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

Identification and in silico analysis of functional SNPs of the BRCA1 gene.

Single Nucleotide Polymorphisms (SNPs) are being intensively studied to understand the biological basis of complex traits and diseases. The Genetics of human phenotype variation could be understood by knowing the functions of SNPs. In this study using computational methods, we analyzed the genetic variations that can alter the expression and function of the CFTR gene responsible candidate for causing cystic fibrosis. We applied an evolutionary perspective to screen the SNPs using a sequence homology-based SIFT tool, which suggested that 17 nsSNPs (44%) were found to be deleterious. The structure-based approach PolyPhen server suggested that 26 nsSNPS (66%) may disrupt protein function and structure. The PupaSuite tool predicted the phenotypic effect of SNPs on the structure and function of the affected protein. Structure analysis was carried out with the major mutation that occurred in the native protein coded by CFTR gene, and which is at amino acid position F508C for nsSNP with id (rs1800093). The amino acid residues in the native and mutant modeled protein were further analyzed for solvent accessibility, secondary structure and stabilizing residues to check the stability of the proteins. The SNPs were further subjected to iHAP analysis to identify htSNPs, and we report potential candidates for future studies on CFTR mutations.

/pdf/a-novel-computational-and-structural-analysis-of-nssnps-in-210jchbspg.pdf

A novel computational and structural analysis of nsSNPs in CFTR gene.

Single nucleotide polymorphisms (SNPs) are the most common type of genetic variations in humans Understanding the functions of SNPs can greatly help to understand the genetics of the human phenotype variation and especially the genetic basis of human complex diseases The method to identify functional SNPs from a pool, containing both functional and neutral SNPs is challenging by experimental protocols To explore possible relationships between genetic mutation and phenotypic variation, different computational algorithm tools like Sorting Intolerant from Tolerant, Polymorphism Phenotyping, UTRscan, FASTSNP, and PupaSuite were used for prioritization of high-risk SNPs in coding region (exonic nonsynonymous SNPs) and noncoding regions (intronic and exonic 5' and 3'-untranslated region (UTR) SNPs) In this work, we have analyzed the SNPs that can alter the expression and function of transcriptional factor TP53 as a pipeline and for providing a guide to experimental work We identified the possible mutations and proposed modeled structure for the mutant proteins and compared them with the native protein These nsSNPs play a critical role in cancer association studies aiming to explain the disparity in cancer treatment responses as well as to improve the effectiveness of the cancer treatments Our results endorse the study with in vivo experimental protocols

Applications of computational algorithm tools to identify functional SNPs

Aberrant aggregation in proteins leads to increased propensity of β-sheets, thereby increasing the toxicity level Numerous neurological disorders are triggered due to aggregation in protein Superoxide dismutase 1 (SOD1) is one such protein that leads to familial amyotrophic lateral sclerosis, a devastating neurodegenerative disorder In our study, the aggregation effect in native and the fatal mutant (Ala4Val) SOD1 was examined, using tCONCOORD Experimental studies reported that the naturally obtained polyphenol has an inhibitory effect on the aggregated protein Consequently, we predominantly focused on curcumin, a natural occurring polyphenol, to inhibit the aggregation in SOD1 In view of that, curcumin was computationally docked with both the native and mutant SOD1, using Autodock Thus, our analysis suggested that curcumin showed an enhanced binding affinity in the mutant SOD1 with increased hydrophobic interactions as compared to native SOD1 Further investigations were accomplished, using steered molecular dynamics and conformational sampling on both the bound complexes of native and mutant SOD1 with curcumin to unravel the effect of disaggregation In addition, we also elucidated the variations in the free energy landscape of native and mutant SOD1 in their unbound and bound states to differentiate the aggregation Hence, the study postulated a classical treatment against mutant SOD1, using the naturally occurring polyphenol (curcumin) via the computational framework for designing therapeutics against ALS

R. Rajasekaran

Papers

Identification and in silico analysis of functional SNPs of the BRCA1 gene.

A novel computational and structural analysis of nsSNPs in CFTR gene.

Applications of computational algorithm tools to identify functional SNPs

Computational investigation of curcumin, a natural polyphenol that inhibits the destabilization and the aggregation of human SOD1 mutant (Ala4Val)

Computational and structural investigation of deleterious functional SNPs in breast cancer BRCA2 gene.