to male recipient minor histocompatibility antigens targeted by donor female T-cells 1), increased non-relapse mortality, and decreased overall survival, the mechanisms underlying sex-determinants on hematopoiesis and post-transplant recovery are not clear. In this manuscript we have identified: 1) unique expression of hematopoietic niche factors in the BM and spleens of male and female mice, 2) altered kinetics of hematopoietic reconstitution following transplantation when male vs. female BM is used as the donor cell source, 3) a sex-specific role for the recipient niche in promoting post HST recovery, and 4) a dose-dependent role for exogenous sex hormones in maintaining hematopoietic stem and progenitor cells (HSPCs). Taken together, these data demonstrate that sex-specific cellular and molecular signaling occurs during hematopoietic regeneration. Further identifying novel sex-dependent determinants of regeneration following transplantation will not only enhance understanding of steady state versus regeneration hematopoiesis but may also reveal unique (and potentially sex-specific) therapeutic targets to accelerate hematologic recovery. Key PointsO_LIMale and female mice display altered kinetics of regeneration following HST due to unique niche factors in hematopoietic compartments. C_LIO_LIExogenous steroid sex hormones uniquely regulate the pool of hematopoietic stem and progenitor cells and may impact transplantation outcomes. C_LI

immunology↗

bioRxiv2022

A histone deacetylase network regulates epigenetic reprogramming and viral silencing in HIV infected cells

Approximately 70% of the HIV-1 latent reservoir originates from infections of CD4 T cells that occur in the months near the time of ART initiation, raising the possibility that interventions during this period might prevent reservoir seeding and reduce reservoir size. We identify class 1 histone deacetylase inhibitors (HDACi) as potent agents of latency prevention. Inhibiting HDACs in productively infected cells caused extended maintenance of HIV expression and this activity was associated with persistently elevated H3K9 acetylation and reduced H3K9 methylation at the viral LTR promoter region. HDAC inhibition in HIV-infected CD4 T cells during effector-to-memory transition led to striking changes in the memory phenotype of infected cells. Proviral silencing is accomplished through distinct activities of HDAC1/2 and HDAC3. Thus HDACs regulate a critical gateway process for HIV latency establishment and are required for the development of CD4 T-cell memory subsets that preferentially harbor long-lived, latent provirus.

molecular biology↗

bioRxiv2021

Male sex and age biases viral burden, viral shedding, and type 1 and 2 interferon responses during SARS-CoV-2 infection in ferrets

SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) hospitalizations and deaths disportionally affect males and the elderly. Here we investigated the impact of male sex and age by infecting adult male, aged male, and adult female ferrets with SARS-CoV-2. Aged male ferrets had a decrease in temperature which was accompanied by prolonged viral replication with increased pathology in the upper respiratory tract after infection. Transcriptome analysis of the nasal turbinates and lungs indicated that female ferrets had significant increases in interferon response genes (OASL, MX1, ISG15, etc.) on day 2 post infection which was delayed in aged males. In addition, genes associated with taste and smell such as RTP1, CHGA, and CHGA1 at later time points were upregulated in males but not in females. These results provide insight into COVID-19 and suggests that older males may play a role in viral transmission due to decreased antiviral responses.

microbiology↗

bioRxiv2020

Climate influences the response of community functional traits to local conditions

Functional traits determine an organisms performance in a given environment and as such determine which organisms will be found where. Species respond to local conditions, but also to larger scale gradients, such as climate. Trait ecology links these responses of species to community composition and species distributions. Yet, we often do not know which environmental gradients are most important in determining community trait composition at either local or biogeographical scales, or their interaction. Here we quantify the relative contribution of local and climatic conditions to the structure and composition of functional traits found within bromeliad invertebrate communities. We conclude that climate explains more variation in invertebrate trait composition within bromeliads than does local conditions. Importantly, climate mediated the response of traits to local conditions; for example, invertebrates with benthic life-history traits increased with bromeliad water volume only under certain precipitation regimes. Our ability to detect this and other patterns hinged on the compilation of multiple fine-grained datasets, allowing us to contrast the effect of climate vs. local conditions. We suggest that, in addition to sampling communities at local scales, we need to aggregate studies that span large ranges in climate variation in order to fully understand trait filtering at local, regional and global scales.

ecology↗

bioRxiv2019

Oral tenofovir disoproxil fumarate/emtricitabine for HIV pre-exposure prophylaxis increases expression of type I/III interferon-stimulated factors in the gastrointestinal tract but not in the blood

Tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) are used for HIV treatment and prevention. Previously, we found that topical rectal tenofovir gel caused immunological changes in the mucosa. Here we assessed the effect of oral TDF/FTC in three HIV pre-exposure prophylaxis trials, two with gastrointestinal and one with cervicovaginal biopsies. TDF/FTC induced type I/III interferon-related (IFN I/III) genes in the gastrointestinal tract, but not blood, with strong correlations between the two independent rectal biopsy groups (Spearman r=0.91) and between the rectum and duodenum (r=0.81). Gene set testing also indicated stimulation of type I/III pathways in the ectocervix, as well as of cellular proliferation in the duodenum. mRNA sequencing, digital droplet PCR, proteomics, and immunofluorescence staining confirmed IFN I/III pathway stimulation in the gastrointestinal tract. Thus, oral TDF/FTC stimulates an IFN-I/III signature throughout the gut, which could increase antiviral efficacy but also cause chronic immune activation in HIV prevention and treatment settings.

immunology↗

bioRxiv2018

ICTD: Inference of cell types and deconvolution -- a next-generation deconvolution method for accurate assess cell population and activities in tumor microenvironment.

We developed a novel deconvolution method, namely Inference of Cell Types and Deconvolution (ICTD) that addresses the fundamental issue of identifiability and robustness in current tissue data deconvolution problem. ICTD provides substantially new capabilities for omics data based characterization of a tissue microenvironment, including (1) maximizing the resolution in identifying resident cell and sub types that truly exists in a tissue, (2) identifying the most reliable marker genes for each cell type, which are tissue and data set specific, (3) handling the stability problem with co-linear cell types, (4) co-deconvoluting with available matched multi-omics data, and (5) inferring functional variations specific to one or several cell types. ICTD is empowered by (i) rigorously derived mathematical conditions of identifiable cell type and cell type specific functions in tissue transcriptomics data and (ii) a semi supervised approach to maximize the knowledge transfer of cell type and functional marker genes identified in single cell or bulk cell data in the analysis of tissue data, and (iii) a novel unsupervised approach to minimize the bias brought by training data. Application of ICTD on real and single cell simulated tissue data validated that the method has consistently good performance for tissue data coming from different species, tissue microenvironments, and experimental platforms. Other than the new capabilities, ICTD outperformed other state-of-the-art devolution methods on prediction accuracy, the resolution of identifiable cell, detection of unknown sub cell types, and assessment of cell type specific functions. The premise of ICTD also lies in characterizing cell-cell interactions and discovering cell types and prognostic markers that are predictive of clinical outcomes.

bioinformatics↗