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7 Pág. Departamento de Biotecnología, Protein kinase C (PKC) comprises a family of multifunctional lipid-dependent serine/threonine kinases that are implicated in the transduction of signals for a wide range of cellular processes, such as apoptosis, differentiation, proliferation, cellular transformation, motility, adhesion, and angiogenesis, among others. PKCs have also been involved in different steps during viral replication, and their role in virus infections has been largely analyzed, including that concerning relevant human pathogens such as Zika virus, human immunodeficiency virus, and influenza virus. In the case of Zika virus and other related flaviviruses, depending on the infecting virus, disparate results have been reported concerning the role of PKCs in their replication. In fact, PKCs are currently being investigated as a target of drug development for the treatment of viral infections and other important human disorders. Here we present a brief description of PKC structures and functions, with special emphasis on what is currently known about their role during Zika and other related flavivirus infections.

T-cell self-recognition of antigen presenting molecules is led by antigen-dependent or independent mechanisms. The endothelial protein C receptor (EPCR) shares remarkable similarity with CD1d, including a lipid binding cavity. We have identified EPCR-specific α/β T-cells in the peripheral blood of healthy donors. The average frequency in the CD3+ leukocyte pool is comparable to other autoreactive T-cell subsets that specifically bind MHC-like receptors. Alteration of the EPCR lipid cargo, revealed by X-ray diffraction studies, points to a prevalent, yet not exclusive, lipid-independent self-recognition. In addition, we solve the EPCR lipidome, and detect species not yet described as EPCR ligands. These studies report, for the first time, novel recognition by circulating α/β T-cells and provide grounds for EPCR and lipid mediated T-cell restriction.

The Mg24+C12 fusion reaction was used to perform a detailed γ-ray spectroscopy study of the astrophysically important nucleus Ar34. In particular, an experimental setup, coupling the advanced γ-ray tracking array GRETINA with the well-established Argonne fragment mass analyzer (FMA), was employed to obtain excitation energies and spin-parity assignments for excited states in Ar34, both above and below the proton separation energy. For the first time, an angular distribution analysis of in-beam γ rays from fusion-evaporation reactions, using a tracking array, has been performed and Coulomb energy differences of analog states in the T=1, A=34 mirror system, explored from 0 to 6 MeV. Furthermore, we present a comprehensive discussion of the astrophysical Cl33(p,γ) stellar reaction rate, together with implications for the identification of nova presolar grains from sulfur isotopic abundances., This work was supported by the U. S. Department of Energy, Office of Science, Office of Nuclear Physics, under Contract No. DEAC02-06CH11357 and Grants No. DEFG02- 94-ER40834, No. DEFG02-97-ER41041, No. DEFG02- 97-ER41043, No. DEFG02-94-ER40848, and No. DESC0014231. United Kingdom personnel were supported by the Science and Technologies Facilities Council (STFC) and C.A. was supported by the Natural Sciences and Engineering Research Council of Canada. J.J. acknowledges support from Spanish MINECO Grant No. AYA2017-86274-P, the E.U. FEDER funds, and AGAUR/Generalitat de Catalunya Grant No. SGR-661/2017. This research uses resources of ANL’s ATLAS facility, which is a DOE Office of Science User facility

Introduction The role of Olanzapine therapeutic drug monitoring is controversial. The present study explores the associations of Olanzapine plasma concentrations with clinical response and metabolic side effects in first episode psychosis (FEP) after 2 months of treatment. Methods Forty-seven patients were included. Improvement in clinical symptomatology was assessed using the PANSS. Metabolic assessment included weight, blood pressure, waist circumference, blood glucose, total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides. Results The Olanzapine plasma concentrations after 2 months of treatment were positively correlated with weight gain (r = 0.49, p = 0.003), and a concentration > 23.28 ng/mL was identified as a positive predictor of weight gain (>= 7%). The Olanzapine concentration to dose (C/D) ratio was positively correlated with the percentage of improvement in the total PANSS (r = 0.46, p = 0.004), and a C/D ratio > 2.12 was identified as a positive predictor of a good response (percentage of improvement > 30%) after 2 months of treatment. We also identified several factors that could alter Olanzapine pharmacokinetics: gender (p = 0.03), diagnosis (p = 0.05), smoking habit (p = 0.05), and co-medications such as valproic acid (p = 0.05) and anxiolytics (p = 0.01). Discussion In conclusion, our results suggest that therapeutic drug monitoring of Olanzapine could be helpful to evaluate therapeutic efficacy and metabolic dysfunction in FEP patients treated with Olanzapine.

The discovery of presolar grains in primitive meteorites has initiated a new era of research in the study of stellar nucleosynthesis. However, the accurate classification of presolar grains as being of specific stellar origins is particularly challenging. Recently, it has been suggested that sulfur isotopic abundances may hold the key to definitively identifying presolar grains with being of nova origins and, in this regard, the astrophysical Cl33(p,γ)Ar34 reaction is expected to play a decisive role. As such, we have performed a detailed γ-ray spectroscopy study of Ar34. Excitation energies have been measured with high precision and spin-parity assignments for resonant states, located above the proton threshold in Ar34, have been made for the first time. Uncertainties in the Cl33(p,γ) reaction have been dramatically reduced and the results indicate that a newly identified ℓ =0 resonance at Er=396.9(13) keV dominates the entire rate for T=0.25-0.40 GK. Furthermore, nova hydrodynamic simulations based on the present work indicate an ejected S32/S33 abundance ratio distinctive from type-II supernovae and potentially compatible with recent measurements of a presolar grain.

The prolongation of the QT interval represents the main feature of the long QT syndrome (LQTS), a life-threatening genetic disease. The heterozygous SCN5A V411M mutation of the human sodium channel leads to a LQTS type 3 with severe proarrhythmic effects due to an increase in the late component of the sodium current (INaL). The two sodium blockers flecainide and ranolazine are equally recommended by the current 2015 ESC guidelines to treat patients with LQTS type 3 and persistently prolonged QT intervals. However, awareness of pro-arrhythmic effects of flecainide in LQTS type 3 patients arose upon the study of the SCN5A E1784K mutation. Regarding SCN5A V411M individuals, flecainide showed good results albeit in a reduced number of patients and no evidence supporting the use of ranolazine has ever been released. Therefore, we ought to compare the effect of ranolazine and flecainide in a SCN5A V411M model using an in-silico modeling and simulation approach. We collected clinical data of four patients. Then, we fitted four Markovian models of the human sodium current (INa) to experimental and clinical data. Two of them correspond to the wild type and the heterozygous SCN5A V411M scenarios, and the other two mimic the effects of flecainide and ranolazine on INa. Next, we inserted them into three isolated cell action potential (AP) models for endocardial, midmyocardial and epicardial cells and in a one-dimensional tissue model. The SCN5A V411M mutation produced a 15.9% APD90 prolongation in the isolated endocardial cell model, which corresponded to a 14.3% of the QT interval prolongation in a one-dimensional strand model, in keeping with clinical observations. Although with different underlying mechanisms, flecainide and ranolazine partially countered this prolongation at the isolated endocardial model by reducing the APD90 by 8.7 and 4.3%, and the QT interval by 7.2 and 3.2%, respectively. While flecainide specifically targeted the mutation-induced increase in peak INaL, ranolazine reduced it during the entire AP. Our simulations also suggest that ranolazine could prevent early afterdepolarizations triggered by the SCN5A V411M mutation during bradycardia, as flecainide. We conclude that ranolazine could be used to treat SCN5A V411M patients, specifically when flecainide is contraindicated.

Se relacionaron los datos del estudio bacteriológico de 596 cultivos de esputo, con la clínica y resultados terapéuticos en pacientes con diversas infecciones respiratorias. Los resultados se resumen en lo siguiente: 1) En el 51, 7 % de los casos, no pudo demostrarse un agente bacteriano responsable de la infección respiratoria. 2) La mayor proporción de infecciones respiratorias bacterianas se debieron a gérmenes Gram positivos (60 % de los casos) siendo los antibióticos más eficaces "in vitro", independientemente del tipo de germen, las cefalosporinas, gentamicina y bacitracina. 3) La clínica es poco característica. Una velocidad de sedimentación muy elevada, junto con leucocitosis, orienta hacia la existencia de pseudomonas. Cuando además existe fiebre, dolor de costado y opacidad radiológica es muy probable que se trate de un estafilococo coagulasa positivo. 4) La participación en el proceso inflamatorio de las vías respiratorias, se ha presentado en el 75 % de los casos, siendo la bronquitis crónica, la infección más frecuente (48,64 %) y el estreptococo y neumococo sus principales agentes etiológicos, mientras que los cuadros neumónicos son producidos más frecuentemente por estafilococos, pseudomonas y klebsiellas.