Specialised adaptors in immune cells

Adaptors are modular proteins implicated in the orchestration of intracellular signalling pathways. Studies of adaptors specifically expressed in immune cells have provided clear examples of the importance of adaptor molecules in normal mammalian biology. Moreover, they have led to the identification of naturally occurring mutations in adaptors that can be linked to human diseases. Lastly, they have highlighted the plasticity of protein-protein interaction modules, and have shed light onto the mechanisms dictating the specificity of adaptor-mediated signals.     

Specialised plasma membranes in the preovulatory follicle op the fowl

Summary In the hen's follicle processes from the zona granulosa cells extend into the zona radiata. The terminal plasma membrane of these processes has a total thickness of around 160 Å and consists of five layers. Small granules spaced at regular intervals are attached to the cytoplasmic aspect of the inner layer by short stalks. In the 2 mm and 7 mm follicles the plasma membrane of the ovum facing the specialised terminal membranes has a striated appearance and shows a regular arrangement of granules attached by stalks to both its inner and outer aspects. The terminal and striated membranes are separated by an interval although there are areas of closer contact. In the 15 mm and 35 mm pre-ovulatory follicles the plasma membrane round the whole surface of the ovum is now typical striated membrane with bristles and attached granules. No explanation can be given at present of the function of the terminal membranes of the granulosa processes. They may indicate some change in the permeability permitting the intercellular diffusion of particles. It is suggested that the striated ovum plasma membrane is associated with the adsorption and transport of substances into the ovum for yolk synthesis.     

The Implicitome: A Resource for Rationalizing Gene-Disease Associations

High-throughput experimental methods such as medical sequencing and genome-wide association studies (GWAS) identify increasingly large numbers of potential relations between genetic variants and diseases. Both biological complexity (millions of potential gene-disease associations) and the accelerating rate of data production necessitate computational approaches to prioritize and rationalize potential gene-disease relations. Here, we use concept profile technology to expose from the biomedical literature both explicitly stated gene-disease relations (the explicitome) and a much larger set of implied gene-disease associations (the implicitome). Implicit relations are largely unknown to, or are even unintended by the original authors, but they vastly extend the reach of existing biomedical knowledge for identification and interpretation of gene-disease associations. The implicitome can be used in conjunction with experimental data resources to rationalize both known and novel associations. We demonstrate the usefulness of the implicitome by rationalizing known and novel gene-disease associations, including those from GWAS. To facilitate the re-use of implicit gene-disease associations, we publish our data in compliance with FAIR Data Publishing recommendations [https://www.force11.org/group/fairgroup] using nanopublications. An online tool (http://knowledge.bio) is available to explore established and potential gene-disease associations in the context of other biomedical relations.     

Oil,Gas and Conflict: A Mathematical Model for the Resource Curse

Oil and natural gas are highly valuable natural resources, but many countries with large untapped reserves suffer from poor economic and social-welfare performance. This conundrum is known as the resource curse. The resource curse is a result of poor governance and wealth distribution structures that allow the elite to monopolize resources for self-gain. When rival social groups compete for natural resources, civil unrest soon follows. While conceptually easy to follow, there have been few formal attempts to study this phenomenon. Thus, we develop a mathematical model that captures the basic elements and dynamics of this dilemma. We show that when resources are monopolized by the elite, increased exportation leads to decreased domestic production. This is due to under-provision of the resource-embedded energy and industrial infrastructure. Decreased domestic production then lowers the marginal return on productive activities, and insurgency emerges. The resultant conflict further displaces human, built, and natural capital. It forces the economy into a vicious downward spiral. Our numerical results highlight the importance of governance reform and productivity growth in reducing oil-and-gas-related conflicts, and thus identify potential points of intervention to break the downward spiral.     

Wastewater: A Potential Bioenergy Resource

Wastewaters are a rich source of nutrients for microorganisms. However, if left unattended the biodegradation may lead to severe environmental hazards. The wastewaters can thus be utilized for the production of various value added products including bioenergy (H₂ and CH₄). A number of studies have reported utilization of various wastewaters for energy production. Depending on the nature of the wastewater, different reactor configurations, wastewater and inoculum pretreatments, co-substrate utilizations along with other process parameters have been studied for efficient product formation. Only a few studies have reported sequential utilization of wastewaters for H₂ and CH₄ production despite its huge potential for complete waste degradation.     

A structure filter for the Eukaryotic Linear Motif Resource

Background  

Many proteins are highly modular, being assembled from globular domains and segments of natively disordered polypeptides. Linear motifs, short sequence modules functioning independently of protein tertiary structure, are most abundant in natively disordered polypeptides but are also found in accessible parts of globular domains, such as exposed loops. The prediction of novel occurrences of known linear motifs attempts the difficult task of distinguishing functional matches from stochastically occurring non-functional matches. Although functionality can only be confirmed experimentally, confidence in a putative motif is increased if a motif exhibits attributes associated with functional instances such as occurrence in the correct taxonomic range, cellular compartment, conservation in homologues and accessibility to interacting partners. Several tools now use these attributes to classify putative motifs based on confidence of functionality.     

FMiR: A Curated Resource of Mitochondrial DNA Information for Fish

Mitochondrial genome sequences have been widely used for evolutionary and phylogenetic studies. Among vertebrates, fish are an important, diverse group, and their mitogenome sequences are growing rapidly in public repositories. To facilitate mitochondrial genome analysis and to explore the valuable genetic information, we developed the Fish Mitogenome Resource (FMiR) database to provide a workbench for mitogenome annotation, species identification and microsatellite marker mining. The microsatellites are also known as simple sequence repeats (SSRs) and used as molecular markers in studies on population genetics, gene duplication and marker assisted selection. Here, easy-to-use tools have been implemented for mining SSRs and for designing primers to identify species/habitat specific markers. In addition, FMiR can analyze complete or partial mitochondrial genome sequence to identify species and to deduce relational distances among sequences across species. The database presently contains curated mitochondrial genomes from 1302 fish species belonging to 297 families and 47 orders reported from saltwater and freshwater ecosystems. In addition, the database covers information on fish species such as conservation status, ecosystem, family, distribution and occurrence downloaded from the FishBase and IUCN Red List databases. Those fish information have been used to browse mitogenome information for the species belonging to a particular category. The database is scalable in terms of content and inclusion of other analytical modules. The FMiR is running under Linux operating platform on high performance server accessible at URL http://mail.nbfgr.res.in/fmir.     

InterStoreDB:A Generic Integration Resource for Genetic and Genomic Data

Associating phenotypic traits and quantitative trait loci (QTL) to causative regions of the underlying genome is a key goal in agricultural research.InterStoreDB is a suite of integrated databases designed to assist in this process.The individual databases are species independent and generic in design,providing access to curated datasets relating to plant populations,phenotypic traits,genetic maps,marker loci and QTL,with links to functional gene annotation and genomic sequence data.Each component database provides access to associated metadata,including data provenance and parameters used in analyses,thus providing users with information to evaluate the relative worth of any associations identified.The databases include CropStoreDB,for management of population,genetic map,QTL and trait measurement data,SeqStoreDB for sequence-related data and AlignStoreDB,which stores sequence alignment information,and allows navigation between genetic and genomic datasets.Genetic maps are visualized and compared using the CMAP tool,and functional annotation from sequenced genomes is provided via an EnsEMBL-based genome browser.This framework facilitates navigation of the multiple biological domains involved in genetics and genomics research in a transparent manner within a single portal.We demonstrate the value of InterStoreDB as a tool for Brassica research.InterStoreDB is available from:http://www.interstoredb.org     

SysPTM: A Systematic Resource for Proteomic Research on Post-translational Modifications

With the rapid expansion of protein post-translational modification (PTM) research based on large-scale proteomic work, there is an increasing demand for a suitable repository to analyze PTM data. Here we present a curated, web-accessible PTM data base, SysPTM. SysPTM provides a systematic and sophisticated platform for proteomic PTM research equipped not only with a knowledge base of manually curated multi-type modification data but also with four fully developed, in-depth data mining tools. Currently, SysPTM contains data detailing 117,349 experimentally determined PTM sites on 33,421 proteins involving nearly 50 PTM types, curated from public resources including five data bases and four web servers and more than one hundred peer-reviewed mass spectrometry papers. Protein annotations including Pfam domains, KEGG pathways, GO functional classification, and ortholog groups are integrated into the data base. Four online tools have been developed and incorporated, including PTMBlast, to compare a user''s PTM dataset with PTM data in SysPTM; PTMPathway, to map PTM proteins to KEGG pathways; PTMPhylog, to discover potentially conserved PTM sites; and PTMCluster, to find clusters of multi-site modifications. The workflow of SysPTM was demonstrated by analyzing an in-house phosphorylation dataset identified by MS/MS. It is shown that in SysPTM, the role of single-type and multi-type modifications can be systematically investigated in a full biological context. SysPTM could be an important contribution to modificomics research. SysPTM is freely available online at www.sysbio.ac.cn/SysPTM.Post-translational modifications (PTMs)¹ are various processing events that change the maturity, activity, and/or turnover of proteins. More than 200 different types of PTMs have been found, with new ones still being reported (1). PTMs not only change the physicochemical properties of proteins (2) but also dynamically regulate various biological events such as protein degradation, subcellular localization, conformational change, protein-protein interaction, and signal transduction (3–5). Previous studies have revealed the central roles of PTMs in human health and disease. For example, phosphorylation of pRB1 has been associated with tumorigenesis through controlling cell division (6); S-nitrosylation of parkin regulates its E3 ligase activity, resulting in protein accumulation in sporadic Parkinson disease (7); and defects in protein glycosylation have been related to several forms of congenital muscular dystrophy (8). Given this important role in health and disease, PTMs have been regarded as potential disease biomarkers or therapeutic targets. For example, Erlotinib (Tarceva), an inhibitor of epidermal growth factor receptor tyrosine kinase, has been approved by the Food and Drug Administration to treat non-small cell lung cancer (9); and histone deacetylase inhibitors have been demonstrated to have a potential therapeutic role in Huntington disease (10). The broad range of important roles played by PTMs in physiological and pathological processes has made PTM research an active field in recent years. Yet we remain limited in our knowledge of the full scope of PTM distribution on proteins and the precise location of PTM sites.There are two major kinds of experimental methods to identify PTMs: 1) traditional biological experiments such as radiolabeling PTM proteins (11), Western analysis with antibodies against specific modifications (12), and site-directed mutagenesis of potential modification sites (13); and 2) large-scale proteomic experiments, especially multiple-dimensional liquid chromatography tandem mass spectrometry. Traditional experiments are laborious and time-consuming, resulting in slow data accumulation. By contrast, more recent MS/MS experiments have led to the discovery of thousands of new phosphorylation (14), glycosylation (15), acetylation (16), sumoylation (17), S-nitrosylation (18), and other modification sites. For example, based on MS/MS data, more than 6,000 phosphopeptides have been reported in HeLa cells (14), and 159 candidate sumoylated proteins have been found in yeast (17). Although advanced technologies have allowed PTM data to accumulate rapidly, it is impossible to identify all PTM sites for a set of proteins in one experiment, due to biased modification enrichment related to experimental protocol, limited sensitivity of mass spectrometer instrumentation, and failures in spectrum matching. Data bases are needed to amass PTM data from various experiments for comprehensive understanding of PTMs.Most data bases for storing PTM information have fallen into two general classes. One class focuses on a single modification type, such as Phospho.ELM (19) for phosphorylation or O-GLYCBASE (20) for glycosylation. Although these data bases have been widely used, they are limited in utility due to recording only a single modification type. The other class of PTM data base is the primary protein data base; these data bases collect PTM information with multiple modification types but are more broadly focused on providing diverse information about proteins, rather than PTM information specifically. Swiss-Prot (21) and HPRD (22) are examples of such data bases. As compared with either of the above two types of data base, integrated PTM data bases are more desirable. One example is dbPTM (23), which integrated experimentally determined PTM information from four external data bases. PhosphoSite started the harvesting of phosphorylation sites from published literature with a focus on in vivo mammalian phosphorylation data (24), but recently it has expanded to integrate nine other modification types. Even integrated data bases, however, have not taken into full consideration the aforementioned quickly accumulating PTM data from MS/MS experiments. These data, many of which are reported in the published literature but not collected in any data base, continue to increase rapidly due to new experiments. Such a wealth of information should be incorporated more comprehensively into the current PTM knowledge domain.At the same time, the high-throughput nature and complexity of MS/MS data pose computational challenges for proteome-scale PTM analyses in a biological context. A pure data repository is insufficient for such tasks. Powerful computational tools must accompany data repositories to allow knowledge extraction.To address these needs, we developed a systematic resource for PTM research, SysPTM, consisting of a PTM data base and four analysis tools. The SysPTM data base incorporates the existing features of numerous previous data bases, with an emphasis on collecting modification datasets from MS/MS experiments reported in the literature. The current release of SysPTM (v1.1) contains data detailing 117,349 PTM sites on 33,421 proteins involving nearly 50 modification types. The four analysis tools are PTMBlast, PTMPathway, PTMPhylog, and PTMCluster, which, respectively, can compare user PTM datasets with PTM data stored in SysPTM, map PTM proteins to KEGG pathways, discover potentially conserved PTM sites, and find significant clusters of multi-site modifications.In this work, an in-house MS/MS phosphorylation dataset from mouse embryonic stem cells was analyzed to demonstrate the SysPTM workflow. SysPTM can be accessed online.     

A Curated Resource for Phosphosite-specific Signature Analysis

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Highlights

• •Database of PTM site-specific phosphorylation signatures of kinases, perturbations and signaling pathways (PTMsigDB).
• •PTM signature enrichment analysis (PTM-SEA) outperformed gene-centric analysis in detection of EGF induced phospho signaling events.
• •PI3K perturbation signatures were readily detected in PI3Ka inhibited human breast cancer cells.
• •PTMsigDB and PTM-SEA can be freely accessed at https://github.com/broadinstitute/ssGSEA2.0.

     

Specialised host-use and phenophase tracking in restio leafhoppers (Cicadellidae: Cephalelini) in the Cape Floristic Region

The Cape Floristic Region (CFR) has exceptionally high plant diversity, but because there are so few studies on insect diversity and diet breadth, little is known about the relationship between plant and insect diversity. One possibility is that plant and insect diversity in the CFR are linked through host specialisation. Alternatively, the nutrient-poor soils of the CFR may favour generalist feeding strategies with insects tracking the favourable phenophases of a variety of host plants. We studied Cephalelus, a genus of leafhoppers apparently specialised on the Restionaceae, a diverse and dominant plant family in the CFR. We examined patterns of Cephalelus host association at a single site during a 24 month field survey to determine whether Cephalelus diversity is related to the partitioning of host plant or temporal niches; or whether Cephalelus tracks the most nutritive phenophases of restios by temporal host-switching. Seven Cephalelus species were recorded which varied in their seasonal abundance patterns. The majority of these species exhibited specialised host use on different Restionaceae species, with the exception of C. pickeri. This species specialised on two host plants. The populations of two dominant species, C. pickeri and C.uncinatus, tracked the phenology of their primary host plants but not of the Restionaceae in general. To conclude; we find no evidence for host-switching or generalism in Cephalelus. Instead, they appear to be host-specialised, suggesting coupling between their diversity and that of their host plants; the Restionaceae in the CFR.