CHOPIN: a web resource for the structural and functional proteome of Mycobacterium tuberculosis.

Tuberculosis kills more than a million people annually and presents increasingly high levels of resistance against current first line drugs. Structural information about Mycobacterium tuberculosis (Mtb) proteins is a valuable asset for the development of novel drugs and for understanding the biology of the bacterium; however, only about 10% of the ∼4000 proteins have had their structures determined experimentally. The CHOPIN database assigns structural domains and generates homology models for 2911 sequences, corresponding to ∼73% of the proteome. A sophisticated pipeline allows multiple models to be created using conformational states characteristic of different oligomeric states and ligand binding, such that the models reflect various functional states of the proteins. Additionally, CHOPIN includes structural analyses of mutations potentially associated with drug resistance. Results are made available at the web interface, which also serves as an automatically updated repository of all published Mtb experimental structures. Its RESTful interface allows direct and flexible access to structures and metadata via intuitive URLs, enabling easy programmatic use of the models.This work was supported by the Bill & Melinda Gates Foundation (RG60453). University of Cambridge for facilities and support [to TLB]. Funding for open access charge: Bill & Melinda Gates Foundation.This is the final published version. It first appeared at http://database.oxfordjournals.org/content/2015/bav026.long

Mutations at protein-protein interfaces: Small changes over big surfaces have large impacts on human health.

Many essential biological processes including cell regulation and signalling are mediated through the assembly of protein complexes. Changes to protein-protein interaction (PPI) interfaces can affect the formation of multiprotein complexes, and consequently lead to disruptions in interconnected networks of PPIs within and between cells, further leading to phenotypic changes as functional interactions are created or disrupted. Mutations altering PPIs have been linked to the development of genetic diseases including cancer and rare Mendelian diseases, and to the development of drug resistance. The importance of these protein mutations has led to the development of many resources for understanding and predicting their effects. We propose that a better understanding of how these mutations affect the structure, function, and formation of multiprotein complexes provides novel opportunities for tackling them, including the development of small-molecule drugs targeted specifically to mutated PPIs.H.J. is currently funded by an Astex Pharmaceuticals Sustaining Innovation Postdoctoral Fellowship hosted at the Wellcome Trust Sanger Institute. M.A.T was supported by scholarships from Promega Corporation, as well as the College of Agricultural and Life Sciences and the Department of Biochemistry at the University of Wisconsin-Madison, USA. B.O.M was supported by the Bill and Melinda Gates Foundation. D.B.A is the recipient of a C. J. Martin Research Fellowship from the National Health and Medical Research Council of Australia (APP1072476) and is funded by the Wellcome Trust and Jack Brockhoff Foundation (JBF 4186, 2016). T.L.B. receives funding from the University of Cambridge and The Wellcome Trust for facilities and support

SInCRe—structural interactome computational resource for Mycobacterium tuberculosis

We have developed an integrated database for Mycobacterium tuberculosis H37Rv (Mtb) that collates information on protein sequences, domain assignments, functional annotation and 3D structural information along with protein–protein and protein–small molecule interactions. SInCRe (Structural Interactome Computational Resource) is developed out of CamBan (Cambridge and Bangalore) collaboration. The motivation for development of this database is to provide an integrated platform to allow easily access and interpretation of data and results obtained by all the groups in CamBan in the field of Mtb informatics. In-house algorithms and databases developed independently by various academic groups in CamBan are used to generate Mtb-specific datasets and are integrated in this database to provide a structural dimension to studies on tuberculosis. The SInCRe database readily provides information on identification of functional domains, genome-scale modelling of structures of Mtb proteins and characterization of the small-molecule binding sites within Mtb. The resource also provides structure-based function annotation, information on small-molecule binders including FDA (Food and Drug Administration)-approved drugs, protein–protein interactions (PPIs) and natural compounds that bind to pathogen proteins potentially and result in weakening or elimination of host–pathogen protein–protein interactions. Together they provide prerequisites for identification of off-target binding

'Candidatus Ornithobacterium hominis': insights gained from draft genomes obtained from nasopharyngeal swabs.

'Candidatus Ornithobacterium hominis' represents a new member of the Flavobacteriaceae detected in 16S rRNA gene surveys of people from South-East Asia, Africa and Australia. It frequently colonizes the infant nasopharynx at high proportional abundance, and we demonstrate its presence in 42 % of nasopharyngeal swabs from 12-month-old children in the Maela refugee camp in Thailand. The species, a Gram-negative bacillus, has not yet been cultured, but the cells can be identified in mixed samples by fluorescent hybridization. Here, we report seven genomes assembled from metagenomic data, two to improved draft standard. The genomes are approximately 1.9 Mb, sharing 62 % average amino acid identity with the only other member of the genus, the bird pathogen Ornithobacterium rhinotracheale. The draft genomes encode multiple antibiotic-resistance genes, competition factors, Flavobacterium johnsoniae-like gliding motility genes and a homologue of the Pasteurella multocida mitogenic toxin. Intra- and inter-host genome comparison suggests that colonization with this bacterium is both persistent and strain exclusive

Synthetic viability genomic screening defines Sae2 function in DNA repair.

DNA double-strand break (DSB) repair by homologous recombination (HR) requires 3' single-stranded DNA (ssDNA) generation by 5' DNA-end resection. During meiosis, yeast Sae2 cooperates with the nuclease Mre11 to remove covalently bound Spo11 from DSB termini, allowing resection and HR to ensue. Mitotic roles of Sae2 and Mre11 nuclease have remained enigmatic, however, since cells lacking these display modest resection defects but marked DNA damage hypersensitivities. By combining classic genetic suppressor screening with high-throughput DNA sequencing, we identify Mre11 mutations that strongly suppress DNA damage sensitivities of sae2∆ cells. By assessing the impacts of these mutations at the cellular, biochemical and structural levels, we propose that, in addition to promoting resection, a crucial role for Sae2 and Mre11 nuclease activity in mitotic DSB repair is to facilitate the removal of Mre11 from ssDNA associated with DSB ends. Thus, without Sae2 or Mre11 nuclease activity, Mre11 bound to partly processed DSBs impairs strand invasion and HR.We thank M.P. Longhese, R. Rothstein and J. Haber for providing strains and plasmids; Sir T. Blundell and T. Ochi for advice on structural biology and for providing comments to the manuscript. Research in the Jackson laboratory is funded by Cancer Research UK Programme Grant C6/A11224, the European Research Council and the European Community Seventh Framework Programme Grant Agreement No. HEALTH‐F2‐2010‐259893 (DDResponse). Core funding is provided by CRUK (C6946/A14492) and the Wellcome Trust (WT092096). SPJ receives his salary from the University of Cambridge, UK, supplemented by CRUK. TO, IG and FP were funded by Framework Programme Grant Agreement No. HEALTH‐F2‐2010‐259893 (DDResponse). FP also received funding from EMBO (Fellowship ALTF 1287‐2011); NG and IS are funded by the Wellcome Trust (101126/Z/13/Z). DJA and TMK were supported by Cancer Research UK and the Wellcome Trust (WT098051). PS and HN were supported by NIH grants RO1ES007061 and K99ES021441, respectively.This is the final version. It was first published by EMBO at http://emboj.embopress.org/content/early/2015/04/21/embj.201590973.lon

Synthetic viability genomic screening defines Sae2 function in DNA repair.

DNA double-strand break (DSB) repair by homologous recombination (HR) requires 3' single-stranded DNA (ssDNA) generation by 5' DNA-end resection. During meiosis, yeast Sae2 cooperates with the nuclease Mre11 to remove covalently bound Spo11 from DSB termini, allowing resection and HR to ensue. Mitotic roles of Sae2 and Mre11 nuclease have remained enigmatic, however, since cells lacking these display modest resection defects but marked DNA damage hypersensitivities. By combining classic genetic suppressor screening with high-throughput DNA sequencing, we identify Mre11 mutations that strongly suppress DNA damage sensitivities of sae2∆ cells. By assessing the impacts of these mutations at the cellular, biochemical and structural levels, we propose that, in addition to promoting resection, a crucial role for Sae2 and Mre11 nuclease activity in mitotic DSB repair is to facilitate the removal of Mre11 from ssDNA associated with DSB ends. Thus, without Sae2 or Mre11 nuclease activity, Mre11 bound to partly processed DSBs impairs strand invasion and HR.We thank M.P. Longhese, R. Rothstein and J. Haber for providing strains and plasmids; Sir T. Blundell and T. Ochi for advice on structural biology and for providing comments to the manuscript. Research in the Jackson laboratory is funded by Cancer Research UK Programme Grant C6/A11224, the European Research Council and the European Community Seventh Framework Programme Grant Agreement No. HEALTH‐F2‐2010‐259893 (DDResponse). Core funding is provided by CRUK (C6946/A14492) and the Wellcome Trust (WT092096). SPJ receives his salary from the University of Cambridge, UK, supplemented by CRUK. TO, IG and FP were funded by Framework Programme Grant Agreement No. HEALTH‐F2‐2010‐259893 (DDResponse). FP also received funding from EMBO (Fellowship ALTF 1287‐2011); NG and IS are funded by the Wellcome Trust (101126/Z/13/Z). DJA and TMK were supported by Cancer Research UK and the Wellcome Trust (WT098051). PS and HN were supported by NIH grants RO1ES007061 and K99ES021441, respectively.This is the final version. It was first published by EMBO at http://emboj.embopress.org/content/early/2015/04/21/embj.201590973.lon

Genome3D: exploiting structure to help users understand their sequences.

Genome3D (http://www.genome3d.eu) is a collaborative resource that provides predicted domain annotations and structural models for key sequences. Since introducing Genome3D in a previous NAR paper, we have substantially extended and improved the resource. We have annotated representatives from Pfam families to improve coverage of diverse sequences and added a fast sequence search to the website to allow users to find Genome3D-annotated sequences similar to their own. We have improved and extended the Genome3D data, enlarging the source data set from three model organisms to 10, and adding VIVACE, a resource new to Genome3D. We have analysed and updated Genome3D's SCOP/CATH mapping. Finally, we have improved the superposition tools, which now give users a more powerful interface for investigating similarities and differences between structural models

XSuLT: a web server for structural annotation and representation of sequence-structure alignments

The web server XSuLT, an enhanced version of the protein alignment annotation program JoY, formats a submitted multiple-sequence alignment using three-dimensional (3D) structural information in order to assist in the comparative analysis of protein evolution and in the optimization of alignments for comparative modelling and construct design. In addition to the features analysed by JoY, which include secondary structure, solvent accessibility and sidechain hydrogen bonds, XSuLT annotates each amino acid residue with residue depth, chain and ligand interactions, inter-residue contacts, sequence entropy, root mean square deviation and secondary structure and disorder prediction. It is also now integrated with built-in 3D visualization which interacts with the formatted alignment to facilitate inspection and understanding. Results can be downloaded as stand-alone HTML for the formatted alignment and as XML with the underlying annotation data. XSuLT is freely available at http://structure.bioc.cam.ac.uk/xsult/.Bill & Melinda Gates Foundation [RG60453 to B.O.M.]; Bill & Melinda Gates HIT-TB (to T.L.B.); EU MM4TB [260872 to T.L.B.]; Wellcome Trust Programme Grant [093167/Z/10/Z to T.L.B.] and Investigator Award [200814/Z/16/Z to T.L.B.]; Medical Research Council Newton Fund RCUK-CONFAP Grant [MR/M026302/1 to T.L.B.]. Funding for open access charge: Wellcome Trust

COVID-19 outbreaks in a transmission control scenario: challenges posed by social and leisure activities, and for workers in vulnerable conditions, Spain, early summer 2020

Severe acute respiratory syndrome coronavirus 2 community-wide transmission declined in Spain by early May 2020, being replaced by outbreaks and sporadic cases. From mid-June to 2 August, excluding single household outbreaks, 673 outbreaks were notified nationally, 551 active (>6,200 cases) at the time. More than half of these outbreaks and cases coincided with: (i) social (family/friends’ gatherings or leisure venues) and (ii) occupational (mainly involving workers in vulnerable conditions) settings. Control measures were accordingly applied