Chance-lowering causes

Philosophers have long been fascinated by the connection between cause and effect: are 'causes' things we can experience, or are they concepts provided by our minds? The study of causation goes back to Aristotle, but resurged with David Hume and Immanuel Kant, and is now one of the most important topics in metaphysics. Most of the recent work done in this area has attempted to place causation in a deterministic, scientific, worldview. But what about the unpredictable and chancey world we actually live in: can one theory of causation cover all instances of cause and effect?Cause and Chance: Causation in an Indeterministic Worldis a collection of specially written papers by world-class metaphysicians. Its focus is the problem facing the 'reductionist' approach to causation: the attempt to cover all types of causation, deterministic and indeterministic, with one basic theory.

Robust parameter settings of evolutionary algorithms for the optimisation of agricultural systems models

Numerical optimisation methods are being more commonly applied to agricultural systems models, to identify the most profitable management strategies. The available optimisation algorithms are reviewed and compared, with literature and our studies identifying evolutionary algorithms (including genetic algorithms) as superior in this regard to simulated annealing, tabu search, hill-climbing, and direct-search methods. Results of a complex beef property optimisation, using a real-value genetic algorithm, are presented. The relative contributions of the range of operational options and parameters of this method are discussed, and general recommendations listed to assist practitioners applying evolutionary algorithms to the solution of agricultural systems. (C) 2001 Elsevier Science Ltd. All rights reserved.

Sludge population optimisation: a new dimension for the control of biological wastewater treatment systems

The activated sludge comprises a complex microbiological community. The structure (what types of microorganisms are present) and function (what can the organisms do and at what rates) of this community are determined by external physico -chemical features and by the influent to the sewage treatment plant. The external features we can manipulate but rarely the influent. Conventional control and operational strategies optimise activated sludge processes more as a chemical system than as a biological one. While optimising the process in a short time period, these strategies may deteriorate the long-term performance of the process due to their potentially adverse impact on the microbial properties. Through briefly reviewing the evidence available in the literature that plant design and operation affect both the structure and function of the microbial community in activated sludge, we propose to add sludge population optimisation as a new dimension to the control of biological wastewater treatment systems. We stress that optimising the microbial community structure and property should be an explicit aim for the design and operation of a treatment plant. The major limitations to sludge population optimisation revolve around inadequate microbiological data, specifically community structure, function and kinetic data. However, molecular microbiological methods that strive to provide that data are being developed rapidly. The combination of these methods with the conventional approaches for kinetic study is briefly discussed. The most pressing research questions pertaining to sludge population optimisation are outlined. (C) 2002 Elsevier Science Ltd. All rights reserved.

Conformationally constrained macrocycles that mimic tripeptide beta-strands in water and aprotic solvents

The beta-strand conformation is unknown for short peptides in aqueous solution, yet it is a fundamental building block in proteins and the crucial recognition motif for proteolytic enzymes that enable formation and turnover of all proteins. To create a generalized scaffold as a peptidomimetic that is preorganized in a beta-strand, we individually synthesized a series of 15-22-membered macrocyclic analogues of tripeptides and analyzed their structures. Each cycle is highly constrained by two trans amide bonds and a planar aromatic ring with a short nonpeptidic linker between them. A measure of this ring strain is the restricted rotation of the component tyrosinyl aromatic ring (DeltaG(rot) 76.7 kJ mol(-1) (16-membered ring), 46.1 kJ mol(-1) (17-membered ring)) evidenced by variable temperature proton NMR spectra (DMF-d(7), 200-400 K). Unusually large amide coupling constants ((3)J(NH-CHalpha) 9-10 Hz) corresponding to large dihedral angles were detected in both protic and aprotic solvents for these macrocycles, consistent with a high degree of structure in solution. The temperature dependence of all amide NH chemical shifts (Deltadelta/T7-12 ppb/deg) precluded the presence of transannular hydrogen bonds that define alternative turn structures. Whereas similar sized conventional cyclic peptides usually exist in solution as an equilibrium mixture of multiple conformers, these macrocycles adopt a well-defined beta-strand structure even in water as revealed by 2-D NMR spectral data and by a structure calculation for the smallest (15-membered) and most constrained macrocycle. Macrocycles that are sufficiently constrained to exclusively adopt a beta-strand-mimicking structure in water may be useful pre-organized and generic templates for the design of compounds that interfere with beta-strand recognition in biology.

Regioselective synthesis of antiparallel loops on a macrocyclic scaffold constrained by oxazoles and thiazoles

[GRAPHICS] The regioselective syntheses and structures are reported for two tris-macrocylic compounds, each possessing two antiparallel loops on a macrocyclic scaffold constrained by two oxazoles and two thiazoles. NMR solution structures show the loops projecting from the same face of the macrocycle. Such molecules are shown to be prototypes for mimicking multiple loops of proteins.

Species richness in agamid lizards: chance, body size, sexual selection or ecology?

Why does species richness vary so greatly across lineages? Traditionally, variation in species richness has been attributed to deterministic processes, although it is equally plausible that it may result from purely stochastic processes. We show that, based on the best available phylogenetic hypothesis, the pattern of cladogenesis among agamid lizards is not consistent with a random model, with some lineages having more species, and others fewer species, than expected by chance. We then use phylogenetic comparative methods to test six types of deterministic explanation for variation in species richness: body size, life history, sexual selection, ecological generalism, range size and latitude. Of eight variables we tested, only sexual size dimorphism and sexual dichromatism predicted species richness. Increases in species richness are associated with increases in sexual dichromatism but reductions in sexual size dimorphism. Consistent with recent comparative studies, we find no evidence that species richness is associated with small body size or high fecundity. Equally, we find no evidence that species richness covaries with ecological generalism, latitude or range size.

Synthesis, stability, antiviral activity, and protease-bound structures of substrate-mimicking constrained macrocyclic inhibitors of HIV-1 protease

Three new peptidomimetics (1-3) have been developed with highly stable and conformationally constrained macrocyclic components that replace tripeptide segments of protease substrates. Each compound inhibits both HIV-1 protease and viral replication (HIV-I, HIV-2) at nanomolar concentrations without cytotoxicity to uninfected cells below 10 mu M. Their activities against HIV-1 protease (K-i 1.7 nM (1), 0.6 nM (2), 0.3 nM (3)) are 1-2 orders of magnitude greater than their antiviral potencies against HIV-1-infected primary peripheral blood mononuclear cells (IC50 45 nM (1), 56 nM (2), 95 nM (3)) or HIV-1-infected MT2 cells (IC50 90 nM (1), 60 nM (2)), suggesting suboptimal cellular uptake. However their antiviral potencies are similar to those of indinavir and amprenavir under identical conditions. There were significant differences in their capacities to inhibit the replication of HIV-1 and HIV-2 in infected MT2 cells, 1 being ineffective against HIV-2 while 2 was equally effective against both virus types. Evidence is presented that 1 and 2 inhibit cleavage of the HIV-1 structural protein precursor Pr55(gag) to p24 in virions derived from chronically infected cells, consistent with inhibition of the viral protease in cells. Crystal structures refined to 1.75 Angstrom (1) and 1.85 Angstrom (2) for two of the macrocyclic inhibitors bound to HIV-1 protease establish structural mimicry of the tripeptides that the cycles were designed to imitate. Structural comparisons between protease-bound macrocyclic inhibitors, VX478 (amprenavir), and L-735,524 (indinavir) show that their common acyclic components share the same space in the active site of the enzyme and make identical interactions with enzyme residues. This substrate-mimicking minimalist approach to drug design could have benefits in the context of viral resistance, since mutations which induce inhibitor resistance may also be those which prevent substrate processing.

CP properties of symmetry-constrained two-Higgs-doublet models

The two-Higgs-doublet model can be constrained by imposing Higgs-family symmetries and/or generalized CP symmetries. It is known that there are only six independent classes of such symmetry-constrained models. We study the CP properties of all cases in the bilinear formalism. An exact symmetry implies CP conservation. We show that soft breaking of the symmetry can lead to spontaneous CP violation (CPV) in three of the classes.

A practical approach for profit-based unit commitment with emission limitations

This paper proposes a practical approach for profit-based unit commitment (PBUC) with emission limitations. Under deregulation, unit commitment has evolved from a minimum-cost optimisation problem to a profit-based optimisation problem. However, as a consequence of growing environmental concern, the impact of fossil-fuelled power plants must be considered, giving rise to emission limitations. The simultaneous address of the profit with the emission is taken into account in our practical approach by a multiobjective optimisation (MO) problem. Hence, trade-off Curves between profit and emission are obtained for different energy price profiles, in a way to aid decision-makers concerning emission allowance trading. Moreover, a new parameter is presented, ratio of change, and the corresponding gradient angle, enabling the proper selection of a compromise commitment for the units. A case study based on the standard IEEE 30-bus system is presented to illustrate the proficiency Of Our practical approach for the new competitive and environmentally constrained electricity supply industry.

Unit Commitment in a Competitive and Emission Constrained Environment

This paper is on the unit commitment problem, considering not only the economic perspective, but also the environmental perspective. We propose a bi-objective approach to handle the problem with conflicting profit and emission objectives. Numerical results based on the standard IEEE 30-bus test system illustrate the proficiency of the proposed approach.