Magbubah Essack

Conotoxins that confer therapeutic possibilities

Cone snails produce a distinctive repertoire of venom peptides that are used both as a defense mechanism and also to facilitate the immobilization and digestion of prey. These peptides target a wide variety of voltage- and ligand-gated ion channels, which make them an invaluable resource for studying the properties of these ion channels in normal and diseased states, as well as being a collection of compounds of potential pharmacological use in their own right. Examples include the United States Food and Drug Administration (FDA) approved pharmaceutical drug, Ziconotide (Prialt®; Elan Pharmaceuticals, Inc.) that is the synthetic equivalent of the naturally occurring ω-conotoxin MVIIA, whilst several other conotoxins are currently being used as standard research tools and screened as potential therapeutic drugs in pre-clinical or clinical trials. These developments highlight the importance of driving conotoxin-related research. A PubMed query from 1 January 2007 to 31 August 2011 combined with hand-curation of the retrieved articles allowed for the collation of 98 recently identified conotoxins with therapeutic potential which are selectively discussed in this review. Protein sequence similarity analysis tentatively assigned uncharacterized conotoxins to predicted functional classes. Furthermore, conotoxin therapeutic potential for neurodegenerative disorders (NDD) was also inferred.

Recently Confirmed Apoptosis-Inducing Lead Compounds Isolated from Marine Sponge of Potential Relevance in Cancer Treatment

Despite intense efforts to develop non-cytotoxic anticancer treatments, effective agents are still not available. Therefore, novel apoptosis-inducing drug leads that may be developed into effective targeted cancer therapies are of interest to the cancer research community. Targeted cancer therapies affect specific aberrant apoptotic pathways that characterize different cancer types and, for this reason, it is a more desirable type of therapy than chemotherapy or radiotherapy, as it is less harmful to normal cells. In this regard, marine sponge derived metabolites that induce apoptosis continue to be a promising source of new drug leads for cancer treatments. A PubMed query from 01/01/2005 to 31/01/2011 combined with hand-curation of the retrieved articles allowed for the identification of 39 recently confirmed apoptosis-inducing anticancer lead compounds isolated from the marine sponge that are selectively discussed in this review.

Insights into the Transcriptional Architecture of Behavioral Plasticity in the Honey Bee Apis mellifera

Honey bee colonies exhibit an age-related division of labor, with worker bees performing discrete sets of behaviors throughout their lifespan. These behavioral states are associated with distinct brain transcriptomic states, yet little is known about the regulatory mechanisms governing them. We used CAGEscan (a variant of the Cap Analysis of Gene Expression technique) for the first time to characterize the promoter regions of differentially expressed brain genes during two behavioral states (brood care (aka “nursing”) and foraging) and identified transcription factors (TFs) that may govern their expression. More than half of the differentially expressed TFs were associated with motifs enriched in the promoter regions of differentially expressed genes (DEGs), suggesting they are regulators of behavioral state. Strikingly, five TFs (nf-kb, egr, pax6, hairy, and clockwork orange) were predicted to co-regulate nearly half of the genes that were upregulated in foragers. Finally, differences in alternative TSS usage between nurses and foragers were detected upstream of 646 genes, whose functional analysis revealed enrichment for Gene Ontology terms associated with neural function and plasticity. This demonstrates for the first time that alternative TSSs are associated with stable differences in behavior, suggesting they may play a role in organizing behavioral state.

Network analysis of microRNAs and their regulation in human ovarian cancer

BackgroundMicroRNAs (miRNAs) are small non-coding RNA molecules that repress the translation of messenger RNAs (mRNAs) or degrade mRNAs. These functions of miRNAs allow them to control key cellular processes such as development, differentiation and apoptosis, and they have also been implicated in several cancers such as leukaemia, lung, pancreatic and ovarian cancer (OC). Unfortunately, the specific machinery of miRNA regulation, involving transcription factors (TFs) and transcription co-factors (TcoFs), is not well understood. In the present study we focus on computationally deciphering the underlying network of miRNAs, their targets, and their control mechanisms that have an influence on OC development.ResultsWe analysed experimentally verified data from multiple sources that describe miRNA influence on diseases, miRNA targeting of mRNAs, and on protein-protein interactions, and combined this data with ab initio transcription factor binding site predictions within miRNA promoter regions. From these analyses, we derived a network that describes the influence of miRNAs and their regulation in human OC. We developed a methodology to analyse the network in order to find the nodes that have the largest potential of influencing the networks behaviour (network hubs). We further show the potentially most influential miRNAs, TFs and TcoFs, showing subnetworks illustrating the involved mechanisms as well as regulatory miRNA network motifs in OC. We find an enrichment of miRNA targeted OC genes in the highly relevant pathways cell cycle regulation and apoptosis.ConclusionsWe combined several sources of interaction and association data to analyse and place miRNAs within regulatory pathways that influence human OC. These results represent the first comprehensive miRNA regulatory network analysis for human OC. This suggests that miRNAs and their regulation may play a major role in OC and that further directed research in this area is of utmost importance to enhance our understanding of the molecular mechanisms underlying human cancer development and OC in particular.

Aerobic methanotrophic communities at the Red Sea brine-seawater interface

The central rift of the Red Sea contains 25 brine pools with different physicochemical conditions, dictating the diversity and abundance of the microbial community. Three of these pools, the Atlantis II, Kebrit and Discovery Deeps, are uniquely characterized by a high concentration of hydrocarbons. The brine-seawater interface, described as an anoxic-oxic (brine-seawater) boundary, is characterized by a high methane concentration, thus favoring aerobic methane oxidation. The current study analyzed the aerobic free–living methane-oxidizing bacterial communities that potentially contribute to methane oxidation at the brine-seawater interfaces of the three aforementioned brine pools, using metagenomic pyrosequencing, 16S rRNA pyrotags and pmoA library constructs. The sequencing of 16S rRNA pyrotags revealed that these interfaces are characterized by high microbial community diversity. Signatures of aerobic methane-oxidizing bacteria were detected in the Atlantis II Interface (ATII-I) and the Kebrit Deep Upper (KB-U) and Lower (KB-L) brine-seawater interfaces. Through phylogenetic analysis of pmoA, we further demonstrated that the ATII-I aerobic methanotroph community is highly diverse. We propose four ATII-I pmoA clusters. Most importantly, cluster 2 groups with marine methane seep methanotrophs, and cluster 4 represent a unique lineage of an uncultured bacterium with divergent alkane monooxygenases. Moreover, non-metric multidimensional scaling (NMDS) based on the ordination of putative enzymes involved in methane metabolism showed that the Kebrit interface layers were distinct from the ATII-I and DD-I brine-seawater interfaces.

Mining Chemical Activity Status from High-Throughput Screening Assays.

High-throughput screening (HTS) experiments provide a valuable resource that reports biological activity of numerous chemical compounds relative to their molecular targets. Building computational models that accurately predict such activity status (active vs. inactive) in specific assays is a challenging task given the large volume of data and frequently small proportion of active compounds relative to the inactive ones. We developed a method, DRAMOTE, to predict activity status of chemical compounds in HTP activity assays. For a class of HTP assays, our method achieves considerably better results than the current state-of-the-art-solutions. We achieved this by modification of a minority oversampling technique. To demonstrate that DRAMOTE is performing better than the other methods, we performed a comprehensive comparison analysis with several other methods and evaluated them on data from 11 PubChem assays through 1,350 experiments that involved approximately 500,000 interactions between chemicals and their target proteins. As an example of potential use, we applied DRAMOTE to develop robust models for predicting FDA approved drugs that have high probability to interact with the thyroid stimulating hormone receptor (TSHR) in humans. Our findings are further partially and indirectly supported by 3D docking results and literature information. The results based on approximately 500,000 interactions suggest that DRAMOTE has performed the best and that it can be used for developing robust virtual screening models. The datasets and implementation of all solutions are available as a MATLAB toolbox online at www.cbrc.kaust.edu.sa/dramote and can be found on Figshare.

DEOP: a database on osmoprotectants and associated pathways

Microorganisms are known to counteract salt stress through salt influx or by the accumulation of osmoprotectants (also called compatible solutes). Understanding the pathways that synthesize and/or breakdown these osmoprotectants is of interest to studies of crops halotolerance and to biotechnology applications that use microbes as cell factories for production of biomass or commercial chemicals. To facilitate the exploration of osmoprotectants, we have developed the first online resource, ‘Dragon Explorer of Osmoprotection associated Pathways’ (DEOP) that gathers and presents curated information about osmoprotectants, complemented by information about reactions and pathways that use or affect them. A combined total of 141 compounds were confirmed osmoprotectants, which were matched to 1883 reactions and 834 pathways. DEOP can also be used to map genes or microbial genomes to potential osmoprotection-associated pathways, and thus link genes and genomes to other associated osmoprotection information. Moreover, DEOP provides a text-mining utility to search deeper into the scientific literature for supporting evidence or for new associations of osmoprotectants to pathways, reactions, enzymes, genes or organisms. Two case studies are provided to demonstrate the usefulness of DEOP. The system can be accessed at. Database URL: http://www.cbrc.kaust.edu.sa/deop/

FARNA: knowledgebase of inferred functions of non-coding RNA transcripts.

Abstract Non-coding RNA (ncRNA) genes play a major role in control of heterogeneous cellular behavior. Yet, their functions are largely uncharacterized. Current available databases lack in-depth information of ncRNA functions across spectrum of various cells/tissues. Here, we present FARNA, a knowledgebase of inferred functions of 10,289 human ncRNA transcripts (2,734 microRNA and 7,555 long ncRNA) in 119 tissues and 177 primary cells of human. Since transcription factors (TFs) and TF co-factors (TcoFs) are crucial components of regulatory machinery for activation of gene transcription, cellular processes and diseases in which TFs and TcoFs are involved suggest functions of the transcripts they regulate. In FARNA, functions of a transcript are inferred from TFs and TcoFs whose genes co-express with the transcript controlled by these TFs and TcoFs in a considered cell/tissue. Transcripts were annotated using statistically enriched GO terms, pathways and diseases across cells/tissues based on guilt-by-association principle. Expression profiles across cells/tissues based on Cap Analysis of Gene Expression (CAGE) are provided. FARNA, having the most comprehensive function annotation of considered ncRNAs across widest spectrum of human cells/tissues, has a potential to greatly contribute to our understanding of ncRNA roles and their regulatory mechanisms in human. FARNA can be accessed at: http://cbrc.kaust.edu.sa/farna

Distinct profiling of antimicrobial peptide families

Motivation: The increased prevalence of multi-drug resistant (MDR) pathogens heightens the need to design new antimicrobial agents. Antimicrobial peptides (AMPs) exhibit broad-spectrum potent activity against MDR pathogens and kills rapidly, thus giving rise to AMPs being recognized as a potential substitute for conventional antibiotics. Designing new AMPs using current in-silico approaches is, however, challenging due to the absence of suitable models, large number of design parameters, testing cycles, production time and cost. To date, AMPs have merely been categorized into families according to their primary sequences, structures and functions. The ability to computationally determine the properties that discriminate AMP families from each other could help in exploring the key characteristics of these families and facilitate the in-silico design of synthetic AMPs. Results: Here we studied 14 AMP families and sub-families. We selected a specific description of AMP amino acid sequence and identified compositional and physicochemical properties of amino acids that accurately distinguish each AMP family from all other AMPs with an average sensitivity, specificity and precision of 92.88%, 99.86% and 95.96%, respectively. Many of our identified discriminative properties have been shown to be compositional or functional characteristics of the corresponding AMP family in literature. We suggest that these properties could serve as guides for in-silico methods in design of novel synthetic AMPs. The methodology we developed is generic and has a potential to be applied for characterization of any protein family. Contact: vladimir.bajic@kaust.edu.sa Supplementary information: Supplementary data are available at Bioinformatics online.

Information Exploration System for Sickle Cell Disease and Repurposing of Hydroxyfasudil

Background Sickle cell disease (SCD) is a fatal monogenic disorder with no effective cure and thus high rates of morbidity and sequelae. Efforts toward discovery of disease modifying drugs and curative strategies can be augmented by leveraging the plethora of information contained in available biomedical literature. To facilitate research in this direction we have developed a resource, Dragon Exploration System for Sickle Cell Disease (DESSCD) (http://cbrc.kaust.edu.sa/desscd/) that aims to promote the easy exploration of SCD-related data. Description The Dragon Exploration System (DES), developed based on text mining and complemented by data mining, processed 419,612 MEDLINE abstracts retrieved from a PubMed query using SCD-related keywords. The processed SCD-related data has been made available via the DESSCD web query interface that enables: a/information retrieval using specified concepts, keywords and phrases, and b/the generation of inferred association networks and hypotheses. The usefulness of the system is demonstrated by: a/reproducing a known scientific fact, the “Sickle_Cell_Anemia–Hydroxyurea” association, and b/generating novel and plausible “Sickle_Cell_Anemia–Hydroxyfasudil” hypothesis. A PCT patent (PCT/US12/55042) has been filed for the latter drug repurposing for SCD treatment. Conclusion We developed the DESSCD resource dedicated to exploration of text-mined and data-mined information about SCD. No similar SCD-related resource exists. Thus, we anticipate that DESSCD will serve as a valuable tool for physicians and researchers interested in SCD.