Self-Assembly Behavior of Amphiphilic Janus Dendrimers in Water: A Combined Experimental and Coarse-Grained Molecular Dynamics Simulation Approach

Indexación: Scopus.Acknowledgments: M.E.E.G. thank the Ph. D. scholarship (251115) from CONACyT. The authors would like to thank: Luis Elizalde-Herrera (CIQA) for his help running the NMR spectra; Gloria Macedo-Raygoza and Miguel J. Beltrán-García (UAG), for their help in the measuring of MALDI-TOF mass spectra; and Maricela Rodríguez-Nieto and Jorge Luis Menchaca (UANL), for their help with the AFM measurements. FDGN thanks to the USA Air Force Office of Scientific Research Awards.Amphiphilic Janus dendrimers (JDs) are repetitively branched molecules with hydrophilic and hydrophobic components that self-assemble in water to form a variety of morphologies, including vesicles analogous to liposomes with potential pharmaceutical and medical application. To date, the self-assembly of JDs has not been fully investigated thus it is important to gain insight into its mechanism and dependence on JDs’ molecular structure. In this study, the aggregation behavior in water of a second-generation bis-MPA JD was evaluated using experimental and computational methods. Dispersions of JDs in water were carried out using the thin-film hydration and ethanol injection methods. Resulting assemblies were characterized by dynamic light scattering, confocal microscopy, and atomic force microscopy. Furthermore, a coarse-grained molecular dynamics (CG-MD) simulation was performed to study the mechanism of JDs aggregation. The obtaining of assemblies in water with no interdigitated bilayers was confirmed by the experimental characterization and CG-MD simulation. Assemblies with dendrimersome characteristics were obtained using the ethanol injection method. The results of this study establish a relationship between the molecular structure of the JD and the properties of its aggregates in water. Thus, our findings could be relevant for the design of novel JDs with tailored assemblies suitable for drug delivery systems. © 2018 by the authors.https://www.mdpi.com/1420-3049/23/4/96

Evaluation of VDR gene polymorphisms in Trypanosoma cruzi infection and chronic Chagasic cardiomyopathy

Vitamin D is an important modulator of the immune response. It acts over several immune cell types where the Vitamin D receptor (VDR) is expressed. Due to the high relevance of this signaling pathway, several studies have investigated the possible influence of genes involved in the metabolism of Vitamin D and its receptor in different human diseases. Here, we analyzed whether four single-nucleotide polymorphisms of the VDR gene (rs731236, rs7975232, rs1544410 and rs2228570) are involved in the susceptibility to infection by Trypanosoma cruzi and/or to chronic Chagas cardiomyopathy (CCC) in a Colombian endemic population for this parasite. Our results showed that the rs2228570*A allele is associated with CCC development (P = 4.46E−03, OR = 1.51). In summary, the data presented in this report suggest that variation within the VDR gene may affect the immune response against T. cruzi, increasing the probability of cardiac complications in infected individuals.Peer reviewe

Structure and application of antifreeze proteins from Antarctic bacteria

Indexación: Web of Science; Scopus.Background: Antifreeze proteins (AFPs) production is a survival strategy of psychrophiles in ice. These proteins have potential in frozen food industry avoiding the damage in the structure of animal or vegetal foods. Moreover, there is not much information regarding the interaction of Antarctic bacterial AFPs with ice, and new determinations are needed to understand the behaviour of these proteins at the water/ice interface. Results: Different Antarctic places were screened for antifreeze activity and microorganisms were selected for the presence of thermal hysteresis in their crude extracts. Isolates GU1.7.1, GU3.1.1, and AFP5.1 showed higher thermal hysteresis and were characterized using a polyphasic approach. Studies using cucumber and zucchini samples showed cellular protection when samples were treated with partially purified AFPs or a commercial AFP as was determined using toluidine blue O and neutral red staining. Additionally, genome analysis of these isolates revealed the presence of genes that encode for putative AFPs. Deduced amino acids sequences from GU3.1.1 (gu3A and gu3B) and AFP5.1 (afp5A) showed high similarity to reported AFPs which crystal structures are solved, allowing then generating homology models. Modelled proteins showed a triangular prism form similar to β-helix AFPs with a linear distribution of threonine residues at one side of the prism that could correspond to the putative ice binding side. The statistically best models were used to build a protein-water system. Molecular dynamics simulations were then performed to compare the antifreezing behaviour of these AFPs at the ice/water interface. Docking and molecular dynamics simulations revealed that gu3B could have the most efficient antifreezing behavior, but gu3A could have a higher affinity for ice. Conclusions: AFPs from Antarctic microorganisms GU1.7.1, GU3.1.1 and AFP5.1 protect cellular structures of frozen food showing a potential for frozen food industry. Modeled proteins possess a β-helix structure, and molecular docking analysis revealed the AFP gu3B could be the most efficient AFPs in order to avoid the formation of ice crystals, even when gu3A has a higher affinity for ice. By determining the interaction of AFPs at the ice/water interface, it will be possible to understand the process of adaptation of psychrophilic bacteria to Antarctic ice.https://microbialcellfactories.biomedcentral.com/articles/10.1186/s12934-017-0737-

IL18 Gene Variants Influence the Susceptibility to Chagas Disease

Chagas disease is a parasitic disorder caused by the infection with the flagellated protozoan Trypanosoma cruzi. According to the World Health Organization, more than six million people are currently infected in endemic regions. Genetic factors have been proposed to influence predisposition to infection and development of severe clinical phenotypes like chronic Chagas cardiomyopathy (CCC). Interleukin 18 (IL18) encodes a proinflammatory cytokine that has been proposed to be involved in controlling T. cruzi infection. In this study, we analyzed the possible role of six IL18 gene variants (rs5744258, rs360722, rs2043055, rs187238, rs1946518 and rs360719), which cover most of the variation within the locus, in the susceptibility to infection by T. cruzi and/or CCC. In total, 1,171 individuals from a Colombian region endemic for Chagas disease, classified as seronegative (n = 595), seropositive asymptomatic (n = 175) and CCC (n = 401), were genotyped using TaqMan probes. Significant associations with T. cruzi infection were observed when comparing seronegative and seropositive individuals for rs187238 (P = 2.18E-03, OR = 0.77), rs360719 (P = 1.49E-03, OR = 0.76), rs2043055 (P = 2.52E-03, OR = 1.29), and rs1946518 (P = 0.0162, OR = 1.22). However, dependence analyses suggested that the association was mainly driven by the polymorphism rs360719. This variant is located within the promoter region of the IL18 gene, and it has been described that it creates a binding site for the transcription factor OCT-1 affecting IL-18 expression levels. In addition, no evidence of association was observed between any of the analyzed IL18 gene polymorphisms and the development of CCC. In summary, our data suggest that genetic variation within the promoter region of IL18 is directly involved in the susceptibility to infection by T. cruzi, which provides novel insight into disease pathophysiology and adds new perspectives to achieve a more effective disease control.This work is part of the doctoral thesis “Estudio de las bases genéticas de la enfermedad de Chagas” from the Biomedicine PhD program at the Universidad de Granada (Spain).Peer reviewe

Parâmetros hematológicos e bioquímicos em três raças de cavalos de alta performance do Sul do Brasil

The hematological and biochemical parameters are useful tools for clinics and feeding management of athlete equines. The population of high performance horses consists of different breed groups, displaying specific phenotypic and metabolic characteristics related to the type of sport activity they perform. In the state of Rio Grande do Sul, in the South of Brazil, racing, jumping, polo, endurance, reigning, and dressage are the main activities. This study investigated the hemato-biochemical parameters in three high performance horse breeds from Southern Brazil. A total number of 154 horses belonging to the breeds Thoroughbred, Brasileiro de Hipismo, and Criollo, were selected for this study. Within each breed, samples were collected from males (n=12) and non-pregnant females (n=12) of two ages: 1 to 3 years of age (n=12) and over five years of age (n=12). Hematological (total count of erythrocytes and leukocytes, blood cell volume, hemoglobin, and differential count of leukocytes) and biochemical (lactate, fructosamine, glucose, cholesterol, total protein, albumin, globulins, fibrinogen, urea, calcium, magnesium, phosphorus, and enzymes LDH, AST, GGT, and CK) parameters were analyzed. Significant differences were observed in hematological and biochemical parameters, except for calcium and albumin, among breeds. There was no significant effect of age or sex within breed. This study shows that the local population, the breed and the type of sport activity are important variables to be considered in the analysis of blood parameters of horses.Os parâmetros hematológicos e bioquímicos são ferramentas que auxiliam na clínica e no manejo alimentar do eqüino atleta. Na população eqüina de alta performance existem diferentes grupos raciais que apresentam características fenotípicas e metabólicas específicas, relacionadas com o tipo de atividade esportiva que exercem. Atualmente, no Rio Grande do Sul (Sul do Brasil), são reconhecidas as modalidades esportivas de corrida, salto, polo, enduro, provas de rédeas e provas funcionais. O presente trabalho estudou os parâmetros hemato-bioquímicos em três raças de eqüinos de alta performance no Sul do Brasil. Um total de 154 animais das raças Puro Sangue Inglês, Brasileiro de Hipismo e Crioula foram selecionados para este estudo. Em cada grupo racial foram obtidas amostras de machos (n=12) e fêmeas não gestantes (n=12) e de duas faixas etárias: de 1 a 3 anos (n=12) e de mais de cinco anos (n=12). Foram analisados parâmetros hematológicos (contagem total de eritrócitos e leucócitos, hematócrito, hemoglobina e contagem diferencial de leucócitos) e bioquímicos (lactato, fructosamina, glicose, colesterol, proteína total, albumina, globulinas, fibrinogênio, uréia, cálcio, magnésio, fósforo e enzimas LDH, AST, GGT e CK). Foram observadas diferenças significativas nos parâmetros hematológicos e bioquímicos, exceto para cálcio e albumina, entre os grupos raciais. Não houve efeito significativo da idade e do sexo dentro da mesma raça. O presente trabalho mostra que o fator racial e o tipo de atividade esportiva são variáveis importantes que devem ser consideradas na análise de parâmetros sangüíneos em eqüinos

PTGER4 gene variant rs76523431 is a candidate risk factor for radiological joint damage in rheumatoid arthritis patients: a genetic study of six cohorts

[Introduction] Prostaglandin E receptor 4 (PTGER4) is implicated in immune regulation and bone metabolism. The aim of this study was to analyze its role in radiological joint damage in rheumatoid arthritis (RA).[Methods] Six independent cohorts of patients with RA of European or North American descent were included, comprising 1789 patients with 5083 sets of X-rays. The Hospital Clínico San Carlos Rheumatoid Arthritis, Princesa Early Arthritis Register Longitudinal study, and Hospital Universitario de La Paz early arthritis (Spain) cohorts were used as discovery cohorts, and the Leiden Early Arthritis Clinic (The Netherlands), Wichita (United States), and National Databank for Rheumatic Diseases (United States and Canada) cohorts as replication cohorts. First, the PTGER4 rs6896969 single-nucleotide polymorphism (SNP) was genotyped using TaqMan assays and available Illumina Immunochip data and studied in the discovery and replication cohorts. Second, the PTGER4 gene and adjacent regions were analyzed using Immunochip genotyping data in the discovery cohorts. On the basis of pooled p values, linkage disequilibrium structure of the region, and location in regions with transcriptional properties, SNPs were selected for replication. The results from discovery, replication, and overall cohorts were pooled using inverse-variance–weighted meta-analysis. Influence of the polymorphisms on the overall radiological damage (constant effect) and on damage progression over time (time-varying effect) was analyzed.[Results] The rs6896969 polymorphism showed a significant association with radiological damage in the constant effect pooled analysis of the discovery cohorts, although no significant association was observed in the replication cohorts or the overall pooled analysis. Regarding the analysis of the PTGER4 region, 976 variants were analyzed in the discovery cohorts. From the constant and time-varying effect analyses, 12 and 20 SNPs, respectively, were selected for replication. Only the rs76523431 variant showed a significant association with radiographic progression in the time-varying effect pooled analysis of the discovery, replication, and overall cohorts. The overall pooled effect size was 1.10 (95 % confidence interval 1.05–1.14, p = 2.10 × 10−5), meaning that radiographic yearly progression was 10 % greater for each copy of the minor allele.[Conclusions] The PTGER4 gene is a candidate risk factor for radiological progression in RA.This work was supported by the Instituto de Salud Carlos III (ISCIII), Ministry of Health, Spain [Miguel Servet research contract CP12/03129 (to LRR); Fondo de Investigaciones Sanitarias PI11/02413; and Red de Investigación en Inflamación y Enfermedades Reumáticas RD12/0009/0004, RD12/0009/0011, and RD12/0009/0017]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewe

Statistical disclosure control in tabular data

Data disseminated by National Statistical Agencies (NSAs) can be classified as either microdata or tabular data. Tabular data is obtained from microdata by crossing one or more categorical variables. Although cell tables provide aggregated information, they also need to be protected. This chapter is a short introduction to tabular data protection. It contains three main sections. The first one shows the different types of tables that can be obtained, and how they are modeled. The second describes the practical rules for detection of sensitive cells that are used by NSAs. Finally, an overview of protection methods is provided, with a particular focus on two of them: “cell suppression problem” and “controlled tabular adjustment”.Postprint (published version

A formal characterization of SI-based ROWA replication protocols

Snapshot isolation (SI) is commonly used in some commercial DBMSs with a multiversion concurrency control mechanism since it never blocks read-only transactions. Recent database replication protocols have been designed using SI replicas where transactions are firstly executed in a delegate replica and their updates (if any) are propagated to the rest of the replicas at commit time; i.e. they follow the Read One Write All (ROWA) approach. This paper provides a formalization that shows the correctness of abstract protocols which cover these replication proposals. These abstract protocols differ in the properties demanded for achieving a global SI level and those needed for its generalized SI (GSI) variant ¿ allowing reads from old snapshots. Additionally, we propose two more relaxed properties that also ensure a global GSI level. Thus, some applications can further optimize their performance in a replicated system while obtaining GSI. © 2010 Elsevier B.V. All rights reserved.The authors wish to thank the reviewers for their valuable comments that helped us to greatly improve the quality and readability of this paper. This work has been supported by the Spanish Government under research grant TIN2009-14460-C03. Besides, the authors wish to thank the reviewers for their valuable comments that helped us to greatly improve the quality and readability of this paper.Armendáriz-Iñigo, J.; Juárez-Rodríguez, J.; González De Mendívil, J.; Garitagoitia, J.; Irún Briz, L.; Muñoz Escoí, FD. (2011). A formal characterization of SI-based ROWA replication protocols. Data and Knowledge Engineering. 70(1):21-34. doi:10.1016/j.datak.2010.07.012S213470

Dynamin-2 R465W mutation induces long range perturbation in highly ordered oligomeric structures

High order oligomers are crucial for normal cell physiology, and protein function perturbed by missense mutations underlies several autosomal dominant diseases. Dynamin-2 is one of such protein forming helical oligomers that catalyze membrane fission. Mutations in this protein, where R465W is the most frequent, cause dominant centronuclear myopathy, but the molecular mechanisms underpinning the functional modifications remain to be investigated. To unveil the structural impact of this mutation in dynamin-2, we used full-atom molecular dynamics simulations and coarse-grained models and built dimers and helices of wild-type (WT) monomers, mutant monomers, or both WT and mutant monomers combined. Our results show that the mutation R465W causes changes in the interactions with neighbor amino acids that propagate through the oligomer. These new interactions perturb the contact between monomers and favor an extended conformation of the bundle signaling element (BSE), a dynamin region that transmits the conformational changes from the GTPase domain to the rest of the protein. This extended configuration of the BSE that is only relevant in the helices illustrates how a small change in the microenvironment surrounding a single residue can propagate through the oligomer structures of dynamin explaining how dominance emerges in large protein complexes. © 2020, The Author(s).Indexación Scopushttps://www-nature-com.recursosbiblioteca.unab.cl/articles/s41598-020-75216-

Identifying clinical clusters with distinct trajectories in first-episode psychosis through an unsupervised machine learning technique

The extreme variability in symptom presentation reveals that individuals diagnosed with a first-episode psychosis (FEP) may encompass different sub-populations with potentially different illness courses and, hence, different treatment needs. Previous studies have shown that sociodemographic and family environment factors are associated with more unfavorable symptom trajectories. The aim of this study was to examine the dimensional structure of symptoms and to identify individuals’ trajectories at early stage of illness and potential risk factors associated with poor outcomes at follow-up in non-affective FEP. One hundred and forty-four non-affective FEP patients were assessed at baseline and at 2-year follow-up. A Principal component analysis has been conducted to identify dimensions, then an unsupervised machine learning technique (fuzzy clustering) was performed to identify clinical subgroups of patients. Six symptom factors were extracted (positive, negative, depressive, anxiety, disorganization and somatic/cognitive). Three distinct clinical clusters were determined at baseline: mild; negative and moderate; and positive and severe symptoms, and five at follow-up: minimal; mild; moderate; negative and depressive; and severe symptoms. Receiving a low-dose antipsychotic, having a more severe depressive symptomatology and a positive family history for psychiatric disorders were risk factors for poor recovery, whilst having a high cognitive reserve and better premorbid adjustment may confer a better prognosis. The current study provided a better understanding of the heterogeneous profile of FEP. Early identification of patients who could likely present poor outcomes may be an initial step for the development of targeted interventions to improve illness trajectories and preserve psychosocial functioning