Dissimilarity-based algorithms for selecting structurally diverse sets of compounds.

This paper commences with a brief introduction to modern techniques for the computational analysis of molecular diversity and the design of combinatorial libraries. It then reviews dissimilarity-based algorithms for the selection of structurally diverse sets of compounds in chemical databases. Procedures are described for selecting a diverse subset of an entire database, and for selecting diverse combinatorial libraries using both reagent-based and product-based selection.     

Systemic approaches to biodegradation

Biodegradation, the ability of microorganisms to remove complex chemicals from the environment, is a multifaceted process in which many biotic and abiotic factors are implicated. The recent accumulation of knowledge about the biochemistry and genetics of the biodegradation process, and its categorization and formalization in structured databases, has recently opened the door to systems biology approaches, where the interactions of the involved parts are the main subject of study, and the system is analysed as a whole. The global analysis of the biodegradation metabolic network is beginning to produce knowledge about its structure, behaviour and evolution, such as its free-scale structure or its intrinsic robustness. Moreover, these approaches are also developing into useful tools such as predictors for compounds' degradability or the assisted design of artificial pathways. However, it is the environmental application of high-throughput technologies from the genomics, metagenomics, proteomics and metabolomics that harbours the most promising opportunities to understand the biodegradation process, and at the same time poses tremendous challenges from the data management and data mining point of view.     

Phylogenetic--evolutionary approaches to bioinformatics

Phylogenies of organisms are essential to investigating a range of evolutionary questions of interest to researchers in the field of bioinformatics. Phylogenies not only help to define how to study many evolutionary questions, they must also be taken into account when conducting statistical analyses. Here it is shown how phylogenies can be used to investigate variability along the sites of a gene, reconstruct ancestral states of ancient genes and proteins, identify and characterise events of parallel and convergent evolution, find events of gene duplication, analyse predictions from molecular clocks, seek evidence for correlated changes among different parts of the same gene or genome, and test theories of molecular evolution. A table of statistical and phylogenetic methods is presented.     

Mathematical approaches to decompression

A flexible mathematical treatment of diver decompression has been developed by modifying the classical Haldanian model of inert gas transport. It is based on the assumption that inert gases will remain in solution in the tissues of a diver as long as a particular metastable limit is not exceeded,and that this limit varies with depth, nature of the inert gas,and the specific time constant of its transport in the body. Proposed metastable limits (M-values)of dissolved helium partial pressure have been developed empirically by the Experimental Diving Unit of the United States Navy. These limits permit the design by digital computer of decompression procedures expected to be safer than contemporary decompression tables for extended deep dives.

---

Zusammenfassung Ein flexibles mathematisches Verfahren zur Überwachung der Dekompression bei Tauchern wurde entwickelt, durch Modifikation des klassischen Modells von Haldane für den Transport träger Gase.Es beruht auf der Annahme,dass träge Gase so lange in den Geweben eines Tauchers in Lösung bleiben, als eine bestimmte metastabile Grenze nicht überschritten wird. Diese Grenze ändert sich mit der Tiefe,der Natur des trägen Gases und der spezifischen Zeitkonstante seines Transports im Körper. Die vorgeschlagenen metastabilen Grenzen (M-Werte) des Partialdruckes von gelöstem Helium wurden empirisch entwickelt in der Experimental Diving Unit der Marine der Vereinigten Staaten.Diese Grenzen erlauben die Erfassung der Dekompressionsvorgänge durch Digital Computer und es wird angenommen, dass sie sicherer sind als die gebräuchlichen Dekompressions-Tabellen für langes Tieftauchen.

---

Resume On a établi un procédé mathématique fléxible pour suivre les phénomènes de décompression chez les plongeurs.Pour ce faire, on a modifié le modèle classique de Haldane concernant le transport d'un gaz inerte. Comme base, on admet que les gaz inertes resteront en solution dans les tissues des plongeurs aussi longtemps qu'une limite métastatique n'est pas franchie.Cette limite varie avec la profondeur,la nature du gaz inerte et la constante de temps spécifique de son transport dans le corps. Les limites métastatiques proposées (valeurs-M)de la pression partielle de l'hélium dissous ont été déterminées empiriquement à l' "Expérimental Diving Unit"de la marine des Etats-Unis. Ces limites permettent de calculer les processus de décompression au moyen d'ordinateurs.On admet en outre que ce procédé est plus sûr que les tables de décompression usuelles, surtout dans le cas de plongées profondes et de longue durée.

---

---

Based on a paper presented at the Forth International Biometeorological Congress, New Brunswick, N.J., 26 August – 2 September 1966.     

Economic approaches to smoking

In order to assess regulator's legitimacy in discouraging people from smoking, economists model tobacco addiction. In this paper, we review the extent economic literature about tobacco consumption and tobacco addiction. Two main approaches are singled out. In the first section, we detail the main characteristics of the two main theoretical models : rational addiction on one hand, which stylises individual choosing now to give up their future liberty to choose whether or not to smoke; and health capital on the other hand, following which individuals trade off between current pleasure and life expectancy. Second section gives account of the empirical tests of these two theories, before a last section briefly discusses and concludes. We show that the health capital theory seems to pass the test better than the rational addiction model. It is important to discriminate between these two models, from a political economy point of view. Were rational addiction true, a constant and strong increase of taxes on tobacco would be the soundest policy to curb consumption. On the contrary, if smokers are trapped into addiction and can't stop without pain, then tax increase is imposing too much strain on them, for no result. An efficient policy would be to subsidise quitting programmes, or to help smokers reducing their consumption through partial prohibition (in public transports for instance).     

Synthetic approaches to kasugamine

Reactions are described that lead to an immediate, chemical precursor of kasugamine the amino-sugar component of the aminocyclitol antibiotic kasugamycin. The key reaction involved the introduction of a bromine atom by a stereoselective ring-opening of a benzylidene acetal.     

Oxidation of horseradish peroxidase compound II to compound I.

In the reaction between equimolar amounts of horseradish peroxidase and chlorite, the native enzyme is oxidized directly to Compound II (Hewson, W.D., and Hager, L.P. (1979) J. Biol. Chem. 254, 3175-3181). At acidic pH but not at alkaline values, this initial reaction is followed by oxidation of Compound II to Compound I. The highly pH-dependent chemistry of Compound II can be readily demonstrated by the reduction of Compound I, with ferrocyanide at acidic, neutral, and alkaline pH values. Titration at low pH yields very little Compound II, whereas at high pH, the yield is quantitative. Similarly, the reaction of horseradish peroxidase and chlorite at low pH yields Compound I while only Compound II is formed at high pH. At intermediate pH values both the ferrocyanide reduction and the chlorite reaction produce intermediate yields of Compound II. This behavior is explained in terms of acidic and basic forms of Compound II. The acidic form is reactive and unstable relative to the basic form. Compound II can be readily oxidized to Compound I by either chloride or chlorine dioxide in acidic solution. The oxidation does not occur in alkaline solution, nor will hydrogen peroxide cause the oxidation of Compound II, even at low pH.     

Diagnostic approaches to Alzheimer's disease

The importance of obtaining an accurate and early diagnosis for Alzheimer's disease is now becoming recognized. Nonpharmacological as well as pharmacological therapies can be best initiated once a diagnosis is obtained. Biochemical markers to identify Alzheimer's disease have been sought for many years, with many candidates proposed. Recently criteria were established to evaluate putative diagnostic tests. Several biomarkers now show utility in identifying those with Alzheimer's disease. The ApoE e4 allele, while a risk factor rather than a deterministic gene, in the context of an individual with suspicion of AD has a positive predictive value of 94-98% and may come to have utility in predicting response to certain classes of pharmacological agents. Independent groups have shown that the markers in cerebrospinal fluid tau and Ab42 are, respectively, elevated and reduced in patients with AD versus other patient groups and that the lumbar puncture itself is usually well tolerated. For early-onset AD, sequencing presenilin 1 has come into use and the positive frequency is similar to that found in other genetic-based laboratory tests.     

Therapeutic approaches to Alzheimer's disease

Several recent advances have provided new insights and possibilities in defining therapeutic targets for Alzheimer's disease. Of particular importance is the identification of the beta-secretase enzyme and the demonstration that immunization of a transgenic mouse model of Alzheimer's disease with Abeta(1-42) peptide can prevent or alleviate neuropathological features of the disease.     

Alternative approaches to population structure

There are three approaches to DNA identification: tectonic, halieutic and icarian, of which the tectonic is sensible, the halieutic impractical, and the icarian idiotic. The rationale and consequences of these approaches are detailed.Editor's commentsThe author captures the harsh tone that has often characterized the debate over the use of DNA for human identification. It should be mentioned that D.L. Hartl, E.S. Lander and R.C. Lewontin were invited to respond. The positions of these three authors are contained in their papers, listed in the Bibliography. Readers should note, in particular, Budowle and Lander (1994).     

Global approaches to understanding ubiquitination

Ubiquitination - the linkage of one or more molecules of the protein ubiquitin to another protein - regulates a wide range of biological processes in all eukaryotes. We review the proteome-wide strategies that are being used to study aspects of ubiquitin biology, including substrates, components of the proteasome and ubiquitin ligases, and deubiquitination.     

Computational approaches to protein-protein interaction

The interactions between proteins allow the cell's life. A number of experimental, genome-wide, high-throughput studies have been devoted to the determination of protein-protein interactions and the consequent interaction networks. Here, the bioinformatics methods dealing with protein-protein interactions and interaction network are overviewed. 1. Interaction databases developed to collect and annotate this immense amount of data; 2. Automated data mining techniques developed to extract information about interactions from the published literature; 3. Computational methods to assess the experimental results developed as a consequence of the finding that the results of high-throughput methods are rather inaccurate; 4. Exploitation of the information provided by protein interaction networks in order to predict functional features of the proteins; and 5. Prediction of protein-protein interactions.