Biology subjects

Batson, J.

Publications and source records attributed to Batson, J..

7 recordsLinked to original sources

bioRxiv2024

The splicing factor kinase SRPK1 is a therapeutic target for Peripheral Vascular Disease

IntroductionIn peripheral arterial disease (PAD) anti-angiogenic VEGF-A165b isoform overexpression in monocytes contributes to impaired collateralisation. Serine-arginine protein-kinase-1 (SRPK1) regulates VEGF splicing. To determine whether SRPK1 controlled monocytic VEGF, impairing collateralisation, we investigated SRPK1 inhibition and monocyte-specific knockout in mouse models of and in human monocytes from PAD. MethodsVEGF-A165b activity was measured by co-culture of PAD patients monocytes with endothelial cells with SRPK1 inhibition. Mice with impaired revascularisation due to soluble-frizzled-related-protein-5 knockout (Sfrp5-/-), monocyte-specific Wnt5a gain-of-function (LysM-Wnt5aGOF), or obese mice on a high-fat high-sucrose (HF/HS) diet were subjected to femoral artery ligation and treated with SRPK1 inhibitor. We generated an SRPK1 conditional knockout and crossed it with monocyte-specific (LysM-Cre) driver line to specifically knockout SRPK1 in monocyte lineages. Blood flow was measured by Laser Speckle Imaging before, and for 28 days after surgery. ResultsMonocytes from PAD patients significantly inhibited endothelial cell migration, which was reversed by an anti-VEGF-A165b antibody. Surprisingly, migration was stimulated by SRPK1 inhibition, switching splicing from VEGF-A165b to VEGF-A165a. In Sfrp5-/-, LysM-Wnt5aGOF and HF/HS mouse models of PAD, blood flow was improved by SRPK1 inhibition. Impaired revascularisation in LysM-Wnt5aGOF mice was rescued in LysM-Wnt5aGOF:SRPK1MoKO mice, which had a phenotypic shift towards M2 macrophages. Impaired blood flow recovery was also rescued in obese-SRPK1MoKO mice. ConclusionVEGF splicing in monocytes is regulated differently from VEGF splicing in epithelial or cancer cells suggesting that control of splicing is dependent on cell type and/or environment. SRPK1 inhibition enhances collateralisation in mice, and in human in vitro models of monocyte-dependent impaired angiogenesis. New and NoteworthyA novel potential treatment for peripheral arterial disease (PAD) is described. Inhibition of SRPK1, or knockout in monocytes, induces angiogenesis by preventing splicing to anti-angiogenic VEGF (VEGF-A165b) in patients and animal models. In PAD, monocyte splicing control is different from other cell types and SRPK1 inhibition by drug like compounds can alter macrophage phenotype and reverse PAD in mice using a new cell specific SRPK1-LoxP mouse.

physiology↗

bioRxiv2022

Accumulated metagenomic studies reveal recent migration, whole genome evolution, and taxonomic incompleteness of orthomyxoviruses

Metagenomic studies have uncovered many novel viruses by looking beyond hosts of public health or economic interest. However, the resulting viral genomes are often incomplete, and analyses largely characterize the distribution of viruses over their dynamics. Here, we integrate accumulated data from metagenomic studies to reveal geographic and evolutionary dynamics in a case study of Orthomyxoviridae, the RNA virus family that includes influenza virus. First, we use sequences of the orthomyxovirid W[u]han mosquito virus 6 to track the migrations of its host. We then look at orthomyxovirus genome evolution, finding gene gain and loss across members of the family, especially in the surface proteins responsible for cell and host tropism. We find that the surface protein of W[u]han mosquito virus 6 exhibits accelerated non-synonymous evolution suggestive of antigenic evolution i.e. vertebrate infection, and belongs to a wider quaranjavirid group bearing highly diverged surface proteins. Finally we quantify the progress of orthomyxovirus discovery and forecast that many diverged Orthomyxoviridae members remain to be found. We argue that continued metagenomic studies will be fruitful for understanding the dynamics, evolution, ecology of viruses and their hosts, regardless of whether novel viruses are identified or not, as long as study designs allowing for the resolution of complete viral genomes are employed. 0.1 ImportanceThe number of known virus species has increased dramatically through metagenomic studies, which search genetic material sampled from a host for non-host genes. Here, we focus on an important viral family that includes influenza viruses, the Orthomyxoviridae, with over a hundred recently discovered viruses infecting hosts from humans to fish. We find one virus called W[u]han mosquito virus 6, discovered in mosquitoes in China, has spread across the globe very recently. Surface proteins used to enter cells show signs of rapid evolution in W[u]han mosquito virus 6 and its relatives which suggests an ability to infect vertebrate animals. We compute the rate at which new orthomyxovirus species discovered add evolutionary history to the tree of life, predict that many viruses remain to be discovered, and discuss what appropriately designed future studies can teach us about how diseases cross between continents and species.

evolutionary biology↗

bioRxiv2022

Patch2Self denoising of Diffusion MRI with Self-Supervision and Matrix Sketching

Diffusion-weighted magnetic resonance imaging (DWI) is the only noninvasive method for quantifying microstructure and reconstructing white-matter pathways in the living human brain. Fluctuations from multiple sources create significant additive noise in DWI data which must be suppressed before subsequent microstructure analysis. We introduce a self-supervised learning method for denoising DWI data, Patch2Self (P2S), which uses the entire volume to learn a full-rank locally linear denoiser for that volume. By taking advantage of the oversampled q-space of DWI data, P2S can separate structure from noise without requiring an explicit model for either. The setup of P2S however can be resource intensive, both in terms of running time and memory usage, as it uses all voxels (n) from all-but-one held-in volumes (d - 1) to learn a linear mapping {Phi} : [R]nx(d-1) [&map;] [R]n for denoising the held-out volume. We exploit the redundancy imposed by P2S to alleviate its performance issues and inspect regions that influence the noise disproportionately. Specifically we introduce P2S-sketch, which makes a two-fold contribution: (1) P2S-sketch uses matrix sketching to perform self-supervised denoising. By solving a sub-problem on a smaller sub-space, so called, coreset, we show how P2S can yield a significant speedup in training time while using less memory. (2) We show how the so-called statistical leverage scores can be used to interpret the denoising of dMRI data, a process that was traditionally treated as a black-box. Our experiments conducted on simulated and real data clearly demonstrate that P2S via matrix sketching (P2S-sketch) does not lead to any loss in denoising quality, while yielding significant speedup and improved memory usage by training on a smaller fraction of the data. With thorough comparisons on real and simulated data, we show that Patch2Self outperforms the current state-of-the-art methods for DWI denoising both in terms of visual conspicuity and downstream modeling tasks. We demonstrate the effectiveness of our approach via multiple quantitative metrics such as fiber bundle coherence, R2 via cross-validation on model fitting, mean absolute error of DTI residuals across a cohort of sixty subjects.

neuroscience↗

bioRxiv2020

Identification of a polymorphism in the N gene of SARS-CoV-2 that adversely impacts detection by a widely-used RT-PCR assay

We identify a mutation in the N gene of SARS-CoV-2 that adversely affects annealing of a commonly used RT-PCR primer; epidemiologic evidence suggests the virus retains pathogenicity and competence for spread. This reinforces the importance of using multiple targets, preferably in at least 2 genes, for robust SARS-CoV-2 detection. Article Summary LineA SARS-CoV-2 variant that occurs worldwide and has spread in California significantly affects diagnostic sensitivity of an N gene assay, highlighting the need to employ multiple viral targets for detection.

molecular biology↗

bioRxiv2020

Single mosquito metatranscriptomics recovers mosquito species, blood meal sources, and microbial cargo, including viral dark matter

Mosquitoes are major infectious disease-carrying vectors. Assessment of current and future risks associated with the mosquito population requires knowledge of the full repertoire of pathogens they carry, including novel viruses, as well as their blood meal sources. Unbiased metatranscriptomic sequencing of individual mosquitoes offers a straightforward, rapid and quantitative means to acquire this information. Here, we profile 148 diverse wild-caught mosquitoes collected in California and detect sequences from eukaryotes, prokaryotes, 24 known and 46 novel viral species. Importantly, sequencing individuals greatly enhanced the value of the biological information obtained. It allowed us to a) speciate host mosquito, b) compute the prevalence of each microbe and recognize a high frequency of viral co-infections, c) associate animal pathogens with specific blood meal sources, and d) apply simple co-occurrence methods to recover previously undetected components of highly prevalent segmented viruses. In the context of emerging diseases, where knowledge about vectors, pathogens, and reservoirs is lacking, the approaches described here can provide actionable information for public health surveillance and intervention decisions.

microbiology↗

bioRxiv2019

Molecular Cross-Validation for Single-Cell RNA-seq

Single-cell RNA sequencing enables researchers to study the gene expression of individual cells. However, in high-throughput methods the portrait of each individual cell is noisy, representing thousands of the hundreds of thousands of mRNA molecules originally present. While many methods for denoising single-cell data have been proposed, a principled procedure for selecting and calibrating the best method for a given dataset has been lacking. We present \"molecular cross-validation,\" a statistically principled and data-driven approach for estimating the accuracy of any denoising method without the need for ground-truth. We validate this approach for three denoising methods--principal component analysis, network diffusion, and a deep autoencoder--on a dataset of deeply-sequenced neurons. We show that molecular cross-validation correctly selects the optimal parameters for each method and identifies the best method for the dataset.

bioinformatics↗

bioRxiv2018

FLASH: A next-generation CRISPR diagnostic for multiplexed detection of antimicrobial resistance sequences

The growing prevalence of deadly microbes with resistance to previously life-saving drug therapies is a dire threat to human health. Detection of low abundance pathogen sequences remains a challenge for metagenomic Next Generation Sequencing (NGS). We introduce FLASH (Finding Low Abundance Sequences by Hybridization), a next-generation CRISPR/Cas9 diagnostic method that takes advantage of the efficiency, specificity and flexibility of Cas9 to enrich for a programmed set of sequences. FLASH-NGS achieves up to 5 orders of magnitude of enrichment and sub-attomolar gene detection with minimal background. We provide an open-source software tool (FLASHit) for guide RNA design. Here we applied it to detection of antimicrobial resistance genes in respiratory fluid and dried blood spots, but FLASH-NGS is applicable to all areas that rely on multiplex PCR.

microbiology↗