Improved homology-driven computational validation of protein-protein interactions motivated by the evolutionary gene duplication and divergence hypothesis

<p>Abstract</p> <p>Background</p> <p>Protein-protein interaction (PPI) data sets generated by high-throughput experiments are contaminated by large numbers of erroneous PPIs. Therefore, computational methods for PPI validation are necessary to improve the quality of such data sets. Against the background of the theory that most extant PPIs arose as a consequence of gene duplication, the sensitive search for homologous PPIs, i.e. for PPIs descending from a common ancestral PPI, should be a successful strategy for PPI validation.</p> <p>Results</p> <p>To validate an experimentally observed PPI, we combine FASTA and PSI-BLAST to perform a sensitive sequence-based search for pairs of interacting homologous proteins within a large, integrated PPI database. A novel scoring scheme that incorporates both quality and quantity of all observed matches allows us (1) to consider also tentative paralogs and orthologs in this analysis and (2) to combine search results from more than one homology detection method. ROC curves illustrate the high efficacy of this approach and its improvement over other homology-based validation methods.</p> <p>Conclusion</p> <p>New PPIs are primarily derived from preexisting PPIs and not invented <it>de novo</it>. Thus, the hallmark of true PPIs is the existence of homologous PPIs. The sensitive search for homologous PPIs within a large body of known PPIs is an efficient strategy to separate biologically relevant PPIs from the many spurious PPIs reported by high-throughput experiments.</p

Computational Identification of Transcriptional Regulators in Human Endotoxemia

One of the great challenges in the post-genomic era is to decipher the underlying principles governing the dynamics of biological responses. As modulating gene expression levels is among the key regulatory responses of an organism to changes in its environment, identifying biologically relevant transcriptional regulators and their putative regulatory interactions with target genes is an essential step towards studying the complex dynamics of transcriptional regulation. We present an analysis that integrates various computational and biological aspects to explore the transcriptional regulation of systemic inflammatory responses through a human endotoxemia model. Given a high-dimensional transcriptional profiling dataset from human blood leukocytes, an elementary set of temporal dynamic responses which capture the essence of a pro-inflammatory phase, a counter-regulatory response and a dysregulation in leukocyte bioenergetics has been extracted. Upon identification of these expression patterns, fourteen inflammation-specific gene batteries that represent groups of hypothetically ‘coregulated’ genes are proposed. Subsequently, statistically significant cis-regulatory modules (CRMs) are identified and decomposed into a list of critical transcription factors (34) that are validated largely on primary literature. Finally, our analysis further allows for the construction of a dynamic representation of the temporal transcriptional regulatory program across the host, deciphering possible combinatorial interactions among factors under which they might be active. Although much remains to be explored, this study has computationally identified key transcription factors and proposed a putative time-dependent transcriptional regulatory program associated with critical transcriptional inflammatory responses. These results provide a solid foundation for future investigations to elucidate the underlying transcriptional regulatory mechanisms under the host inflammatory response. Also, the assumption that coexpressed genes that are functionally relevant are more likely to share some common transcriptional regulatory mechanism seems to be promising, making the proposed framework become essential in unravelling context-specific transcriptional regulatory interactions underlying diverse mammalian biological processes

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Reactions within molecular single crystals of inorganic and organometallic compounds : recent advances and implications for catalysis

Find the answer within: Transformations within molecular single crystals of organometallic compounds are very rare and usually involve (reversible) loss of solvent molecules or ligands. A great stride forward in the field of such transformations was recently made, involving the first selective catalytic transformation within single crystals, which neither was on surface or surface sites, nor in solution

Negishi cross-coupling reactions catalyzed by an aminophosphine-based nickel system : a reliable and general applicable reaction protocol for the high-yielding synthesis of biaryls

Treatment of NMP solutions of NiCl(2) with 1,1',1''-(phosphanetriyl)tripiperidine (≈2.05 equiv), dissolved in THF, in air at 25°C forms a highly active catalytic system for the cross-coupling of a large variety of electronically activated, non-activated, deactivated, and ortho-substituted, heterocyclic, and functionalized aryl bromides and aryl chlorides with diarylzinc reagents. Very high levels of conversion and yields were obtained within 2 h at 60°C in the presence of only 0.1 mol% of catalyst (based on nickel) and thus at catalyst loadings far lower than typically reported for nickel-catalyzed versions of the Negishi reaction. Various aryl halides-which may contain trifluoromethyl groups, fluorides, or other functional groups such as acetals, ketones, ethers, esters, lactones, amides, imines, anilines, alkenes, pyridines, quinolines, and pyrimidines-were successfully converted into the corresponding biaryls. Electronic and steric variations are tolerated in both reaction partners. Experimental observations indicate that a molecular (Ni(I)/Ni(III)) mechanism is operative

Alkyne hydrothiolation catalyzed by a dichlorobis(aminophosphine) complex of palladium : selective formation of cis-configured vinyl thioethers

Vinyl sulfides are very important synthetic intermediates in total syntheses and as precursors to a wide range of functionalized molecules. Furthermore, sulfur-containing organiccompounds commonly exhibit biological activity, and hence are frequently found in naturally occuring compounds. Moreover, these compounds have found applications in materials science, and thus are valuable synthetic targets. The increasing demand for vinyl thioethers expedited the development of new synthetic methods for these target compounds. The most attractive process for their preparation is the (100% atom efficient) alkyne hydrothiolation reactio

Direct observation of reductive elimination of methyl iodide from a rhodium(III) pincer complex : the importance of sterics

A rare case of directly observed alkyl halide reductive elimination from rhodium is reported. Treatment of the naphthyl-based PCP-type Rh(III) methyl complexes 2a,b [(C10H5(CH2PR2)2)Rh(CH3)(I)] (R = iPr 2a, R = tBu 2b) with CO resulted in facile reductive elimination of methyl iodide in the case of 2b, yielding the Rh(I) carbonyl complex [(C10H5(CH2PR2)2)Rh(CO)] 3b (R = tBu), while the less bulky 2a formed CO adducts and did not undergo reductive elimination, contrary to expectations based on electron density considerations. Moreover, 3b oxidatively added methyl iodide, while 3a did not. CD3I/CH3I exchange studies in the absence of CO indicate that reversible formation of (ligated) methyl iodide takes place in both systems. Subsequently, when CO is present, it displaces methyl iodide in the bulkier tBu system, whereas with the iPr system formation of the Rh(III) CO adducts is favored. Iodide dissociation followed by its attack on the rhodium-methyl group is unlikely

Pincer-type Heck catalysts and mechanisms based on PdIV intermediates : a computational study

Pincer-type palladium complexes are among the most active Heck catalysts. Due to their exceptionally high thermal stability and the fact that they contain Pd(II) centers, controversial Pd(II)/Pd(IV) cycles have been often proposed as potential catalytic mechanisms. However, pincer-type Pd(IV) intermediates have never been experimentally observed, and computational studies to support the proposed Pd(II)/Pd(IV) mechanisms with pincer-type catalysts have never been carried out. In this computational study the feasibility of potential catalytic cycles involving Pd(IV) intermediates was explored. Density functional calculations were performed on experimentally applied aminophosphine-, phosphine-, and phosphite-based pincer-type Heck catalysts with styrene and phenyl bromide as substrates and (E)-stilbene as coupling product. The potential-energy surfaces were calculated in dimethylformamide (DMF) as solvent and demonstrate that Pd(II)/Pd(IV) mechanisms are thermally accessible and thus a true alternative to formation of palladium nanoparticles

Mizoroki–Heck reactions catalyzed by palladium dichloro-bis(aminophosphine) complexes under mild reaction conditions : the importance of ligand composition on the catalytic activity

Dichloro-bis(aminophosphine) complexes of palladium with the general formula [(P{(NC5H10)3−n(C6H11)n})2Pd(Cl)2] (where n=0-2) are easily accessible, cheap and air stable, highly active and universally applicable C–C cross-coupling catalysts, which exhibit an excellent functional group tolerance. The ligand composition of amine-substituted phosphines (controlled by the number of P–N bonds) was found to effectively determine their catalytic activity in the Heck reaction, for which nanoparticles were demonstrated to be their catalytically active form. While dichloro{bis[1,1′,1′′-(phosphinetriyl)tripiperidine]}palladium (1), the least stable complex (towards protons) within the series of [(P{(NC5H10)3−n(C6H11)n})2Pd(Cl)2] (where n=0-3), is a highly active Heck catalyst at 100°C and, hence, a rare example of an effective and versatile Heck catalyst that efficiently operates under mild reaction conditions (100 °C or below), a significant successive drop in activity was noticed for dichloro-bis(1,1′-(cyclohexylphosphinediyl)dipiperidine)palladium (2, with n=1), dichloro-bis(1-(dicyclohexylphosphinyl)piperidine)palladium (3, with n=2) and dichloro-bis(tricyclohexylphosphine)palladium (4, with n=3), of which the latter is essentially inactive (at least under the reaction conditions applied). This trend was explained by the successively increasing complex stability and its ensuing retarding effect on the (water-induced) generation of palladium nanoparticles thereof. This interpretation was experimentally confirmed (initial reductions of 1-4 into palladium(0) complexes of the type [Pd(P{(NC5H10)3−n(C6H11)n})2] (where n=0-3) were excluded to be the reason for the activity difference observed as well as molecular (Pd0/PdII) mechanisms were excluded to be operative) and thus demonstrates that the catalytic activity of dichloro-bis(aminophosphine) complexes of palladium can – in reactions where nanoparticles are involved – effectively be controlled by the number of P–N bonds in the ligand system