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S.B. Ficarro et al., "Phosphoproteome analysis by mass spectrometry and its application to Saccharomyces cerevisiae," Nature Biotechnology, 20[3]:301-5, March 2002. "This is a long-awaited paper detailing more than 200 phosphorylation sites from Saccharomyces cerevisiae. The authors used immobilized metal affinity chromatography (IMAC) to selectively isolate phosphopeptides from nonphosphopeptides. The new advance is the selectivity of the IMAC column when utilized after methylation of aspartate and glutamate residues. These amino acids normally bind to IMAC columns as contaminating peptides. A finding that should be evaluated further is that 67% of the phosphopeptides detected were doubly phosphorylated, suggesting that the IMAC separation might need to be modified. This is the largest phosphoproteomics experiment to date, but it appears as a technical note. With only one figure and one table, I wished the authors had made a full paper out of it." —Steven Gygi, Harvard Medical School, US M. Sato et al., "Fluorescent indicators for imaging protein phosphorylation in single living cells," Nature Biotechnology, 20[3]:287-94, March 2002. "The authors describe the use of genetically encoded fluorescent indicators to visualize signal transduction based on protein phosphorylation in living cells. The strategy relies on the use of two different color mutants of green fluorescent protein that serve as the donor and acceptor fluorophores for fluorescent resonance energy transfer (FRET) after appropriate phosphorylation events. The method should provide a general approach to study spatio-temporal dynamics of protein phosphorylation-dependent signaling in any living cells." —Steve Ward, University of Bath, UK SNP Genotyping J.S. Sinsheimer et al., "SNPs and snails and puppy dogs' tails: Analysis of SNP haplotype data using the gamete competition model," Annals of Human Genetics, 65[Pt 5]:483-90, September 2001. "[Here is] a method to use haplotype data in family-based association studies. The popular transmission disequilibrium test (TDT) cannot be used on multiple marker data; the authors describe an extension to the gamete competition model that allows for testing association with data on multiple markers at a time, using pedigree data. The method is implemented in MENDEL version 4.0." —Alejandro Schaffer, National Institutes of Health, US Inhibitor Design B.A. Grzybowski et al., "Combinatorial computational method gives new picomolar ligands for a known enzyme," Proceedings of the National Academy of Sciences, 99[3]:1270-3, Feb. 5, 2002. "As a successful example for de novo design of strong-binding enzyme inhibitors by computational ligand screening, a new strong inhibitor (Kd ca. 30 pM) was identified in this study for human carbonic anhydrase. The computational method, called CombiSMoG (combinatorial small molecule growth algorithm), uses a simple and fast-to-compute knowledge-based potential (see R.S. DeWitte, E.I. Shakhnovich, "SMoG: de novo design method based on simple, fast, and accurate free energy estimates. 1. Methodology and supporting evidence," Journal of the American Chemical Society, 118:11733-44, 1996) derived from a set of 1,000 protein-ligand complexes. About 50,000 putative ligands can be screened per day on a standard workstation. The predictions were verified by synthesizing the compounds and determining crystal structures of complexes with HCA." —Volkhard Helms, Max Planck Institute of Biophysics, Germany Diabetes Research S.E. Lamhamedi-Cherradi et al., "Further mapping of the Idd5.1 locus for autoimmune diabetes in NOD mice," Diabetes, 50[12]:2874-8, December 2001. "[These researchers] use novel non-obese diabetic (NOD) congenic strains to refine the map location of the Idd5.1 locus and exclude two potential candidate genes, Casp8 and Cflar. Ctla4, which also maps to the Idd5.1 interval, is expressed at a lower level on activated T cells in NOD mice compared to non-autoimmune strains, data consistent with it being a candidate for Idd5.1. However, activated T cells from an Idd5.1 congenic strain express Ctla4 at the same level as the NOD parent strain, making it unlikely that the decrease in Ctla4 expression is determined at the Ctla4 locus itself or at a linked locus in the Idd5.1 interval." —Paul Lyons, Cambridge Institute for Medical Research, UK M. Grattan et al., "Congenic mapping of the diabetogenic locus Idd4 to a 5.2-cM region of chromosome 11 in NOD mice: Identification of two potential candidate subloci," Diabetes, 51[1]:215-23, January 2002. "Here, the authors use NOD congenic strains to localize the Idd4 locus to a 5.2 cM interval on mouse chromosome 11. Further mapping shows that Idd4 is made up of at least two subloci, Idd4.1 and Idd4.2, an observation that is becoming increasingly common as polygenic disease loci are dissected using congenic strains." —Paul Lyons Proteomics A.J. Enright, C.A. Ouzounis, "Functional associations of proteins in entire genomes by means of exhaustive detection of gene fusions," Genome Biology, 2[9]: research0034.1-7, 2001. "Another excellent example of an in silico experiment that becomes feasible as whole genome sequences are made available. The hypothesis underlying this study is that proteins that interact or form a complex, while they may be found at distant locations in some genomes, will be found physically adjacent in others. Although this type of gene fusion is probably rare, this very fact makes it possible to detect them as novel events by comparing diverse organisms. This group has published a couple of good papers on this method, and this paper presents the results of an extensive analysis (the actual data are available to search on a Web site). In the context of mass two-hybrid screening in yeast, and similar discussion in other genome networks, the clues obtained from bioinformatic analyses of this type should prove valuable—not least monetarily, by focusing experimentation! The more they are backed up by laboratory experiments in one organism, the more generally useful they become for hypothesis-generation across phyla." —Sara Melville, University of Cambridge, UK

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