An Expanded Evaluation of Protein Function Prediction Methods Shows an Improvement In Accuracy

Background: A major bottleneck in our understanding of the molecular underpinnings of life is the assignment of function to proteins. While molecular experiments provide the most reliable annotation of proteins, their relatively low throughput and restricted purview have led to an increasing role for computational function prediction. However, assessing methods for protein function prediction and tracking progress in the field remain challenging. Results: We conducted the second critical assessment of functional annotation (CAFA), a timed challenge to assess computational methods that automatically assign protein function. We evaluated 126 methods from 56 research groups for their ability to predict biological functions using Gene Ontology and gene-disease associations using Human Phenotype Ontology on a set of 3681 proteins from 18 species. CAFA2 featured expanded analysis compared with CAFA1, with regards to data set size, variety, and assessment metrics. To review progress in the field, the analysis compared the best methods from CAFA1 to those of CAFA2. Conclusions: The top-performing methods in CAFA2 outperformed those from CAFA1. This increased accuracy can be attributed to a combination of the growing number of experimental annotations and improved methods for function prediction. The assessment also revealed that the definition of top-performing algorithms is ontology specific, that different performance metrics can be used to probe the nature of accurate predictions, and the relative diversity of predictions in the biological process and human phenotype ontologies. While there was methodological improvement between CAFA1 and CAFA2, the interpretation of results and usefulness of individual methods remain context-dependent

GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors

OBJECTIVE: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. METHODS: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. RESULTS: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values \u3c5×10 CONCLUSIONS: This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

A concise synthesis of asymmetrical N,N\u27-disubstituted guanidines

We present a new and concise method for the preparation of asymmetrical N,N?-disubstituted guanidines starting from thiourea via the reaction of N-Boc-protected N?-alkyl/aryl substituted thioureas with an amine in the presence of mercury(II) chloride and triethylamine

The rational design and synthesis of novel a-2 andrenoceptor antagonists as potential antidepressants

THESIS 9667Depression is one of the leading causes of illness worldwide and has been closely linked to low concentrations of monoaminergic neurotransmitters in the brain. Activation of presynaptic alpha-2 adrenoceptors (a2-AR) by the endogenous ligands noradrenaline (NA) and adrenaline (AD) results in a decrease in the release of monoaminergic neurotransmitters. Therefore, the administration of a2-AR antagonists leads to increased concentrations of brain monoamines and constitutes a viable strategy for the treatment for depression

Lobbying the European Commission: Open or secret?

Little transparency in the EU black?box of policy making means that there is limited citizen knowledge of which interest groups are operating in Brussels, what they seek to influence, how much resources they put into lobbying and the impact this has had on EU?s already large democratic deficit. As such, mass publics have held few tools to better understand, and get involved in changing, EU politics. In order to combat this problem, observers have considered the need to pursue \u27sunshine\u27 laws, a significant one being the regulation of lobbying. With this in mind, this paper asks: what has the Commission done with regard to regulating lobbyists and how does this compare from an international perspective; what insights can be gained about how the Commission register has evolved and the actors involved in policy making; and what lessons can be learned from this experience and is it really an antidote for the lack of genuine popular involvement in EU policy making? To answer these questions, there are three main sections. The first examines what is meant by the term \u27lobbying regulation\u27 and, from a comparative international perspective, it analyzes the Commission\u27s attempts to increase transparency through its establishment of its \u27voluntary\u27 register in June 2008. The second considers the evolution of the register since its establishment, offering a novel, yet simple, analysis of the register\u27s statistics between June 2008 and October 2010, focusing on registrations by consultancies, law firms, in?house corporate lobbies, NGOs and others. It also considers registration dynamics in one of the most significant and globalized sectors in the economy, namely the automobile sector. The third section closes with lessons to be learned from a comparative perspective and ponders the structural changes that may be considered by the Commission in order to establish genuine popular involvement in EU policy making

Renal and hepatic nitrogen metabolism during nh4cl ingestion in protein-deprived rats

Three groups of rats were given either a standard protein diet, a protein-free diet, or a protein-free diet with the inclusion of 0.28 M NH4Cl in their drinking water, for 10 days. Body, liver and kidney masses were decreased similarly in the protein-free and protein-free NH4Cl groups. Ingestion of protein-free diet resulted in profound systemic acidosis in both groups, the simultaneous consumption of NH4Cl having no further effect. The activities of the urea-cycle enzymes carbamoyl-phosphate synthease, ornithine transcarbamoylase, arginosuccinate lyase and arginase were significantly reduced in the protein-foe group, and the simultaneous ingestion of NH4Cl had no further effect. These results indicate that ammonium ingestion does not prevent the decrease in urea cycle enzyme activities during a period of dietary-protein deprivation. Renal phosphate-dependent glutaminase activity was unchanged in the protein-free group, but was significantly higher with simultaneous NH4Cl consumption, suggesting that the renal adaptation to acid ingestion is not compromised by a lack of dietary protein. Urinary ammonia excretion also increased in rats consuming protein-free diet and NH4Cl. Urinary urea excretion was greater in rats receiving protein-free diet and NH4Cl than in rats receiving protein-free diet only, at all time-points examined. These data demonstrate that urea synthesis is driven primarily by the need to dispose of protein-derived ammonia rather than bicarbonate

Understanding the DNA binding of novel non-symmetrical guanidinium/2-aminoimidazolinium derivatives.

Biophysical studies have been carried out on a family of asymmetric guanidinium-based diaromatic derivatives to assess their potential as DNA minor groove binding agents. To experimentally assess the binding of these compounds to DNA, solution phase biophysical studies have been performed. Thus, surface plasmon resonance, UV-visible spectroscopy and circular and linear dichroism have been utilized to evaluate binding constants, stoichiometry and mode of binding. In addition, the thermodynamics of the binding process have been determined by using isothermal titration calorimetry. These results show significant DNA binding affinity that correlates with the expected 1 : 1 binding ratio usually observed for minor groove binders. Moreover, a simple computational approach has been devised to assess the potential as DNA binders of this family of compounds