Diversity in the intrinsic apoptosis pathway of nematodes.

Early studies of the free-living nematode C. elegans informed us how BCL-2-regulated apoptosis in humans is regulated. However, subsequent studies showed C.

Strategies to enable large-scale proteomics for reproducible research.

Reproducible research is the bedrock of experimental science. To enable the deployment of large-scale proteomics, we assess the reproducibility of mass spectrometry (MS) over time and across instruments and develop computational methods for improving quantitative accuracy. We perform 1560 data independent acquisition (DIA)-MS runs of eight samples containing known proportions of ovarian and prostate cancer tissue and yeast, or control HEK293T cells.

Regulation through MicroRNAs in Response to Low-Energy N Ion Irradiation in Oryza sativa.

MicroRNAs (miRNAs) are a non-coding regulatory RNAs that play significant roles in plant growth and development, especially in the stress response. Low-energy ion radiation, a type of environmental stress, can cause multiple biological effects. To understand the roles of miRNAs in response to low-energy N ion radiation in Oryza sativa, high-throughput sequencing of small RNAs was carried out to detect the expression of miRNAs in the shoots of the rice after 2 × 10 N+/cm irradiation.

Cross-strand disulfides in the hydrogen bonding site of antiparallel β-sheet (aCSDhs): Forbidden disulfides that are highly strained, easily broken.

Some disulfide bonds perform important structural roles in proteins, but another group has functional roles via redox reactions. Forbidden disulfides are stressed disulfides found in recognizable protein contexts, which currently constitute more than 10% of all disulfides in the PDB. They likely have functional redox roles and constitute a major subset of all redox-active disulfides.

Interleukin 33 Signaling Restrains Sporadic Colon Cancer in an Interferon-γ-Dependent Manner.

Interleukin 33 (IL33) is an inflammatory cytokine released during necrotic cell death. The epithelium and stroma of the intestine express large amounts of IL33 and its receptor St2. IL33 is therefore continuously released during homeostatic turnover of the intestinal mucosa.

Mapping genotype-phenotype associations of nsSNPs in coiled-coil oligomerization domains of the human proteome.

We assessed the impact of disease mutations (DMs) versus polymorphisms (PYs) in coiled-coil (CC) domains in UniProt by modeling the structural and functional impact of variants in silico with the CC prediction program Multicoil. The structural impact of variants was evaluated with respect to three main metrics: the oligomerization score-to determine whether the variant is stabilizing or destabilizing-the oligomerization state, and the register-specific score. The functional impact was queried indirectly in several ways.

NKX2-5 mutations causative for congenital heart disease retain functionality and are directed to hundreds of targets.

We take a functional genomics approach to congenital heart disease mechanism. We used DamID to establish a robust set of target genes for NKX2-5 wild type and disease associated NKX2-5 mutations to model loss-of-function in gene regulatory networks. NKX2-5 mutants, including those with a crippled homeodomain, bound hundreds of targets including NKX2-5 wild type targets and a unique set of "off-targets", and retained partial functionality.

Novel therapeutics for coronary artery disease from genome-wide association study data.

Background: Coronary artery disease (CAD), one of the leading causes of death globally, is influenced by both environmental and genetic risk factors. Gene-centric genome-wide association studies (GWAS) involving cases and controls have been remarkably successful in identifying genetic loci contributing to CAD. Modern in silico platforms, such as candidate gene prediction tools, permit a systematic analysis of GWAS data to identify candidate genes for complex diseases like CAD.

Potential role of glutathione in evolution of thiol-based redox signaling sites in proteins.

Cysteine is susceptible to a variety of modifications by reactive oxygen and nitrogen oxide species, including glutathionylation; and when two cysteines are involved, disulfide formation. Glutathione-cysteine adducts may be removed from proteins by glutaredoxin, whereas disulfides may be reduced by thioredoxin. Glutaredoxin is homologous to the disulfide-reducing thioredoxin and shares similar binding modes of the protein substrate.

Identification of novel therapeutics for complex diseases from genome-wide association data.

Background: Human genome sequencing has enabled the association of phenotypes with genetic loci, but our ability to effectively translate this data to the clinic has not kept pace. Over the past 60 years, pharmaceutical companies have successfully demonstrated the safety and efficacy of over 1,200 novel therapeutic drugs via costly clinical studies. While this process must continue, better use can be made of the existing valuable data.

Candidate disease gene prediction using Gentrepid: application to a genome-wide association study on coronary artery disease.

Current single-locus-based analyses and candidate disease gene prediction methodologies used in genome-wide association studies (GWAS) do not capitalize on the wealth of the underlying genetic data, nor functional data available from molecular biology. Here, we analyzed GWAS data from the Wellcome Trust Case Control Consortium (WTCCC) on coronary artery disease (CAD). Gentrepid uses a multiple-locus-based approach, drawing on protein pathway- or domain-based data to make predictions.

Gentrepid V2.0: a web server for candidate disease gene prediction.

Background: Candidate disease gene prediction is a rapidly developing area of bioinformatics research with the potential to deliver great benefits to human health. As experimental studies detecting associations between genetic intervals and disease proliferate, better bioinformatic techniques that can expand and exploit the data are required.

Description: Gentrepid is a web resource which predicts and prioritizes candidate disease genes for both Mendelian and complex diseases.

Epistatic effects of potassium channel variation on cardiac repolarization and atrial fibrillation risk.

Objectives: The aim of this study was to evaluate the role of cardiac K(+) channel gene variants in families with atrial fibrillation (AF).

Background: The K(+) channels play a major role in atrial repolarization but single mutations in cardiac K(+) channel genes are infrequently present in AF families. The collective effect of background K(+) channel variants of varying prevalence and effect size on the atrial substrate for AF is largely unexplored.

Analysis of genome-wide association study data using the protein knowledge base.

Background: Genome-wide association studies (GWAS) aim to identify causal variants and genes for complex disease by independently testing a large number of SNP markers for disease association. Although genes have been implicated in these studies, few utilise the multiple-hit model of complex disease to identify causal candidates. A major benefit of multi-locus comparison is that it compensates for some shortcomings of current statistical analyses that test the frequency of each SNP in isolation for the phenotype population versus control.

Web tools for the prioritization of candidate disease genes.

Despite increasing sequencing capacity, genetic disease investigation still frequently results in the identification of loci containing multiple candidate disease genes that need to be tested for involvement in the disease. This process can be expedited by prioritizing the candidates prior to testing. Over the last decade, a large number of computational methods and tools have been developed to assist the clinical geneticist in prioritizing candidate disease genes.

Thiol-based redox signalling: rust never sleeps.

Cysteine residues in proteins are covalently modified under conditions of oxidative and nitrosative stress by oxidation, nitrosation, glutathionylation and disulfide formation. Modifications induce conformational changes in substrate proteins, effecting signal cascades that evoke a biological response. A growing number of structures with modified cysteines are allowing a piecemeal understanding of the mechanistic aspects of these signalling pathways to emerge.

Cell cycle sensing of oxidative stress in Saccharomyces cerevisiae by oxidation of a specific cysteine residue in the transcription factor Swi6p.

Yeast cells begin to bud and enter the S phase when growth conditions are favorable during the G(1) phase. When subjected to some oxidative stresses, cells delay entry at G(1), allowing repair of cellular damage. Hence, oxidative stress sensing is coordinated with the regulation of cell cycle.

Two novel missense mutations in HAIRY-AND-ENHANCER-OF-SPLIT-7 in a family with spondylocostal dysostosis.

Spondylocostal dysostosis (SCD) is an inherited disorder with abnormal vertebral segmentation that results in extensive hemivertebrae, truncal shortening and abnormally aligned ribs. It arises during embryonic development by a disruption of formation of somites (the precursor tissue of the vertebrae, ribs and associated tendons and muscles). Four genes causing a subset of autosomal recessive forms of this disease have been identified: DLL3 (SCDO1: MIM 277300), MESP2 (SCDO2: MIM 608681), LFNG (SCDO3: MIM609813) and HES7 (SCDO4).

Disulfides as redox switches: from molecular mechanisms to functional significance.

The molecular mechanisms underlying thiol-based redox control are poorly defined. Disulfide bonds between Cys residues are commonly thought to confer extra rigidity and stability to their resident protein, forming a type of proteinaceous spot weld. Redox biologists have been redefining the role of disulfides over the last 30-40 years.

Conformational changes in redox pairs of protein structures.

Disulfides are conventionally viewed as structurally stabilizing elements in proteins but emerging evidence suggests two disulfide subproteomes exist. One group mediates the well known role of structural stabilization. A second redox-active group are best known for their catalytic functions but are increasingly being recognized for their roles in regulation of protein function.

Comparison of automated candidate gene prediction systems using genes implicated in type 2 diabetes by genome-wide association studies.

Background: Automated candidate gene prediction systems allow geneticists to hone in on disease genes more rapidly by identifying the most probable candidate genes linked to the disease phenotypes under investigation. Here we assessed the ability of eight different candidate gene prediction systems to predict disease genes in intervals previously associated with type 2 diabetes by benchmarking their performance against genes implicated by recent genome-wide association studies.

Results: Using a search space of 9556 genes, all but one of the systems pruned the genome in favour of genes associated with moderate to highly significant SNPs.

Identifying foldable regions in protein sequence from the hydrophobic signal.

Structural genomics initiatives aim to elucidate representative 3D structures for the majority of protein families over the next decade, but many obstacles must be overcome. The correct design of constructs is extremely important since many proteins will be too large or contain unstructured regions and will not be amenable to crystallization. It is therefore essential to identify regions in protein sequences that are likely to be suitable for structural study.

Mechanism of allosteric regulation of transglutaminase 2 by GTP.

Allosteric regulation is a fundamental mechanism of biological control. Here, we investigated the allosteric mechanism by which GTP inhibits cross-linking activity of transglutaminase 2 (TG2), a multifunctional protein, with postulated roles in receptor signaling, extracellular matrix assembly, and apoptosis. Our findings indicate that at least two components are involved in functionally coupling the allosteric site and active center of TG2, namely (i) GTP binding to mask a conformationally destabilizing switch residue, Arg-579, and to facilitate interdomain interactions that promote adoption of a compact, catalytically inactive conformation and (ii) stabilization of the inactive conformation by an uncommon H bond between a cysteine (Cys-277, an active center residue) and a tyrosine (Tyr-516, a residue located on a loop of the beta-barrel 1 domain that harbors the GTP-binding site).

Analysis of protein sequence and interaction data for candidate disease gene prediction.

Linkage analysis is a successful procedure to associate diseases with specific genomic regions. These regions are often large, containing hundreds of genes, which make experimental methods employed to identify the disease gene arduous and expensive. We present two methods to prioritize candidates for further experimental study: Common Pathway Scanning (CPS) and Common Module Profiling (CMP).