I read this book the same weekend that the Packers took on the Rams, and the experience of the latter event, obviously, colored my judgment. Although I abhor anything that smacks of being a handbook (like, \"How to Earn a Merit Badge in Neurosurgery\") because too many volumes in biomedical science already evince a boyscout-like approach, I must confess that parts of this volume are fast, scholarly, and significant, with certain reservations. I like parts of this well-illustrated book because Dr. Sj6strand, without so stating, develops certain subjects on technique in relation to the acquisition of judgment and sophistication. And this is important! So, given that the author (like all of us) is somewhat deficient in some areas, and biased in others, the book is still valuable if the uninitiated reader swallows it in a general fashion, realizing full well that what will be required from the reader is a modulation to fit his vision, propreception, adaptation and response, and the kind of problem he is undertaking. A major deficiency of this book is revealed by comparison of its use of physics and of chemistry to provide understanding and background for the application of high resolution electron microscopy to problems in biology. Since the volume is keyed to high resolution electron microscopy, which is a sophisticated form of structural analysis, but really morphology in a modern guise, the physical and mechanical background of The instrument and its ancillary tools are simply and well presented. The potential use of chemical or cytochemical information as it relates to biological fine structure , however, is quite deficient. I wonder when even sophisticated morphol-ogists will consider fixation a reaction and not a technique; only then will the fundamentals become self-evident and predictable and this sine qua flon will become less mystical. Staining reactions (the most inadequate chapter) ought to be something more than a technique to selectively enhance contrast of morphological elements; it ought to give the structural addresses of some of the chemical residents of cell components. Is it pertinent that auto-radiography gets singled out for more complete coverage than other significant aspects of cytochemistry by a high resolution microscopist, when it has a built-in minimal error of 1,000 A in standard practice? I don't mean to blind-side (in strict football terminology) Dr. Sj6strand's efforts for what is \"routinely used in our laboratory\"; what is done is usually well done. It's just that …

Methods in Enzymology.

AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore

PL02-05 

All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.

Patterns of Somatic Mutation in Human Cancer Genomes

The International HapMap Consortium. The International HapMap Project (Co-PI of Hong Kong Centre which responsible for 2.5% of genome)

Spectrometric Identification of Organic Compounds

Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural and dynamic characterization of all species along the pathways from monomers to fibrils is challenging by experimental and computational means because they involve intrinsically disordered proteins in most diseases. Yet understanding how amyloid species become toxic is the challenge in developing a treatment for these diseases. Here we review what computer, in vitro, in vivo, and pharmacological experiments tell us about the accumulation and deposition of the oligomers of the (Aβ, tau), α-synuclein, IAPP, and superoxide dismutase 1 proteins, which have been the mainstream concept underlying Alzheimer's disease (AD), Parkinson's disease (PD), type II diabetes (T2D), and amyotrophic lateral sclerosis (ALS) research, respectively, for many years.

Amyloid oligomers: A joint experimental/computational perspective on Alzheimer's disease, Parkinson's disease, type II diabetes, and amyotrophic lateral sclerosis

In this present study, we computationally identified the germline missense mutation in the E-cadherin (CDH1) gene causing hereditary diffuse gastric cancer (HDGC). The analysis was initiated with SIFT followed by PolyPhen and I-Mutant2.0 programs with the help of 68 CDH1 variants retrieved from dbSNP. The analysis indicates that 10 variants such as P201R, A298T, E336D, C695R, N751K, Y755C, D768N, G879S, D882N and R169H were commonly found to be less stable and damaging by SIFT, PolyPhen and I-Mutant2.0 programs. Furthermore, SNPs&GO was used to predict the disease related mutations from the protein sequence. Finally, the affinities for the cetuximab with CDH1 variants were examined by using molecular docking algorithm. The result showed that P201R, A298T, E336D and R169H variants were found to be highly significant than the other mutations considered in our analysis. We sincerely hope that these findings certainly helpful for the experimental biologist working in HDGC drug development. DOI: http://dx.doi.org/10.3329/bjp.v8i2.14679

/pdf/computational-analysis-of-cdh1-missense-mutations-in-the-1905c8hn6b.pdf

Computational analysis of cdh1 missense mutations in the cause of hereditary diffuse gastric cancer

We report the results on the computation of binding affinity, electrostatic free energies, contact free energies, secondary structures, stabilization centers and stabilizing residues of binding residues during the molecular docking of selected scorpion neurotoxins with D2 dopamine receptor. All the scorpion neurotoxins showed a good and satisfactory docking with the D2 receptor molecule except one neurotoxin 2SN3. We computed multiple alignment studies, solvent accessibility calculations, secondary structure analysis, stabilization centers and stabilizing residues before and after the docking process. Overall, we emphasize that the results obtained in this work will be very helpful in further enhancement of understanding the research on modeling and drug design with respect to the D2 dopamine receptor. 2008 Elsevier Ltd. All rights reserved.

Analysisofbindingresiduesbetweenscorpionneurotoxinsand D2dopaminereceptor:Acomputationaldockingstudy

Inherited disease susceptibility in humans is most often associated with single nucleotide polymorphisms (SNPs). In this study, we computationally identified the most detrimental missense mutations in SH2 (Src homology 2) domain of SAP (signaling lymphocyte activation molecule (SLAM)-associated protein). Out of 20 variants, 14 missense mutations were commonly found to be less stable, deleterious and damaging by I-Mutant2.0, SIFT and PolyPhen programs, respectively. Subsequently, we performed modeling for these 14 variants to understand the conformational changes with respect to the native structure of SAP by computing their RMSD (root mean square deviation). The superimposed structures between native and these 14 mutants established the RMSD in the range of 0.02 A to 0.14 A. Further, the native and 14 mutants were docked with SLAMpeptide to explain the binding affinity of these detrimental missense mutations. From this analysis, we found that a total of 14 mutants, namely, H8D, G16D, G27S, L31P, R32T, D33Y, C42W, T53I, Y54C, R55L, I84T, F87S, Q99P and V102G showed less binding affinity with the SLAM-peptide in the form of Rosetta energy score. Finally, we analyzed that the loss of binding affinity of these 14 mutants of SAP, was due to altered flexibility in their binding amino acids with SLAM-peptide as compared with native type by normal mode analysis.

In Silico Analysis of Detrimental Missense Mutations on SAP and Its Effect on Interactions with SLAM

In this work, the most detrimental missense mutations of Mad1 protein that cause various types of cancer were identified computationally and the substrate binding efficiencies of those missense mutations were analyzed. Out of 13 missense mutations, IMutant 2.0, SIFTand PolyPhen programs identified 3 variants that were less stable, deleterious and damaging respectively. Subsequently, modeling of these 3 variants was performed to understand the change in their conformations with respect to the native Mad1 by computing their root mean squared deviation (RMSD). Furthermore, the native protein and the 3 mutants were docked with the binding partner Mad2 to explain the substrate binding efficiencies of those detrimental missense mutations. The docking studies identified that all the 3 mutants caused lower binding affinity for Mad2 than the native protein. Finally, normal mode analysis determined that the loss of binding affinity of these 3 mutants was caused by altered flexibility in the amino acids that bind to Mad2 compared with the native protein. Thus, the present study showed that majority of the substrate binding amino acids in those 3 mutants displayed loss of flexibility, which could be the theoretical explanation of decreased binding affinity between the mutant Mad1 and Mad2.

A computational approach to explore the functional missense mutations in the spindle check point protein Mad1

The computational identification of missense mutation in CST3 (CYSTATIN 3 or CYSTATIN C) gene has been done in the present study. The missense mutations in the CST3 gene will leads to hereditary cerebral amyloid angiopathy  The initiation of the analysis was done with SIFT followed by POLYPHEN-2 and I-Mutant 2.0 using 24 variants of CST3 gene of Homo sapiens which were derived from dbSNP. The analysis showed that 5 variants (Y60C, C123Y, L19P, Y88C, L94Q) were found to be less stable and damaging by SIFT, POLYPHEN-2 and I-MUTANT2.0. Furthermore the outputs of SNP & GO are collaborated with PHD-SNP (Predictor of Human Deleterious-Single Nucleotide Polymorphism) and PANTHER to predict 5 variants (Y60C, Y88C, C123Y, L19P, and L94Q) having clinical impact in causing the disease.  These findings will be certainly helpful for the present medical practitioners for the treatment of cerebral amyloid angiopathy. DOI: http://dx.doi.org/10.3329/bjp.v8i4.16524 Bangladesh Journal of Pharmacology Vol.8(4) 2013 390-394

/pdf/in-silico-prediction-of-functional-loss-of-cst3-gene-in-2yuj2lf0rv.pdf

R. Rajasekaran

Papers

Computational analysis of cdh1 missense mutations in the cause of hereditary diffuse gastric cancer

Analysisofbindingresiduesbetweenscorpionneurotoxinsand D2dopaminereceptor:Acomputationaldockingstudy

In Silico Analysis of Detrimental Missense Mutations on SAP and Its Effect on Interactions with SLAM

A computational approach to explore the functional missense mutations in the spindle check point protein Mad1

In silico prediction of functional loss of cst3 gene in hereditary cerebral amyloid angiopathy