PDBsum1 : A standalone program for generating PDBsum analyses

PDBsum1 is a standalone set of programs to perform the same structural analyses as provided by the PDBsum web server (https://www.ebi.ac.uk/pdbsum). The server has pages for every entry in the Protein Data Bank (PDB) and can also process user‐uploaded PDB files, returning a password‐protected set of pages that are retained for around 3 months. The standalone version described here allows for in‐house processing and indefinite retention of the results. All data files and images are pre‐generated, rather than on‐the‐fly as in the web version, so can be easily accessed. The program runs on Linux, Windows, and mac operating systems and is freely available for academic use at https://www.ebi.ac.uk/thornton-srv/software/PDBsum1.     

PDBsum extras: SARS‐CoV‐2 and AlphaFold models

The PDBsum web server provides structural analyses of the entries in the Protein Data Bank (PDB). Two recent additions are described here. The first is the detailed analysis of the SARS‐CoV‐2 virus protein structures in the PDB. These include the variants of concern, which are shown both on the sequences and 3D structures of the proteins. The second addition is the inclusion of the available AlphaFold models for human proteins. The pages allow a search of the protein against existing structures in the PDB via the Sequence Annotated by Structure (SAS) server, so one can easily compare the predicted model against experimentally determined structures. The server is freely accessible to all at http://www.ebi.ac.uk/pdbsum.     

DichroWeb,a website for calculating protein secondary structure from circular dichroism spectroscopic data

Circular dichroism (CD) spectroscopy is a widely‐used method for characterizing the secondary structures of proteins. The well‐established and highly used analysis website, DichroWeb (located at: http://dichroweb.cryst.bbk.ac.uk/html/home.shtml) enables the facile quantitative determination of helix, sheet, and other secondary structure contents of proteins based on their CD spectra. DichroWeb includes a range of reference datasets and algorithms, plus graphical and quantitative methods for determining the quality of the analyses produced. This article describes the current website content, usage and accessibility, as well as the many upgraded features now present in this highly popular tool that was originally created nearly two decades ago.     

The Anaphase Promoting Complex Regulates Yeast Lifespan and rDNA Stability by Targeting Fob1 for Degradation

Genomic stability, stress response, and nutrient signaling all play critical, evolutionarily conserved roles in lifespan determination. However, the molecular mechanisms coordinating these processes with longevity remain unresolved. Here we investigate the involvement of the yeast anaphase promoting complex (APC) in longevity. The APC governs passage through M and G1 via ubiquitin-dependent targeting of substrate proteins and is associated with cancer and premature aging when defective. Our two-hybrid screen utilizing Apc5 as bait recovered the lifespan determinant Fob1 as prey. Fob1 is unstable specifically in G1, cycles throughout the cell cycle in a manner similar to Clb2 (an APC target), and is stabilized in APC (apc5^CA) and proteasome (rpn10∆) mutants. Deletion of FOB1 increased replicative lifespan (RLS) in wild type (WT), apc5^CA, and apc10∆ cells, and suppressed apc5^CA cell cycle progression and rDNA recombination defects. Alternatively, increased FOB1 expression decreased RLS in WT cells, but did not reduce the already short apc5^CA RLS, suggesting an epistatic interaction between apc5^CA and fob1∆. Mutation to a putative L-Box (Fob1^E420V), a Destruction Box-like motif, abolished Fob1 modifications, stabilized the protein, and increased rDNA recombination. Our work provides a mechanistic role played by the APC to promote replicative longevity and genomic stability in yeast.     

Too Much of a Good Thing: The Unique and Repeated Paths Toward Copper Adaptation

Copper is a micronutrient essential for growth due to its role as a cofactor in enzymes involved in respiration, defense against oxidative damage, and iron uptake. Yet too much of a good thing can be lethal, and yeast cells typically do not have tolerance to copper levels much beyond the concentration in their ancestral environment. Here, we report a short-term evolutionary study of Saccharomyces cerevisiae exposed to levels of copper sulfate that are inhibitory to the initial strain. We isolated and identified adaptive mutations soon after they arose, reducing the number of neutral mutations, to determine the first genetic steps that yeast take when adapting to copper. We analyzed 34 such strains through whole-genome sequencing and by assaying fitness within different environments; we also isolated a subset of mutations through tetrad analysis of four lines. We identified a multilayered evolutionary response. In total, 57 single base-pair mutations were identified across the 34 lines. In addition, gene amplification of the copper metallothionein protein, CUP1-1, was rampant, as was chromosomal aneuploidy. Four other genes received multiple, independent mutations in different lines (the vacuolar transporter genes VTC1 and VTC4; the plasma membrane H+-ATPase PMA1; and MAM3, a protein required for normal mitochondrial morphology). Analyses indicated that mutations in all four genes, as well as CUP1-1 copy number, contributed significantly to explaining variation in copper tolerance. Our study thus finds that evolution takes both common and less trodden pathways toward evolving tolerance to an essential, but highly toxic, micronutrient.     

Distinctive Behaviors of Druggable Proteins in Cellular Networks

The interaction environment of a protein in a cellular network is important in defining the role that the protein plays in the system as a whole, and thus its potential suitability as a drug target. Despite the importance of the network environment, it is neglected during target selection for drug discovery. Here, we present the first systematic, comprehensive computational analysis of topological, community and graphical network parameters of the human interactome and identify discriminatory network patterns that strongly distinguish drug targets from the interactome as a whole. Importantly, we identify striking differences in the network behavior of targets of cancer drugs versus targets from other therapeutic areas and explore how they may relate to successful drug combinations to overcome acquired resistance to cancer drugs. We develop, computationally validate and provide the first public domain predictive algorithm for identifying druggable neighborhoods based on network parameters. We also make available full predictions for 13,345 proteins to aid target selection for drug discovery. All target predictions are available through canSAR.icr.ac.uk. Underlying data and tools are available at https://cansar.icr.ac.uk/cansar/publications/druggable_network_neighbourhoods/.     

A Toolbox for Representational Similarity Analysis

Neuronal population codes are increasingly being investigated with multivariate pattern-information analyses. A key challenge is to use measured brain-activity patterns to test computational models of brain information processing. One approach to this problem is representational similarity analysis (RSA), which characterizes a representation in a brain or computational model by the distance matrix of the response patterns elicited by a set of stimuli. The representational distance matrix encapsulates what distinctions between stimuli are emphasized and what distinctions are de-emphasized in the representation. A model is tested by comparing the representational distance matrix it predicts to that of a measured brain region. RSA also enables us to compare representations between stages of processing within a given brain or model, between brain and behavioral data, and between individuals and species. Here, we introduce a Matlab toolbox for RSA. The toolbox supports an analysis approach that is simultaneously data- and hypothesis-driven. It is designed to help integrate a wide range of computational models into the analysis of multichannel brain-activity measurements as provided by modern functional imaging and neuronal recording techniques. Tools for visualization and inference enable the user to relate sets of models to sets of brain regions and to statistically test and compare the models using nonparametric inference methods. The toolbox supports searchlight-based RSA, to continuously map a measured brain volume in search of a neuronal population code with a specific geometry. Finally, we introduce the linear-discriminant t value as a measure of representational discriminability that bridges the gap between linear decoding analyses and RSA. In order to demonstrate the capabilities of the toolbox, we apply it to both simulated and real fMRI data. The key functions are equally applicable to other modalities of brain-activity measurement. The toolbox is freely available to the community under an open-source license agreement (http://www.mrc-cbu.cam.ac.uk/methods-and-resources/toolboxes/license/).

This is a PLOS Computational Biology Software Article

     

Genetics of Lipid-Storage Management in Caenorhabditis elegans Embryos

Lipids play a pivotal role in embryogenesis as structural components of cellular membranes, as a source of energy, and as signaling molecules. On the basis of a collection of temperature-sensitive embryonic lethal mutants, a systematic database search, and a subsequent microscopic analysis of >300 interference RNA (RNAi)–treated/mutant worms, we identified a couple of evolutionary conserved genes associated with lipid storage in Caenorhabditis elegans embryos. The genes include cpl-1 (cathepsin L–like cysteine protease), ccz-1 (guanine nucleotide exchange factor subunit), and asm-3 (acid sphingomyelinase), which is closely related to the human Niemann-Pick disease–causing gene SMPD1. The respective mutant embryos accumulate enlarged droplets of neutral lipids (cpl-1) and yolk-containing lipid droplets (ccz-1) or have larger genuine lipid droplets (asm-3). The asm-3 mutant embryos additionally showed an enhanced resistance against C band ultraviolet (UV-C) light. Herein we propose that cpl-1, ccz-1, and asm-3 are genes required for the processing of lipid-containing droplets in C. elegans embryos. Owing to the high levels of conservation, the identified genes are also useful in studies of embryonic lipid storage in other organisms.     

The Myriapoda and Onychophora collection (MY) of the Muséum national d’Histoire naturelle (MNHN,Paris)

The Myriapoda and Onychophora collection dataset inventories the occurrence records of the collection of myriapods and onychophorans in the Muséum national d’Histoire naturelle, Paris. The dataset currently consists of 202 lots of onychophorans, representing all of those present, and almost ten thousand (9 795) lots of myriapods, representing 33 to 40% of the MNHN Myriapoda collection. This collection, which is of key historic importance, represents the results of two centuries of myriapod and onychophoran studies. The sources of the collection are worldwide, with a high representation for metropolitan France for the myriapods. None of the occurrences are yet georeferenced. Access to the dataset via the data portals of the MNHN and the GBIF has been made possible through the e-ReColNat project (ANR-11-INBS-0004).The Myriapoda and Onychophora collection of MNHN is actively expanding, hence both the collection and dataset are in continuous growth. The dataset can be accessed through the portals of GBIF at http://www.gbif.org/dataset/3287044c-8c48-4ad6-81d4-4908071bc8db and the MNHN at http://science.mnhn.fr/institution/mnhn/collection/my/item/search/form.     

Developmental Defects in a Caenorhabditis elegans Model for Type III Galactosemia

Type III galactosemia is a metabolic disorder caused by reduced activity of UDP-galactose-4-epimerase, which participates in galactose metabolism and the generation of various UDP-sugar species. We characterized gale-1 in Caenorhabditis elegans and found that a complete loss-of-function mutation is lethal, as has been hypothesized for humans, whereas a nonlethal partial loss-of-function allele causes a variety of developmental abnormalities, likely resulting from the impairment of the glycosylation process. We also observed that gale-1 mutants are hypersensitive to galactose as well as to infections. Interestingly, we found interactions between gale-1 and the unfolded protein response.     

Recent Epidemiological Trends of Dengue in the French Territories of the Americas (2000–2012): A Systematic Literature Review

Dengue is a public health concern across the globe, and an escalating problem in the Americas. As part of a wider programme (covering Latin America and South East Asia) to characterize the epidemiology of dengue in dengue endemic areas, we undertook a systematic literature review to assess epidemiological trends (incidence, timing and duration of outbreaks/epidemics, age and sex distribution, serotype distribution, seroprevalence and disease severity) for dengue across the French Territories of the Americas (FTA), in French Guiana, Guadeloupe, Martinique, Saint Martin and Saint Barthélemy between 2000 and 2012 (CRD42012002341: http://www.crd.york.ac.uk/prospero/display_record.asp?ID=CRD42012002341). Of 413 relevant data sources identified, 45 were eligible for inclusion. A large proportion of the available data were from national surveillance reports, and 12 publications were from peer-reviewed journals. During the review period, 3–5 epidemics were identified in each of the island territories and French Guiana, and epidemics were often associated with a shift in the predominant circulating dengue virus serotype. Substantial gaps in epidemiological knowledge were identified. In particular, information regarding dengue virus genotype distribution, seroprevalence and age distribution of dengue were lacking. Additionally, much of the available data were from epidemic years; data from inter-epidemic periods were sparse. Nevertheless, the available epidemiological data showed that dengue is endemic across the FTA and suggest an evolution towards hyperendemicity, highlighting the need to continue the efforts with the existing surveillance programmes to assist in planning an effective vaccination programme once a dengue vaccine is deployed.

Protocol registration

PROSPERO CRD42012002341     

Chaste: An Open Source C++ Library for Computational Physiology and Biology

Chaste — Cancer, Heart And Soft Tissue Environment — is an open source C++ library for the computational simulation of mathematical models developed for physiology and biology. Code development has been driven by two initial applications: cardiac electrophysiology and cancer development. A large number of cardiac electrophysiology studies have been enabled and performed, including high-performance computational investigations of defibrillation on realistic human cardiac geometries. New models for the initiation and growth of tumours have been developed. In particular, cell-based simulations have provided novel insight into the role of stem cells in the colorectal crypt. Chaste is constantly evolving and is now being applied to a far wider range of problems. The code provides modules for handling common scientific computing components, such as meshes and solvers for ordinary and partial differential equations (ODEs/PDEs). Re-use of these components avoids the need for researchers to ‘re-invent the wheel’ with each new project, accelerating the rate of progress in new applications. Chaste is developed using industrially-derived techniques, in particular test-driven development, to ensure code quality, re-use and reliability. In this article we provide examples that illustrate the types of problems Chaste can be used to solve, which can be run on a desktop computer. We highlight some scientific studies that have used or are using Chaste, and the insights they have provided. The source code, both for specific releases and the development version, is available to download under an open source Berkeley Software Distribution (BSD) licence at http://www.cs.ox.ac.uk/chaste, together with details of a mailing list and links to documentation and tutorials.

This is a PLOS Computational Biology Software Article

     

EMu: probabilistic inference of mutational processes and their localization in the cancer genome

The spectrum of mutations discovered in cancer genomes can be explained by the activity of a few elementary mutational processes. We present a novel probabilistic method, EMu, to infer the mutational signatures of these processes from a collection of sequenced tumors. EMu naturally incorporates the tumor-specific opportunity for different mutation types according to sequence composition. Applying EMu to breast cancer data, we derive detailed maps of the activity of each process, both genome-wide and within specific local regions of the genome. Our work provides new opportunities to study the mutational processes underlying cancer development. EMu is available at http://www.sanger.ac.uk/resources/software/emu/.