Biology subjects

Burrows, J.

Publications and source records attributed to Burrows, J..

4 recordsLinked to original sources

bioRxiv2025

A Diverse Genetic Basis for Metabolic Reactions is Revealed Through Pangenome analysis

Sequenced genomes for thousands of strains of a bacterial species allow for a comprehensive analysis of its pangenome. We present a pangenome study of Escherichia colis metabolism by formulating gene-to-protein-to-reaction associations (GPRs) for about 2,700 metabolic reactions in 2,377 fully sequenced strains. On one hand, these GPRs reconstruct strain-specific networks that allow computational predictions (and experimental validation) of metabolic phenotypes, while on the other hand, they give the genetic basis for a given metabolic reaction in every strain. A pangenome-wide analysis of GPRs shows that: 1) We can reveal the genetic basis for a specific metabolic property at the species level; 2) The genetic basis for many metabolic reactions is diverse; 3) Many rare genes show variation in the genes genomic neighborhood which often contain genes from transposable elements, 4) Many rare genes show large-scale fragmentation and horizontal gene transfer (>11,000 rare genes in 2,377 strains); and 5) The aromatic amino acids and branched chain amino acids pathways are enriched with rare genes, with Acetolactate synthase having 29 distinct genes. Thus, analysis of GPRs across the pangenome reveals a complex dynamic evolutionary history of metabolism, revealing the role of conserved, fragmented, and horizontally transferred metabolic genes.

systems biology↗

bioRxiv2022

Multistage and transmission-blocking tubulin targeting potent antimalarial discovered from the open access MMV Pathogen Box

Development of resistance to current antimalarial therapies remains a significant source of concern. To address this risk, new drugs with novel targets in distinct developmental stages of Plasmodium parasites are required. In our current work, we have targeted P. falciparum Tubulin (PfTubulin) proteins which represent some of the potential drug targets for malaria chemotherapy. Plasmodial Microtubules play a crucial role during parasite proliferation, growth, and transmission, which render them highly desirable targets for the development of next-generation chemotherapeutics. Towards this, we have evaluated the antimalarial activity of Tubulin targeting compounds received from the Medicines for Malaria Venture (MMV) "Pathogen Box" against the human malaria parasite, P. falciparum (including 3D7, RKL-9 (Chloroquine resistant) and R539T (Artemisinin resistant) strains). At nanomolar concentrations, filtered out compounds exhibited pronounced multistage antimalarial effects across the parasite life cycle, including intra-erythrocytic blood stages, liver stage parasites, gametocytes and ookinetes. Concomitantly, these compounds were found to impede male gamete ex-flagellation, thus showing transmission-blocking potential of these compounds. Target mining of these potent compounds, by combining in silico, biochemical and biophysical assays, implicated PfTubulin as their molecular target, which may possibly act by disrupting microtubule assembly dynamics by binding at the interface of -{beta}Tubulin-dimer. Further, promising ADME profile of the parent scaffold supported its consideration as a lead compound for further development. Thus, our work highlights the potential of targeting PfTubulin proteins in discovering and developing next-generation, multistage antimalarial agents for treating Multi-Drug Resistant (MDR) malaria parasites. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/488926v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@ae9713org.highwire.dtl.DTLVardef@40950forg.highwire.dtl.DTLVardef@1fa34f2org.highwire.dtl.DTLVardef@1aa1cae_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2019

A Novel Taxon of RNA Viruses Endemic to Planarian Flatworms

The phylum Platyhelminthes is composed of both parasitic and non-parasitic flatworms. While the parasitic species have drawn attention for their wide effects on human and livestock heath, free-living flatworms, such as freshwater planarians, have become molecular models of regeneration and stem cell biology in the laboratory. However, one aspect of planarian biology that remains understudied is the relationship between host and any endemic viruses. Here we used searches of multiple transcriptomes from Schmidtea mediterranea asexual strain CIW4 and detected a novel, double-stranded RNA (dsRNA) virus, named S. mediterranea tricladivirus (SmedTV), which represents a distinct taxon (proposed new genus) within a larger taxon of monosegmented dsRNA viruses of diverse hosts. Experimental evidence for SmedTV in S. mediterranea CIW4 was obtained through whole-mount in situ hybridization (WISH). SmedTV "expression" (detected by both sense and anti-sense probes) was discrete yet variable from worm to worm and cell type to cell type, suggesting a persistent infection. Single-cell RNA sequencing (scRNAseq) further supported that SmedTV expression was low in stem cells, but substantially higher in multiple, though not all, differentiated tissues, with notable neural enrichment. Interestingly, knockdown of SmedTV by RNA-interference resulted in a "cure" of SmedTV after 10 RNAi doses, and expression remained undetectable by WISH even after 90 days. Due to being able to evade host defenses and the endogenous RNAi pathway, we believe SmedTV represents a novel animal model to study host-virus evolution. Statement of significancePlanarians are freshwater flatworms and emerging models to study the molecular mechanisms of adult stem cell and regenerative biology. However, they also live in aquatic environments with high amounts of viruses, bacteria, fungi, and protist pathogens. How the planarian immune system copes with all of these is largely unknown and only 2 types of virus have been described. Here we find a novel dsRNA virus, endemic to multiple types of flatworms. We show that it is a persistent infection, and likely transmits from stem cell to differentiated cell in the planarian, while avoiding endogenous RNA-interference machinery and mechanisms used to suppress viruses. We present this as a new model to study host-virus defense and evolution.

microbiology↗

bioRxiv2018

The three dimensional structure of Bovine Salivary Protein 30b (BSP30b) and its interaction with specific rumen bacteria

Bovine Salivary Protein 30b (BSP30b) is a member of the tubular lipid-binding (TULIP) superfamily that includes the human bactericidal/permeability-increasing proteins (BPI), lipopolysaccharide binding proteins (LBP) and palate, lung, and nasal epithelium carcinoma-21 associated proteins (PLUNC). BSP30b is most closely related to the PLUNC family and is predominantly found in bovine saliva. There are four BSP30 isoforms (BSP30a-d) and collectively, they are the most abundant protein component of bovine saliva. The PLUNC family members are proposed to be lipid binding proteins, although in most cases their lipid ligands are unknown. Here, we present the X-ray crystal structure of BSP30b at 2.0 [A] resolution. We used a double methionine mutant and Se-Met SAD phasing to solve the structure. The structure adopts a curved cylindrical form with a hydrophobic channel formed by an /{beta} wrap, which is consistent with the TULIP superfamily. The structure of BSP30b in complex with oleic acid is also presented where the ligand is accommodated within the hydrophobic channel. The electron density for oleic acid suggests that the ligand is only partially occupied in the binding site implying that oleic acid may not be the preferred ligand. GFP-tagged BSP30b binds to the surface of olive oil droplets, as observed under fluorescent microscopy, and acts as a surfactant consistent with its association with decreased susceptibility to bloat in cattle. Bacteria extracted directly from bovine rumen contents indicate that the GFP_BSP30b fusion protein binds to a small number of selected bacterial species in vivo. These results suggest that BSP30b may bind to bacterial lipids from specific species and that this abundant protein may have important biological roles via interacting with rumen bacteria during feeding and rumination.

biochemistry↗