Autogenous Control of 5'TOP mRNA Stability by 40S Ribosomes.

Ribosomal protein (RP) expression in higher eukaryotes is regulated translationally through the 5'TOP sequence. This mechanism evolved to more rapidly produce RPs on demand in different tissues. Here we show that 40S ribosomes, in a complex with the mRNA binding protein LARP1, selectively stabilize 5'TOP mRNAs, with disruption of this complex leading to induction of the impaired ribosome biogenesis checkpoint (IRBC) and p53 stabilization. The importance of this mechanism is underscored in 5q− syndrome, a macrocytic anemia caused by a large monoallelic deletion, which we found to also encompass the LARP1 gene. Critically, depletion of LARP1 alone in human adult CD34+ bone marrow precursor cells leads to a reduction in 5'TOP mRNAs and the induction of p53. These studies identify a 40S ribosome function independent of those in translation that, with LARP1, mediates the autogenous control of 5'TOP mRNA stability, whose disruption is implicated in the pathophysiology of 5q− syndrome.

Three double-dose reinforced hepatitis B revaccination scheme for patients with cirrhosis unresponsive to the standard regimen: an open-label randomised clinical trial.

OBJECTIVE: We aimed to compare the response rates between two different hepatitis B virus vaccination schedules for cirrhotic subjects who were non-responders to the first three 40 µg doses (month 0-1-2), and identify factors associated with the final response. DESIGN: A total of 120 cirrhotic patients (72.5% decompensated) were randomised at a 1:1 ratio to receive a single 40 µg booster vaccination at month 6 (classical arm) versus an additional round of three new 40 µg doses administered at monthly intervals (experimental arm). The main outcome was the rate of postvaccinal anti-hepatitis B surface antibodies levels ≥10 mIU/mL. RESULTS: Efficacy by ITT analysis was higher in the experimental arm (46.7%) than in the classical one (25%); OR 2.63, p=0.013. The experimental arm increased response rates compared with the classical one from 31% to 68% (OR 4.72; p=0.007), from 24.4% to 50% (OR 3.09; p=0.012) and from 24.4% to 53.8% (OR 3.62; p=0.007), in Child A, Model for End-Stage Liver Disease (MELD) <15 and MELD-Na<15 patients, respectively. Patients with more advanced liver disease did not benefit from the reinforced scheme. Both regimens showed similar safety profiles. Multivariable analysis showed that the experimental treatment was independently response associated when adjusted across three logistic regression models indicating equivalent cirrhosis severity. CONCLUSION: For cirrhotic patients, the revaccination of non-responders to the first three dose cycle, with three additional 40 µg doses, achieved significantly better response rates to those obtained with an isolated 40 µg booster dose. TRIAL REGISTRATION NUMBER: NCT01884415.

Body-weight support gait training in neurological intensive care: safety, feasibility, and delays before walking with or without suspension.

BACKGROUND: Early Mobilization in Intensive Care Units (ICUs) enhances patients' evolution, but has been rarely studied in neurological ICUs. The aim of this study was to assess gait training with body-weight support (BWS) in neuroICU, and to report on its safety, feasibility and on delays before walking with and without BWS. METHODS: This study was an observational one-year single-center study. Inclusion criteria were adults with a neurological injury requiring mechanical ventilation. Exclusion criteria were early death or ICU transfer. After weaning from ventilation, patients were screened for indications of BWS walking using predefined criteria. RESULTS: Patients' conditions were mostly brain injuries: 32% subarachnoid hemorrhages, 42% focal strokes, and 12% traumatic brain injuries. Out of 272 admissions, 136 patients were excluded, 78 were eligible, and 33 performed BWS walking. Among non-eligible patients, 36 walked unsuspended upon ventilation weaning, 17 presented too severe impairments. Among the 45 eligible patients who did not receive BWS training, main reasons were workload and weekends (31%), medical barriers (29%), and early ICU discharge (22%). 78 BWS sessions were performed on the 33 beneficiaries (median sessions per patient 2, max 10). Pre-session, most patients had inadequate response to pain, orders, or simple orientation questions. Sitting without support was impossible for 74%. Most pre-post changes in hemodynamic, respiratory, and pain parameters were small, and recovered spontaneously after the session. Eight sessions were interrupted; reasons were pain, fatigue or major imbalance (4), syncope (1), occurrence of stool (2), and battery failure (1). None of these adverse events required medical intervention, patients recovered upon session interruption. Median session duration was 31 min, patients walked on median 17 m. First BWS session occurred on median 3 days after ventilation weaning, and 11 days before patients were able to walk unsuspended. CONCLUSIONS: Verticalization and walking using a suspension device in patients in neuroICU allows early gait training, despite challenging neurological impairments. It is safe and generally well tolerated. TRIAL REGISTRATION: ClinicalTrials database (ID: NCT04300491).

Craniopagus parasiticus: successful separation of a 28-week preterm newborn from parasite sibling twin bearing lethal congenital anomalies associated to Cantrell's pentad and sirenomelia-case-based review of the literature.

PURPOSE: This paper reviews the plausible etiological mechanisms, clinical features, preoperative analysis, and documented modern-day craniopagus parasiticus surgical separation attempts as well as an historical review of the few cases documented in the literature. METHODS: We describe the successful separation of a 28-week preterm newborn from its parasite sibling twin bearing lethal congenital anomalies associated to Cantrell's pentad and sirenomelia. Description of the case, plausible explanations on the mechanisms of conjointment along with the associated congenital abnormalities of the deceased twin are examined along with an historical revision of craniopagus parasiticus and their separation attempts with special attention to the previously undocumented attempt of the Dominican CP separation surgery by Lazareff et al. RESULTS: The use of the deceased twin cranial vault tissues (skin, bone, and duramater) as an autologous implant due to the identical genetical profile served to remodel and close the skull of the surviving twin with good esthetic results and no tissue rejection. To our knowledge, this is the youngest preterm set of craniopagus parasiticus separated in an emergency fashion with good functional and esthetic outcome. CONCLUSIONS: Craniopagus parasiticus is an infrequent subvariant of this rare form of twin conjointment which may require urgent separation due to the associated malformations of the parasitic twin; therefore, the fact that both siblings are genetically identical may prove as an advantage to use duramater, bone, and soft tissues from the parasitic twin as ideal grafts for covering the resultant defect after the separation has been performed.

ICO amplicon NGS data analysis: a Web tool for variant detection in common high-risk hereditary cancer genes analyzed by amplicon GS Junior next-generation sequencing.

Next-generation sequencing (NGS) has revolutionized genomic research and is set to have a major impact on genetic diagnostics thanks to the advent of benchtop sequencers and flexible kits for targeted libraries. Among the main hurdles in NGS are the difficulty of performing bioinformatic analysis of the huge volume of data generated and the high number of false positive calls that could be obtained, depending on the NGS technology and the analysis pipeline. Here, we present the development of a free and user-friendly Web data analysis tool that detects and filters sequence variants, provides coverage information, and allows the user to customize some basic parameters. The tool has been developed to provide accurate genetic analysis of targeted sequencing of common high-risk hereditary cancer genes using amplicon libraries run in a GS Junior System. The Web resource is linked to our own mutation database, to assist in the clinical classification of identified variants. We believe that this tool will greatly facilitate the use of the NGS approach in routine laboratories.

Prediction of multi-target networks of neuroprotective compounds with entropy indices and synthesis, assay, and theoretical study of new asymmetric 1,2-rasagiline carbamates.

In a multi-target complex network, the links (L(ij)) represent the interactions between the drug (d(i)) and the target (t(j)), characterized by different experimental measures (K(i), K(m), IC50, etc.) obtained in pharmacological assays under diverse boundary conditions (c(j)). In this work, we handle Shannon entropy measures for developing a model encompassing a multi-target network of neuroprotective/neurotoxic compounds reported in the CHEMBL database. The model predicts correctly >8300 experimental outcomes with Accuracy, Specificity, and Sensitivity above 80%-90% on training and external validation series. Indeed, the model can calculate different outcomes for >30 experimental measures in >400 different experimental protocolsin relation with >150 molecular and cellular targets on 11 different organisms (including human). Hereafter, we reported by the first time the synthesis, characterization, and experimental assays of a new series of chiral 1,2-rasagiline carbamate derivatives not reported in previous works. The experimental tests included: (1) assay in absence of neurotoxic agents; (2) in the presence of glutamate; and (3) in the presence of H2O2. Lastly, we used the new Assessing Links with Moving Averages (ALMA)-entropy model to predict possible outcomes for the new compounds in a high number of pharmacological tests not carried out experimentally.

Synthetic Peptides Elicit Humoral Response against Porcine Reproductive and Respiratory Syndrome Virus in Swine.

The aim of this study was to analyze the immunogenic response elicited in swine by two synthetic peptides derived from GP5 to understand the role of lineal B epitopes in the humoral and B-cell-mediated response against the porcine reproductive and respiratory syndrome virus (PRRSV). For inoculation, twenty-one-day-old pigs were allocated into six groups: control, vehicle, vaccinated (Ingelvac-PRRSV, MLV®), non-vaccinated and naturally infected, GP5-B and GP5-B3. At 2 days post-immunization (dpi), the GP5-B3 peptide increased the serum concentrations of cytokines associated with activate adaptive cellular immunity, IL-1ß (1.15 ± 1.15 to 10.17 ± 0.94 pg/mL) and IL-12 (323.8 ± 23.3 to 778.5 ± 58.11 pg/mL), compared to the control group. The concentration of IgGs anti-GP5-B increased in both cases at 21 and 42 dpi compared to that at 0 days (128.3 ± 8.34 ng/mL to 231.9 ± 17.82 and 331 ± 14.86 ng/mL), while IgGs anti-GP5-B3 increased at 21 dpi (105.1 ± 19.06 to 178 ± 15.09 ng/mL) and remained at the same level until 42 dpi. Also, antibody-forming/Plasma B cells (CD2+/CD21-) increased in both cases (9.85 ± 0.7% to 13.67 ± 0.44 for GP5-B and 15.72 ± 1.27% for GP5-B3). Furthermore, primed B cells (CD2-/CD21+) from immunized pigs showed an increase in both cases (9.62 ± 1.5% to 24.51 ± 1.3 for GP5-B and 34 ± 2.39% for GP5-B3) at 42 dpi. Conversely the naïve B cells from immunized pigs decreased compared with the control group (8.84 ± 0.63% to 6.25 ± 0.66 for GP5-B and 5.78 ± 0.48% for GP5-B3). Importantly, both GP5-B and GP5-B3 peptides exhibited immunoreactivity against serum antibodies from the vaccinated group, as well as the non-vaccinated and naturally infected group. In conclusion, GP5-B and GP5-B3 peptides elicited immunogenicity mediated by antigen-specific IgGs and B cell activation.

An observational study investigating soluble immune checkpoints as indicators of severe COVID-19.

This study aimed to investigate the immunomodulatory behavior of soluble immune checkpoints (sICPs) and other biomarkers in the pathophysiology of SARS-CoV-2 infection. The study included 59 adult participants, 43 of whom tested positive for SARS-CoV-2. Patients were divided into three cohorts: those with moderate disease (n = 16), recovered patients with severe disease (n = 13), and deceased patients with severe disease (n = 16). In addition, 16 participants were pre-pandemic subjects negative for SARS-CoV-2. The relative activity of neutralizing antibodies (rNAbs) against SARS-CoV-2 and the values of 14 sICPs in peripheral blood were compared between the four groups. Because the increase of markers values of inflammation [NLR > 12; CRP > 150 mg/L] and venous thromboembolism [D-dimer > 0.5 mg/L] has been associated with mortality from COVID-19, the total and differential leukocyte counts, the NLR, and CRP and D-dimer values were obtained in patients with severe disease. No differences in rNAbs were observed between the cohorts. Only the levels of five sICPs, sCD27, sHVEM sTIM-3, sPD-1, and sPDL-1, were significantly higher in patients with severe rather than moderate disease. The sPDL-2 level and NLR were higher in deceased patients than in recovered patients. However, there was no difference in CRP and D-dimer values between the two groups. Of the five soluble biomarkers compared among patients with severe disease, only sPDL-2 was higher in deceased patients than in recovered patients. This suggests that immuno-inhibitory sICPs might be used as indicators for severe COVID-19, with sPDL-2 used to assess individual risk for fatality.IMPORTANCECOVID-19, the disease caused by a SARS-CoV-2 infection, generates a broad spectrum of clinical symptoms, progressing to multiorgan failure in the most severe cases. As activation of the immune system is pivotal to eradicating the virus, future research should focus on identifying reliable biomarkers to efficiently predict the outcome in severe COVID-19 cases. Soluble immune checkpoints represent the function of the immune system and are easily determined in peripheral blood. This research could lead to implementing more effective severity biomarkers for COVID-19, which could increase patients' survival rate and quality of life.

Synthesis of biocompatible hydrogel of alginate-chitosan enriched with iron sulfide nanocrystals.

This work aimed to synthesize and characterize a biocompatible hydrogel of alginate and chitosan enriched with iron sulfide nanocrystals. Three concentrations of iron sulfide nanocrystals (FeS2NCs) 0.03905, 0.0781, and 0.2343 mg/ml were used. Gel swelling was determined using phosphate-buffered saline solution at 1, 2, 4, 6, 24, 48, and 72 h. The microstructure, the morphology, and the elastic strength were determined by optical microscopy, scanning electron microscopy, and rheological studies, respectively. The functional groups were identified through Fourier Transform Infrared spectroscopy. Biocompatibility was determined in a murine model; after seven days of subdermal inoculation, histological sections stained with H&E were analyzed, and then histopathological features were evaluated. All the compounds obtained showed a loss modulus lower than the storage modulus. The 0.2343 mg/ml FeS2NCs hydrogel showed higher swelling than the control. In the in vivo evaluation, no adverse effects were found. The presence of FeS2NCs was well tolerated in the subcutaneous tissue of mice, according to histopathological analysis. The hydrogels synthesized with added FeS2NCs demonstrate a swelling ratio of 150 %, rheologically exhibiting gel-like behavior rather than viscous liquids. Furthermore, they did not present any adverse effects on the subcutaneous tissue.

TOPS-MODE model of multiplexing neuroprotective effects of drugs and experimental-theoretic study of new 1,3-rasagiline derivatives potentially useful in neurodegenerative diseases.

The interest on computational techniques for the discovery of neuroprotective drugs has increased due to recent fail of important clinical trials. In fact, there is a huge amount of data accumulated in public databases like CHEMBL with respect to structurally heterogeneous series of drugs, multiple assays, drug targets, and model organisms. However, there are no reports of multi-target or multiplexing Quantitative Structure-Property Relationships (mt-QSAR/mx-QSAR) models of these multiplexing assay outcomes reported in CHEMBL for neurotoxicity/neuroprotective effects of drugs. Accordingly, in this paper we develop the first mx-QSAR model for multiplexing assays of neurotoxicity/neuroprotective effects of drugs. We used the method TOPS-MODE to calculate the structural parameters of drugs. The best model found correctly classified 4393 out of 4915 total cases in both training and validation. This is representative of overall train and validation Accuracy, Sensitivity, and Specificity values near to 90%, 98%, and 80%, respectively. This dataset includes multiplexing assay endpoints of 2217 compounds. Every one compound was assayed in at least one out of 338 assays, which involved 148 molecular or cellular targets and 35 standard type measures in 11 model organisms (including human). The second aim of this work is the exemplification of the use of the new mx-QSAR model with a practical case of study. To this end, we obtained again by organic synthesis and reported, by the first time, experimental assays of the new 1,3-rasagiline derivatives 3 different tests: assay (1) in absence of neurotoxic agents, (2) in the presence of glutamate, and (3) in the presence of H2O2. The higher neuroprotective effects found for each one of these assays were for the stereoisomers of compound 7: compound 7b with protection=23.4% in assay (1) and protection=15.2% in assay (2); and for compound 7a with protection=46.2% in assay (3). Interestingly, almost all compounds show protection values >10% in assay (3) but not in the other 2 assays. After that, we used the mx-QSAR model to predict the more probable response of the new compounds in 559 unique pharmacological tests not carried out experimentally. The results obtained are very significant because they complement the pharmacological studies of these promising rasagiline derivatives. This work paves the way for further developments in the multi-target/multiplexing screening of large libraries of compounds potentially useful in the treatment of neurodegenerative diseases.

Gender identity in informal care: impact on health in Spanish caregivers.

We examined the influence of gender identity on men's and women's perceptions of assuming the caregiver role to identify different coping strategies and the effects on caregiver health and quality of life. The study, performed in Andalusia, Spain, was based on a sociological analysis of the narratives produced during semistructured interviews with primary informal caregivers (16 men and 16 women) of different profiles. We observed a cultural assumption that women should assume the caregiver role and found that women shouldered the bulk of caregiving responsibilities and did not usually seek support. This might explain the high prevalence of chronic health disorders, stress, anxiety, depression, neglect of health, and social isolation we observed among women caregivers. Because the caregiver role was not socially imposed on men in our setting, men caregivers adopted a flexible attitude and tended to seek external support before their health and quality of life were seriously affected.

Guiding the retraining of convolutional neural networks against adversarial inputs.

Background: When using deep learning models, one of the most critical vulnerabilities is their exposure to adversarial inputs, which can cause wrong decisions (e.g., incorrect classification of an image) with minor perturbations. To address this vulnerability, it becomes necessary to retrain the affected model against adversarial inputs as part of the software testing process. In order to make this process energy efficient, data scientists need support on which are the best guidance metrics for reducing the adversarial inputs to create and use during testing, as well as optimal dataset configurations. Aim: We examined six guidance metrics for retraining deep learning models, specifically with convolutional neural network architecture, and three retraining configurations. Our goal is to improve the convolutional neural networks against the attack of adversarial inputs with regard to the accuracy, resource utilization and execution time from the point of view of a data scientist in the context of image classification. Method: We conducted an empirical study using five datasets for image classification. We explore: (a) the accuracy, resource utilization, and execution time of retraining convolutional neural networks with the guidance of six different guidance metrics (neuron coverage, likelihood-based surprise adequacy, distance-based surprise adequacy, DeepGini, softmax entropy and random), (b) the accuracy and resource utilization of retraining convolutional neural networks with three different configurations (one-step adversarial retraining, adversarial retraining and adversarial fine-tuning). Results: We reveal that adversarial retraining from original model weights, and by ordering with uncertainty metrics, gives the best model w.r.t. accuracy, resource utilization, and execution time. Conclusions: Although more studies are necessary, we recommend data scientists use the above configuration and metrics to deal with the vulnerability to adversarial inputs of deep learning models, as they can improve their models against adversarial inputs without using many inputs and without creating numerous adversarial inputs. We also show that dataset size has an important impact on the results.

Identification of intergenerational epigenetic inheritance by whole genome DNA methylation analysis in trios.

Genome-wide association studies have identified thousands of loci associated with common diseases and traits. However, a large fraction of heritability remains unexplained. Epigenetic modifications, such as the observed in DNA methylation have been proposed as a mechanism of intergenerational inheritance. To investigate the potential contribution of DNA methylation to the missing heritability, we analysed the methylomes of four healthy trios (two parents and one offspring) using whole genome bisulphite sequencing. Of the 1.5 million CpGs (19%) with over 20% variability between parents in at least one family and compatible with a Mendelian inheritance pattern, only 3488 CpGs (0.2%) lacked correlation with any SNP in the genome, marking them as potential sites for intergenerational epigenetic inheritance. These markers were distributed genome-wide, with some preference to be located in promoters. They displayed a bimodal distribution, being either fully methylated or unmethylated, and were often found at the boundaries of genomic regions with high/low GC content. This analysis provides a starting point for future investigations into the missing heritability of simple and complex traits.

Response of lymphocytes from pigs naturally infected with porcine respiratory disease complex at 3 different stages of development.

The objective of this study was to analyze the response of lymphocytes from pigs naturally infected with porcine respiratory disease complex (PRDC) at 3 different stages of development. Porcine respiratory disease complexes were isolated from 2 groups: The infected group, consisting of pigs with PRDC and no vaccination against any virus (n = 24), and the control group, consisting of vaccinated and noninfected piglets (n = 24). Both groups were sampled at 3 stages of development: Weaning (WEA) (n = 8), initiation (INI) (n = 8), and growth (GRO) (n = 8). The PRDC status was confirmed by serological testing against porcine circovirus type 2 (PCV-2), porcine reproductive and respiratory syndrome virus (PRRSV), swine influenza virus (H1N1), and Mycoplasma hyopneumoniae. PCV-2+ cells were quantified by flow cytometry. Weight gain was registered at each stage. PCV-2+ cells, CD4+ cells, monocytes and lymphocytes populations were measured. Gene expression in CD4+ cells was quantified for interferon-γ (IFN-γ), GATA binding protein 3 (GATA3), T-box transcription factor (T-bet), interleukin-10 (IL-10), and IL-4. Control piglets gained approximately 35% more weight than those infected with PRDC. Specifically, PCV-2+ cells were detected in piglets from the infected group in the following proportions: WEA ≤ INI ≤ GRO. In infected piglets, the CD4+ count increased at WEA and decreased at GRO, CD4+ expression profile showed an overexpression of T-bet at INI and GRO, and the expression of IFN-γ was lower at WEA and GRO. In contrast, IL-4 was overexpressed at all 3 stages. GATA3 was overexpressed at INI and GRO. The infected piglets showed lymphopenia and less CD4+ cells. CD4+ cells showed a different expression profile than the control group, in which IFN-γ was less expressed, whereas IL-4 and T-bet were overexpressed.

L'objectif de cette étude était d'analyser la réponse des lymphocytes de porcs naturellement infectés par le complexe respiratoire porcin (PRDC) à trois stades de développement différents. Des PRDC ont été isolés à partir de deux groupes : le groupe infecté, composé de porcs atteints de PRDC et non vaccinés contre un virus (n = 24), et le groupe témoin, composé de porcelets vaccinés et non infectés (n = 24). Les deux groupes ont été échantillonnés à trois stades de développement : sevrage (WEA) (n = 8), initiation (INI) (n = 8) et croissance (GRO) (n = 8). Le statut de PRDC a été confirmé par des tests sérologiques contre le circovirus porcin de type 2 (PCV-2), le virus du syndrome reproducteur et respiratoire porcin (PRRSV), le virus de la grippe porcine (H1N1) et Mycoplasma hyopneumoniae. Les cellules PCV-2+ ont été quantifiées par cytométrie en flux. Un gain de poids a été enregistré à chaque étape. Les populations de cellules PCV-2+, de cellules CD4+, de monocytes et de lymphocytes ont été mesurées. L'expression génique dans les cellules CD4+ a été quantifiée pour l'interféron-γ (IFN-γ), la protéine de liaison GATA 3 (GATA3), le facteur de transcription T-box (T-bet), l'interleukine-10 (IL-10) et l'IL-4. Les porcelets témoins ont pris environ 35 % de poids en plus que ceux infectés par le PRDC. Plus précisément, des cellules PCV-2+ ont été détectées chez les porcelets du groupe infecté dans les proportions suivantes : WEA ≤ INI ≤ GRO. Chez les porcelets infectés, le nombre de CD4+ a augmenté à WEA et diminué à GRO, le profil d'expression de CD4+ a montré une surexpression de T-bet à INI et GRO, et l'expression d'IFN-γ était plus faible à WEA et GRO. En revanche, l'IL-4 était surexprimée aux trois stades. GATA3 était surexprimé à INI et GRO. Les porcelets infectés présentaient une lymphopénie et moins de cellules CD4+. Les cellules CD4+ ont montré un profil d'expression différent de celui du groupe témoin, dans lequel l'IFN-γ était moins exprimé, tandis que l'IL-4 et le T-bet étaient surexprimés.(Traduit par Docteur Serge Messier).

Glycoprotein 5-Derived Peptides Induce a Protective T-Cell Response in Swine against the Porcine Reproductive and Respiratory Syndrome Virus.

We analyzed the T-cell responses induced by lineal epitopes of glycoprotein 5 (GP5) from PRRSV to explore the role of this protein in the immunological protection mediated by T-cells. The GP5 peptides were conjugated with a carrier protein for primary immunization and booster doses. Twenty-one-day-old pigs were allocated into four groups (seven pigs per group): control (PBS), vehicle (carrier), PTC1, and PTC2. Cytokine levels were measured at 2 days post-immunization (DPI) from serum samples. Cytotoxic T-lymphocytes (CTLs, CD8+) from peripheral blood were quantified via flow cytometry at 42 DPI. The cytotoxicity was evaluated by co-culturing primed lymphocytes with PRRSV derived from an infectious clone. The PTC2 peptide increased the serum concentrations of pro-inflammatory cytokines (i.e., TNF-α, IL-1ß, IL-8) and cytokines that activate the adaptive cellular immunity associated with T-lymphocytes (i.e., IL-4, IL-6, IL-10, and IL-12). The concentration of CTLs (CD8+) was significantly higher in groups immunized with the peptides, which suggests a proliferative response in this cell population. Primed CTLs from immunized pigs showed cytolytic activity in PRRSV-infected cells in vitro. PTC1 and PTC2 peptides induced a protective T-cell-mediated response in pigs immunized against PRRSV, due to the presence of T epitopes in their sequences.

Abdominal obesity and myocardial infarction risk - We demonstrate the anthropometric and mathematical reasons that justify the association bias of the waist-to-hip ratio.

INTRODUCTION: Antecedentes: el índice cintura-cadera (ICC) se utiliza ampliamente para evaluar la asociación de la obesidad abdominal con el infarto de miocardio (IM). Objetivo: nuestro propósito era determinar si el riesgo asociado a la ICC produce sesgo. Métodos: estudio de casos y controles en 252 varones. Usamos la estratificación como criterio para eliminar los efectos del sesgo. Creamos una covariable basal (ICC0,95-0,99) para una nueva muestra emparejada en el estrato de valores entre 0,95 y 0,99. Este estrato coincide con el área común de solapamiento de la distribución de puntos, donde todos los sujetos tienen un índice de propensión similar. Consideramos otra covariable (ICCS) condicionada en ICC < 1 y una circunferencia de cintura (CC) donde la asignación de riesgo fuera espúrea. Hipotetizamos que restando CC del valor de la cadera se calculaba otra variable aritmética (DCC) que podría ser esencial para evidenciar el efecto de confusion que genera el ICC. Resultados: IMC: ABC: 0,694, IC 95 % (0,628-0,760); OR: 3,8. CC: ABC: 0,743, IC 95 % (0,681-0,805); OR: 5,7. ICC: ABC: 0,798, IC 95 % (0,740-0,855); OR: 8,6. Índice cintura-talla (ICT): ABC: 0,782, IC 95 % (0,724-0,840); OR: 8,5. DCC: ABC: 0,204, IC 95 % (0,146-0,261); OR: 0,36. Prevalencia en los casos: ICC ≥ 0,95 (84,1 % vs. 38 %; OR: 8,6); ICC < 1 (36,3 % vs. 85,7 %; OR: 2,3); ICC ≥ 1 (63,4 % vs. 14,2 %; OR: 4,4); CC ≥ 94,4 (71,4 % vs. 30,1 %; OR: 5,7); DCC ≥ 2,2 (27,7 % vs. 75,3 %; OR: 7,9); ICCs (50 % vs. 25 %; OR: 2). Conclusiones: el ICC produce un sesgo de asociación en los casos de IM. Ello puede extrapolarse a otras poblaciones de estudio. El sesgo se explica por un error de concepto matemático que sobreestima el efecto protector de la cadera con respecto a la CC y la altura. El riesgo asociado al ICC por encima del de la CC o el ICT presenta inconsistencia antropométrica y sesgo, llegando a ser epidemiológicamente falso.

INTRODUCCIÓN: Background: the waist-to-hip ratio (WHR) is widely used to evaluate the association of abdominal obesity with myocardial infarction (MI). Objective: our aim was to determine whether WHR-associated risk provides a bias. Methods: a case-control study in 252 men. Stratification was used as an approach for removing bias effects. We created a baseline covariate (WHR0.95-0.99) from a new matched sample in the stratum between 0.95 and 0.99. This stratum coincides with the overlap area of the distribution, where all subjects have a similar propensity score. We considered other covariate (WHRS), conditioned on WHR < 1 and waist circumference (WC) being assigned a spurious risk. We hypothesized that subtracting hip circumference from WC (WHD) can be essential to observe the confounding effect provided by WHR. Results: BMI: AUC: 0.694, 95 % CI (0.628-0.760); OR: 3.8. WC: AUC: 0.743, 95 % CI (0.681-0.805); OR: 5.7. WHR: AUC: 0.798, 95 % CI (0.740-0.855); OR: 8.6. Waist-height ratio (WHtR): AUC: 0.782, 95 % CI (0.724-0.840); OR: 8.5. WHD: AUC: 0.204, 95 % CI (0.146-0.261); OR: 0.36. Prevalence in cases: WHR ≥ 0.95 (84.1 % vs. 38 %; OR: 8.6); WHR < 1 (36.3 % vs. 85.7 %; OR: 2.3); WHR ≥ 1 (63.4 % vs. 14.2 %; OR: 4.4); WC ≥ 94.4 (71.4 % vs. 30.1 %; OR: 5.7); WHD ≥ 2.2 (27.7 % vs. 75.3 %; OR: 7.9); WHRs (50 % vs. 25 %; OR: 2). Conclusions: WHR provides an association bias in MI cases. This can be extrapolated to other study populations. The bias is explained by a mathematical misconception where the protective effect of HC is overestimated concerning WC and height. The risk associated with WHR as higher than that associated with WC and WHtR entails anthropometric inconsistency and bias, to the extent of becoming epidemiologically false.

Comparison of clinical characteristics of Zika and dengue symptomatic infections and other acute illnesses of unidentified origin in Mexico.

BACKGROUND: Our purpose was to provide a detailed clinical description, of symptoms and laboratory abnormalities, and temporality in patients with confirmed Zika and dengue infections, and other acute illnesses of unidentified origin (AIUO). METHODS/ PRINCIPAL FINDINGS: This was a two-year, multicenter, observational, prospective, cohort study. We collected data from patients meeting the Pan American Health Organization's modified case-definition criteria for probable Zika infection. We identified Zika, dengue chikungunya by RT-PCR in serum and urine. We compared characteristics between patients with confirmed Zika and dengue infections, Zika and AIUO, and Dengue and AIUO at baseline, Days 3,7,28 and 180 of follow-up. Most episodes (67%) consistent with the PAHO definition of probable Zika could not be confirmed as due to any flavivirus and classified as Acute Illnesses of Unidentified Origin (AIUO). Infections by Zika and dengue accounted for 8.4% and 16% of episodes. Dengue patients presented with fever, generalized non-macular rash, arthralgia, and petechiae more frequently than patients with Zika during the first 10 days of symptoms. Dengue patients presented with more laboratory abnormalities (lower neutrophils, lymphocytosis, thrombocytopenia and abnormal liver function tests), with thrombocytopenia lasting for 28 days. Zika patients had conjunctivitis, photophobia and localized macular rash more frequently than others. Few differences persisted longer than 10 days after symptoms initiation: conjunctivitis in Zika infections, and self-reported rash and petechia in dengue infections. CONCLUSIONS: Our study helps characterize the variety and duration of clinical features in patients with Zika, dengue and AIUO. The lack of diagnosis in most patients points to need for better diagnostics to assist clinicians in making specific etiologic diagnoses.

Toxicity and antimicrobial effect of silver nanoparticles in swine sperms.

Bacterial contamination in swine semen affects the quality and longevity of sperm and consequently fertility is reduced. Antibiotics have been used to prevent bacterial growth, but the frequency of bacterial resistance to various antibiotics are increasing. Silver nanoparticles (AgNPs) of 10-20 nm in size have shown a biocide effect in bacteria and fungi microorganisms without toxicity to certain mammalian cells. The goal of this study was to analyze both, antimicrobial activity against Staphylococcus aureus and toxicity in swine sperms after 10-20 nm AgNPs treatment. S. aureus proliferation decreased when concentrations from 0.4 to 10 mM AgNPs were assayed. Also, sperm viability measured by mitochondrial metabolism after AgNPs treatment up to a concentration of 10 mM, was viable. In addition, viability determined by membrane integrity of sperms showed that AgNPs treatment up to a concentration of 10 mM was safe. Sperm morphology was evaluated by automated quantification of proximal and distal drops and whiptails. Data indicated that AgNPs treatment up to a concentration of 4 mM were harmless. Finally, sperm capacitation and acrosome reactions were determined by (chlortetracycline) CTC assay. Data showed that no changes in sperm capacitation were observed when sperms were treated with 2 mM of AgNPs, but data showed increased calcium mobilization when treated with 10 mM AgNPs, which suggested sperm capacitation. Finally, there were no significant changes encountered on sperm acrosome reaction for any of the treatments after AgNPs treatment. Taken together, these results show the potential of AgNPs as an alternative to conventional antimicrobial agents that are currently used in extenders to preserve semen required for storage. ABBREVIATIONS: AgNPs: silver nanoparticles; AMK: amikacin; AMP: adenosine monophosphate; AR: acrosome reaction; C: capacitation; CF: cefallotin; CFU: colony-forming unit; CTC: chlortetracycline; CXM: cefuroxime; DMSO: dimethyl sulfoxide; NC: non-capacitation; NOM: Norma Oficial Mexicana; PBS: phosphate buffered saline; RLUs: relative light units; ROS: reactive oxygen species; SQS: Seminal Quality System.

Oncogenic MYC Induces the Impaired Ribosome Biogenesis Checkpoint and Stabilizes p53 Independent of Increased Ribosome Content.

The role of MYC in regulating p53 stability as a function of increased ribosome biogenesis is controversial. On the one hand, it was suggested that MYC drives the overexpression of ribosomal proteins (RP)L5 and RPL11, which bind and inhibit HDM2, stabilizing p53. On the other, it has been proposed that increased ribosome biogenesis leads the consumption of RPL5/RPL11 into nascent ribosomes, reducing p53 levels and enhancing tumorigenesis. Here, we show that the components that make up the recently described impaired ribosome biogenesis checkpoint (IRBC) complex, RPL5, RPL11, and 5S rRNA, are reduced following MYC silencing. This leads to a rapid reduction in p53 protein half-life in an HDM2-dependent manner. In contrast, MYC induction leads to increased ribosome biogenesis and p53 protein stabilization. Unexpectedly, there is no change in free RPL5/RPL11 levels, but there is a striking increase in IRBC complex bound to HDM2. Our data support a cell-intrinsic tumor-suppressor response to MYC expression, which is presently being exploited to treat cancer. SIGNIFICANCE: Oncogenic MYC induces the impaired ribosome biogenesis checkpoint, which could be potentially targeted for cancer treatment.

Obesity and risk of myocardial infarction in a sample of European males. Waist to-hip-ratio presents information bias of the real risk of abdominal obesity / Obesidad y riesgo de infarto de miocardio en una muestra de varones europeos. El índice cintura-cadera sesga el riesgo real de la obesidad abdominal

Background: Obesity is a coronary risk factor associated to myocardial infarction although waist to-hip-ratio has shown higher predictive power. Objective: The aim of this study was a Receiver Operating Characteristic anthropometric analysis in infarcted males to identify the strength of association for simple measurements, obesity and indicators such as, waist to-hip-ratios, waist to-height-ratios and conicity index. Methods:Case-control study of myocardial infarction in European males. One hundred and twelve cases and 112 controls aged 30-74 years were enrolled. We measured weight, height, waist circumference, umbilical waist circumference and hip circumference. We calculated various anthropometric indicators. We obtained the areas under the ROC curves, the odds ratio and correlations for measurements and anthropometric indicators. Results: Body mass index [AUC: 0.686, 95% CI (0.616-0.755); OR: 3.3], waist circumference [AUC: 0.734, 95% CI (0.668-0.800); OR: 5.7], height [AUC: 0.623, 95% CI (0.550-0.696); OR: 2.3], hip circumference [AUC: 0.555, 95% CI (0.479-0.631); OR: 1], waist to-hip-ratio [AUC: 0.796, 95% CI (0.737-0.855); OR: 9.9], umbilical waist to-hip-ratio [AUC: 0.830, 95% CI (0.729-0.847); OR: 5.5], umbilical waist to-height-ratio [AUC: 0.788, 95% CI (0.729-0.847); OR: 7.5], conicity index [AUC: 0.795; 95% CI (0.738-0.853); OR: 9]. The correlations for waist to-height-ratios and conicity index were strong (all r ≥ 0.85; p < 0.001). Conclusions: Waist and height are measurements of associated independent risk. Hip circumference does no show discriminatory power. Obesity and waist-ratios are associated to myocardial infarction with different strength. Between other indicators, general obesity is more weakly associated. Waist to-hip-ratios present the best ROC curves but it occur information bias of their predictive power of risk. Umbilical waist to-height-ratio and conicity index present high discriminatory power and the best anthropometric risk correlations that support its use for the identification of obesity as risk factor associated to myocardial infarction and in all strategies for coronary health promotion.

Introducción: la obesidad es un factor de riesgo asociado al infarto de miocardio aunque el índice cintura-cadera ha mostrado mayor poder predictivo. Objetivo: análisis antropométrico Receiver Operating Characteristic (ROC) en infartados para identificar la fuerza discriminatoria de mediciones, obesidad, ratios cintura-cadera, ratios cintura-talla e índice de conicidad. Métodos: estudio caso-control de infarto miocárdico en varones europeos. Ciento doce casos/112 controles de 30-74 años fueron reclutados. Se midieron: peso, talla, cintura, cintura umbilical y cadera. Se obtuvieron las áreas bajo la curva (ABC), las odds ratio y correlaciones de medidas e indicadores. Resultados: IMC [ABC: 0,686 (0,616-0,755); OR: 3,3], cintura [ABC: 0,734 (0,668-0,800); OR: 5,7], talla [ABC: 0,623 (0,550-0,696); OR: 2,3], cadera [ABC: 0,555 (0,479-0,631); OR: 1], cintura-cadera [ABC: 0,796 (0,737-0,855); OR: 9,9]; cintura umbilical-cadera [ABC:0,830 (0,775-0,885); OR: 5,5], cintura umbilical-talla [ABC: 0,788 (0,729-0,847); OR: 7,5]; conicidad [ABC: 0,795 (0,738-0,853); OR:9]. Cintura-talla y conicidad presentaron altas correlaciones de riesgo (todas r ≥ 0,85; p < 0,001). Conclusiones: cintura y talla son medidas con riesgo independiente asociado. La circunferencia de cadera no es discriminatoria. Obesidad e índices de cintura están asociados al infarto con diferente fuerza. La obesidad presenta una asociación débil. Los índices cintura-cadera presentan las mejores curvas ROC, pero sesgadas en su poder predictivo de riesgo. Cintura umbilical-talla y conicidad presentan alto poder discriminatorio y mejores correlaciones antropométricas de riesgo, por lo que se recomienda su uso en la identificación de la obesidad como factor asociado al infarto de miocardio y en todas las estrategias de promoción de la salud coronaria.