Determination of chromophore charge states in the low pH color transition of the fluorescent protein Rtms5(H146S) via time-dependent DFT

The red fluorescent protein Rtms5H146S displays a transition from blue (absorbance λmax 590 nm) to yellow (absorbance λmax not, vert, similar453 nm) upon titration to low pH. The pKa of the reaction depends on the concentration of halide, offering promise for new expressible halide sensors. The protonation state involved in the low pH form of the chromophore remains, however, ambiguous. We report calculated excitation energies of different protonation states of an RFP chromophore model. These suggest that the relevant titration site is the phenoxy moiety of the chromophore, and the relevant base and conjugate acid are anionic and neutral chromophore species, respectively.

Documenting the heroin shortage in New South Wales

Australian heroin markets have recently undergone dramatic change, sparking debate about the nature of such markets. This study aimed to determine the onset, peak and decline of the heroin shortage in New South Wales (NSW), using the most appropriate available methods to detect market level changes. The parameters of the heroin shortage were determined by reviewing: reports of heroin users about availability and price (derived from the existing literature and the Illicit Drug Reporting System); qualitative interviews with injecting drug users, and health and law enforcement professionals working in the illicit drug field; and examining data on heroin seizures over the past decade. There was a marked reduction in heroin supply in NSW in early 2001. An increase in the price of heroin occurred in 2001, whereas it had decreased steadily since 1996. A reduction in purity also occurred, as reported by drug users and heroin seizures. The peak period of the shortage appears to have been January to April 2001. The market appears to have stabilised since that time, although it has not returned to pre- 2001 levels: heroin prices have decreased in NSW for street grams, but not to former levels, and the price of `caps' (street deals) remain elevated. Heroin purity in NSW has remained low, with perhaps a 10% increase above the lowest recorded levels. These data support the notion that the heroin market in NSW underwent significant changes, which appear to have involved a lasting shift in the nature of the market.

Dual-symmetric Lagrangians in quantum electrodynamics: I. Conservation laws and multi-polar coupling

By using a complex field with a symmetric combination of electric and magnetic fields, a first-order covariant Lagrangian for Maxwell's equations is obtained, similar to the Lagrangian for the Dirac equation. This leads to a dual-symmetric quantum electrodynamic theory with an infinite set of local conservation laws. The dual symmetry is shown to correspond to a helical phase, conjugate to the conserved helicity. There is also a scaling symmetry, conjugate to the conserved entanglement. The results include a novel form of the photonic wavefunction, with a well-defined helicity number operator conjugate to the chiral phase, related to the fundamental dual symmetry. Interactions with charged particles can also be included. Transformations from minimal coupling to multi-polar or more general forms of coupling are particularly straightforward using this technique. The dual-symmetric version of quantum electrodynamics derived here has potential applications to nonlinear quantum optics and cavity quantum electrodynamics.

Lipidation and glycosylation of a T cell antigen receptor (TCR) transmembrane hvdrophobic peptide dramatically enhances in vitro and in vivo function

A T cell antigen receptor (TCR) transmembrane sequence derived peptide (CP) has been shown to inhibit T cell activation both in vitro and in vivo at the membrane level of the receptor signal transduction. To examine the effect of sugar or lipid conjugations on CP function, we linked CP to 1-aminoglucosesuccinate (GS), N-myristate (MYR), mono-di-tripalmitate (LP1, LP2, or LP3), and a lipoamino acid (LA) and examined the effects of these compounds on T cell activation in vitro and by using a rat model of adjuvant-induced arthritis, in vivo. In vitro, antigen presentation results demonstrated that lipid conjugation enhanced CP's ability to lower IL-2 production from 56.99% +/- 15.69 S.D. observed with CP, to 12.08% +/- 3.34 S.D. observed with LA. The sugar conjugate GS resulted in only a mild loss of in vitro activity compared to CP (82.95% +/- 14.96 S.D.). In vivo, lipid conjugation retarded the progression of adjuvant-induced arthritis by approximately 50%, whereas the sugar. conjugated CP, GS, almost completely inhibited the progression of arthritis. This study demonstrates that hydrophobic peptide activity is markedly enhanced in vitro and in vivo by conjugation to lipids or sugars. This may have practical applications in drug delivery and bioavailability of hydrophobic peptides. (c) 2006 Elsevier B.V. All rights reserved.

A PALAVRA DE JAVÉ EM JEREMIAS 7,1 8,3: UMA ANÁLISE DA PROFECIA COMO PORTADORA DE UM CONFLITO SOCIAL ORIUNDO DA COBRANÇA EXCESSIVA DE TRIBUTO

Esta pesquisa privilegia o enfoque histórico ao analisar o texto bíblico, como produto histórico-social, a partir do método sociológico. O material disposto ao longo desta investigação pretende ser uma ajuda para a compreensão de alguns textos do profeta Jeremias. Partindo do princípio de que o texto possui um vínculo com a sociedade na qual foi criado e fazendo uso da metodologia exegética, realiza-se uma análise histórico-sociológica da palavra de Javé em Jeremias 7,1 8,3 como portadora de um conflito social oriundo da cobrança excessiva de tributo em uma sociedade judaíta marcadamente tributária. Busca-se, por esse meio, o sentido do texto dentro do provável cenário histórico-social que permeia o escrito. Para isso, faz-se necessária a investigação dos aspectos preliminares que envolvem tanto o livro de Jeremias, sobretudo, os polêmicos caps. 7,1 8,3, como também a questão do estudo da pesquisa moderna acerca dessa magnífica obra. Vale a pena também salientar o conceito semiótico da poética sociológica que procura estudar a interação causal entre literatura e seu meio social. Além disso, avalia-se o âmbito histórico social da unidade literária alvo de nossa pesquisa, situando-a em seu provável contexto histórico social e determinando a datação, o cenário político e o modo de produção vigente nesse período. Não olvidando, contudo, do fator desencadeador do conflito social e o papel da religião nesse cenário. Além do mais, examina-se o sentido dos textos específicos ou unidades literárias concluídas (perícopes) presentes nos caps. 7,1 8,3, tendo como pressuposto o modelo teórico do modo de produção tributário e os passos da exegese histórico-social. O mecanismo socioanalítico do modo de produção tributário servirá como instrumento de análise da condição socioeconômica, centrando-se nos componentes externos incorporados na coletânea, não em sua história redacional, mas sim em sua formação social.

Impacto do contexto de trabalho e da resiliência sobre o bem-estar no trabalho de profissionais dos Centros de Atenção Psicossocial

Este estudo teve como intuito investigar o impacto do contexto de trabalho e da resiliência sobre o bem-estar no trabalho em profissionais dos Centros de Atenção Psicossocial (CAPS). Os CAPS são serviços públicos substitutivos ao modelo asilar para tratamento de pessoas em sofrimento psíquico, preconizado e fundamentado na Política Nacional de Saúde Mental (PNSM). Para medir o contexto de trabalho utilizou-se a Escala de Avaliação do Contexto de Trabalho (EACT) que investiga as condições de trabalho, a organização do trabalho e as relações sócio profissionais. Já o instrumento utilizado para medir a capacidade dos trabalhadores em manter o nível de desempenho no trabalho mesmo em situações complexas e desgastantes foi a Escala de Avaliação de Resiliência no Trabalho (EART). Por último, investigou-se o nível de bem-estar do público pesquisado através do Inventário de Bem- Estar no Trabalho (IBET-13). O bem-estar no trabalho tem sido considerado como um construto psicológico resultado de vínculos positivos com o trabalho e com a organização. Participaram 81 profissionais dos CAPS das cidades de Petrolina PE e São Bernardo do Campo SP, com idade média de 37 anos (DP= 10,45), em sua maioria do sexo feminino (65,4%), com níveis de escolaridade acima do ensino superior e pós-graduação completa (ambos com 29%), que se declararam casados ou em união estável (39%). Neste estudo, considerou-se bem-estar no trabalho como variável critério e resiliência no trabalho e contexto de trabalho como preditores. Foram realizadas análises estatísticas exploratórias e descritivas, análises de regressão e análises de variância (ANOVA) para descrever participantes, variáveis e testar o modelo. Os resultados apoiaram parcialmente o modelo de predição, pois apenas o fator relações sócio profissionais se confirmou como preditor significativo de Bem-estar no Trabalho, e não houve predição significativa com as demais variáveis (Condições de Trabalho, Organização do Trabalho e Resiliência no Trabalho). Estes dados podem revelar que boas relações sócio profissionais tendem a aumentar o nível de satisfação e comprometimento organizacional afetivo com a instituição, bem como o aumento do nível de envolvimento desses profissionais com seu trabalho.

Glacial geomorphology of the Altai and Western Sayan Mountains, Central Asia

In this article, we present a map of the glacial geomorphology of the Altai andWestern Sayan Mountains, covering an area of almost 600,000 km2. Although numerous studies provide evidence for restricted Pleistocene glaciations in this area, others have hypothesized the past existence of an extensive ice sheet. To provide a framework for accurate glacial reconstructions of the Altai and Western Sayan Mountains, we present a map at a scale of 1:1,000,000 based on a mapping from 30 m resolution ASTER DEM and 15 m/30 mresolution Landsat ETM+ satellite imagery. Four landform classes have been mapped: marginal moraines, glacial lineations, hummocky terrain, and glacial valleys. Our mapping reveals an abundance of glacial erosional and depositional landforms. The distribution of these glacial landforms indicates that the Altai and Western Sayan Mountains have experienced predominantly alpine-style glaciations, with some small ice caps centred on the higher mountain peaks. Large marginal moraine complexes mark glacial advances in intermontane basins. By tracing the outer limits of present-day glaciers, glacial valleys, and moraines, we estimate that the past glacier coverage have totalled to 65,000 km2 (10.9% of the mapped area), whereas present-day glacier coverage totals only 1300 km2 (0.2% of the mapped area). This demonstrates the usefulness of remote sensing techniques for mapping the glacial geomorphology in remote mountain areas and for quantifying the past glacier dimensions. The glacial geomorphological map presented here will be used for further detailed reconstructions of the paleoglaciology and paleoclimate of the region.

Time trials on second-order and variable-learning-rate algorithms

The performance of seven minimization algorithms are compared on five neural network problems. These include a variable-step-size algorithm, conjugate gradient, and several methods with explicit analytic or numerical approximations to the Hessian.

Methods and trends of performance benchmarking in UK utility regulation

Regulation is subject to information asymmetries that can lead to allocative and productive inefficiencies. One solution, suggested by Shleifer in 1985 and now adopted by many regulatory bodies round the world, is 'benchmarking', which is sometimes called 'yardstick competition'. In this paper we consider Shleifer's original approach to benchmarking and contrast this with the actual use of benchmarking by UK regulatory bodies in telecommunications, water and the energy sector since the privatizations of the 1980s and early 1990s. We find that benchmarking plays only one part and sometimes a small part in the setting of regulatory price caps in the UK. We also find that in practice benchmarking has been subject to a number of difficulties, which mean that it is never likely to be more than one tool in the regulator's armoury. The UK's experience provides lessons for regulation internationally. © 2006 Elsevier Ltd. All rights reserved.

Regulatory price performance, excess cost indexes and profitability:how effective is price cap regulation in the water industry?

In this study we apply an index number approach to allow for cross sectional comparisons of relative profitability, productivity and price performance of the regulated Water and Sewerage companies (WaSCs) in England and Wales during the years 1991-2008. In order to better analyse the impact of regulation on WaSC performance, we decompose actual economic profits into spatial multilateral Fisher productivity (TFP) index, the inverse of which is demonstrated to be a regulatory excess cost index that measures the deviation of a firm’s actual costs from benchmark costs, and a newly developed regulatory total price performance (TPP) index, which measures the excess of regulated revenues relative to benchmark costs. Increases (decreases) in regulatory price performance are indicative of the loosening (tightening) of price cap regulation. Moreover, we also show that the relationship between actual economic profitability, regulatory excess costs and regulatory price performance indices can be used to categorize regulatory price caps as “weak”, “powerful” or “catch-up promoting”. The results indicated that throughout the entire 1991-2008 period, price caps were never “powerful”, in the sense that they required less productive firms to immediately and fully catch-up to the most productive firm to regain economic profitability. More specifically, during the years 1991-2000 price caps were “weak” as prices were high enough for the firms to achieve economic profits despite their low productivity levels. However, after 2001 prices became “catch up promoting” as they required less productive companies to eliminate at least some excess costs in order to eliminate economic losses. Finally, we emphasize that as our results also clearly demonstrated a much closer alignment between allowed revenues and benchmark costs after 2001, Ofwat’s approach during this period was not only appropriate, but should also be continued in the 2009 price review.

Data assimilation for precipitation nowcasting using Bayesian inference

This work introduces a new variational Bayes data assimilation method for the stochastic estimation of precipitation dynamics using radar observations for short term probabilistic forecasting (nowcasting). A previously developed spatial rainfall model based on the decomposition of the observed precipitation field using a basis function expansion captures the precipitation intensity from radar images as a set of ‘rain cells’. The prior distributions for the basis function parameters are carefully chosen to have a conjugate structure for the precipitation field model to allow a novel variational Bayes method to be applied to estimate the posterior distributions in closed form, based on solving an optimisation problem, in a spirit similar to 3D VAR analysis, but seeking approximations to the posterior distribution rather than simply the most probable state. A hierarchical Kalman filter is used to estimate the advection field based on the assimilated precipitation fields at two times. The model is applied to tracking precipitation dynamics in a realistic setting, using UK Met Office radar data from both a summer convective event and a winter frontal event. The performance of the model is assessed both traditionally and using probabilistic measures of fit based on ROC curves. The model is shown to provide very good assimilation characteristics, and promising forecast skill. Improvements to the forecasting scheme are discussed

Soft hydrogels from nanotubes of poly(ethylene oxide)−tetraphenylalanine conjugates prepared by click chemistry

A new poly(ethylene oxide)-tetraphenylalanine polymer-peptide conjugate has been prepared via a “click” reaction between an alkyne-modified peptide and an azide-terminated PEO oligomer. Self-assembled nanotubes are formed after dialysis of a THF solution of this polymer-peptide conjugate against water. The structure of these nanotubes has been probed by circular dichroism, IR, TEM, and SAXS. From these data, it is apparent that self-assembly involves the formation of antiparallel ß-sheets and p-p-stacking. Nanotubes are formed at concentrations between 2 and 10 mg mL-1. Entanglement between adjacent nanotubes occurs at higher concentrations, resulting in the formation of soft hydrogels. Gel strength increases at higher polymer-peptide conjugate concentration, as expected.

The effect of PEO length on the self-assembly of poly(ethylene oxide)−tetrapeptide conjugates prepared by “click” chemistry

Two series of poly(ethylene oxide)-tetrapeptide conjugates have been prepared using a “Click” reaction between an alkyne-modified tetra(phenylalanine) or tetra(valine) and various azide-terminated poly(ethylene oxide) (PEO) oligomers. Three different PEO precursors were used to prepare these conjugates, with number-average molecular weights of 350, 1200, and 1800 Da. Assembly of mPEO-F4-OEt and mPEO-V4-OEt conjugates was achieved by dialysis of a THF solution of the conjugate against water or by direct aqueous rehydration of a thin film. The PEO length has a profound effect on the outcome of the self-assembly, with the F4 conjugates giving rise to nanotubes, fibers, and wormlike micelles, respectively, as the length of the PEO block is increased. For the V4 series, the propensity to form ß-sheets dominates, and hence, the self-assembled structures are reminiscent of those formed by peptides alone, even at the longer PEO lengths. Thus, this systematic study demonstrates that the self-assembly of PEO-peptides depends on both the nature of the peptides and the relative PEO block length.

Using interior point algorithms for the solution of linear programs with special structural features

Linear Programming (LP) is a powerful decision making tool extensively used in various economic and engineering activities. In the early stages the success of LP was mainly due to the efficiency of the simplex method. After the appearance of Karmarkar's paper, the focus of most research was shifted to the field of interior point methods. The present work is concerned with investigating and efficiently implementing the latest techniques in this field taking sparsity into account. The performance of these implementations on different classes of LP problems is reported here. The preconditional conjugate gradient method is one of the most powerful tools for the solution of the least square problem, present in every iteration of all interior point methods. The effect of using different preconditioners on a range of problems with various condition numbers is presented. Decomposition algorithms has been one of the main fields of research in linear programming over the last few years. After reviewing the latest decomposition techniques, three promising methods were chosen the implemented. Sparsity is again a consideration and suggestions have been included to allow improvements when solving problems with these methods. Finally, experimental results on randomly generated data are reported and compared with an interior point method. The efficient implementation of the decomposition methods considered in this study requires the solution of quadratic subproblems. A review of recent work on algorithms for convex quadratic was performed. The most promising algorithms are discussed and implemented taking sparsity into account. The related performance of these algorithms on randomly generated separable and non-separable problems is also reported.

Synthesis of triplex-forming oligonucleotide conjugates of the anticancer drug temodal

Covalent attachment of the anticancer drugs temozolomide (Temodal) and mitozolomide to triplex-forming oligonucleotides (TFOs) is a potential way of targeting these alkylating agents to specific gene sequences to maximise site-selectivity. In this work, polypyrimidine TFO conjugates of both drugs were synthesised and targeted to duplex DNA in an attempt to effect site-specific alkylation of guanine residues. Concurrently, in an attempt to enhance the triple helix stability of TFOs at neutral pH, the thermal stabilities of triplexes formed from TFOs containing isoguanine, 2-O-benzyl- and 2-O-allyl-adenine were evaluated. A novel cleavage and deprotection procedure was developed which allowed for the solid phase synthesis of the base-sensitive TFO-drug conjugates using a recently developed silyl-linked controlled pore glass (SLCPG) support. Covalent attachment of either temozolomide or mitozolomide at the 5'-end of TFO conjugates caused no destabilisation of the triplexes studied. The synthesis of a phosphoramidite derivative of mitozolomide enabled direct incorporation of this reagent into a model sequence during DNA synthesis. After cleavage and deprotection of the TFO-drug conjugate, the 5'-end mitozolomide residue was found to have decomposed presumably as a result of ring-opening of the tetrazinone ring. The base-sensitive antibacterial and antitumour agent, metronidazole, was also successfully incorporated at the 5'-end of the oligonucleotide d(T8) using conventional methods. Two C2-substituted derivatives of 2'-deoxyadenosine containing 2-O-benzyl and 2-O-allyl groups were synthesised. Hydrogenolysis of the 2-O-benzyl analogue provided a useful route, amenable to scale-up, for the synthesis of the rare nucleoside 2'-deoxyisoguanosine (isoG). Both the 2-O-allyl and 2-O-benzyl derivatives were incorporated into TFO sequences using phosphoramidite methodology. Thermal melting experiments showed that the 2-O-allyl and 2-O-benzyl groups caused marked destabilisation of the triple helices studied, in contrast to hexose-DNA duplexes, where aralkyl substituents caused significant stabilisation of duplexes. TFOs containing isoG were synthesised by Pd(O)-catalysed deallylation of 2-0-allyl adenine residues. These sequences containing isoG, in its N3- or 02-H tautomeric form, formed triple helices which were equally as stable as those containing adenine.