Welcome Ashraf Bazan, who has joined the lab and the McMaster Biochemistry & Biomedical Sciences graduate program! A familiar face in the IIDR as he started if the Coombes lab, Ashraf joins us to lead an antimicrobial resistance (AMR) metagenomics investigation of azithromycin treatment of childhood diarrheal disease in Botswana, in collaboration with Dr. Jeffrey Pernica. Welcome Ashraf!

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Banerjee, A., J.A. Nasir, P. Budylowski, L. Yip, P. Aftanas, N. Christie, A. Ghalami, K. Baid, A.R. Raphenya, J.A. Hirota, M.S. Miller, A.J. McGeer, M.A. Ostrowski, R.A. Kozak, A.G. McArthur, K. Mossman, & S. Mubareka

bioRxiv doi:10.1101/2020.04.11.037382

SARS-CoV-2 emerged in December 2019 in Wuhan, China and has since infected over 1.5 million people, of which over 100,000 have died. As SARS-CoV-2 spreads across the planet, speculations remain about the evolution of the virus and the range of human cells that can be infected by SARS-CoV-2. In this study, we report the isolation of SARS-CoV-2 from two COVID-19 patients in Toronto, Canada. We determined the genomic sequences of the two isolates and identified single nucleotide changes in representative populations of our virus stocks. More importantly, we have tested a wide range of human immune cells for infectivity with SARS-CoV-2. We confirm from our studies that human primary peripheral blood mononuclear cells (PBMCs) are not permissive to SARS-CoV-2. As SARS-CoV-2 continues to spread globally, it is essential to monitor any small nucleotide polymorphisms in the virus and to continue to isolate circulating strains of the virus to determine cell susceptibility and pathogenicity using in vitro and in vivo infection models.

Hear Arinjay & Andrew talk about their SARS-CoV-2 work: https://www.youtube.com/watch?v=SVzDHESnssg

See also: McMaster researcher plays key role in isolating COVID-19 virus for use in urgent research

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COVID19 kept us from celebrating together, but we are very proud of the work you have accomplished!

Rachel Tran | Biochem 4T15 – Exploring the diversity of clinical multidrug resistance in Hamilton, Canada

Arman Edalatmand | Biochem 4T15 – Improving upon CARD*Shark and contextualizing antimicrobial resistance genes

Marcel Jansen | Biochem 4T15 – Translating the Comprehensive Antimicrobial Resistance Database to act as a stopgap for MEGARes

William Huynh | Biochem 4T15 – Expansion of Resistance Gene Identifier allows the identification of putative and novel frameshift mutations

Sohaib Syed | BiomedDC 4A15 – Expanding the scope of antimicrobial resistance surveillance of Mycobacterium tuberculosis in the Comprehensive Antibiotic Resistance Database

Thanks also goes to our 3rd year students Corie Niu (Biochem 3R06), Hamna Imtiaz (Biochem 3R06), Anna-Lisa Nguyen (HthSci 4D03), Sarah Yaqoob (Science 3RP3), & Hafsa Omer (LifeSci 3RP3)!

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Congratulations to lab member Sohaib Syed and the team at Bisep for winning the 2002 Synapse Competition!

Innovation Factory awards $100,000 in cash and in-kind prizes at the seventh annual Synapse Life Science Competition

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Quick update on the status of the McArthur Lab and the Comprehensive Antibiotic Resistance Database. While our home institution McMaster University is closed to on-site research and undergraduate/graduate teaching, all McArthur Lab members and CARD staff are working from home. However, like many genomics labs in Canada we are directly helping our clinical colleagues in analysis of SARS-CoV-2 sequences, lending processing power, staff time, and expertise. Response time for CARD might be a bit slow as we are stretched a bit thin. But on May 1st, 2020 we will be joined by William Huynh as Junior CARD Curator & Help Desk manager. We are excited to have William join us and expect to come back strong supporting the AMR research community in May.

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Nasir, J.A., D.J. Speicher, R.A. Kozak, H.N. Poinar, M.S. Miller, & A.G. McArthur.

Preprints 2020, 2020020385.

SARS-CoV-2 is a novel betacoronavirus and the aetiological agent of the current COVID-19 outbreak that originated in Hubei Province, China. While polymerase chain reaction is the front-line tool for SARS-CoV-2 surveillance, application of amplification-free and culture-free methods for isolation of SARS-CoV-2 RNA, partnered with next-generation sequencing, would provide a useful tool for both surveillance and research of SARS-CoV-2. We here release into the public domain a set of bait capture hybridization probe sequences for enrichment of SARS-CoV-2 RNA from complex biological samples. These probe sequences have been designed using rigorous bioinformatics methods to provide sensitivity, accuracy, and minimal off-target hybridization. Probe design was based on existing, validated approaches for detecting antimicrobial resistance genes in complex samples and it is our hope that this SARS-CoV-2 bait capture platform, once validated by those with samples in hand, will be of aid in combating the current outbreak.

Data, Software, and Sequences: https://github.com/jaleezyy/covid-19-baits

Full Story at Brighter World: McMaster develops tool for coronavirus battle

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Chen CY, Clark CG, Langner S, Boyd DA, Bharat A, McCorrister SJ, McArthur AG, Graham MR, Westmacott GR, Van Domselaar G

Proteomics Clin Appl. 2019 Dec 24 [Epub ahead of print]

PURPOSE: Antimicrobial resistance (AMR), especially multidrug resistance, is one of the most serious global threats facing public health. We performed a proof of concept study assessing the suitability of shotgun proteomics as a complementary approach to whole-genome sequencing (WGS) for detecting AMR determinants.

EXPERIMENTAL DESIGN: We used previously published shotgun proteomics and WGS data on four isolates of Campylobacter jejuni to perform AMR detection by searching the Comprehensive Antibiotic Resistance Database, and we assessed their detection ability relative to genomics screening and traditional phenotypic testing measured by minimum inhibitory concentration.

RESULTS: Both genomic and proteomic approaches identified the wild type and variant molecular determinants responsible for resistance to tetracycline and ciprofloxacin, in agreement with phenotypic testing. In contrast, the genomic method identified the presence of the β-lactamase gene, blaOXA-61 , in three isolates. However, its corresponding protein product was detected in only a single isolate, consistent with results obtained from phenotypic testing.

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Day EA, Ford RJ, Smith BK, Mohammadi-Shemirani P, Morrow MR, Gutgesell RM, Lu R, Raphenya AR, Kabiri M, McArthur AG, McInnes N, Hess S, Paré G, Gerstein HC, Steinberg GR

Nature Metabolism 2019 Dec. 9 [Epub ahead of print]

Metformin is the most commonly prescribed medication for type 2 diabetes, owing to its glucose-lowering effects, which are mediated through the suppression of hepatic glucose production. However, in addition to its effects on the liver, metformin reduces appetite and in preclinical models exerts beneficial effects on ageing and a number of diverse diseases (for example, cognitive disorders, cancer, cardiovascular disease) through mechanisms that are not fully understood. Given the high concentration of metformin in the liver and its many beneficial effects beyond glycemic control, we reasoned that metformin may increase the secretion of a hepatocyte-derived endocrine factor that communicates with the central nervous system4. Here we show, using unbiased transcriptomics of mouse hepatocytes and analysis of proteins in human serum, that metformin induces expression and secretion of growth differentiating factor 15 (GDF15). In primary mouse hepatocytes, metformin stimulates the secretion of GDF15 by increasing the expression of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP; also known as DDIT3). In wild-type mice fed a high-fat diet, oral administration of metformin increases serum GDF15 and reduces food intake, body mass, fasting insulin and glucose intolerance; these effects are eliminated in GDF15 null mice. An increase in serum GDF15 is also associated with weight loss in patients with type 2 diabetes who take metformin. Although further studies will be required to determine the tissue source(s) of GDF15 produced in response to metformin in vivo, our data indicate that the therapeutic benefits of metformin on appetite, body mass and serum insulin depend on GDF15.

See the Commentary in SciTechDaily.

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Ahmad S, Wang B, Walker MD, Tran H-KR, Stogios PJ, Savchenko A, Grant RA, McArthur AG, Laub MT, Whitney JC

Nature 2019 Nov 6. [Epub ahead of print]

Bacteria have evolved sophisticated mechanisms to inhibit the growth of competitors. One such mechanism involves type VI secretion systems, which bacteria can use to inject antibacterial toxins directly into neighbouring cells. Many of these toxins target the integrity of the cell envelope, but the full range of growth inhibitory mechanisms remains unknown. Here we identify a type VI secretion effector, Tas1, in the opportunistic pathogen Pseudomonas aeruginosa. The crystal structure of Tas1 shows that it is similar to enzymes that synthesize (p)ppGpp, a broadly conserved signalling molecule in bacteria that modulates cell growth rate, particularly in response to nutritional stress. However, Tas1 does not synthesize (p)ppGpp; instead, it pyrophosphorylates adenosine nucleotides to produce (p)ppApp at rates of nearly 180,000 molecules per minute. Consequently, the delivery of Tas1 into competitor cells drives rapid accumulation of (p)ppApp, depletion of ATP, and widespread dysregulation of essential metabolic pathways, thereby resulting in target cell death. Our findings reveal a previously undescribed mechanism for interbacterial antagonism and demonstrate a physiological role for the metabolite (p)ppApp in bacteria.

See the Commentary at Nature.

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Alcock BP, Raphenya AR, Lau TTY, Tsang KK, Bouchard M, Edalatmand A, Huynh W, Nguyen A-LV, Cheng AA, Liu S, Min SY, Miroshnichenko A, Tran H-K, Werfalli RE, Nasir JA, Oloni M, Speicher DJ, Florescu A, Singh B, Faltyn M, Hernandez-Koutoucheva A, Sharma AN, Bordeleau E, Pawlowski AC, Zubyk HL, Dooley D, Griffiths E, Maguire F, Winsor GL, Beiko RG, Brinkman FSL, Hsiao WWL, Van Domselaar G, McArthur AG.

Nucleic Acids Research 2019 Oct 29. [Epub ahead of print]

The Comprehensive Antibiotic Resistance Database (CARD; https://card.mcmaster.ca) is a curated resource providing reference DNA and protein sequences, detection models and bioinformatics tools on the molecular basis of bacterial antimicrobial resistance (AMR). CARD focuses on providing high-quality reference data and molecular sequences within a controlled vocabulary, the Antibiotic Resistance Ontology (ARO), designed by the CARD biocuration team to integrate with software development efforts for resistome analysis and prediction, such as CARD’s Resistance Gene Identifier (RGI) software. Since 2017, CARD has expanded through extensive curation of reference sequences, revision of the ontological structure, curation of over 500 new AMR detection models, development of a new classification paradigm and expansion of analytical tools. Most notably, a new Resistomes & Variants module provides analysis and statistical summary of in silico predicted resistance variants from 82 pathogens and over 100 000 genomes. By adding these resistance variants to CARD, we are able to summarize predicted resistance using the information included in CARD, identify trends in AMR mobility and determine previously undescribed and novel resistance variants. Here, we describe updates and recent expansions to CARD and its biocuration process, including new resources for community biocuration of AMR molecular reference data.

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