Many proteins exist and function as oligomers. While hydrophobic interactions have been recognized as the major driving force for oligomerization, detailed molecular mechanisms for the assembly are unknown. Here, we used 14-3-3σ as a model protein and investigated the role of hydrophobic residues at the dimeric interface using MD simulations and coimmunoprecipitations. We found that a half-exposed and half-buried residue in the interface, Phe25, plays a more important role in promoting homodimerization than the hydrophobic core residues by organizing both favorable hydrophobic and hydrophilic interactions. Phe25 is critical in packing and stabilizing hydrophobic core residues. We conclude that the structural stability of hydrophobic cores is critical for a stable homodimer complex and this stable property can be bestowed by residues outside of hydrophobic core. The important organizing activity of Phe25 for homodimerization of 14-3-3σ originates from its unique physical location, rigidity, size, and hydrophobicity. Thus, hydrophobic residues that are not deeply buried at the oligomeric interface may play important but different roles from the buried core residues and they may promote oligomerization by organizing co-operativity of core and other residues for favorable hydrophobic and electrostatic interactions.
Rapid advancement of next-generation sequencing (NGS) technologies has facilitated the search for genetic susceptibility factors that influence disease risk in the field of human genetics. In particular whole genome sequencing (WGS) has been used to obtain the most comprehensive genetic variation of an individual and perform detailed evaluation of all genetic variation. To this end, sophisticated methods to accurately call high-quality variants and genotypes simultaneously on a cohort of individuals from raw sequence data are required. On chromosome 22 of 818 WGS data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), which is the largest WGS related to a single disease, we compared two multi-sample variant calling methods for the detection of single nucleotide variants (SNVs) and short insertions and deletions (indels) in WGS: (1) reduce the analysis-ready reads (BAM) file to a manageable size by keeping only essential information for variant calling (“REDUCE”) and (2) call variants individually on each sample and then perform a joint genotyping analysis of the variant files produced for all samples in a cohort (“JOINT”). JOINT identified 515,210 SNVs and 60,042 indels, while REDUCE identified 358,303 SNVs and 52,855 indels. JOINT identified many more SNVs and indels compared to REDUCE. Both methods had concordance rate of 99.60% for SNVs and 99.06% for indels. For SNVs, evaluation with HumanOmni 2.5M genotyping arrays revealed a concordance rate of 99.68% for JOINT and 99.50% for REDUCE. REDUCE needed more computational time and memory compared to JOINT. Our findings indicate that the multi-sample variant calling method using the JOINT process is a promising strategy for the variant detection, which should facilitate our understanding of the underlying pathogenesis of human diseases.
Remote voting has been an active research field for application of cryptographic techniques in the last two decades with many schemes and systems in publication. In this paper we present an overview of recent efforts in developing voting schemes and security models that involve a variety of real world constraints to ensure election integrity. We classify voting schemes based on their primary cryptographic techniques. We analyze recent typical schemes and systems against the basic and counter attack requirements with brief description. Such analysis shows difference among these security requirements and aids in design of future schemes. Our conclusion is provided regarding suitability of a particular voting system/scheme under various conditions.
Dams are vital for water resource utilization, and river diversion is key for dam construction safety. As sandy river basins are important exploitation areas that have special diversion features, the impact of sediment on the risk of river diversion during dam construction should be assessed. Diversion uncertainty is the origin of diversion risk, and sediment uncertainty changes the storage and discharge patterns of the diversion system. Two Gumbel-Hougaard (GH) copula functions are adopted to couple the random variables of flood and sediment, so that the sediment impacts on diversion storage and discharge can be obtained by the sampling of flood peaks. Based on variable coupling and sediment amendment, a method of Monte Carlo simulation (MCS) with a water balance calculation can quantitatively assess the risk of sandy river diversion, by evaluating the probability of upstream cofferdam overtopping. By introducing one diversion project on the Jing River in China with a clear water contrast, the risk values of dam construction diversion with or without sediment impacts can be obtained. Results show that the MCS method is feasible for diversion risk assessment; sediment has a negative impact on the risk of river diversion during dam construction, and this degradation effect is more evident for high-assurance diversion schemes.
Large biomedical abstract databases such as MEDLINE enable users to search for large bodies of biomedical knowledge quickly. In this study, we describe a new framework to improve the performance of MEDLINE document retrieval. We first analysed and built a normalized term frequency distributions for 1.8 million terms by sampling from 1,500,000 MEDLINE abstracts. Then, we developed a statistical model to identify significantly observed terms ('gists') in a document as additional document keywords to help improve document retrieval precisions. To improve document recalls, we integrated several biological ontologies that can expand user queries with semantically compatible terms. The framework was implemented in Oracle 10g.
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