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      A genome-wide overexpression screen reveals Mycobacterium smegmatis growth inhibitors encoded by mycobacteriophage Hammy

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          Abstract

          During infection, bacteriophages produce diverse gene products to overcome bacterial antiphage defenses, to outcompete other phages, and to take over cellular processes. Even in the best-studied model phages, the roles of most phage-encoded gene products are unknown, and the phage population represents a largely untapped reservoir of novel gene functions. Considering the sheer size of this population, experimental screening methods are needed to sort through the enormous collection of available sequences and identify gene products that can modulate bacterial behavior for downstream functional characterization. Here, we describe the construction of a plasmid-based overexpression library of 94 genes encoded by Hammy, a Cluster K mycobacteriophage closely related to those infecting clinically important mycobacteria. The arrayed library was systematically screened in a plate-based cytotoxicity assay, identifying a diverse set of 24 gene products (representing ∼25% of the Hammy genome) capable of inhibiting growth of the host bacterium Mycobacterium smegmatis. Half of these are related to growth inhibitors previously identified in related phage Waterfoul, supporting their functional conservation; the other genes represent novel additions to the list of known antimycobacterial growth inhibitors. This work, conducted as part of the HHMI-supported Science Education Alliance Gene-function Exploration by a Network of Emerging Scientists (SEA-GENES) project, highlights the value of parallel, comprehensive overexpression screens in exploring genome-wide patterns of phage gene function and novel interactions between phages and their hosts.

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          Most cited references48

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          Application of phylogenetic networks in evolutionary studies.

          The evolutionary history of a set of taxa is usually represented by a phylogenetic tree, and this model has greatly facilitated the discussion and testing of hypotheses. However, it is well known that more complex evolutionary scenarios are poorly described by such models. Further, even when evolution proceeds in a tree-like manner, analysis of the data may not be best served by using methods that enforce a tree structure but rather by a richer visualization of the data to evaluate its properties, at least as an essential first step. Thus, phylogenetic networks should be employed when reticulate events such as hybridization, horizontal gene transfer, recombination, or gene duplication and loss are believed to be involved, and, even in the absence of such events, phylogenetic networks have a useful role to play. This article reviews the terminology used for phylogenetic networks and covers both split networks and reticulate networks, how they are defined, and how they can be interpreted. Additionally, the article outlines the beginnings of a comprehensive statistical framework for applying split network methods. We show how split networks can represent confidence sets of trees and introduce a conservative statistical test for whether the conflicting signal in a network is treelike. Finally, this article describes a new program, SplitsTree4, an interactive and comprehensive tool for inferring different types of phylogenetic networks from sequences, distances, and trees.
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            Search and sequence analysis tools services from EMBL-EBI in 2022

            The EMBL-EBI search and sequence analysis tools frameworks provide integrated access to EMBL-EBI’s data resources and core bioinformatics analytical tools. EBI Search ( https://www.ebi.ac.uk/ebisearch ) provides a full-text search engine across nearly 5 billion entries, while the Job Dispatcher tools framework ( https://www.ebi.ac.uk/services ) enables the scientific community to perform a diverse range of sequence analysis using popular bioinformatics applications. Both allow users to interact through user-friendly web applications, as well as via RESTful and SOAP-based APIs. Here, we describe recent improvements to these services and updates made to accommodate the increasing data requirements during the COVID-19 pandemic. Graphical Abstract Overview of the tools and data resources provided by EBI Search and Job Dispatcher services accessible via their webpage and programmatic interfaces.
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              Engineered bacteriophages for treatment of a patient with a disseminated drug resistant Mycobacterium abscessus

              A 15-year-old cystic fibrosis patient with a disseminated Mycobacterium abscessus infection was treated with a three-phage cocktail following bilateral lung transplantation. Effective lytic phage derivatives that efficiently kill the infectious M. abscessus strain were developed by genome engineering and forward genetics. Intravenous phage treatment was well tolerated and associated with objective clinical improvement including sternal wound closure, improved liver function, and substantial resolution of infected skin nodules.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                G3 (Bethesda)
                Genetics
                g3journal
                G3: Genes|Genomes|Genetics
                Oxford University Press (US )
                2160-1836
                December 2023
                02 November 2023
                02 November 2023
                : 13
                : 12
                : jkad240
                Affiliations
                Center for the Advancement of Science Leadership and Culture, Howard Hughes Medical Institute , Chevy Chase, MD 20185, USA
                Center for the Advancement of Science Leadership and Culture, Howard Hughes Medical Institute , Chevy Chase, MD 20185, USA
                Center for the Advancement of Science Leadership and Culture, Howard Hughes Medical Institute , Chevy Chase, MD 20185, USA
                School of Biological, Environmental, and Earth Sciences, University of Southern Mississippi , Hattiesburg, MS 39406, USA
                School of Biological, Environmental, and Earth Sciences, University of Southern Mississippi , Hattiesburg, MS 39406, USA
                Department of Biology, University of Maryland Baltimore County , Baltimore, MD 21250, USA
                School of Biological, Environmental, and Earth Sciences, University of Southern Mississippi , Hattiesburg, MS 39406, USA
                School of Biological, Environmental, and Earth Sciences, University of Southern Mississippi , Hattiesburg, MS 39406, USA
                School of Biological, Environmental, and Earth Sciences, University of Southern Mississippi , Hattiesburg, MS 39406, USA
                School of Biological, Environmental, and Earth Sciences, University of Southern Mississippi , Hattiesburg, MS 39406, USA
                School of Biological, Environmental, and Earth Sciences, University of Southern Mississippi , Hattiesburg, MS 39406, USA
                School of Biological, Environmental, and Earth Sciences, University of Southern Mississippi , Hattiesburg, MS 39406, USA
                School of Biological, Environmental, and Earth Sciences, University of Southern Mississippi , Hattiesburg, MS 39406, USA
                School of Biological, Environmental, and Earth Sciences, University of Southern Mississippi , Hattiesburg, MS 39406, USA
                School of Biological, Environmental, and Earth Sciences, University of Southern Mississippi , Hattiesburg, MS 39406, USA
                School of Biological, Environmental, and Earth Sciences, University of Southern Mississippi , Hattiesburg, MS 39406, USA
                Department of Biology, James Madison University , Harrisonburg, VA 22807, USA
                Department of Biology, James Madison University , Harrisonburg, VA 22807, USA
                Department of Biology, James Madison University , Harrisonburg, VA 22807, USA
                Department of Biology, James Madison University , Harrisonburg, VA 22807, USA
                Department of Biology, James Madison University , Harrisonburg, VA 22807, USA
                School of Biological, Environmental, and Earth Sciences, University of Southern Mississippi , Hattiesburg, MS 39406, USA
                Center for the Advancement of Science Leadership and Culture, Howard Hughes Medical Institute , Chevy Chase, MD 20185, USA
                Center for the Advancement of Science Leadership and Culture, Howard Hughes Medical Institute , Chevy Chase, MD 20185, USA
                Author notes
                Corresponding author: Email: hellerd@ 123456hhmi.org

                Isabel Amaya, Kaylia Edwards, Bethany M Wise and Danielle Heller contributed equally to this work.

                Conflicts of interest statement The authors declare no conflict of interest.

                Author information
                https://orcid.org/0000-0002-6169-9711
                https://orcid.org/0009-0009-6775-779X
                https://orcid.org/0009-0004-8293-8015
                https://orcid.org/0000-0001-7163-4543
                https://orcid.org/0000-0002-6581-1256
                Article
                jkad240
                10.1093/g3journal/jkad240
                10700055
                37934806
                c72700ca-931f-4e6e-86a5-45aa9de902d8
                © The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 25 June 2023
                : 06 October 2023
                : 02 November 2023
                Page count
                Pages: 10
                Funding
                Funded by: HHMI-supported Science Education Alliance GENES;
                Funded by: Gene function Exploration;
                Funded by: Network of Emerging Scientists;
                Categories
                Mutant Screen Report
                AcademicSubjects/SCI01180
                AcademicSubjects/SCI01140

                Genetics
                mycobacteriophage,mycobacterium smegmatis,cytotoxicity
                Genetics
                mycobacteriophage, mycobacterium smegmatis, cytotoxicity

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