Biology subjects

Ho, C.

Publications and source records attributed to Ho, C..

29 records · Page 2Linked to original sources

bioRxiv2021

ePlant in 2021: New Species, Viewers, Data Sets, and Widgets

ePlant was introduced in 2017 for exploring large Arabidopsis thaliana data sets from the kilometre to nanometre scales. In the past four years we have used the ePlant framework to develop ePlants for 15 agronomically-important species: maize, poplar, tomato, Camelina sativa, soybean, potato, barley, Medicago truncatula, eucalyptus, rice, willow, sunflower, Cannabis sativa, wheat and sugarcane. We also updated the interface to improve performance and accessibility, and added two new views to the Arabidopsis ePlant - the Navigator and Pathways viewers. The former shows phylogenetic relationships between homologs in other species and their expression pattern similarities, with links to view data for those genes in the respective ePlants. The latter shows Plant Reactome metabolic reactions. We also describe new Arabidopsis data sets including single cell RNA-seq data from roots, and how to embed ePlant eFP expression pictographs into any web page.

bioinformatics↗

bioRxiv2021

Evidence-based precision nutrition improves clinical outcomes by analyzing human and microbial molecular data with artificial intelligence

Many studies have shown that foods and nutritional ingredients play an important role in healthy human homeostasis, either directly or via the microbiome. We have developed an objective, integrated, and automated approach to personalized food and supplement recommendations that is powered by artificial intelligence and individualized molecular data from the gut microbiome, the human host, and their interactions. The process starts with a clinically validated transcriptomic analysis of a persons stool (and some cases also blood) sample, from which the following molecular data are computed using clinically validated bioinformatics: 1. Quantitative strain-level taxonomic classification of all microorganisms, 2. Gene expression level for microbial genes, 3. Gene expression level for all human genes. These molecular data are converted into personalized nutritional recommendations (foods and supplements) using algorithms derived from clinical research studies and domain knowledge. We describe an application of our precision nutrition technology platform to human populations with irritable bowel syndrome (IBS), depression, anxiety, and type 2 diabetes (T2D). In these pilot interventional studies, our precision nutrition program achieved significant improvements in clinical outcomes of IBS (39% for severe IBS), depression (31% for severe depression), anxiety (31% for severe anxiety), and the risk score for T2D (>30% reduction relative to the control arm). These data support the integration of data-driven precision nutrition into the standard of care.

systems biology↗

bioRxiv2020

mRNA vaccine CVnCoV protects non-human primates from SARS-CoV-2 challenge infection

The ongoing severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic necessitates the fast development of vaccines to meet a worldwide need. mRNA-based vaccines are the most promising technology for rapid and safe SARS-CoV-2 vaccine development and production. We have designed CVnCoV, a lipid-nanoparticle (LNP) encapsulated, sequence optimised mRNA-based SARS-CoV-2 vaccine that encodes for full length, pre-fusion stabilised Spike protein. Unlike other mRNA-based approaches, CVnCoV exclusively consists of non-chemically modified nucleotides and can be applied at comparatively low doses. Here we demonstrate that CVnCoV induces robust humoral and cellular responses in non-human primates (NHPs). Animals vaccinated with 8 g of CVnCoV were protected from challenge infection with SARS-CoV-2. Comprehensive analyses of pathological changes in challenged animals via lung histopathology and Computed Tomography (CT) scans gave no indication of enhanced disease upon CVnCoV vaccination. These results demonstrate safety, immunogenicity, and protective efficacy of CVnCoV in NHPs that extend our previously published preclinical data and provide strong support for further clinical testing in ongoing phase 2b/3 efficacy studies.

immunology↗

bioRxiv2020

Immunological and pathological outcomes of SARS-CoV-2 challenge after formalin-inactivated vaccine immunisation of ferrets and rhesus macaques

There is an urgent requirement for safe and effective vaccines to prevent novel coronavirus disease (COVID-19) caused by SARS-CoV-2. A concern for the development of new viral vaccines is the potential to induce vaccine-enhanced disease (VED). This was reported in several preclinical studies with both SARS-CoV-1 and MERS vaccines but has not been reported with SARS-CoV-2 vaccines. We have used ferret and rhesus macaques challenged with SARS-CoV-2 to assess the potential for VED in animals vaccinated with formaldehyde-inactivated SARS-CoV-2 (FIV) formulated with Alhydrogel, compared to a negative control vaccine in ferrets or unvaccinated macaques. We showed no evidence of enhanced disease in ferrets or rhesus macaques given FIV except for mild transient enhanced disease seen at seven days post infection in ferrets. This increased lung pathology was observed early in the infection (day 7) but was resolved by day 15. We also demonstrate that formaldehyde treatment of SARS-CoV-2 reduces exposure of the spike receptor binding domain providing a mechanistic explanation for suboptimal immunity.

pathology↗

bioRxiv2020

ORCESTRA: a platform for orchestrating and sharing high-throughput pharmacogenomic analyses

Reproducibility is essential to open science, as there is limited relevance for findings that can not be reproduced by independent research groups, regardless of its validity. It is therefore crucial for scientists to describe their experiments in sufficient detail so they can be reproduced, scrutinized, challenged, and built upon. However, the intrinsic complexity and continuous growth of biomedical data makes it increasingly difficult to process, analyze, and share with the community in a FAIR (findable, accessible, interoperable, and reusable) manner. To overcome these issues, we created a cloud-based platform called ORCESTRA (orcestra.ca), which provides a flexible framework for the reproducible processing of multimodal biomedical data. It enables processing of clinical, genomic and perturbation profiles of cancer samples through automated processing pipelines that are user-customizable. ORCESTRA creates integrated and fully documented data objects with persistent identifiers (DOI) and manages multiple dataset versions, which can be shared for future studies.

bioinformatics↗

bioRxiv2020

KuLGaP: A Selective Measure for Assessing Therapy Response in Patient-Derived Xenografts

Quantifying response to drug treatment in mouse models of human cancer is important for treatment development and assignment, and yet remains a challenging task. A preferred measure to quantify this response should take into account as much of the experimental data as possible, i.e. both tumor size over time and the variation among replicates. We propose a theoretically grounded measure, KuLGaP, to compute the difference between the treatment and control arms. KuLGaP is more selective than currently existing measures, reduces the risk of false positive calls and improves translation of the lab results to clinical practice.

bioinformatics↗

bioRxiv2020

Rapid and robust antibody Fab fragment crystallization utilizing edge-to-edge beta-sheet packing

Antibody therapeutics are one of the most important classes of drugs. Antibody structures have become an integral part of predicting the behavior of potential therapeutics, either directly or as the basis of modeling. Structures of Fab:antigen complexes have even greater value. While the crystallization and structure determination of Fabs is easy relative to many other protein classes, especially membrane proteins, broad screening and optimization of crystalline hits is still necessary. Through a comprehensive review of rabbit Fab crystal contacts and their incompatibility with human Fab structures, we identified a small secondary structural element from the rabbit light chain constant domain potentially responsible for hindering the crystallization of human Fabs. Upon replacing the human kappa constant domain FG loop (HQGLSSP) with the two residue shorter rabbit loop (QGTTS), we dramatically improved the crystallization of human Fabs and Fab:antigen complexes. Our design, which we call "Crystal Kappa", enables rapid crystallization of human fabs and fab complexes in a broad range of conditions, with less material in smaller screens or from dilute solutions.

immunology↗

bioRxiv2019

Interleukin-4 signaling plays a major role in urogenital schistosomiasis-associated bladder pathogenesis

IL-4 is crucial in many helminth infections, but its role in urogenital schistosomiasis, infection with Schistosoma haematobium worms, remains poorly understood due to a historical lack of animal models. The bladder pathology of urogenital schistosomiasis is caused by immune responses to eggs deposited in the bladder wall. A range of pathology occurs, including urothelial hyperplasia and cancer, but associated mechanisms and links to IL-4 are largely unknown. We modeled urogenital schistosomiasis by injecting the bladder walls of IL-4 receptor-alpha knockout(Il4ra-/-) and wild type mice with S. haematobium eggs. Readouts included bladder histology and ex vivo assessments of urothelial proliferation, cell cycle and ploidy status. We also quantified the effects of exogenous IL-4 on urothelial cell proliferation in vitro, including cell cycle status and phosphorylation patterns of major downstream regulators in the IL-4 signaling pathway. There was a significant decrease in the intensity of granulomatous responses to bladder-wall injected S. haematobium eggs in Il4ra-/- versus wild type mice. S. haematobium egg injection triggered significant urothelial proliferation, including evidence of urothelial hyperdiploidy and cell cycle skewing in wild type but not Il4ra-/- mice. Urothelial exposure to IL-4 in vitro led to cell cycle polarization and increased phosphorylation of AKT. Our results show IL-4 signaling is required for key pathogenic features of urogenital schistosomiasis, and that particular aspects of this signaling pathway may exert these effects directly on the urothelium. These findings point to potential mechanisms by which urogenital schistosomiasis promotes bladder carcinogenesis.

immunology↗

bioRxiv2019

A reference library for the identification of Canadian invertebrates: 1.5 million DNA barcodes, voucher specimens, and genomic samples

The reliable taxonomic identification of organisms through DNA sequence data requires a well parameterized library of curated reference sequences. However, it is estimated that just 15% of described animal species are represented in public sequence repositories. To begin to address this deficiency, we provide DNA barcodes for 1,500,003 animal specimens collected from 23 terrestrial and aquatic ecozones at sites across Canada, a nation that comprises 7% of the planets land surface. In total, 14 phyla, 43 classes, 163 orders, 1123 families, 6186 genera, and 64,264 Barcode Index Numbers (BINs; a proxy for species) are represented. Species-level taxonomy was available for 38% of the specimens, but higher proportions were assigned to a genus (69.5%) and a family (99.9%). Voucher specimens and DNA extracts are archived at the Centre for Biodiversity Genomics where they are available for further research. The corresponding sequence and taxonomic data can be accessed through the Barcode of Life Data System, GenBank, the Global Biodiversity Information Facility, and the Global Genome Biodiversity Network Data Portal.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=61 SRC=\"FIGDIR/small/701805v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (17K):\norg.highwire.dtl.DTLVardef@5c6449org.highwire.dtl.DTLVardef@1bc0224org.highwire.dtl.DTLVardef@309dddorg.highwire.dtl.DTLVardef@1cc2cc8_HPS_FORMAT_FIGEXP M_FIG C_FIG

ecology↗

bioRxiv2017

A general method to predict the effect of single amino acid substitutions on enzyme catalytic activity

Over the past thirty years, site-directed mutagenesis has become established as one of the most powerful techniques to probe enzyme reaction mechanisms1-3. Substitutions of active site residues are most likely to yield significant perturbations in kinetic parameters, but there are many examples of profound changes in these values elicited by remote mutations4-6. Ortholog comparisons of extant sequences show that many mutations do not have profound influence on enzyme function. As the number of potential single natural amino acid substitutions that can be introduced in a protein of N amino acids in length by directed mutation is very large (19 * N), it would be useful to have a method to predict which amino acid substitutions are more likely to introduce significant changes in kinetic parameters in order to design meaningful probes into enzyme function. What is especially desirable is the identification of critical residues that do not contact the substrate directly, and may be remote from the active site.\n\nWe collected literature data reflecting the effects of 2,804 mutations on kinetic properties for 12 enzymes. These data along with characteristic predictors were used in a machine-learning scheme to train a classifier to predict the effect of mutation. Use of this algorithm allows one to predict with a 2.5-fold increase in precision, if a given mutation, made anywhere in the enzyme, will cause a decrease in kcat/Km value of [≥] 95%. The improved precision allows the experimentalist to reduce the number of mutations necessary to probe the enzyme reaction mechanism.

bioinformatics↗

bioRxiv2017

PharmacoDB: an integrative database for mining in vitro anticancer drug screening studies

Recent pharmacogenomic studies profiled large panels of cancer cell lines against hundreds of approved drugs and experimental chemical compounds. The overarching goal of these screens is to measure sensitivity of cell lines to chemical perturbation, correlate these measures to genomic features, and thereby develop novel predictors of drug response. However, leveraging this valuable data is challenging due to the lack of standards for annotating cell lines and chemical compounds, and quantifying drug response. Moreover, it has been recently shown that the complexity and complementarity of the experimental protocols used in the field result in high levels of technical and biological variation in the in vitro pharmacological profiles. There is therefore a need for new tools to facilitate rigorous comparison and integrative analysis of large-scale drug screening datasets. To address this issue, we have developed PharmacoDB (pharmacodb.pmgenomics.ca), a database integrating the largest pharmacogenomic studies published to date. Here, we describe how the curation of cell line and chemical compound identifiers maximizes the overlap between datasets and how users can leverage such data to compare and extract robust drug phenotypes. PharmacoDB provides a unique resource to mine a compendium of curated pharmacogenomic datasets that are otherwise disparate and difficult to integrate.\n\nKey pointsO_LICuration of cell line and drug identifiers in the largest pharmacogenomic studies published to date\nC_LIO_LIUniform processing of drug sensitivity data to reduce heterogeneity across studies\nC_LIO_LIMultiple drug response summary metrics enabling visual comparison and integrative analysis\nC_LI

bioinformatics↗