Probability Distributions.- Linear Models for Regression.- Linear Models for Classification.- Neural Networks.- Kernel Methods.- Sparse Kernel Machines.- Graphical Models.- Mixture Models and EM.- Approximate Inference.- Sampling Methods.- Continuous Latent Variables.- Sequential Data.- Combining Models.

Pattern Recognition and Machine Learning

Data Mining Practical Machine Learning Tools and Techniques

The Huisgen 1,3-dipolar cycloaddition reaction of organic azides and alkynes has gained considerable attention in recent years due to the introduction in 2001 of Cu(1) catalysis by Tornoe and Meldal, leading to a major improvement in both rate and regioselectivity of the reaction, as realized independently by the Meldal and the Sharpless laboratories. The great success of the Cu(1) catalyzed reaction is rooted in the fact that it is a virtually quantitative, very robust, insensitive, general, and orthogonal ligation reaction, suitable for even biomolecular ligation and in vivo tagging or as a polymerization reaction for synthesis of long linear polymers. The triazole formed is essentially chemically inert to reactive conditions, e.g. oxidation, reduction, and hydrolysis, and has an intermediate polarity with a dipolar moment of ∼5 D. The basis for the unique properties and rate enhancement for triazole formation under Cu(1) catalysis should be found in the high ∆G of the reaction in combination with the low character of polarity of the dipole of the noncatalyzed thermal reaction, which leads to a considerable activation barrier. In order to understand the reaction in detail, it therefore seems important to spend a moment to consider the structural and mechanistic aspects of the catalysis. The reaction is quite insensitive to reaction conditions as long as Cu(1) is present and may be performed in an aqueous or organic environment both in solution and on solid support.

Cu-catalyzed azide-alkyne cycloaddition.

KEGG(Kyoto Encyclopedia of Genes and Genomes)〔和文〕 (特集 ゲノム医学の現在と未来--基礎と臨床) -- (データベース)

Degeneration and regeneration of the nervous system

http://www.cell.com/article/S2589004222010860/pdf

Uncertainty quantification: Can we trust artificial intelligence in drug discovery?

The transcriptional coactivator and histone acetyltransferase (HAT) p300 acetylates the four core histones and other transcription factors to regulate a plethora of fundamental biological processes including cell growth, development, oncogenesis and apoptosis. Recent structural and biochemical studies on the p300 HAT domain revealed a Theorell–Chance, or “hit-and-run”, catalytic mechanism. Nonetheless, the chemical mechanism of the entire reaction process including the proton transfer (PT) scheme and consequent acetylation reaction route remains unclear. In this study, a combined computational strategy consisting of molecular modeling, molecular dynamic (MD) simulation, and quantum mechanics/molecular mechanics (QM/MM) simulation was applied to elucidate these important issues. An initial p300/H3/Ac-CoA complex structure was modeled and optimized using a 100 ns MD simulation. Residues that play important roles in substrate binding and the acetylation reaction were comprehensively investigated. For the first time, these studies reveal a plausible PT scheme consisting of Y1394, D1507, and a conserved crystallographic water molecule, with all components of the scheme being stable during the MD simulation and the energy barrier low for PT to occur. The two-dimensional potential energy surface for the nucleophilic attack process was also calculated. The comparison of potential energies for two possible elimination half-reaction mechanisms revealed that Y1467 reprotonates the coenzyme-A leaving group to form product. This study provides new insights into the detailed catalytic mechanism of p300 and has important implications for the discovery of novel small molecule regulators for p300.

Catalytic Mechanism of Histone Acetyltransferase p300: From the Proton Transfer to Acetylation Reaction

The invention discloses a substituted-1H-indole compound with general formula as formula (I) and medically acceptable salt, solvent complex or hydrate, wherein Ar, R1, R2, n, X and Rx in the formula is defined as instruction; the compound has better prevention and cure action for experimental inflammation; the compound is dual inhibitor of epoxy oxygenase and 5-lipoxidas, which displays strong effective inhibitor for 5-lipoxidas; therefore the compound can be developed into safe non-steroidal anti-inflammatory agent to treat asthma, allergy and other immune disease and cardiovascular disease and/or prevention drug. The invention also provides the making method of the compound and its drug composition.

Substituted-1H- indoles compound, method for preparing the same, application and pharmaceutical composition of the same

OBJECTIVE To investigate the role of Mcl-1 gene in resistance of all-trans retinoic acid (ATRA) of leukemia cells. METHODS Long-term, intermittent and repetitive exposure of HL-60 cells to ATRA was used to establish a multidrug-resistance cell line (HL-60/ATRA). HL-60/ATRA cells were transfected with Mcl-1 small interference RNA (siRNA) by Lipofectamine 2000. Western blot was used to detect the expression of Mcl-1. The proliferation, apoptosis and differentiation were evaluated by MTT assay, in situ nick end-labeling (TUNEL) and NBT assay, respectively. RESULTS The HL-60/ATRA could keep its undifferentiated and proliferative status to a high concentration of ATRA (100 nmol/L) with highly expressed Mcl-1 protein (relative grey scale 0.624 +/- 0.127). Mcl-1 gene knockdown by siRNA (relative grey scale 0.267 +/- 0.086) could reverse the resistance of ATRA of HL-60/ATRA by inhibiting proliferation, and inducing differentiation and apoptosis [apoptosis rate (18.5 +/- 4.5)%]. CONCLUSION Mcl-1 gene might be involved in ATRA resistance in HL-60 cells and inhibiting its expression could be a new approach to ATRA resistance reversion.

Mingyue Zheng

Papers

Uncertainty quantification: Can we trust artificial intelligence in drug discovery?

Catalytic Mechanism of Histone Acetyltransferase p300: From the Proton Transfer to Acetylation Reaction

Substituted-1H- indoles compound, method for preparing the same, application and pharmaceutical composition of the same

[The effects of Mcl-1 gene on ATRA-resistant HL-60 cell].

Recent Advances in Neuraminidase Inhibitor Development as Antiinfluenza Drugs