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 structural comparison of deleterious mutations in nsSNPs of ABL1 gene in chronic myeloid leukemia: A bio-informatics study

Beta-2 microglobulin (β2m) is an amyloidogenic protein belongs to the immunoglobulin superfamily, responsible for the dialysis-related amyloidosis (DRA). Misfolding of β2m is a prerequisite to the formation of systemic amyloidosis that has an effect on the structure and function of the affected organ. The aim of our present study is to intensively explore the structural characterization of amyloid aggregation propensity of recently identified natural mutation D76N by applying the classical molecular dynamics (MD) approach. The MD result revealed that mutant D76N exhibited a wide variation in the evolutionarily conserved secondary structure profile. Due to an unsatisfied position of main chain donor/acceptor atoms that unable to form essential hydrogen bonds resulted to cause misfolding of mutant D76N by disrupting the local folding of β-strands and turn region. Analysis of time evolution of various structural properties, especially those of the functionally important residues: aggregation determining, initiating, and gatekeeper residues gave some possible insights into the structural characteristics of the disease mutant D76N. In a nutshell, compared to the wild-type β2m, aggregation promoting propensity of mutant D76N has established a long β-strand D owing to an inward movement of residue, Asp(53). Besides, aggregation forming characteristic of the DE loop in mutant D76N showed greater flexibility along the first principal eigenvector that favored to enhance an unusual conformational dynamics may lead toward self-aggregation and amyloid fibrils.

A systematic molecular dynamics approach to the structural characterization of amyloid aggregation propensity of β2-microglobulin mutant D76N.

In this work, we identified the detrimental missense mutations (point mutations) in epidermal growth factor receptor (EGFR) and its binding efficiency with the inhibitors namely Erlotinib, Gefitinib, and Lapatinib. Out of 26 point mutations on EGFR, 12 point mutations were commonly less stable, deleterious, and damaged as shown by all the three servers, I-Mutant2.0, SIFT, and PolyPhen. Further, we modeled 12 mutants and superimposed with the native EGFR to get RMSD values. Docking studies showed that Erlotinib had lesser binding affinity against both native and all the 12 mutants. Gefitinib had maximum binding affinity only with two mutants, viz., R748P and L858R. Lapatinib had maximum binding affinity with both native and other 10 mutants. Based on our computational analysis, we recommend that the combined administration of Gefitinib and Lapatinib could give a better effect in combating the disease.

In silico identification of significant detrimental missense mutations of EGFR and their effect with 4-anilinoquinazoline-based drugs.

The recent H1N1 influenza pandemic has attracted worldwide attention due to the high infection rate. Oseltamivir is a new class of anti-viral agent approved for the treatment and prevention of influenza infections. The principal target for this drug is a virus surface glycoprotein, neuraminidase (NA), which facilitates the release of nascent virus and thus spreads infection. Until recently, only a low prevalence of neuraminidase inhibitor (NAI) resistance (<1 %) had been detected in circulating viruses. However, there have been reports of significant numbers of A (H1N1) influenza strains with a N294S neuraminidase mutation that was highly resistant to the NAI, oseltamivir. Hence, in the present study, we highlight the effect of point mutation-induced oseltamivir resistance in H1N1 subtype neuraminidases by molecular simulation approach. The docking analysis reveals that mutation (N294S) significantly affects the binding affinity of oseltamivir with mutant type NA. This is mainly due to the decrease in the flexibility of binding site residues and the difference in prevalence of hydrogen bonds in the wild and mutant structures. This study throws light on the possible effects of drug-resistant mutations on the large functionally important collective motions in biological systems.

R. Rajasekaran

Papers

Identification and structural comparison of deleterious mutations in nsSNPs of ABL1 gene in chronic myeloid leukemia: A bio-informatics study

A systematic molecular dynamics approach to the structural characterization of amyloid aggregation propensity of β2-microglobulin mutant D76N.

In silico identification of significant detrimental missense mutations of EGFR and their effect with 4-anilinoquinazoline-based drugs.

In silico analysis of drug-resistant mutant of neuraminidase (N294S) against oseltamivir.

Computational Resources for Designing Peptide Based Drugs Preferred in the Field of Nanomedicine