Noniterative approach to the total asymmetric synthesis of 15-carbon polyketides and analogs with high stereodiversity

Starting from inexpensive furan and furfuryl alcohol, a noniterative approach to the synthesis of pentadeca-1,3,5,7,9,11,13,15-octols and their derivatives has been developed. The method relies upon the double [4+3]-cycloaddition of 1,1,3-trichloro-2-oxylallyl cation with 2,2'-methylenedifuran and conversion of the adducts into meso and (±)-threo-1,1'-methylenebis (cis- and trans-4,6-dihydroxycyclohept-1-ene) derivatives. The latter undergo oxidative cleavage of their alkene moieties, generating 5-hydroxy-7-oxoaldehydes that are reduced diastereoselectively into either syn or anti-5,7-diols. Asymmetry is realized using either chiral desymmetrization with Sharpless asymmetric dihydroxylation or by kinetic resolution of polyols using lipase-catalyzed acetylations. All of the possible stereomeric pentadeca-1,3,5,7,9,11,13,15-octols and derivatives can be obtained with high stereoselectivity applying simple operations, thus demonstrating the high stereodiversity of this new, noniterative approach to the asymmetric synthesis of long-chain polyketide

Assessment of anogenital distance as a diagnostic tool in polycystic ovary syndrome

©. This manuscript version is made available under the CC-BY-NC 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ This document is the, Accepted, version of a Published Work that appeared in final form in Reproductive BioMedicine Online. To access the final edited and published work see: https://doi.org/10.1016/j.rbmo.2018.08.020Is anogenital distance (AGD) a useful clinical tool for predicting polycystic ovarian syndrome (PCOS) and its main National Institutes of Health (NIH) phenotypes? Case-control study conducted between September 2014 and May 2016 at the Department of Obstetrics and Gynecology of the University Clinical Hospital 'Virgen de la Arrixaca' in the Murcia region (south-eastern Spain). One hundred and twenty-six cases of PCOS and 159 controls without PCOS were included. AGD measurements were taken from the anterior clitoral surface to the upper verge of the anus (AGDAC), and from the posterior fourchette to the upper verge of the anus (AGDAF). Parametric and non-parametric tests and receiver operating characteristic (ROC) curves were used to assess associations between AGD and the presence of PCOS and its phenotypes. AGDAC, but not AGDAF, was associated with PCOS and all its phenotypes (P-values < 0.001 to 0.048). The highest area under the curve (0.62; 95% confidence interval 0.55 to 0.71) was obtained for all PCOS with AGDAC with a sensitivity and specificity of 50.0% and 73.0%, and positive and negative predictive value of 59.0% and 64.4%, respectively. AGDAC could moderately discriminate the presence of PCOS and may be a useful clinical tool

Synthesis and Biological Evaluation of Modified 2-Deoxystreptamine Dimers

Aminoglycosides are powerful antibiotics, but the emergence of resistant bacterial strains has prompted the search for analogues with better pharmacological profiles. The synthesis of 2-deoxystreptamine (2-DOS) dimers linked by polyamines and analogues based on furylcarbopeptoid skeletons is described. Potent and selective ligands for bacterial 16S rRNA were identified using microarray techniques by determining the affinity of these derivatives toward bacterial and human ribosomal RNA

Synthesis and cancer growth inhibitory activities of 2-fatty-alkylated pyrrolidine-3,4-diol derivatives

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Hepatic proteome changes in solea senegalensis exposed to contaminated estuarine sediments: a laboratory and in situ survey

Assessing toxicity of contaminated estuarine sediments poses a challenge to ecotoxicologists due to the complex geochemical nature of sediments and to the combination of multiple classes of toxicants. Juvenile Senegalese soles were exposed for 14 days in the laboratory and in situ (field) to sediments from three sites (a reference plus two contaminated) of a Portuguese estuary. Sediment characterization confirmed the combination of metals, polycyclic aromatic hydrocarbons and organochlorines in the two contaminated sediments. Changes in liver cytosolic protein regulation patterns were determined by a combination of two-dimensional electrophoresis with de novo sequencing by tandem mass spectrometry. From the forty-one cytosolic proteins found to be deregulated, nineteen were able to be identified, taking part in multiple cellular processes such as anti-oxidative defence, energy production, proteolysis and contaminant catabolism (especially oxidoreductase enzymes). Besides a clear distinction between animals exposed to the reference and contaminated sediments, differences were also observed between laboratory- and in situ-tested fish. Soles exposed in the laboratory to the contaminated sediments failed to induce, or even markedly down-regulated, many proteins, with the exception of a peroxiredoxin (an anti-oxidant enzyme) and a few others, when compared to reference fish. In situ exposure to the contaminated sediments revealed significant up-regulation of basal metabolism-related enzymes, comparatively to the reference condition. Down-regulation of basal metabolism enzymes, related to energy production and gene transcription, in fish exposed in the laboratory to the contaminated sediments, may be linked to sedimentbound contaminants and likely compromised the organisms’ ability to deploy adequate responses against insult.info:eu-repo/semantics/publishedVersio

Estudio y planificación de contenidos, materiales y metodologías docentes según el EEES: Itinerario Ocio Digital (Cuarto Curso de Ingeniería Multimedia)

En esta memoria se describe el proyecto realizado para la planificación de contenidos, materiales y metodología docente, y el seguimiento de las asignaturas del itinerario de Creación y Entretenimiento digital del cuarto curso del Grado en Ingeniería Multimedia de la Escuela Politécnica Superior, como continuación del planteamiento realizado en el proyecto de la red de cuarto curso configurada en el año 2012-13 (identificador 2687). En el marco creado por los nuevos estudios dentro del EEES, el proyecto ha tenido como objetivo principal la preparación, coordinación y seguimiento de las asignaturas del citado itinerario, teniendo en cuenta la aplicación de la metodología de Aprendizaje Basado en Proyectos (ABP). A partir de la experiencia adquirida en la planificación de cursos previos, se han elaborado las guías docentes de las asignaturas ajustando las del curso anterior. También se presentan los resultados obtenidos en la primera experiencia llevada a cabo en este curso, expresados en horas de dedicación al proyecto y en grado de satisfacción tanto del alumnado como del profesorado con la metodología ABP. Por último, se ha creado una página web informativa del itinerario explicando todos los aspectos de la metodología, y se han elaborado dos artículos detallando toda la labor realizada

Exploring Multi-Subsite Binding Pockets in Proteins:DEEP-STD NMR Fingerprinting and Molecular Dynamics Unveil a Cryptic Subsite at the GM1 Binding Pocket of Cholera Toxin B

Ligand-based NMR techniques to study protein–ligand interactions are potent tools in drug design. Saturation transfer difference (STD) NMR spectroscopy stands out as one of the most versatile techniques, allowing screening of fragments libraries and providing structural information on binding modes. Recently, it has been shown that a multi-frequency STD NMR approach, differential epitope mapping (DEEP)-STD NMR, can provide additional information on the orientation of small ligands within the binding pocket. Here, the approach is extended to a so-called DEEP-STD NMR fingerprinting technique to explore the binding subsites of cholera toxin subunit B (CTB). To that aim, the synthesis of a set of new ligands is presented, which have been subject to a thorough study of their interactions with CTB by weak affinity chromatography (WAC) and NMR spectroscopy. Remarkably, the combination of DEEP-STD NMR fingerprinting and Hamiltonian replica exchange molecular dynamics has proved to be an excellent approach to explore the geometry, flexibility, and ligand occupancy of multi-subsite binding pockets. In the particular case of CTB, it allowed the existence of a hitherto unknown binding subsite adjacent to the GM1 binding pocket to be revealed, paving the way to the design of novel leads for inhibition of this relevant toxin

Haplotype analysis of the internationally distributed BRCA1 c.3331_3334delCAAG founder mutation reveals a common ancestral origin in Iberia

BACKGROUND: The BRCA1 c.3331_3334delCAAG founder mutation has been reported in hereditary breast and ovarian cancer families from multiple Hispanic groups. We aimed to evaluate BRCA1 c.3331_3334delCAAG haplotype diversity in cases of European, African, and Latin American ancestry. METHODS: BC mutation carrier cases from Colombia (n = 32), Spain (n = 13), Portugal (n = 2), Chile (n = 10), Africa (n = 1), and Brazil (n = 2) were genotyped with the genome-wide single nucleotide polymorphism (SNP) arrays to evaluate haplotype diversity around BRCA1 c.3331_3334delCAAG. Additional Portuguese (n = 13) and Brazilian (n = 18) BC mutation carriers were genotyped for 15 informative SNPs surrounding BRCA1. Data were phased using SHAPEIT2, and identical by descent regions were determined using BEAGLE and GERMLINE. DMLE+ was used to date the mutation in Colombia and Iberia. RESULTS: The haplotype reconstruction revealed a shared 264.4-kb region among carriers from all six countries. The estimated mutation age was ~ 100 generations in Iberia and that it was introduced to South America early during the European colonization period. CONCLUSIONS: Our results suggest that this mutation originated in Iberia and later introduced to Colombia and South America at the time of Spanish colonization during the early 1500s. We also found that the Colombian mutation carriers had higher European ancestry, at the BRCA1 gene harboring chromosome 17, than controls, which further supported the European origin of the mutation. Understanding founder mutations in diverse populations has implications in implementing cost-effective, ancestry-informed screening

Evaluation of the integrated intervention for dual problems and early action among latino immigrants with co-occurring mental health and substance misuse symptoms: A randomized clinical trial

Importance: Immigrants are at an increased risk for co-occurring mental health and substance misuse symptoms; however, effective treatments are lacking. Objective: To evaluate the effectiveness of the Integrated Intervention for Dual Problems and Early Action (IIDEA) program compared with enhanced usual care. Design, Setting, and Participants: This effectiveness randomized clinical trial was conducted from September 2, 2014, to February 2, 2017, in 17 clinics or emergency departments and 24 community sites in Boston, Massachusetts, as well as in Madrid and Barcelona, Spain. Equal randomization (1:1) in 2-person blocks was used, assigning participants to either the IIDEA treatment group (n = 172) or the enhanced usual care control group (n = 169). Intent-to-treat analyses assessed effectiveness, and post hoc analyses examined whether results varied by symptom severity or treatment dose. Eligible participants were between 18 and 70 years of age, self-identified as Latino, screened positive for co-occurring symptoms, and were not receiving specialty behavioral health services. Interventions: Participants were randomized to a 10-session IIDEA treatment or to enhanced usual care. Main Outcomes and Measures: Primary outcomes were changes in alcohol and drug misuse and results of a urine test for drug metabolites but not for alcohol misuse. Secondary outcomes were symptoms of depression, generalized anxiety, posttraumatic stress disorder, and overall mental health. Results: In total, 341 participants were randomized to either the IIDEA treatment group (n = 172; 94 [54.7%] female, mean [SD] age, 33.5 [11.6] years) or the enhanced usual care control group (n = 169; 80 [47.3%] female, mean [SD] age, 34.3 [11.8] years). No statistically significant effects of IIDEA were found for primary drug and alcohol outcomes (ASI Lite-drug score: β = -0.02 [SE, 0.69; P = .88; Cohen d, 0.00; 95% CI, -0.17 to 0.17]; ASI Lite-alcohol score: β = -0.01 [SE, 1.19; P = .66; Cohen d, 0.00; 95% CI, -0.12 to 0.12]; urine drug test result: β = -0.36 [SE, 0.43; P = .50; OR, 0.70; 95% CI, 0.30-1.61]), but statistically significant effects were observed for secondary mental health outcomes. The IIDEA treatment was effective in reducing depressive symptoms per the Public Health Questionnaire-9 score (β = -1.14; SE, 0.47; P = .02; Cohen d, 0.20 [95% CI, 0.04-0.36]), posttraumatic stress disorder symptoms per the Posttraumatic Stress Disorder Checklist-5 score (β = -3.23; SE, 1.59; P = .04; Cohen d, 0.25 [95% CI, 0.01-0.37]), and overall mental health symptoms per the Hopkins Symptom Checklist-20 (β = -0.20; SE, 0.07; P = .01; Cohen d, 0.25 [95% CI, 0.08-0.42]) and composite mental health (β = -3.70; SE, 1.75; P = .04; Cohen d, 0.19 [95% CI, 0.01-0.36]) scores at the 6-month follow-up. Exploratory analyses suggested that 6-month treatment effects occurred for patients whose drug misuse was moderate to severe at the baseline assessment. Among patients with moderate to severe substance misuse, IIDEA substantially reduced substance use per the urine test results (odds ratio, 0.25 [95% CI, 0.09-0.67]; P = .01). Treatment dose showed small to large effect sizes by outcome. Conclusions and Relevance: The IIDEA treatment did not change drug misuse but did improve secondary mental health and substance misuse outcomes for a heterogeneous population with moderate to severe symptoms; this finding provides a path for treating Latino immigrants with co-occurring mental health and substance misuse symptoms. Trial Registration: ClinicalTrials.gov Identifier: NCT02038855.This study was funded in part by grant R01DA034952 from NIDA of the National Institutes of Health; grant R01MH100155-01S1 from NIMH; and grants ISCII PI13/02200 and PI16/01852 from Instituto de Salud Carlos III, grant 20151073 from Delegación del Gobierno para el Plan Nacional de Drogas, and grant LSRG-1-005-16 from the American Foundation for Suicide Prevention (Dr Baca-García