DomainRBF: a Bayesian regression approach to the prioritization of candidate domains for complex diseases

BACKGROUND: Domains are basic units of proteins, and thus exploring associations between protein domains and human inherited diseases will greatly improve our understanding of the pathogenesis of human complex diseases and further benefit the medical prevention, diagnosis and treatment of these diseases. Within a given domain-domain interaction network, we make the assumption that similarities of disease phenotypes can be explained using proximities of domains associated with such diseases. Based on this assumption, we propose a Bayesian regression approach named domainRBF (domain Rank with Bayes Factor) to prioritize candidate domains for human complex diseases. RESULTS: Using a compiled dataset containing 1,614 associations between 671 domains and 1,145 disease phenotypes, we demonstrate the effectiveness of the proposed approach through three large-scale leave-one-out cross-validation experiments (random control, simulated linkage interval, and genome-wide scan), and we do so in terms of three criteria (precision, mean rank ratio, and AUC score). We further show that the proposed approach is robust to the parameters involved and the underlying domain-domain interaction network through a series of permutation tests. Once having assessed the validity of this approach, we show the possibility of ab initio inference of domain-disease associations and gene-disease associations, and we illustrate the strong agreement between our inferences and the evidences from genome-wide association studies for four common diseases (type 1 diabetes, type 2 diabetes, Crohn\u27s disease, and breast cancer). Finally, we provide a pre-calculated genome-wide landscape of associations between 5,490 protein domains and 5,080 human diseases and offer free access to this resource. CONCLUSIONS: The proposed approach effectively ranks susceptible domains among the top of the candidates, and it is robust to the parameters involved. The ab initio inference of domain-disease associations shows strong agreement with the evidence provided by genome-wide association studies. The predicted landscape provides a comprehensive understanding of associations between domains and human diseases

Structures of two fimbrial adhesins, AtfE and UcaD, from the uropathogen Proteus mirabilis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146321/1/ayd2jb5004.pd

PENGARUH DEWAN KOMISARIS ASING, DEWAN KOMISARIS INDEPENDEN DAN KEPEMILIKAN SAHAM ASING TERHADAP NILAI PERUSAHAAN (STUDI EMPIRIS PADA PERUSAHAAN MANUFAKTUR YANG TERDAFTAR DI BEI TAHUN 2009-2011)

Penelitian ini bertujuan untuk menguji pengaruh dewan komisaris asing, dewan komisaris independen dan kepemilikan saham asing terhadap nilai perusahaan manufaktur yang terdaftar di BEI (Bursa Efek Indonesia) selama periode pengamatan (2009-2011).Penelitian ini merupakan penelitian empiris dengan pendekatan kuantitatif yang melibatkan penggunaan analisa statistik. Penelitian ini menggunakan data sekunder. Alat analisisnyang digunakan dalam penelitian ini adalah regresi linier berganda dengan bantuan sofware SPSS (Statistical Package for Social Scienc) Hasil penelitian menunjukkan bahwa dewan komisaris asing dan kepemilikan saham asing berpengaruh positif dan signifikan terhadap nilai perusahaan, sedangkan variabel dewan komisaris independen tidak mempunyai pengaruh yang signifikan terhadap nilai perusahaan

Of spiders, bugs, and men : Structural and functional studies of proteins involved in assembly

Protein assembly enables complex machineries while being economical with genetic information. However, protein assembly also constitutes a potential threat to the host, and needs to be carefully regulated. Sulfate is a common source of sulfur for cysteine synthesis in bacteria. A putative sulfate permease CysZ from Escherichia coli appears much larger than its apparent molecular mass when analyzed by chromatography and native gel. Clearly CysZ undergoes homo-oligomerization. Using isothermal titration calorimetry, we confirmed that CysZ binds to its putative substrate sulfate, and also sulfite with higher affinity. CysZ-mediated sulfate transport—in both E. coli whole cells and proteoliposomes—was inhibited in the presence of sulfite, indicating a feedback inhibition mechanism. Proteus mirabilis is a Gram-negative bacterium causing urinary tract infections. Its simultaneous expression of multiple fimbriae enables colonization and biofilm formation. Fimbriae are surface appendages assembled from protein subunits, with distal adhesins specifically recognizing host-cell receptors. We present the first three structures of P. mirabilis fimbrial adhesins. While UcaD and AtfE adopt the canonical immunoglobulin-like fold, MrpH has a previously unknown fold. The coordination of Zn or Cu ion by three conserved histidine residues in MrpH is required for MrpH-dependent biofilm formation. Spider silk is an assembly of large proteins called spidroins. The N-terminal domain (NT) of spidroins senses the pH decrease along the silk spinning gland, and transits from monomer to dimer. A locked NT dimer interlinks spidroin molecules into polymers. We identified a new asymmetric dimer form of NT by x-ray crystallography. With additional evidence from small angle x-ray scattering (SAXS), we propose the asymmetric dimer as a common intermediate of NT in silk formation. Alzheimer’s disease is a life-threatening dementia, where aggregation-prone Aβ peptides self-assemble into amyloid fibrils. Bri2 BRICHOS is a molecular chaperone that efficiently delays Aβ fibrillation, and protects the region of its pro-protein with high β-propensity from aggregation. Combining SAXS and microscale thermophoresis data, we confirmed binding between Bri2 BRICHOS and its native client peptide. Using site-directed mutagenesis, we showed that three conserved tyrosine residues in Bri2 BRICHOS are important for its anti-Aβ fibrillation activity

Of spiders, bugs, and men : Structural and functional studies of proteins involved in assembly

Protein assembly enables complex machineries while being economical with genetic information. However, protein assembly also constitutes a potential threat to the host, and needs to be carefully regulated. Sulfate is a common source of sulfur for cysteine synthesis in bacteria. A putative sulfate permease CysZ from Escherichia coli appears much larger than its apparent molecular mass when analyzed by chromatography and native gel. Clearly CysZ undergoes homo-oligomerization. Using isothermal titration calorimetry, we confirmed that CysZ binds to its putative substrate sulfate, and also sulfite with higher affinity. CysZ-mediated sulfate transport—in both E. coli whole cells and proteoliposomes—was inhibited in the presence of sulfite, indicating a feedback inhibition mechanism. Proteus mirabilis is a Gram-negative bacterium causing urinary tract infections. Its simultaneous expression of multiple fimbriae enables colonization and biofilm formation. Fimbriae are surface appendages assembled from protein subunits, with distal adhesins specifically recognizing host-cell receptors. We present the first three structures of P. mirabilis fimbrial adhesins. While UcaD and AtfE adopt the canonical immunoglobulin-like fold, MrpH has a previously unknown fold. The coordination of Zn or Cu ion by three conserved histidine residues in MrpH is required for MrpH-dependent biofilm formation. Spider silk is an assembly of large proteins called spidroins. The N-terminal domain (NT) of spidroins senses the pH decrease along the silk spinning gland, and transits from monomer to dimer. A locked NT dimer interlinks spidroin molecules into polymers. We identified a new asymmetric dimer form of NT by x-ray crystallography. With additional evidence from small angle x-ray scattering (SAXS), we propose the asymmetric dimer as a common intermediate of NT in silk formation. Alzheimer’s disease is a life-threatening dementia, where aggregation-prone Aβ peptides self-assemble into amyloid fibrils. Bri2 BRICHOS is a molecular chaperone that efficiently delays Aβ fibrillation, and protects the region of its pro-protein with high β-propensity from aggregation. Combining SAXS and microscale thermophoresis data, we confirmed binding between Bri2 BRICHOS and its native client peptide. Using site-directed mutagenesis, we showed that three conserved tyrosine residues in Bri2 BRICHOS are important for its anti-Aβ fibrillation activity

Of spiders, bugs, and men : Structural and functional studies of proteins involved in assembly

Protein assembly enables complex machineries while being economical with genetic information. However, protein assembly also constitutes a potential threat to the host, and needs to be carefully regulated. Sulfate is a common source of sulfur for cysteine synthesis in bacteria. A putative sulfate permease CysZ from Escherichia coli appears much larger than its apparent molecular mass when analyzed by chromatography and native gel. Clearly CysZ undergoes homo-oligomerization. Using isothermal titration calorimetry, we confirmed that CysZ binds to its putative substrate sulfate, and also sulfite with higher affinity. CysZ-mediated sulfate transport—in both E. coli whole cells and proteoliposomes—was inhibited in the presence of sulfite, indicating a feedback inhibition mechanism. Proteus mirabilis is a Gram-negative bacterium causing urinary tract infections. Its simultaneous expression of multiple fimbriae enables colonization and biofilm formation. Fimbriae are surface appendages assembled from protein subunits, with distal adhesins specifically recognizing host-cell receptors. We present the first three structures of P. mirabilis fimbrial adhesins. While UcaD and AtfE adopt the canonical immunoglobulin-like fold, MrpH has a previously unknown fold. The coordination of Zn or Cu ion by three conserved histidine residues in MrpH is required for MrpH-dependent biofilm formation. Spider silk is an assembly of large proteins called spidroins. The N-terminal domain (NT) of spidroins senses the pH decrease along the silk spinning gland, and transits from monomer to dimer. A locked NT dimer interlinks spidroin molecules into polymers. We identified a new asymmetric dimer form of NT by x-ray crystallography. With additional evidence from small angle x-ray scattering (SAXS), we propose the asymmetric dimer as a common intermediate of NT in silk formation. Alzheimer’s disease is a life-threatening dementia, where aggregation-prone Aβ peptides self-assemble into amyloid fibrils. Bri2 BRICHOS is a molecular chaperone that efficiently delays Aβ fibrillation, and protects the region of its pro-protein with high β-propensity from aggregation. Combining SAXS and microscale thermophoresis data, we confirmed binding between Bri2 BRICHOS and its native client peptide. Using site-directed mutagenesis, we showed that three conserved tyrosine residues in Bri2 BRICHOS are important for its anti-Aβ fibrillation activity

Integrating multiple protein-protein interaction networks to prioritize disease genes: a Bayesian regression approach

Abstract Background The identification of genes responsible for human inherited diseases is one of the most challenging tasks in human genetics. Recent studies based on phenotype similarity and gene proximity have demonstrated great success in prioritizing candidate genes for human diseases. However, most of these methods rely on a single protein-protein interaction (PPI) network to calculate similarities between genes, and thus greatly restrict the scope of application of such methods. Meanwhile, independently constructed and maintained PPI networks are usually quite diverse in coverage and quality, making the selection of a suitable PPI network inevitable but difficult. Methods We adopt a linear model to explain similarities between disease phenotypes using gene proximities that are quantified by diffusion kernels of one or more PPI networks. We solve this model via a Bayesian approach, and we derive an analytic form for Bayes factor that naturally measures the strength of association between a query disease and a candidate gene and thus can be used as a score to prioritize candidate genes. This method is intrinsically capable of integrating multiple PPI networks. Results We show that gene proximities calculated from PPI networks imply phenotype similarities. We demonstrate the effectiveness of the Bayesian regression approach on five PPI networks via large scale leave-one-out cross-validation experiments and summarize the results in terms of the mean rank ratio of known disease genes and the area under the receiver operating characteristic curve (AUC). We further show the capability of our approach in integrating multiple PPI networks. Conclusions The Bayesian regression approach can achieve much higher performance than the existing CIPHER approach and the ordinary linear regression method. The integration of multiple PPI networks can greatly improve the scope of application of the proposed method in the inference of disease genes.</p

The Escherichia coli CysZ is a pH dependent sulfate transporter that can be inhibited by sulfite

The Escherichia coli inner membrane protein CysZ mediates the sulfate uptake subsequently utilized for the synthesis of sulfur-containing compounds in cells. Here we report the purification and functional characterization of CysZ. Using Isothermal Titration Calorimetry, we have observed interactions between CysZ and its putative substrate sulfate. Additional sulfur-containing compounds from the cysteine synthesis pathway have also been analyzed for their abilities to interact with CysZ. Our results suggest that CysZ is dedicated to a specific pathway that assimilates sulfate for the synthesis of cysteine. Sulfate uptake via CysZ into E. coli whole cells and proteoliposome offers direct evidence of CysZ being able to mediate sulfate uptake. In addition, the cysteine synthesis pathway intermediate sulfite can interact directly with CysZ with higher affinity than sulfate. The sulfate transport activity is inhibited in the presence of sulfite, suggesting the existence of a feedback inhibition mechanism in which sulfite regulates sulfate uptake by CysZ. Sulfate uptake assays performed at different extracellular pH and in the presence of a proton uncoupler indicate that this uptake is driven by the proton gradient

Molecular and Biochemical Analysis of Chalcone Synthase from Freesia hybrid in Flavonoid Biosynthetic Pathway

Chalcone synthase (CHS) catalyzes the first committed step in the flavonoid biosynthetic pathway. In this study, the cDNA (FhCHS1) encoding CHS from Freesia hybrida was successfully isolated and analyzed. Multiple sequence alignments showed that both the conserved CHS active site residues and CHS signature sequence were found in the deduced amino acid sequence of FhCHS1. Meanwhile, crystallographic analysis revealed that protein structure of FhCHS1 is highly similar to that of alfalfa CHS2, and the biochemical analysis results indicated that it has an enzymatic role in naringenin biosynthesis. Moreover, quantitative real-time PCR was performed to detect the transcript levels of FhCHS1 in flowers and different tissues, and patterns of FhCHS1 expression in flowers showed significant correlation to the accumulation patterns of anthocyanin during flower development. To further characterize the functionality of FhCHS1, its ectopic expression in Arabidopsis thaliana tt4 mutants and Petunia hybrida was performed. The results showed that overexpression of FhCHS1 in tt4 mutants fully restored the pigmentation phenotype of the seed coats, cotyledons and hypocotyls, while transgenic petunia expressing FhCHS1 showed flower color alteration from white to pink. In summary, these results suggest that FhCHS1 plays an essential role in the biosynthesis of flavonoid in Freesia hybrida and may be used to modify the components of flavonoids in other plants