123 research outputs found

    Network Science and Group Fusion Similarity-Based Searching to Explore the Chemical Space of Antiparasitic Peptides

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    Antimicrobial peptides (AMPs) have appeared as promising compounds to treat a wide range of diseases. Their clinical potentialities reside in the wide range of mechanisms they can use for both killing microbes and modulating immune responses. However, the hugeness of the AMPs’ chemical space (AMPCS), represented by more than 1065 unique sequences, has represented a big challenge for the discovery of new promising therapeutic peptides and for the identification of common structural motifs. Here, we introduce network science and a similarity searching approach to discover new promising AMPs, specifically antiparasitic peptides (APPs). We exploited the network-based representation of APPs’ chemical space (APPCS) to retrieve valuable information by using three network types: chemical space (CSN), half-space proximal (HSPN), and metadata (METN). Some centrality measures were applied to identify in each network the most important and nonredundant peptides. Then, these central peptides were considered as queries (Qs) in group fusion similarity-based searches against a comprehensive collection of known AMPs, stored in the graph database StarPepDB, to propose new potential APPs. The performance of the resulting multiquery similarity-based search models (mQSSMs) was evaluated in five benchmarking data sets of APP/non-APPs. The predictions performed by the best mQSSM showed a strong-to-very-strong performance since their external Matthews correlation coefficient (MCC) values ranged from 0.834 to 0.965. Outstanding MCC values (>0.85) were attained by the mQSSM with 219 Qs from both networks CSN and HSPN with 0.5 as similarity threshold in external data sets. Then, the performance of our best mQSSM was compared with the APPs prediction servers AMPDiscover and AMPFun. The proposed model showed its relevance by outperforming state-of-the-art machine learning models to predict APPs. After applying the best mQSSM and additional filters on the non-APP space from StarPepDB, 95 AMPs were repurposed as potential APP hits. Due to the high sequence diversity of these peptides, different computational approaches were applied to identify relevant motifs for searching and designing new APPs. Lastly, we identified 11 promising APP lead candidates by using our best mQSSMs together with diversity-based network analyses, and 24 web servers for activity/toxicity and drug-like properties. These results support that network-based similarity searches can be an effective and reliable strategy to identify APPs. The proposed models and pipeline are freely available through the StarPep toolbox software at http://mobiosd-hub.com/starpep

    Dryad_Nerophis_lumbriciformis

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    Microsatellite data from the Viana (Portugal) Nerophis lumbriciformis population. On the first page, the unique adult genotypes are presented (used for the construction of Table 1, using GENALEX and CERVUS). The second page contains the genotypes of embryos and potential parents, including recaptures (used in PARFEX for the parentage analysis)

    Small Molecules in the Cone Snail Arsenal

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    Cone snails are renowned for producing peptide-based venom, containing conopeptides and conotoxins, to capture their prey. A novel small-molecule guanine derivative with unprecedented features, genuanine, was isolated from the venom of two cone snail species. Genuanine causes paralysis in mice, indicating that small molecules and not just polypeptides may contribute to the activity of cone snail venom

    Pyrosequencing Characterization of the Microbiota from Atlantic Intertidal Marine Sponges Reveals High Microbial Diversity and the Lack of Co-Occurrence Patterns

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    <div><p>Sponges are ancient metazoans that host diverse and complex microbial communities. Sponge-associated microbial diversity has been studied from wide oceans across the globe, particularly in subtidal regions, but the microbial communities from intertidal sponges have remained mostly unexplored. Here we used pyrosequencing to characterize the microbial communities in 12 different co-occurring intertidal marine sponge species sampled from the Atlantic coast, revealing a total of 686 operational taxonomic units (OTUs) at 97% sequence similarity. Taxonomic assignment of 16S ribosomal RNA tag sequences estimated altogether 26 microbial groups, represented by bacterial (75.5%) and archaeal (22%) domains. <i>Proteobacteria</i> (43.4%) and <i>Crenarchaeota</i> (20.6%) were the most dominant microbial groups detected in all the 12 marine sponge species and ambient seawater. The <i>Crenarchaeota</i> microbes detected in three Atlantic Ocean sponges had a close similarity with <i>Crenarchaeota</i> from geographically separated subtidal Red Sea sponges. Our study showed that most of the microbial communities observed in sponges (73%) were also found in the surrounding ambient seawater suggesting possible environmental acquisition and/or horizontal transfer of microbes. Beyond the microbial diversity and community structure assessments (NMDS, ADONIS, ANOSIM), we explored the interactions between the microbial communities coexisting in sponges using the checkerboard score (C-score). Analyses of the microbial association pattern (co-occurrence) among intertidal sympatric sponges revealed the random association of microbes, favoring the hypothesis that the sponge-inhabiting microbes are recruited from the habitat mostly by chance or influenced by environmental factors to benefit the hosts.</p></div

    Adaptation of the Mitochondrial Genome in Cephalopods: Enhancing Proton Translocation Channels and the Subunit Interactions

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    <div><p>Mitochondrial protein-coding genes (mt genes) encode subunits forming complexes of crucial cellular pathways, including those involved in the vital process of oxidative phosphorylation (OXPHOS). Despite the vital role of the mitochondrial genome (mt genome) in the survival of organisms, little is known with respect to its adaptive implications within marine invertebrates. The molluscan Class Cephalopoda is represented by a marine group of species known to occupy contrasting environments ranging from the intertidal to the deep sea, having distinct metabolic requirements, varied body shapes and highly advanced visual and nervous systems that make them highly competitive and successful worldwide predators. Thus, cephalopods are valuable models for testing natural selection acting on their mitochondrial subunits (mt subunits). Here, we used concatenated mt genes from 17 fully sequenced mt genomes of diverse cephalopod species to generate a robust mitochondrial phylogeny for the Class Cephalopoda. We followed an integrative approach considering several branches of interest–covering cephalopods with distinct morphologies, metabolic rates and habitats–to identify sites under positive selection and localize them in the respective protein alignment and/or tridimensional structure of the mt subunits. Our results revealed significant adaptive variation in several mt subunits involved in the energy production pathway of cephalopods: ND5 and ND6 from Complex I, CYTB from Complex III, COX2 and COX3 from Complex IV, and in ATP8 from Complex V. Furthermore, we identified relevant sites involved in protein-interactions, lining proton translocation channels, as well as disease/deficiencies related sites in the aforementioned complexes. A particular case, revealed by this study, is the involvement of some positively selected sites, found in Octopoda lineage in lining proton translocation channels (site 74 from ND5) and in interactions between subunits (site 507 from ND5) of Complex I.</p></div

    Structural features of the Hh proteins.

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    <p>The hedgehog proteins are composed by two main domains: the Hedge (N-terminal) and Hog (C-terminal) domains. The Hedge domain forms the HhN portion of the Hh proteins (together with the signaling sequence, SS) that is separated from the rest of protein by an auto-cleavage reaction preformed by the Hog domain <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0074132#pone.0074132-Lee1" target="_blank">[4]</a>. The Hog domain forms the HhC portion of the Hh proteins and shares similarity with self-splicing Inteins on the Hint module <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0074132#pone.0074132-Burglin2" target="_blank">[22]</a>. The auto-cleavage reaction occurs on a GCF (glycine-cysteine-phenylalanine) motif that forms the boundary between the two main parts of the Hh proteins, with the cysteine residue initiating a nucleophilic attack on the carbonyl carbon of the preceding residue, the glycine <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0074132#pone.0074132-Beachy1" target="_blank">[5]</a>. The sterol-recognition region (SRR) forms the C-terminal region of the Hog domain and binds a cholesterol moiety that acts as an electron donor on a second nucleophilic attack that results in the cleavage of the bound between the glycine and cystein residues and in the attachment of the cholesterol moiety to the glycine residue <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0074132#pone.0074132-Beachy1" target="_blank">[5]</a>. After auto-cleavage, the sterified HhN fragment is further palmitoylated on the cystein residue immediately after the SS region <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0074132#pone.0074132-Chamoun1" target="_blank">[13]</a> and leaves the endoplasmic reticulum (ER) for later export <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0074132#pone.0074132-Chen3" target="_blank">[11]</a>.</p

    Evolutionary Genomics and Adaptive Evolution of the Hedgehog Gene Family (<i>Shh, Ihh and Dhh</i>) in Vertebrates

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    <div><p>The Hedgehog (<i>Hh</i>) gene family codes for a class of secreted proteins composed of two active domains that act as signalling molecules during embryo development, namely for the development of the nervous and skeletal systems and the formation of the testis cord. While only one <i>Hh</i> gene is found typically in invertebrate genomes, most vertebrates species have three (Sonic hedgehog – <i>Shh</i>; Indian hedgehog – <i>Ihh</i>; and Desert hedgehog – <i>Dhh</i>), each with different expression patterns and functions, which likely helped promote the increasing complexity of vertebrates and their successful diversification. In this study, we used comparative genomic and adaptive evolutionary analyses to characterize the evolution of the <i>Hh</i> genes in vertebrates following the two major whole genome duplication (WGD) events. To overcome the lack of <i>Hh</i>-coding sequences on avian publicly available databases, we used an extensive dataset of 45 avian and three non-avian reptilian genomes to show that birds have all three <i>Hh</i> paralogs. We find suggestions that following the WGD events, vertebrate <i>Hh</i> paralogous genes evolved independently within similar linkage groups and under different evolutionary rates, especially within the catalytic domain. The structural regions around the ion-binding site were identified to be under positive selection in the signaling domain. These findings contrast with those observed in invertebrates, where different lineages that experienced gene duplication retained similar selective constraints in the <i>Hh</i> orthologs. Our results provide new insights on the evolutionary history of the <i>Hh</i> gene family, the functional roles of these paralogs in vertebrate species, and on the location of mutational hotspots.</p></div

    IMPACT_S: Integrated Multiprogram Platform to Analyze and Combine Tests of Selection

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    <div><p>Among the major goals of research in evolutionary biology are the identification of genes targeted by natural selection and understanding how various regimes of evolution affect the fitness of an organism. In particular, adaptive evolution enables organisms to adapt to changing ecological factors such as diet, temperature, habitat, predatory pressures and prey abundance. An integrative approach is crucial for the identification of non-synonymous mutations that introduce radical changes in protein biochemistry and thus in turn influence the structure and function of proteins. Performing such analyses manually is often a time-consuming process, due to the large number of statistical files generated from multiple approaches, especially when assessing numerous taxa and/or large datasets. We present IMPACT_S, an easy-to-use Graphical User Interface (GUI) software, which rapidly and effectively integrates, filters and combines results from three widely used programs for assessing the influence of selection: Codeml (PAML package), Datamonkey and TreeSAAP. It enables the identification and tabulation of sites detected by these programs as evolving under the influence of positive, neutral and/or negative selection in protein-coding genes. IMPACT_S further facilitates the automatic mapping of these sites onto the three-dimensional structures of proteins. Other useful tools incorporated in IMPACT_S include Jmol, Archaeopteryx, Gnuplot, PhyML, a built-in Swiss-Model interface and a PDB downloader. The relevance and functionality of IMPACT_S is shown through a case study on the toxicoferan-reptilian Cysteine-rich Secretory Proteins (CRiSPs). IMPACT_S is a platform-independent software released under GPLv3 license, freely available online from <a href="http://impact-s.sourceforge.net" target="_blank">http://impact-s.sourceforge.net</a>.</p></div

    3.DIVERGE

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    Functional divergence results. Alignment and tree used to produce the results

    Morphological and Genetic Evidence for Multiple Evolutionary Distinct Lineages in the Endangered and Commercially Exploited Red Lined Torpedo Barbs Endemic to the Western Ghats of India

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    <div><p>Red lined torpedo barbs (RLTBs) (Cyprinidae: <i>Puntius</i>) endemic to the Western Ghats Hotspot of India, are popular and highly priced freshwater aquarium fishes. Two decades of indiscriminate exploitation for the pet trade, restricted range, fragmented populations and continuing decline in quality of habitats has resulted in their ‘Endangered’ listing. Here, we tested whether the isolated RLTB populations demonstrated considerable variation qualifying to be considered as distinct conservation targets. Multivariate morphometric analysis using 24 size-adjusted characters delineated all allopatric populations. Similarly, the species-tree highlighted a phylogeny with 12 distinct RLTB lineages corresponding to each of the different riverine populations. However, coalescence-based methods using mitochondrial DNA markers identified only eight evolutionarily distinct lineages. Divergence time analysis points to recent separation of the populations, owing to the geographical isolation, more than 5 million years ago, after the lineages were split into two ancestral stocks in the Paleocene, on north and south of a major geographical gap in the Western Ghats. Our results revealing the existence of eight evolutionarily distinct RLTB lineages calls for the re-determination of conservation targets for these cryptic and endangered taxa.</p></div
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