The Eukaryotic Pathogen, Vector and Host Informatics Resource (VEuPathDB, https://veupathdb.org) represents the 2019 merger of VectorBase with the EuPathDB projects. As a Bioinformatics Resource Center funded by the National Institutes of Health, with additional support from the Welllcome Trust, VEuPathDB supports >500 organisms comprising invertebrate vectors, eukaryotic pathogens (protists and fungi) and relevant free-living or non-pathogenic species or hosts. Designed to empower researchers with access to Omics data and bioinformatic analyses, VEuPathDB projects integrate >1700 pre-analysed datasets (and associated metadata) with advanced search capabilities, visualizations, and analysis tools in a graphic interface. Diverse data types are analysed with standardized workflows including an in-house OrthoMCL algorithm for predicting orthology. Comparisons are easily made across datasets, data types and organisms in this unique data mining platform. A new site-wide search facilitates access for both experienced and novice users. Upgraded infrastructure and workflows support numerous updates to the web interface, tools, searches and strategies, and Galaxy workspace where users can privately analyse their own data. Forthcoming upgrades include cloud-ready application architecture, expanded support for the Galaxy workspace, tools for interrogating host-pathogen interactions, and improved interactions with affiliated databases (ClinEpiDB, MicrobiomeDB) and other scientific resources, and increased interoperability with the Bacterial & Viral BRC.

The Eukaryotic Pathogen Genomics Database Resource (EuPathDB, http://eupathdb.org) is a collection of databases covering 170+ eukaryotic pathogens (protists & fungi), along with relevant free-living and non-pathogenic species, and select pathogen hosts. To facilitate the discovery of meaningful biological relationships, the databases couple preconfigured searches with visualization and analysis tools for comprehensive data mining via intuitive graphical interfaces and APIs. All data are analyzed with the same workflows, including creation of gene orthology profiles, so data are easily compared across data sets, data types and organisms. EuPathDB is updated with numerous new analysis tools, features, data sets and data types. New tools include GO, metabolic pathway and word enrichment analyses plus an online workspace for analysis of personal, non-public, large-scale data. Expanded data content is mostly genomic and functional genomic data while new data types include protein microarray, metabolic pathways, compounds, quantitative proteomics, copy number variation, and polysomal transcriptomics. New features include consistent categorization of searches, data sets and genome browser tracks; redesigned gene pages; effective integration of alternative transcripts; and a EuPathDB Galaxy instance for private analyses of a user's data. Forthcoming upgrades include user workspaces for private integration of data with existing EuPathDB data and improved integration and presentation of host–pathogen interactions.

Here we describe a systematic structure-function analysis of the human ubiquitin (Ub) E2 conjugating proteins, consisting of the determination of 15 new high-resolution three-dimensional structures of E2 catalytic domains, and autoubiquitylation assays for 26 Ub-loading E2s screened against a panel of nine different HECT (homologous to E6-AP carboxyl terminus) E3 ligase domains. Integration of our structural and biochemical data revealed several E2 surface properties associated with Ub chain building activity; (1) net positive or neutral E2 charge, (2) an "acidic trough" located near the catalytic Cys, surrounded by an extensive basic region, and (3) similarity to the previously described HECT binding signature in UBE2L3 (UbcH7). Mass spectrometry was used to characterize the autoubiquitylation products of a number of functional E2-HECT pairs, and demonstrated that HECT domains from different subfamilies catalyze the formation of very different types of Ub chains, largely independent of the E2 in the reaction. Our data set represents the first comprehensive analysis of E2-HECT E3 interactions, and thus provides a framework for better understanding the molecular mechanisms of ubiquitylation. Molecular & Cellular Proteomics

EuPathDB (http://eupathdb.org) resources include 11 databases supporting eukaryotic pathogen genomic and functional genomic data, isolate data and phylogenomics. EuPathDB resources are built using the same infrastructure and provide a sophisticated search strategy system enabling complex interrogations of underlying data. Recent advances in EuPathDB resources include the design and implementation of a new data loading workflow, a new database supporting Piroplasmida (i.e. Babesia and Theileria), the addition of large amounts of new data and data types and the incorporation of new analysis tools. New data include genome sequences and annotation, strand-specific RNA-seq data, splice junction predictions (based on RNA-seq), phosphoproteomic data, high-throughput phenotyping data, single nucleotide polymorphism data based on high-throughput sequencing (HTS) and expression quantitative trait loci data. New analysis tools enable users to search for DNA motifs and define genes based on their genomic colocation, view results from searches graphically (i.e. genes mapped to chromosomes or isolates displayed on a map) and analyze data from columns in result tables (word cloud and histogram summaries of column content). The manuscript herein describes updates to EuPathDB since the previous report published in NAR in 2010.

Cul7 is a member of the Cullin Ring Ligase (CRL) family and is required for normal mouse development and cellular proliferation. Recently, a region of Cul7 that is highly conserved in the p53-associated, Parkin-like cytoplasmic protein PARC, was shown to bind p53 directly. Here we identify the CPH domains (conserved domain within Cul7, PARC, and HERC2 proteins) of both Cul7 and PARC as p53 interaction domains using size exclusion chromatography and NMR spectroscopy. We present the first structure of the evolutionarily conserved CPH domain and provide novel insight into the Cul7-p53 interaction. The NMR structure of the Cul7-CPH domain reveals a fold similar to peptide interaction modules such as the SH3, Tudor, and KOW domains. The p53 interaction surface of both Cul7 and PARC CPH domains was mapped to a conserved surface distinct from the analogous peptide-binding regions of SH3, KOW, and Tudor domains, suggesting a novel mode of interaction. The CPH domain interaction surface of p53 resides in the tetramerization domain and is formed by residues contributed by at least two subunits.The ubiquitin-proteosome system plays an important role in controlling diverse biological processes, ranging from signal transduction to cell cycle control (1, 2). These complex processes are controlled via specific degradation of individual or groups of proteins. Protein degradation via the ubiquitin pathway involves two successive steps: tagging of the substrate by covalent attachment of multiple ubiquitin molecules (ubiquitylation) and degradation of the tagged protein by 26 S proteosome complex with release of free and reusable ubiquitin (3).Ubiquitylation is the ultimate result of coordinated activity of an enzymatic cascade, which includes a ubiquitin-activating enzyme (E1), 3 a ubiquitin-conjugating enzyme (E2), and ubiquitin-ligating (E3) enzymes. The E3 ligases are the "brain" of this process and determine substrate specificity (4, 5).Cul7, is a recently identified member of the Cullin family of ubiquitin E3 ligases, localizes predominantly in the cytoplasm (6), and forms a unique Skp1-Cul7-Fbx29-like complex with FBXW8, a WD40 containing F-box protein (7-9). Although a target substrate for FBXW8 has not been yet identified, Cul7 recruits RBX1 to form a Skp1-Cul7-Fbx29-like E3 ubiquitin ligase complex (7,8). The biological function of Cul7 is unclear.However, Cul7 appears to play an important role in development (8, 9), and overexpression of Cul7 accelerates the rate of cell proliferation (6).Cul7 has significant sequence similarity (see Fig. 1) with the p53-associated, Parkin-like cytoplasmic protein, PARC (10). Both proteins contain CPH (domain that is conserved in Cul7, PARC, and HERC2 proteins) (11), DOC (DOC1/APC10), and Cullin homology domains (see Fig. 1A) that are linked with E3 ligase function, suggesting that PARC and Cul7 may both function as E3 ubiquitin ligases. PARC has been shown to sequester p53 in the cytoplasm via interaction between the N terminus of PARC and the C terminus of p53 (10). Cul7 may perform f...

Most Internet online resources for investigating HIV biology contain either bioinformatics tools, protein information or sequence data.

Research is limited on the effect of racism and social determinants of health on HIV pre-exposure prophylaxis (PrEP) use. This study used the PrEP-to-Need Ratio (PNR), which measures PrEP prescriptions divided by HIV diagnoses in the county, to evaluate sufficient PrEP use. AIDSVu datasets were compared to county-level social determinants of health. Standardized regression coefficients (β) were compared to identify strongest associations with PNR. Overall, factors including percent African American and percent uninsured had negative correlations with PNR, whereas median household income and severe housing cost burden had positive associations. Stratifying for population size, percent African American, percent uninsured, and severe housing cost burden were significant for low population areas, whereas median household income, percent in poverty, percent uninsured, and percent African American were significant for large populations. To reduce PrEP disparities, public health must develop strategies to reach those most in need, especially historically disadvantaged communities.

No abstract