Functional site prediction selects correct protein models

<p>Abstract</p> <p>Background</p> <p>The prediction of protein structure can be facilitated by the use of constraints based on a knowledge of functional sites. Without this information it is still possible to predict which residues are likely to be part of a functional site and this information can be used to select model structures from a variety of alternatives that would correspond to a functional protein.</p> <p>Results</p> <p>Using a large collection of protein-like decoy models, a score was devised that selected those with predicted functional site residues that formed a cluster. When tested on a variety of small <it>α</it>/<it>β</it>/<it>α </it>type proteins, including enzymes and non-enzymes, those that corresponded to the native fold were ranked highly. This performance held also for a selection of larger <it>α</it>/<it>β</it>/<it>α </it>proteins that played no part in the development of the method.</p> <p>Conclusion</p> <p>The use of predicted site positions provides a useful filter to discriminate native-like protein models from non-native models. The method can be applied to any collection of models and should provide a useful aid to all modelling methods from <it>ab initio </it>to homology based approaches.</p

The relevance of diatoms for water quality assessment in South Africa: A position paper

Water quality assessment protocols based on the use of diatoms are now well developed and their value substantiated at an international level. The use of diatoms is not designed or intended to be a “rapid” technology. The detailed level of information generated from the procedure outweighs perceived disadvantages of the additional time required for sample preparation and analysis to species level. The method is applicable across a wide range of aquatic ecosystem types, namely freshwater, brackish, and estuarine, and is inclusive of both lentic and lotic environments, wetlands and their associated damp, marginal and littoral zones. Details provided by diatom assemblages support palaeoecological investigations, historical reconstruction of water quality and the determination of prevailing water quality conditions. Deliberate determination of responses to management strategies or impacts arising from a variety of anthropogenic activities can be achieved via the simple expedient of retrieving living material from introduced artificial substrates. Previous studies in South Africa and elsewhere have shown that on a site-by-site basis the use of diatoms provides a fine level of diagnostic resolution of the causes underlying changes in water quality and environmental condition. The South African Diatom Collection (“the Collection”), a repository of diatom specimens and records that spans the length and breadth of this country, contains an as-yet unutilised wealth of ecological and taxonomic information. More importantly, the historical data analysis records provide an insight into water quality conditions prevailing 40 to 50 years ago – in many cases prior to the “development” of many of our rivers, streams and wetlands. The real value of its existence underpins the great potential for renewed attention to the value of diatom-based approaches to water quality assessments. In addition, the Collection provides a ready-made foundation on which a locally relevant tool for water quality assessment may be established to augment the current use of invertebrate indicators. It is now appropriate that the full potential of the use of diatoms in water quality assessments, and the information contained in the Collection, be developed and utilised for water quality assessment in South Africa. Key words: diatoms, water quality, Cholnoky, Archibald, biotic indices Water SA Vol.31(1) 2005: 41-4

Factors determining short- and long-term survival after orthotopic liver homotransplantation in the dog

Without azathioprine therapy, the operative risk with orthotopic liver transplantation is small. Twenty-two of 23 animals survived 2 days or more, and 19 for 6 days or longer. All eventually died of rejection within 10 days. Changes in homograft histology and function were similar to those previously reported, with cellular infiltration and hepatocyte necrosis which was heavily concentrated in the centrilobular areas. In individual experiments, there was little evidence of immunologically induced segmental hepatic arterial or portal venous occlusion; hepatocyte loss was homogeneous, and fibrinoid vascular lesions were uncommon. There was, however, some evidence of damage to the sinusoidal endothelium by adherent mononuclear cells. The changing character of the mononuclear infiltration of the homograft was reflected by widespread proliferation of similar cells in the host lymphoid tissue. Specific changes in other host organs were not noted. Some of the biochemical and histologic alterations caused by unmodified rejection can also be produced by azathioprine. In 18 nontransplanted dogs, acute rises in SGOT, SGPT, and alkaline phosphatase, unaccompanied by hyperbilirubinemia, were noted within a few days after beginning administration of this agent. Although these abnormalities tended to regress within the 40 day period of observation, more than two thirds of the livers showed histologic evidence of centrilobular hepatocyte damage or necrosis-often with intrahepatic cholestasis, but always without mononuclear cell infiltration. The hepatotoxicity was not prevented by methionine. Weight loss and progressive anemia also occurred. Lymphoid tissue was depleted. The mortality from the toxicity study was 33 percent. The use of azathioprine to mitigate rejection increased the early mortality after homotransplantation, 32 of 116 dogs dying within the first week (28 percent), most commonly of pulmonary complications. The 84 animals living longer than 7 days had a greatly potentiated homograft survival, exceeding 25 days in 44 dogs, and 50 days in 24. Fifteen animals are still alive from 62 to 324 days postoperatively. Six dogs had all drugs stopped after 116 to 123 days. Only 1 has had a clinically evident late rejection and 5 are still alive from 63 to 204 days later. Three of these animals had repeat biopsies 77 to 182 days after cessation of therapy; one homograft which was normal at 4 months remained so 6 months later, another had an improved histologic appearance, and the third had deteriorated. The longest mean survival was in those animals receiving adjuvant therapy with L-methionine or S35-methionine, but the variability of the results was so great that a statistically significant advantage of these agents could not be demonstrated. Soon after operation red cell survival was decreased, but in chronic survivors there was no evidence of a grafthost reaction. There was great variability in the vigor of rejection, ranging from the uncontrollable (29 percent) to the clinically undetectable (23 percent). Most of the animals (49 percent) had some biochemical evidence of rejection which proved to be spontaneously reversible, to a greater or lesser degree, since intensification of immunosuppressive therapy was not required. These findings correlate well with the histologic studies. In virtually all animals, azathioprine delayed the onset of rejection but in those dying in the second and third postoperative weeks, the pathologic stigmas of rejection were very similar to the untreated controls. As in the untreated animals, the number of proliferating large pyroninophilic cells in the host's lymphoid tissues was roughly proportional to the number of mononuclear cells invading the homograft liver. After this time, the predominant histologic features in most animals were those of repair and regeneration, with either absent or relatively minor degrees or continuing destruction. Since the major rejection damage was centrizonal, the healing was most prominent in these areas with interconecting fibrosis around the central veins, centrilobular bile canalicular dilatation and cholestasis, and pseudolobule formation. In some of the homografts, increased connective tissue was also present in the portal tracts, but in others including the longest survivor there were no residual abnormalities whatever. In azathioprine-treated animals, damage to the vessels in the homograft portal tracts was found in only one liver. With electron microscopy there was some evidence of damage to the sinusoidal endothelium by adherent mononuclear cells, a finding which could be analogous to that described by Kountz and co-workers11 in the peritubular capillaries of renal homografts. If immunologically mediated hemodynamic alterations play an important role in liver homograft rejection by interrupting the blood supply to the hepatocytes, it seems most likely that they occur at this intrasinusoidal capillary level rather than in the larger vessels. © 1965

Molecular models for the core components of the flagellar type-III secretion complex

We show that by using a combination of computational methods, consistent three-dimensional molecular models can be proposed for the core proteins of the type-III secretion system. We employed a variety of approaches to reconcile disparate, and sometimes inconsistent, data sources into a coherent picture that for most of the proteins indicated a unique solution to the constraints. The range of difficulty spanned from the trivial (FliQ) to the difficult (FlhA and FliP). The uncertainties encountered with FlhA were largely the result of the greater number of helix packing possibilities allowed in a large protein, however, for FliP, there remains an uncertainty in how to reconcile the large displacement predicted between its two main helical hairpins and their ability to sit together happily across the bacterial membrane. As there is still no high resolution structural information on any of these proteins, we hope our predicted models may be of some use in aiding the interpretation of electron microscope images and in rationalising mutation data and experiments

Diatoms as indicators of water quality in the Jukskei-Crocodile river system in 1956 and 1957, a re-analysis of diatom count data generated by BJ Cholnoky

South Africa has a long legacy of diatom research. The eminent diatomist Dr BJ Cholnoky spent much of his working life examining and enumerating diatom communities found in Southern Africa. Most if not all of Cholnoky's collected diatom material in the form of mounted material on glass slides accompanied by diatom analysis sheets is stored in the South African Diatom Collection currently housed at the CSIR in Durban. As Cholnoky only employed enumeration methods yielding a margin of error of 2% or less, Cholnoky's results should provide an accurate reflection of the structure of the diatom communities that he examined. It is the aim of the present study to demonstrate the value of these historical diatom analyses for inferring past water quality conditions using the diatom-based index method. Data for the Jukskei-Crocodile River system were obtained from the South African Diatom Collection for the period 1956/1957. The nomenclature of the diatoms listed on Cholnoky's data sheets was modernised and the data then entered into OMNIDIA v3.1. Diatom index scores generated from OMNIDIA v3.1 were in general in agreement with Cholnoky's own assessment of water quality (especially with reference to organic pollution). It is concluded that the diatom analysis records housed in the South African Diatom Collection constitute a valuable resource for the assessment of past conditions of rivers and streams.. Water SA Vol. 31 (2) 2005: pp.237-24

Spectrin promotes the association of F-actin with the cytoplasmic surface of the human erythrocyte membrane

We studied the binding of actin to the erythrocyte membrane by a novel application of falling ball viscometry. Our approach is based on the notion that if membranes have multiple binding sites for F-actin they will be able to cross-link and increase the viscosity of actin. Spectrin- and actin-depleted inside-out vesicles reconstituted with purified spectrin dimer or tetramer induce large increases in the viscosity of actin. Comparable concentrations of spectrin alone, inside-out vesicles alone, inside-out vesicles plus heat-denatured spectrin dimmer or tetramer induce large increases in the viscosity of actin. Comparable concentrations of spectrin alone, inside-out vesicles alone, inside-out plus heat denatured spectrin, ghosts, or ghosts plus spectrin have no effect on the viscosity of actin. Centrifugation experiments show that the amount of actin bound to the inside-out vesicles is enhanced in the presence of spectrin. The interactions detected by low-shear viscometry reflect actin interaction with membrane- bound spectrin because (a) prior removal of band 4.1 and ankyrin (band 2.1, the high- affinity membrane attachment site for spectrin) reduces both spectrin binding to the inside-out vesicles and their capacity to stimulate increase in viscosity of actin in the presence of spectrin + actin are inhibited by the addition of the water-soluble 72,000- dalton fragment of ankyrin, which is known to inhibit spectrin reassociation to the membrane. The increases in viscosity of actin induced by inside-out vesicles reconstituted with purified spectrin dimer or tetramer are not observed when samples are incubated at 0 degrees C. This temperature dependence may be related to the temperature-dependent associations we observe in solution studies with purified proteins: addition of ankyrin inhibits actin cross-linking by spectrin tetramer plus band 4.1 at 0 degrees C, and enhances it at 32 degrees C. We conclude (a) that falling ball viscometry can be used to assay actin binding to membranes and (b) that spectrin is involved in attaching actin filaments or oligomers to the cytoplasmic surface of the erythrocyte membrane

Bandit Models of Human Behavior: Reward Processing in Mental Disorders

Drawing an inspiration from behavioral studies of human decision making, we propose here a general parametric framework for multi-armed bandit problem, which extends the standard Thompson Sampling approach to incorporate reward processing biases associated with several neurological and psychiatric conditions, including Parkinson's and Alzheimer's diseases, attention-deficit/hyperactivity disorder (ADHD), addiction, and chronic pain. We demonstrate empirically that the proposed parametric approach can often outperform the baseline Thompson Sampling on a variety of datasets. Moreover, from the behavioral modeling perspective, our parametric framework can be viewed as a first step towards a unifying computational model capturing reward processing abnormalities across multiple mental conditions.Comment: Conference on Artificial General Intelligence, AGI-1

Commentary: Ensuring health statistics in conflict are evidence-based

The author argues that measuring mortality in conflict settings is fraught with limitations which mostly result in under-estimation of mortality. Some recent publications on this subject have been based upon convenient surveillance processes, or even press reports. The author calls for vigilance against such studies and argues that war related surveillance-based mortality estimates should include measures of sensitivity and representativeness

Gaussian-process-based demand forecasting for predictive control of drinking water networks

Trabajo presentado a la 9th International Conference on Critical Information Infrastructures Security, celebrada en Limassol (Chipre) del 13 al 15 de octubre de 2014.This paper focuses on short-term water demand forecasting for predictive control of DrinkingWater Networks (DWN) by using Gaussian Process (GP). For the predictive control strategy, system state prediction in a nite horizon are generated by a DWN model and demands are regarded as system disturbances. The goal is to provide a demand estimation within a given condence interval. For the sake of obtaining a desired forecasting performance, the forecasting process is carried out in two parts: the expected part is forecasted by Double-Seasonal Holt-Winters (DSHW) method and the stochastic part is forecasted by GP method. The mean value of water demand is rstly estimated by DSHW while GP provides estimations within a condence interval. GP is applied with random inputs to propagate uncertainty at each step. Results of the application of the proposed approach to a real case study based on the Barcelona DWN have shown that the general goal has been successfully reached.This work is partially supported by the research projects SHERECS DPI-2011-26243 and ECOCIS DPI-2013-48243-C2-1-R, both of the Spanish Ministry of Education, by EFFINET grant FP7-ICT-2012-318556 of the European Commission and by AGAUR Doctorat Industrial 2013-DI-041. Ye Wang also thanks China Scholarship Council for providing postgraduate scholarship.Peer Reviewe