Gemini lipopeptides as vaccine adjuvants: a new role for these versatile carriers

The design of subunit vaccines requires new adjuvant systems. We designed and synthesized new lipopeptides (cysteine-based) of low molecular weight with different hydrophobic chains that dimerize becoming gemini lipopeptides. They were characterized and their adjuvant capacity was tested in mice by the inoculation of a protein antigen formulated with the lipopeptides, with and without the addition of CpG-oligodeoxynucleotides. Formulations were able to induce an immune response and produced no adverse effects. An adjuvant ability is described for the first time for this type of molecules.Fil: Grippo, Lucía Daniela. Universidad Nacional del Litoral. Facultad de Bioquimica y Ciencias Biologicas. Laboratorio de Química Aplicada.; Argentina. Universidad Nacional del Litoral. Facultad de Bioquimica y Ciencias Biologicas. Laboratorio de Inmunologia Experimental.; ArgentinaFil: Reidel, Ivana Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; Argentina. Universidad Nacional del Litoral. Facultad de Bioquimica y Ciencias Biologicas. Laboratorio de Inmunologia Experimental.; ArgentinaFil: García, María Inés. Universidad Nacional del Litoral. Facultad de Bioquimica y Ciencias Biologicas. Laboratorio de Inmunologia Experimental.; ArgentinaFil: Streu, Alexis. Universidad Nacional del Litoral. Facultad de Bioquimica y Ciencias Biologicas. Laboratorio de Química Aplicada.; Argentina. Universidad Nacional del Litoral. Facultad de Bioquimica y Ciencias Biologicas. Laboratorio de Inmunologia Experimental.; ArgentinaFil: Müller, Diana María. Universidad Nacional del Litoral. Facultad de Bioquimica y Ciencias Biologicas. Laboratorio de Química Aplicada.; ArgentinaFil: Veaute, Carolina Melania Isabel. Universidad Nacional del Litoral. Facultad de Bioquimica y Ciencias Biologicas. Laboratorio de Inmunologia Experimental.; Argentin

Supernucleation Dominates Lignin/Poly(ethylene oxide) Crystallization Kinetics

The effect of lignin nanoparticles (LNPs) on the crystallization kinetics of poly(ethylene oxide) (PEO) is examined. Lignin from spruce and ionic isolation was used to prepare LNPs with a number-averaged diameter of 85 nm (with a relatively large polydispersity) by an ultrasonication method. PEO-based nanocomposites with four different LNP contents (5, 10, 15, and 20 wt %) were prepared and subject to isothermal and nonisothermal crystallization protocols in a series of experiments. Scanning electron microscopy (SEM) images showed well-dispersed LNPs in the crystallized PEO matrix. The incorporation of LNPs exponentially increases nucleation density at moderate loadings, with this trend apparently saturating at higher loadings. However, the spherulitic growth rate decreases monotonically with LNP loading. This is attributed to the substantial PEO/LNP affinity, which impacts chain diffusion and induces supernucleation effect (with efficiencies in the order of 200%), but leads to slower growth rates. The overall crystallization kinetics, measured by the DSC, shows faster nanocomposite crystallization rates relative to the neat PEO at all LNP contents examined. This indicates that the supernucleation effect of LNPs dominates over the decrease in the growth rates, although its influence slightly decreases as the LNP content increases. The strong hydrogen-bonded interactions between the LNPs and the PEO are thus reminiscent of confinement effects found in polymer-grafted NP nanocomposites (e.g., PEO-g-SiO2/PEO) in the brush-controlled regime.This work received funding from the Basque Government through grant IT1503 - 22. S.K.K . acknowledges funding by the U.S. Department of Energy, Office of Science, grants DE- SC0018182, DE-SC0018135, and DE-SC0018111. The authors acknowledged the financial support of Fundacion Losano, PIP2011 848, and PUE No. 22920160100007 (CONICET) . The authors acknowledge the support of Ana Martínez Amesti, Microscopy: Polymer Characterization Research Service, SGIker (UPV/EHU)

Obstetricia integral siglo XXI. Tomo II

El libro Obstetricia Integral siglo XXI, Tomo II, es una publicación virtual de la Facultad de Medicina, se trata de la continuación sobre el análisis detallado de los principales tópicos en el área de la obstetricia, realizada por un grupo interdisciplinario de investigadores comprometidos con el mejoramiento de la calidad en el cuidado de la salud de la mujer gestante. Se ha procurado un balance entre los aspectos básicos de fisiopatología y las guías de atención clínica soportadas en evidencias científicas, con el ánimo de brindarle al lector un equilibrio entre las bases biopsico-sociales de la salud y la enfermedad y los aspectos prácticos de la atención clínica.Vargas Fiesco, Diana Carolina and Rubio Romero, Jorge Andrés and Ruiz Parra, Ariel Iván and Rodríguez, Luis Martín and Aragón, Miguel Eduardo and Arteaga Díaz, Clara Eugenia and Riaño, Jorge Enrique and Arenas Gamboa, Jaime and Ramírez Martínez, Javier Andrés and Amaya Guío, Jairo and Gaitán , Magda Alexandry and Gallego Arbeláez, Jaime and Cortés Díaz, Daniel Otálvaro and Ángel Müller, Edith and Bracho Ch., Alcides C. and Bautista Charry, Alejandro and Rodríguez Ramos, Marcela and Navarro Milanés, Alfonso and Díaz Cruz, Luz Amparo and Mercado Pedroza, Manuel Esteban and Gaitán Duarte, Hernando and Gómez Sánchez, Pio Iván and Peña, Diana Marcela and Calvo Gómez, José Manuel and Parra Pineda, Mario Orlando and Cárdenas Muñoz, María Luisa (2010) Obstetricia integral siglo XXI. Tomo II. Facultad de Medicina, Universidad Nacional de Colombia, Bogotá. ISBN 978958447618

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Contributions of mean and shape of blood pressure distribution to worldwide trends and variations in raised blood pressure: A pooled analysis of 1018 population-based measurement studies with 88.6 million participants

© The Author(s) 2018. Background: Change in the prevalence of raised blood pressure could be due to both shifts in the entire distribution of blood pressure (representing the combined effects of public health interventions and secular trends) and changes in its high-blood-pressure tail (representing successful clinical interventions to control blood pressure in the hypertensive population). Our aim was to quantify the contributions of these two phenomena to the worldwide trends in the prevalence of raised blood pressure. Methods: We pooled 1018 population-based studies with blood pressure measurements on 88.6 million participants from 1985 to 2016. We first calculated mean systolic blood pressure (SBP), mean diastolic blood pressure (DBP) and prevalence of raised blood pressure by sex and 10-year age group from 20-29 years to 70-79 years in each study, taking into account complex survey design and survey sample weights, where relevant. We used a linear mixed effect model to quantify the association between (probittransformed) prevalence of raised blood pressure and age-group- and sex-specific mean blood pressure. We calculated the contributions of change in mean SBP and DBP, and of change in the prevalence-mean association, to the change in prevalence of raised blood pressure. Results: In 2005-16, at the same level of population mean SBP and DBP, men and women in South Asia and in Central Asia, the Middle East and North Africa would have the highest prevalence of raised blood pressure, and men and women in the highincome Asia Pacific and high-income Western regions would have the lowest. In most region-sex-age groups where the prevalence of raised blood pressure declined, one half or more of the decline was due to the decline in mean blood pressure. Where prevalence of raised blood pressure has increased, the change was entirely driven by increasing mean blood pressure, offset partly by the change in the prevalence-mean association. Conclusions: Change in mean blood pressure is the main driver of the worldwide change in the prevalence of raised blood pressure, but change in the high-blood-pressure tail of the distribution has also contributed to the change in prevalence, especially in older age groups

Repositioning of the global epicentre of non-optimal cholesterol

High blood cholesterol is typically considered a feature of wealthy western countries(1,2). However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world(3) and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health(4,5). However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol-which is a marker of cardiovascular riskchanged from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million-4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world.Peer reviewe

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

Hepatic levels of S-adenosylmethionine regulate the adaptive response to fasting

26 p.-6 fig.-1 tab.-1 graph. abst.There has been an intense focus to uncover the molecular mechanisms by which fasting triggers the adaptive cellular responses in the major organs of the body. Here, we show that in mice, hepatic S-adenosylmethionine (SAMe)—the principal methyl donor—acts as a metabolic sensor of nutrition to fine-tune the catabolic-fasting response by modulating phosphatidylethanolamine N-methyltransferase (PEMT) activity, endoplasmic reticulum-mitochondria contacts, β-oxidation, and ATP production in the liver, together with FGF21-mediated lipolysis and thermogenesis in adipose tissues. Notably, we show that glucagon induces the expression of the hepatic SAMe-synthesizing enzyme methionine adenosyltransferase α1 (MAT1A), which translocates to mitochondria-associated membranes. This leads to the production of this metabolite at these sites, which acts as a brake to prevent excessive β-oxidation and mitochondrial ATP synthesis and thereby endoplasmic reticulum stress and liver injury. This work provides important insights into the previously undescribed function of SAMe as a new arm of the metabolic adaptation to fasting.M.V.-R. is supported by Proyecto PID2020-119486RB-100 (funded by MCIN/AEI/10.13039/501100011033), Gilead Sciences International Research Scholars Program in Liver Disease, Acción Estratégica Ciberehd Emergentes 2018 (ISCIII), Fundación BBVA, HORIZON-TMA-MSCA-Doctoral Networks 2021 (101073094), and Redes de Investigación 2022 (RED2022-134485-T). M.L.M.-C. is supported by La CAIXA Foundation (LCF/PR/HP17/52190004), Proyecto PID2020-117116RB-I00 (funded by MCIN/AEI/10.13039/501100011033), Ayudas Fundación BBVA a equipos de investigación científica (Umbrella 2018), and AECC Scientific Foundation (Rare Cancers 2017). A.W. is supported by RTI2018-097503-B-I00 and PID2021-127169OB-I00, (funded by MCIN/AEI/10.13039/501100011033) and by “ERDF A way of making Europe,” Xunta de Galicia (Ayudas PRO-ERC), Fundación Mutua Madrileña, and European Community’s H2020 Framework Programme (ERC Consolidator grant no. 865157 and MSCA Doctoral Networks 2021 no. 101073094). C.M. is supported by CIBERNED. P.A. is supported by Ayudas para apoyar grupos de investigación del sistema Universitario Vasco (IT1476-22), PID2021-124425OB-I00 (funded by MCIN/AEI/10.13039/501100011033 and “ERDF A way of making Europe,” MCI/UE/ISCiii [PMP21/00080], and UPV/EHU [COLAB20/01]). M.F. and M.G.B. are supported by PID2019-105739GB-I00 and PID2020-115472GB-I00, respectively (funded by MCIN/AEI/10.13039/501100011033). M.G.B. is supported by Xunta de Galicia (ED431C 2019/013). C.A., T.L.-D., and J.B.-V. are recipients of pre-doctoral fellowships from Xunta de Galicia (ED481A-2020/046, ED481A-2018/042, and ED481A 2021/244, respectively). T.C.D. is supported by Fundación Científica AECC. A.T.-R. is a recipient of a pre-doctoral fellowship from Fundación Científica AECC. S.V.A. and C.R. are recipients of Margarita Salas postdoc grants under the “Plan de Recuperación Transformación” program funded by the Spanish Ministry of Universities with European Union’s NextGeneration EU funds (2021/PER/00020 and MU-21-UP2021-03071902373A, respectively). T.C.D., A.S.-R., and M.T.-C. are recipients of Ayuda RYC2020-029316-I, PRE2019/088960, and BES-2016/078493, respectively, supported by MCIN/AEI/10.13039/501100011033 and by El FSE invierte en tu futuro. S.L.-O. is a recipient of a pre-doctoral fellowship from the Departamento de Educación del Gobierno Vasco (PRE_2018_1_0372). P.A.-G. is recipient of a FPU pre-doctoral fellowship from the Ministry of Education (FPU19/02704). CIC bioGUNE is supported by Ayuda CEX2021-001136-S financiada por MCIN/AEI/10.13039/501100011033. A.B.-C. was funded by predoctoral contract PFIS (FI19/00240) from Instituto de Salud Carlos III (ISCIII) co-funded by Fondo Social Europeo (FSE), and A.D.-L. was funded by contract Juan Rodés (JR17/00016) from ISCIII. A.B.-C. is a Miguel Servet researcher (CPII22/00008) from ISCIII.Peer reviewe

Search for new particles in events with energetic jets and large missing transverse momentum in proton-proton collisions at root s=13 TeV

A search is presented for new particles produced at the LHC in proton-proton collisions at root s = 13 TeV, using events with energetic jets and large missing transverse momentum. The analysis is based on a data sample corresponding to an integrated luminosity of 101 fb(-1), collected in 2017-2018 with the CMS detector. Machine learning techniques are used to define separate categories for events with narrow jets from initial-state radiation and events with large-radius jets consistent with a hadronic decay of a W or Z boson. A statistical combination is made with an earlier search based on a data sample of 36 fb(-1), collected in 2016. No significant excess of events is observed with respect to the standard model background expectation determined from control samples in data. The results are interpreted in terms of limits on the branching fraction of an invisible decay of the Higgs boson, as well as constraints on simplified models of dark matter, on first-generation scalar leptoquarks decaying to quarks and neutrinos, and on models with large extra dimensions. Several of the new limits, specifically for spin-1 dark matter mediators, pseudoscalar mediators, colored mediators, and leptoquarks, are the most restrictive to date.Peer reviewe