In silico/in vivo insights into the functional and evolutionary pathway of Pseudomonas aeruginosa oleate-diol synthase. Discovery of a new bacterial di-heme cytochrome C peroxidase subfamily

As previously reported, P. aeruginosa genes PA2077 and PA2078 code for 10S-DOX (10S-Dioxygenase) and 7,10-DS (7,10-Diol Synthase) enzymes involved in long-chain fatty acid oxygenation through the recently described oleate-diol synthase pathway. Analysis of the amino acid sequence of both enzymes revealed the presence of two heme-binding motifs (CXXCH) on each protein. Phylogenetic analysis showed the relation of both proteins to bacterial di-heme cytochrome c peroxidases (Ccps), similar to Xanthomonas sp. 35Y rubber oxidase RoxA. Structural homology modelling of PA2077 and PA2078 was achieved using RoxA (pdb 4b2n) as a template. From the 3D model obtained, presence of significant amino acid variations in the predicted heme-environment was found. Moreover, the presence of palindromic repeats located in enzyme-coding regions, acting as protein evolution elements, is reported here for the first time in P. aeruginosa genome. These observations and the constructed phylogenetic tree of the two proteins, allow the proposal of an evolutionary pathway for P. aeruginosa oleate-diol synthase operon. Taking together the in silico and in vivo results obtained we conclude that enzymes PA2077 and PA2078 are the first described members of a new subfamily of bacterial peroxidases, designated as Fatty acid-di-heme Cytochrome c peroxidases (FadCcp)

Innovación en políticas públicas en Inmigración del municipio de Amecameca

Innovation in public policies for immigrants is a trend around the world; governments are working to ensure that immigrants' rights are protected, so that they can access essential public services. Municipalities in each state play an important role in the implementation of public policies for immigrants, as they are closer to local communities and can better understand the specific needs of immigrants. Therefore, the objective of the research is to analyze the public policies and programs implemented by the municipal government to protect the rights of immigrants and promote their social and economic inclusion in the municipality. The results obtained in the research indicate that it is necessary to contribute even more in the generation of new public policies for immigrants in the municipality of Amecameca, because these are not enough, since the protection of their rights and their social and economic inclusion are left aside.La innovación en políticas públicas para inmigrantes es una tendencia en todo el mundo; los gobiernos están trabajando para garantizar que los derechos de los inmigrantes sean protegidos, y así estos puedan acceder a servicios públicos esenciales. Los municipios de cada estado desempeñan un papel importante en la implementación de políticas públicas para inmigrantes, pues están más cerca de las comunidades locales y pueden conocer mejor las necesidades específicas de los inmigrantes. Por ello, el objetivo de la investigación es analizar las políticas públicas y programas implementados por el gobierno municipal para proteger los derechos de los inmigrantes y promover su inclusión social y económica en el municipio. Los resultados obtenidos en la investigación indican que se requiere contribuir aún más en la generación de nuevas políticas públicas para inmigrantes en el municipio de Amecameca, debido a que estas no son suficientes, pues se deja de lado la protección de sus derechos y su inclusión social y económica

Deciphering the Molecular Basis of Melatonin Protective E ects on Breast Cells Treated with Doxorubicin: TWIST1 a Transcription Factor Involved in EMT and Metastasis, a Novel Target of Melatonin

Melatonin mitigates cancer initiation, progression and metastasis through inhibition of both the synthesis of estrogens and the transcriptional activity of the estradiol-ER (Estrogen receptor) complex in the estrogen-dependent breast cancer cell line MCF-7. Moreover, melatonin improves the sensitivity of MCF-7 to chemotherapeutic agents and protects against their side e ects. It has been described that melatonin potentiates the anti-proliferative e ects of doxorubicin; however, the molecular changes involving gene expression and the activation/inhibition of intracellular signaling pathways remain largely unknown. Here we found that melatonin enhanced the anti-proliferative e ect of doxorubicin in MCF-7 but not in MDA-MB-231 cells. Strikingly, doxorubicin treatment induced cell migration and invasion, and melatonin e ectively counteracted these e ects in MCF-7 but not in estrogen-independent MDA-MB-231 cells. Importantly, we describe for the first time the ability of melatonin to downregulate TWIST1 (Twist-related protein 1) in estrogen-dependent but not in estrogen-independent breast cancer cells. Combined with doxorubicin, melatonin inhibited the activation of p70S6K and modulated the expression of breast cancer, angiogenesis and clock genes. Moreover, melatonin regulates the levels of TWIST1-related microRNAs, such as miR-10a, miR-10b and miR-34a. Since TWIST1 plays a pivotal role in the epithelial to mesenchymal transition, acquisition of metastatic phenotype and angiogenesis, our results suggest that inhibition of TWIST1 by melatonin might be a crucial mechanism of overcoming resistance and improving the oncostatic potential of doxorubicin in estrogen-dependent breast cancer cells.Funding: The present study was funded by grants from the Spanish Economy and Competitiveness Ministry (SAF2016-77103-P) and from Instituto de Investigación Sanitaria Valdecilla (NVAL 16/01)

Association of smoking with amyotrophic lateral sclerosis risk and survival in men and women: a prospective study

<p>Abstract</p> <p>Background</p> <p>Previous epidemiologic studies have examined the association of smoking with amyotrophic lateral sclerosis (ALS) incidence, but their results have been inconsistent. Moreover, limited information exists on the association between smoking and survival in ALS patients. We evaluated the association of smoking with ALS incidence and survival in a population-based cohort.</p> <p>Methods</p> <p>We conducted a case-control study nested in the General Practice Research Database, a computerized clinical database in the United Kingdom. Cases were 1143 individuals with a diagnosis of ALS; 11,371 matched controls were selected among GPRD participants free of ALS. Predictors of survival were determined in the ALS cases. Smoking information was obtained from the computer database.</p> <p>Results</p> <p>Smoking was not associated with the risk of ALS in this population. The rate ratio (RR) of ALS comparing ever versus never smokers was 1.04, 95% confidence interval (CI) 0.80-1.34. In analysis stratified by gender, however, ever smoking was associated with ALS in women (RR 1.53, 95% CI 1.04-2.23) but not in men (RR 0.75, 95% CI 0.53-1.06). Mortality was 71% after 2.1 average years of follow-up. Old age and female sex were associated with lower survival. Smoking was a predictor of mortality only in women. Comparing ever versus never smokers, RR (95% CI) of death was 1.31 (1.04-1.65) in women, and 0.90 (0.72-1.11) in men.</p> <p>Conclusion</p> <p>In this large population-based study, smoking was associated with ALS risk and worse survival in women but not in men.</p

Theory and phenomenology of two-Higgs-doublet models

We discuss theoretical and phenomenological aspects of two-Higgs-doublet extensions of the Standard Model. In general, these extensions have scalar mediated flavour changing neutral currents which are strongly constrained by experiment. Various strategies are discussed to control these flavour changing scalar currents and their phenomenological consequences are analysed. In particular, scenarios with natural flavour conservation are investigated, including the so-called type I and type II models as well as lepton-specific and inert models. Type III models are then discussed, where scalar flavour changing neutral currents are present at tree level, but are suppressed by either specific ansatze for the Yukawa couplings or by the introduction of family symmetries. We also consider the phenomenology of charged scalars in these models. Next we turn to the role of symmetries in the scalar sector. We discuss the six symmetry-constrained scalar potentials and their extension into the fermion sector. The vacuum structure of the scalar potential is analysed, including a study of the vacuum stability conditions on the potential and its renormalization-group improvement. The stability of the tree level minimum of the scalar potential in connection with electric charge conservation and its behaviour under CP is analysed. The question of CP violation is addressed in detail, including the cases of explicit CP violation and spontaneous CP violation. We present a detailed study of weak basis invariants which are odd under CP. A careful study of spontaneous CP violation is presented, including an analysis of the conditions which have to be satisfied in order for a vacuum to violate CP. We present minimal models of CP violation where the vacuum phase is sufficient to generate a complex CKM matrix, which is at present a requirement for any realistic model of spontaneous CP violation.Comment: v3: 180 pages, 506 references, new chapter 7 with recent LHC results; referee comments taken into account; submitted to Physics Report

Effectiveness of an intervention for improving drug prescription in primary care patients with multimorbidity and polypharmacy:Study protocol of a cluster randomized clinical trial (Multi-PAP project)

This study was funded by the Fondo de Investigaciones Sanitarias ISCIII (Grant Numbers PI15/00276, PI15/00572, PI15/00996), REDISSEC (Project Numbers RD12/0001/0012, RD16/0001/0005), and the European Regional Development Fund ("A way to build Europe").Background: Multimorbidity is associated with negative effects both on people's health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12months, as compared with usual care. Methods/Design: Design:pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65-74years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3months). Sample size: n=400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. Discussion: It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Trial registration: Clinicaltrials.gov, NCT02866799Publisher PDFPeer reviewe

Prospective associations between a priori dietary patterns adherence and kidney function in an elderly Mediterranean population at high cardiovascular risk.

PURPOSE: To assess the association between three different a priori dietary patterns adherence (17-item energy reduced-Mediterranean Diet (MedDiet), Trichopoulou-MedDiet and Dietary Approach to Stop Hypertension (DASH)), as well as the Protein Diet Score and kidney function decline after one year of follow-up in elderly individuals with overweight/obesity and metabolic syndrome (MetS). METHODS: We prospectively analyzed 5675 participants (55-75 years) from the PREDIMED-Plus study. At baseline and at one year, we evaluated the creatinine-based estimated glomerular filtration rate (eGFR) and food-frequency questionnaires-derived dietary scores. Associations between four categories (decrease/maintenance and tertiles of increase) of each dietary pattern and changes in eGFR (ml/min/1.73m2) or ≥ 10% eGFR decline were assessed by fitting multivariable linear or logistic regression models, as appropriate. RESULTS: Participants in the highest tertile of increase in 17-item erMedDiet Score showed higher upward changes in eGFR (β: 1.87 ml/min/1.73m2; 95% CI: 1.00-2.73) and had lower odds of ≥ 10% eGFR decline (OR: 0.62; 95% CI: 0.47-0.82) compared to individuals in the decrease/maintenance category, while Trichopoulou-MedDiet and DASH Scores were not associated with any renal outcomes. Those in the highest tertile of increase in Protein Diet Score had greater downward changes in eGFR (β: - 0.87 ml/min/1.73m2; 95% CI: - 1.73 to - 0.01) and 32% higher odds of eGFR decline (OR: 1.32; 95% CI: 1.00-1.75). CONCLUSIONS: Among elderly individuals with overweight/obesity and MetS, only higher upward change in the 17-item erMedDiet score adherence was associated with better kidney function after one year. However, increasing Protein Diet Score appeared to have an adverse impact on kidney health. TRIAL REGISTRATION NUMBER: ISRCTN89898870 (Data of registration: 2014)

PERSPECTIVA PSICOSOCIAL DE LOS DERECHOS HUMANOS

Hoy en día es imprescindible abordar el problema de los derechos desde una perspectiva holística que integre la posición que el individuo ocupa en la sociedad y el impacto de los hechos sociales sobre su persona. Esta perspectiva va por lo tanto más allá del enfoque clásico de las violaciones a los derechos civiles y políticos de los ciudadanos sino, también incluye sus derechos económicos, sociales y culturales. Cualquier enfoque de tipo holístico debe entender al ser humano en su ambiente, social, cultural, natural y en función a todas las estructuras existentes, por más sutiles que sean o invisibles que parezcan. Precisamente este libro permite apreciar la dimensión amplia y compleja del ser en sociedad y las interacciones que de ambas partes se generan y las ramificaciones que producen. No es un ejercicio fácil y los editores de este volumen han logrado un salto cuántico al poder congregar en un solo espacio miradas que en otras circunstancias podrían haber sido opuestas y hasta contrarias a nuestra comprensión de problemas que, en efecto, tienen raíces comunes. El libro está dividido en 5 secciones, El espíritu de los tiempos actuales y los Derechos Humanos, Construcción ciudadana y ejercicio de los Derechos Humanos, Violaciones a Derechos Humanos, victimizaciones y su atención, Ejercicio de los Derechos Humanos y situaciones disruptivas y Defensa y defensores de Derechos Humanos.Manuel Gutiérrez Romero Jessica Ruiz Magañ

Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER), "A way of making Europe".Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals

Diet and food strategies in a southern al-Andalusian urban environment during Caliphal period, ecija, Sevilla

The Iberian medieval period is unique in European history due to the widespread socio-cultural changes that took place after the arrival of Arabs, Berbers and Islam in 711 AD. Recently, isotopic research has been insightful on dietary shifts, status, resource availability and the impact of environment. However, there is no published isotopic research exploring these factors in southern Iberian populations, and as the history of this area differs to the northern regions, this leaves a significant lacuna in our knowledge. This research fills this gap via isotopic analysis of human (n = 66) and faunal (n = 13) samples from the 9th to the 13th century Écija, a town renowned for high temperatures and salinity. Stable carbon (δ13C) and nitrogen (δ15N) isotopes were assessed from rib collagen, while carbon (δ13C) values were derived from enamel apatite. Human diet is consistent with C3 plant consumption with a very minor contribution of C4 plants, an interesting feature considering the suitability of Écija to C4 cereal production. δ15N values vary among adults, which may suggest variable animal protein consumption or isotopic variation within animal species due to differences in foddering. Consideration of δ13C collagen and apatite values together may indicate sugarcane consumption, while moderate δ15N values do not suggest a strong aridity or salinity effect. Comparison with other Iberian groups shows similarities relating to time and location rather than by religion, although more multi-isotopic studies combined with zooarchaeology and botany may reveal subtle differences unobservable in carbon and nitrogen collagen studies alone.OLC is funded by Plan Galego I2C mod.B (ED481D 2017/014). The research was partially funded by the projects “Galician Paleodiet” and by Consiliencia network (ED 431D2017/08) Xunta de GaliciaS