Development of a Structure-Based, pH-Dependent Lipophilicity Scale of Amino Acids from Continuum Solvation Calculations

Lipophilicity is a fundamental property to characterize the structure and function of proteins, motivating the development of lipophilicity scales. Here we report a versatile strategy to derive a pH-adapted scale that relies on theoretical estimates of distribution coefficients from conformational ensembles of amino acids. This is accomplished by using an accurately parametrized version of the IEFPCM/MST continuum solvation model, as an effective way to describe the partitioning between n-octanol and water, in conjunction with a formalism that combines partition coefficients of neutral and ionic species of residues, and the corresponding pKa of ionizable groups. Two weighting schemes are considered to derive solvent-like and protein-like scales, which have been calibrated by comparison with other experimental scales developed in different chemical/biological environments and pH conditions, as well as by examining properties such as the retention time of small peptides and the recognition of antigenic peptides. A straightforward extension to nonstandard residues is enabled by this efficient methodological strategy

IST-2000-30148 I-METRA: D4 Performance evaluation

This document considers the performance of multiantenna transmit/receive techniques in high-speed downlink and uplink packet access. The evaluation is done using both link and system level simulations by taking into account link adaptation and packet retransmissions. The document is based on the initial studies carried out in deliverables D3.1 and D3.2.Preprin

Comprehensive translational assessment of human-induced pluripotent stem cell derived cardiomyocytes for evaluating drug-induced arrhythmias

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) hold promise for assessment of drug-induced arrhythmias and are being considered for use under the comprehensive in vitro proarrhythmia assay (CiPA). We studied the effects of 26 drugs and 3 drug combinations on 2 commercially available iPSC-CM types using high-throughput voltage-sensitive dye and microelectrode-array assays being studied for the CiPA initiative and compared the results with clinical QT prolongation and torsade de pointes (TdP) risk. Concentration-dependent analysis comparing iPSC-CMs to clinical trial results demonstrated good correlation between drug-induced rate-corrected action potential duration and field potential duration (APDc and FPDc) prolongation and clinical trial QTc prolongation. Of 20 drugs studied that exhibit clinical QTc prolongation, 17 caused APDc prolongation (16 in Cor.4U and 13 in iCell cardiomyocytes) and 16 caused FPDc prolongation (16 in Cor.4U and 10 in iCell cardiomyocytes). Of 14 drugs that cause TdP, arrhythmias occurred with 10 drugs. Lack of arrhythmic beating in iPSC-CMs for the four remaining drugs could be due to differences in relative levels of expression of individual ion channels. iPSC-CMs responded consistently to human ether-a-go-go potassium channel blocking drugs (APD prolongation and arrhythmias) and calcium channel blocking drugs (APD shortening and prevention of arrhythmias), with a more variable response to late sodium current blocking drugs. Current results confirm the potential of iPSC-CMs for proarrhythmia prediction under CiPA, where iPSC-CM results would serve as a check to ion channel and in silico modeling prediction of proarrhythmic risk. A multi-site validation study is warranted

Theoretical study of the conformational energy hypersurface of cyclotrisarcosyl

The multidimensional Conformational Potential Energy Hypersurface (PEHS) of cyclotrisarcosyl was comprehensively investigated at the DFT (B3LYP/6-31G(d), B3LYP/6-31G(d,p) and B3LYP/6-311++G(d,p)), levels of theory. The equilibrium structures, their relative stability, and the Transition State (TS) structures involved in the conformational interconversion pathways were analyzed. Aug-cc-pVTZ//B3LYP/6-311++G(d,p) and MP2/6-31G(d)//B3LYP/6-311++G(d,p) single point calculations predict a symmetric cis-cis-cis crown conformation as the energetically preferred form for this compound, which is in agreement with the experimental data. The conformational interconversion between the global minimum and the twist form requires 20.88 kcal mol-1 at the MP2/6-31G(d)//B3LYP/6- 311++G(d,p) level of theory. Our results allow us to form a concise idea about the internal intricacies of the PEHSs of this cyclic tripeptide, describing the conformations as well as the conformational interconversion processes in this hypersurface. In addition, a comparative analysis between the conformational behaviors of cyclotrisarcosyl with that previously reported for cyclotriglycine was carried out.Fil: Alvarez, Maria de Los Angeles. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química; ArgentinaFil: Saavedra, Edgardo J.. Universidad Nacional de la Patagonia "San Juan Bosco"; ArgentinaFil: Olivella, Mónica Susana. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química; ArgentinaFil: Suvire, Fernando Daniel. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química; ArgentinaFil: Zamora, Miguel Angel. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química; ArgentinaFil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química; Argentin

Novel pathogenic COX20 variants causing dysarthria, ataxia, and sensory neuropathy.

COX20/FAM36A encodes a mitochondrial complex IV assembly factor important for COX2 activation. Only one homozygous COX20 missense mutation has been previously described in two separate consanguineous families. We report four subjects with features that include childhood hypotonia, areflexia, ataxia, dysarthria, dystonia, and sensory neuropathy. Exome sequencing in all four subjects identified the same novel COX20 variants. One variant affected the splice donor site of intron-one (c.41A>G), while the other variant (c.157+3G>C) affected the splice donor site of intron-two. cDNA and protein analysis indicated that no full-length cDNA or protein was generated. These subjects expand the phenotype associated with COX20 deficiency

Clinical characteristics and outcome of Spanish patients with ANCA-associated vasculitides: Impact of the vasculitis type, ANCA specificity, and treatment on mortality and morbidity

Spain; ANCA; VasculitidesEspanya; ANCA; VasculitisEspaña; ANCA; VasculitisThe aim of this study was to describe the clinical characteristics of ANCA-associated vasculitides (AAV) at presentation, in a wide cohort of Spanish patients, and to analyze the impact of the vasculitis type, ANCA specificity, prognostic factors, and treatments administered at diagnosis, in the outcome.A total of 450 patients diagnosed between January 1990 and January 2014 in 20 Hospitals from Spain were included. Altogether, 40.9% had granulomatosis with polyangiitis (GPA), 37.1% microscopic polyangiitis (MPA), and 22% eosinophilic granulomatosis with polyangiitis (EGPA). The mean age at diagnosis was 55.6 ± 17.3 years, patients with MPA being significantly older (P < 0.001). Fever, arthralgia, weight loss, respiratory, and ear-nose-throat (ENT) symptoms, were the most common at disease onset. ANCAs tested positive in 86.4% of cases: 36.2% C-ANCA-PR3 and 50.2% P-ANCA-MPO. P-ANCA-MPO was significantly associated with an increased risk for renal disease (OR 2.6, P < 0.001) and alveolar hemorrhage (OR 2, P = 0.010), while C-ANCA-PR3 was significantly associated with an increased risk for ENT (OR 3.4, P < 0.001) and ocular involvement (OR 2.3, P = 0.002). All patients received corticosteroids (CS) and 74.9% cyclophosphamide (CYC). The median follow-up was 82 months (IQR 100.4). Over this period 39.9% of patients suffered bacterial infections and 14.6% opportunistic infections, both being most prevalent in patients with high-cumulated doses of CYC and CS (P < 0.001). Relapses were recorded in 36.4% of cases with a mean rate of 2.5 ± 2.3, and were more frequent in patients with C-ANCA-PR3 (P = 0.012). The initial disease severity was significantly associated with mortality but not with the occurrence of relapses. One hundred twenty-nine (28.7%) patients (74 MPA, 41 GPA, 14 EGPA) died. The mean survival was 58 months (IQR 105) and was significantly lower for patients with MPA (P < 0.001). Factors independently related to death were renal involvement (P = 0.010), cardiac failure (P = 0.029) and age over 65 years old (P < 0.001) at disease onset, and bacterial infections (P < 0.001). An improved outcome with significant decrease in mortality and treatment-related morbidity was observed in patients diagnosed after 2000, and was related to the implementation of less toxic regimens adapted to the disease activity and stage, and a drastic reduction in the cumulated CYC and CS dose

Mirroring the Zika epidemics in Cuba: The view from a European imported diseases clinic

Dear Editor, the changing epidemiology of Zika virus infection has been described before and in this letter we would like to show how the local epidemiology of Zika in Cuba is reflected in imported cases in returning travellers to Barcelona. The spread of the 2015 Zika epidemic was mostly reported in South America and the Caribbean. While increasing numbers of cases raised in South-America, Cuba was still free of cases. On 2nd March 2016 the first imported case from Cuba (Artemisa province) was reported. The first autochthonous case was reported on 16th March 2016 in La Habana. Onwards, cases were reported in Camagüey, Cienfuegos, Guantánamo, Havana and Santiago. During 2017 transmission has been reported in municipalities of Arroyo Naranjo and Regla in the province of Havana

IST-2000-30148 I-METRA: D3.2 Implementation of relevant algorithms

This deliverable provides a high level description of the software developed within the I-METRA project following the selection reported in D3.1 "Design, Analysis and Selection of Suitable Algorithms".Preprin