DR_SEQAN: a PC/Windows-based software to evaluate drug

This article is available from: http://www.biomedcentral.com/1471-2334/6/44[Background] Genotypic assays based on DNA sequencing of part or the whole reverse transcriptase (RT)- and protease (PR)-coding regions of the human immunodeficiency virus type 1 (HIV-1) genome have become part of the routine clinical management of HIV-infected individuals. However, the results are difficult to interpret due to complex interactions between mutations found in viral genes.[Results] DR_SEQAN is a tool to analyze RT and PR sequences. The program output includes a list containing all of the amino acid changes found in the query sequence in comparison with the sequence of a wild-type HIV-1 strain. Translation of codons containing nucleotide mixtures can result in potential ambiguities or heterogeneities in the amino acid sequence. The program identifies all possible combinations of 2 or 3 amino acids that derive from translation of triplets containing nucleotide mixtures. In addition, when ambiguities affect codons relevant for drug resistance, DR_SEQAN allows the user to select the appropriate mutation to be considered by the program's drug resistance interpretation algorithm. Resistance is predicted using a rule-based algorithm, whose efficiency and accuracy has been tested with a large set of drug susceptibility data. Drug resistance predictions given by DR_SEQAN were consistent with phenotypic data and coherent with predictions provided by other publicly available algorithms. In addition, the program output provides two tables showing published drug susceptibility data and references for mutations and combinations of mutations found in the analyzed sequence. These data are retrieved from an integrated relational database, implemented in Microsoft Access, which includes two sets of nonredundant core tables (one for combinations of mutations in the PR and the other for combinations in the RT)[Conclusion] DR_SEQAN is an easy to use off-line application that provides expert advice on HIV genotypic resistance interpretation. It is coded in Visual Basic for use in PC/Windows-based platforms. The program is freely available under the General Public License. The program (including the integrated database), documentation and a sample sequence can be downloaded from http:// www2.cbm.uam.es:8080/lmenendez/DR_SEQAN.zipThis work has been supported in part by the Fundación para la Investigación y Prevención del SIDA en España (FIPSE), through grants 36200/01 and 36460/05. An institutional grant of Fundación Ramón Areces to Centro de Biología Molecular "Severo Ochoa" is also acknowledged.Peer reviewe

Vegetable-based diets for chronic kidney disease? It Is time to reconsider

Traditional dietary recommendations to renal patients limited the intake of fruits and vegetables because of their high potassium content. However, this paradigm is rapidly changing due to the multiple benefits derived from a fundamentally vegetarian diet such as, improvement in gut dysbiosis, reducing the number of pathobionts and protein-fermenting species leading to a decreased production of the most harmful uremic toxins, while the high fiber content of these diets enhances intestinal motility and short-chain fatty acid production. Metabolic acidosis in chronic kidney disease (CKD) is aggravated by the high consumption of meat and refined cereals, increasing the dietary acid load, while the intake of fruit and vegetables is able to neutralize the acidosis and its deleterious consequences. Phosphorus absorption and bioavailability is also lower in a vegetarian diet, reducing hyperphosphatemia, a known cause of cardiovascular mortality in CKD. The richness of multiple plants in magnesium and vitamin K avoids their deficiency, which is common in these patients. These beneficial e ects, together with the reduction of inflammation and oxidative stress observed with these diets, may explain the reduction in renal patients’ complications and mortality, and may slow CKD progression. Finally, although hyperkalemia is the main concern of these diets, the use of adequate cooking techniques can minimize the amount absorbedThe Renal, Vascular and Diabetes Laboratory is funded by Ministerio de Economia, Industria y competitividad: FIS ISCIII FEDER funds PI16/01298 and Sociedad Madrileña de Nefrologia

Mutational Patterns Associated with the 69 Insertion Complex in Multi-drug-resistant HIV-1 Reverse Transcriptase that Confer Increased Excision Activity and High-level Resistance to Zidovudine

Human immunodeficiency virus type 1 (HIV-1) strains having dipeptide insertions in the fingers subdomain and other drug resistance-related mutations scattered throughout their reverse transcriptase (RT)-coding region show high-level resistance to zidovudine (AZT) and other nucleoside analogues. Those phenotypic effects have been correlated with their increased ATP-dependent phosphorolytic activity on chain-terminated primers. Mutations T69S and T215Y and a dipeptide insertion (i.e. Ser-Ser) between positions 69 and 70 are required to achieve low-level resistance to thymidine analogues. However, additional amino acid substitutions are necessary to achieve the high-level phenotypic resistance to AZT shown by clinical HIV isolates carrying a dipeptide insertion in their RT-coding region. In order to identify those mutations that contribute to resistance in the sequence context of an insertion-containing RT derived from an HIV clinical isolate (designated as SS RT), we expressed and purified a series of chimeric enzymes containing portions of the wild-type or SS RT sequences. ATP-mediated excision activity measurements using AZT- and stavudine (d4T)-terminated primers and phenotypic assays showed that molecular determinants of high-level resistance to AZT were located in the fingers subdomain of the polymerase. Further studies, using recombinant RTs obtained by site-directed mutagenesis, revealed that M41L, A62V and in a lesser extent K70R, were the key mutations that together with T69S, T215Y and the dipeptide insertion conferred high levels of ATP-dependent phosphorolytic activity on AZT and d4T-terminated primers. Excision activity correlated well with AZT susceptibility measurements, and was consistent with phenotypic resistance to d4T. Structural analysis of the location of the implicated amino acid substitutions revealed a coordinated effect of M41L and A62V on the positioning of the β3–β4 hairpin loop, which plays a key role in the resistance mechanismThis work was supported in part by FIPSE (grant 36523/05) and Fondo de Investigación Sanitaria (through “Red Temática Cooperativa de Investigación en SIDA” G03/173). In addition, work in Madrid was supported by grant BIO2003/01175 (Ministerio de Educación y Ciencia) and an institutional grant from Fundación Ramón Areces. Grant BMC2003/2148 (Ministerio de Educación y Ciencia) (to M. A.M.) is also acknowledgedPeer reviewe

Eco-geomorphological connectivity and coupling interactions at hillslope scale in drylands: Concepts and critical examples

The diagnosis of land degradation requires a deep understanding of ecosystem functioning and evolution. In dryland systems, in particular, research efforts must address the redistribution of scarce resources for vegetation, in a context of high spatial heterogeneity and non-linear response. This fact explains the prevalence of eco-hydrological perspectives interested in runoff processes and, the more recent, focused on connectivity as an indicator of system resource optimisation. From a geomorphological perspective and reviewing the concepts of eco-hydro-geomorphological interactions operating in ecosystems, this paper explores the effects of erosion on vegetation configuration through two case studies at different spatio-temporal scales. We focus on the structure-function linkage, specifically on how morphological traits relate with different stages in the erosional sequence, both in the abiotic and the biotic domain. Results suggest that vegetation dynamics are affected by structural boundary conditions at both scales, i.e. by surface armouring related with rock fragments at the patch scale, and by the degree of hillslope-channel coupling at the hillslope scale. Our preliminary results can serve as new working hypotheses about the structure-function interplay on hillslopes. All this, taking advantage of the recent technological achievements for acquiring very high-resolution geospatial data that offer new analytical possibilities in a range of scales

On the control of optical transmission of aluminosilicate glasses manufactured by the laser floating zone process

In this work, a detailed study of the properties of aluminosilicate glass rods manufactured by means of the laser floating zone (LFZ) technique is presented. Samples fabrication was carried out in controlled atmosphere using air, nitrogen, and oxygen. Transmission spectra showed that glasses manufactured in oxygen presented high optical transmission in the visible spectral range compared to those manufactured in other environments, thus allowing us to tune their optical behavior between transparent and nearly opaque through the control of the surrounding atmosphere. Microstructure and thermo- mechanical properties were also assessed, showing similar hardness, toughness, flexural strength and glass transition temperature values, and in the same range as other aluminosilicate glasses. Compositional and structural characterization in terms of energy dispersive X-ray spectroscopy (EDX) and electron paramagnetic resonance (EPR) allowed us to determine the origin of optical transmission dependence on the fabrication atmosphere

Effect of Poly(propylene imine) Glycodendrimers on beta-Amyloid Aggregation in Vitro and in APP/PS1 Transgenic Mice, as a Model of Brain Amyloid Deposition and Alzheimer's Disease

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Mean-field cooperativity in chemical kinetics

We consider cooperative reactions and we study the effects of the interaction strength among the system components on the reaction rate, hence realizing a connection between microscopic and macroscopic observables. Our approach is based on statistical mechanics models and it is developed analytically via mean-field techniques. First of all, we show that, when the coupling strength is set positive, the model is able to consistently recover all the various cooperative measures previously introduced, hence obtaining a single unifying framework. Furthermore, we introduce a criterion to discriminate between weak and strong cooperativity, based on a measure of "susceptibility". We also properly extend the model in order to account for multiple attachments phenomena: this is realized by incorporating within the model $p$-body interactions, whose non-trivial cooperative capability is investigated too.Comment: 25 pages, 4 figure

¿Adelantan el diagnóstico de la diabetes tipo 2 los nuevos criterios de la Asociación Americana de Diabetes?

ObjetivoAnalizar el intervalo temporal entre la primera hiperglucemia basal ocasional (HBO) y el diagnóstico de diabetes mellitus tipo 2 (DM2) al aplicar los criterios de la OMS y de la Asociación Americana de Diabetes (ADA).DiseñoEstudio observacional, retrospectivo. Ámbito del estudio. Centro de atención primaria urbano.SujetosUn total de 104 pacientes con DM2, diagnosticados entre 1991 y 1995, con antecedentes de HBO.Mediciones o intervencionesEdad, género y otros factores de riesgo, fechas de la primera HBO (glucemia basal 3 110 mg/dl), del diagnóstico según criterios OMS (2 glucemias basales 3 140 mg/dl o 3 200 mg/dl a las 2 horas de la sobrecarga oral de glucosa [SOG]) y aplicando criterios ADA (2 glucemias basales 3 126 mg/dl) y los intervalos en meses entre ellas.ResultadosDe los 222 pacientes diagnosticados, 104 (47%) presentaban antecedentes de HBO. La edad en el momento del diagnóstico fue 60,8 años (DE, 10,1), siendo un 53% mujeres. En 51 casos (49%) se realizó SOG. La mediana (rango) del intervalo entre la primera HBO y el diagnóstico fue de 16 meses (0–101) en los que se realizó la SOG y de 45 (1–104) en los que no se practicó (p = 0,003). En estos últimos, los criterios ADA lo redujeron a 31 meses (0–97) (p < 0,001) y en 27 de ellos que no cumplían ambos criterios a la vez el intervalo fue de sólo 10 meses (0–93) (p < 0,001). Conclusiones. La no realización de la SOG comporta un retraso en el diagnóstico que puede ser contrarrestado con la aplicación de los criterios de la ADA.ObjectiveTo analyze the period of time between the first occasional fasting hyperglycaemia (OFH) and the diagnosis of type 2 diabetes mellitus (DM2), using the World Health Organization (WHO) criteria or the American Diabetes Association (ADA) criteria.DesignRetrospective, observational study.SettingUrban primary care centre.Subjects104 patients with DM2 diagnosed between 1991 and 1995 who had a previous OFH.MeasurementsAge, gender and other risk factors, dates of the first OFH (fasting plasma glucose 3 110 mg/dl), the diagnosis according to WHO criteria (2 fasting plasma glucose 3 140 mg/dl or 3 200 mg/dl two hours after the oral glucose test tolerance (OGTT)) or with the ADA criteria (2 fasting plasma glucose 3 126 mg/dl), and the intervals in months between them.ResultsOf the 222 diagnosed patients, 104 (47%) had previous OFH. Age at diagnosis was 60.8 (SD 10.1) and 53% were women. OGTT was performed in 51 cases (49%). The median (range) of the interval between the first OFH and diagnosis was 16 months (0–101) for those who were undertaken an OGTT, and 45 months (1–104) for those who were not (p = 0.003). In these last ones, ADA criteria reduced the interval to 31 months (0–97) (p < 0.001). In 27 of these patients who did not satisfy both criteria at the same time, ADA criteria reduced the interval to 10 months (0–93) (p < 0.001).ConclusionsNot performing the OGTT means a delay in diagnosis which can be countered by applying the ADA criteria