HIVToolbox, an Integrated Web Application for Investigating HIV

Many bioinformatic databases and applications focus on a limited domain of knowledge federating links to information in other databases. This segregated data structure likely limits our ability to investigate and understand complex biological systems. To facilitate research, therefore, we have built HIVToolbox, which integrates much of the knowledge about HIV proteins and allows virologists and structural biologists to access sequence, structure, and functional relationships in an intuitive web application. HIV-1 integrase protein was used as a case study to show the utility of this application. We show how data integration facilitates identification of new questions and hypotheses much more rapid and convenient than current approaches using isolated repositories. Several new hypotheses for integrase were created as an example, and we experimentally confirmed a predicted CK2 phosphorylation site. Weblink: [http://hivtoolbox.bio-toolkit.com

Patient prioritisation methods to shorten waiting times for elective surgery: A systematic review of how to improve access to surgery

BackgroundConcern about long waiting times for elective surgeries is not a recent phenomenon, but it has been heightened by the impact of the COVID-19 pandemic and its associated measures. One way to alleviate the problem might be to use prioritisation methods for patients on the waiting list and a wide range of research is available on such methods. However, significant variations and inconsistencies have been reported in prioritisation protocols from various specialties, institutions, and health systems. To bridge the evidence gap in existing literature, this comprehensive systematic review will synthesise global evidence on policy strategies with a unique insight to patient prioritisation methods to reduce waiting times for elective surgeries. This will provide evidence that might help with the tremendous burden of surgical disease that is now apparent in many countries because of operations that were delayed or cancelled due to the COVID-19 pandemic and inform policy for sustainable healthcare management systems.MethodsWe searched PubMed, EMBASE, SCOPUS, Web of Science, and the Cochrane Library, with our most recent searches in January 2020. Articles published after 2013 on major elective surgery lists of adult patients were eligible, but cancer and cancer-related surgeries were excluded. Both randomised and non-randomised studies were eligible and the quality of studies was assessed with ROBINS-I and CASP tools. We registered the review in PROSPERO (CRD42019158455) and reported it in accordance with the PRISMA statement.ResultsThe electronic search in five bibliographic databases yielded 7543 records (PubMed, EMBASE, SCOPUS, Web of Science, and Cochrane) and 17 eligible articles were identified in the screening. There were four quasi-experimental studies, 11 observational studies and two systematic reviews. These demonstrated moderate to low risk of bias in their research methods. Three studies tested generic approaches using common prioritisation systems for all elective surgeries in common. The other studies assessed specific prioritisation approaches for re-ordering the waiting list for a particular surgical specialty.ConclusionsExplicit prioritisation tools with a standardised scoring system based on clear evidence-based criteria are likely to reduce waiting times and improve equitable access to health care. Multiple attributes need to be considered in defining a fair prioritisation system to overcome limitations with local variations and discriminations. Collating evidence from a diverse body of research provides a single framework to improve the quality and efficiency of elective surgical care provision in a variety of health settings. Universal prioritisation tools with vertical and horizontal equity would help with re-ordering patients on waiting lists for elective surgery and reduce waiting times

A model of IN:LEDGF:viral DNA based on the PFV IN structure.

<p>(<b>A</b>) A model of HIV-1 IN complex with 4 IN subunits, 4 LEDGF subunits (light gray), and two viral DNA strands (dark gray); (<b>A, B</b>) Left panels (IN NTD = green, CCD = blue, CTD = red. (<b>A, B</b>) Right panels show functional sites (green = DNA binding), red = dimerization interface in 1EX4 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020122#pone.0020122-Chen1" target="_blank">[10]</a>, cyan = dimerization interface in 1WJA <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020122#pone.0020122-Cai1" target="_blank">[11]</a>; blue = tetramerization interface in 1K6Y <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020122#pone.0020122-Wang1" target="_blank">[8]</a>; purple = zinc binding site <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020122#pone.0020122-Cai1" target="_blank">[11]</a>; brown = reverse transcriptase binding site <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020122#pone.0020122-Wilkinson1" target="_blank">[31]</a>, light brown = tetramerization residues <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020122#pone.0020122-Lutzke2" target="_blank">[16]</a>. (<b>B</b>) A 90° rotation about the Y-axis of <b>A</b>. Orange arrowhead indicated channel proposed to bind target DNA <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020122#pone.0020122-Hare1" target="_blank">[36]</a>.</p

Sources of data in the HIVToolbox MySQL database.

<p>*Sequence features that are multimerization interfaces were calculated in Molmol based on residues that were less than 3.25 Å away from at least one residue in another subunit <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020122#pone.0020122-Koradi1" target="_blank">[63]</a>.</p

Interactive protein display page for Tat in HIVToolbox.

<p>Sequence window, Structure windows, Log windows, and Sequence Alignment section of HIVToolbox are shown. The interactive results page for HIV-1 tat is shown. The scrollable sequence window shows the protein sequence, domains (with colored fonts), functional residues (highlighted), protein-protein interaction sites (thin lines under sequence), mapped protein structures (thin colored lines over sequence) and minimotifs (figures under sequence). The synchronized interactive structural displays show domains and selected minimotifs (left panel), functional sites and selected protein-protein interaction sites (center panel), and residues conserved at or above a sequence conservation threshold selected with a slider or text box (right panel). The Sequence Alignment section shows alignment of a representative set of 20 sequences with the RefSeq sequence and the structure sequence. A second tab reveals a position specific-scoring matrix of amino acid frequencies at each position in the protein. More details about the features and use of HIVToolbox are in the supplement, and video tutorials are at Bio-Toolkit [<a href="http://www.bio-toolkit.com" target="_blank">http://www.bio-toolkit.com</a>].</p

Diagram of software architecture of HIVToolbox.

<p>Diagram of software architecture of HIVToolbox.</p

Analysis of Integrase model tetramers and hetero-octamers.

<p>Output of HIVToolbox showing surface plots of IN structural models. (<b>A, B</b>) IN tetramers showing domain organization (left panels) and locations of actives site residues (royal blue), proposed viral DNA binding grooves (yellow lines), proposed genomic DNA binding channel (red line), and zinc binding sites (cyan). Yellow numbers indicate the subunit too which the domain belongs. (<b>C</b>) IN:LEDGF hetero-octamers models showing organization of proteins (left panel) and proposed DNA binding groove (middle panel, red line). LEDGF subunits are colored grey. (<b>D</b>) An end-on view of the proposed host DNA binding channel in the IN:LEGDF hetero-octamer model shown in (<b>C</b>) (red circle).</p