Systemic exosomal siRNA delivery reduced alpha-synuclein aggregates in brains of transgenic mice.

Alpha-synuclein (α-Syn) aggregates are the main component of Lewy bodies, which are the characteristic pathological feature in Parkinson's disease (PD) brain. Evidence that α-Syn aggregation can be propagated between neurones has led to the suggestion that this mechanism is responsible for the stepwise progression of PD pathology. Decreasing α-Syn expression is predicted to attenuate this process and is thus an attractive approach to delay or halt PD progression. We have used α-Syn small interfering RNA (siRNA) to reduce total and aggregated α-Syn levels in mouse brains. To achieve widespread delivery of siRNAs to the brain we have peripherally injected modified exosomes expressing Ravies virus glycoprotein loaded with siRNA. Normal mice were analyzed 3 or 7 days after injection. To evaluate whether this approach can decrease α-Syn aggregates, we repeated the treatment using transgenic mice expressing the human phosphorylation-mimic S129D α-Syn, which exhibits aggregation. In normal mice we detected significantly reduced α-Syn messenger RNA (mRNA) and protein levels throughout the brain 3 and 7 days after treatment with RVG-exosomes loaded with siRNA to α-Syn. In S129D α-Syn transgenic mice we found a decreased α-Syn mRNA and protein levels throughout the brain 7 days after injection. This resulted in significant reductions in intraneuronal protein aggregates, including in dopaminergic neurones of the substantia nigra. This study highlights the therapeutic potential of RVG-exosome delivery of siRNA to delay and reverse brain α-Syn pathological conditions

HÁBITOS ALIMENTARIOS DE LAS MUJERES EN RELACIÓN CON EL NIVEL DE CONOCIMIENTOS SOBRE EL CLIMATERIO

Objectives: Knowing the behaviors related to food and toxic habits of women aged 30-60 years in the health area of Vigo.Determine whether menopausal women have healthier behaviors than non menopausal ones. Identify whether any of the socio-demographic variables has an influence on feeding habits or toxic behaviors.Determine whether women with high-very high knowledge have proper habits.Methods: Comparative, observational cross study made of 425 women between 30 and 60 years of age. We used a booklet with personally answered questionnaires, one about menopause and the other about feeding behaviors during the climacteric stage, which includes socio-demographic variables. Data analysis was carried out using SPSS 14.0.Results: A result of 74.3% of the women in the sample has a high/very high level of knowledge but behaviors that do not correlate with this.Conclusions: Women know what they must do to maintain a healthy life, but the majority does not put this into practice. We think it is necessary to introduce in health centers a program about the climacteric stage, coordinated by nurses and midwives and focused on applying to daily life the knowledge that women already have, with the aim of helping them to achieve a better quality of life.This study is part of a wider research on “Knowledge and behaviors related to climacteric stage in women between 30 and 60 years of age in the health area of Vigo sponsored by the “Fondo de Investigaciones Sanitarias” (Spanish Health Research Fund) in 2007Objetivos: Conocer los comportamientos relacionados con la alimentación y hábitos tóxicos de las mujeres de edad comprendida entre 30-60 años del área sanitaria de Vigo.Averiguar si las mujeres menopáusicas tienen comportamientos más saludables que las no menopáusicas.Identificar si alguna de las variables sociodemográficas influye en los comportamientos sobre la alimentación y hábitos tóxicos. Determinar si las mujeres con conocimientos altos-muy altos tienen comportamientos adecuadosMétodos: Estudio comparativo, observacional, transversal, realizado a 425 mujeres de 30-60 años. Se utilizó un cuadernillo con dos cuestionarios autocumplimentados, uno de conocimientos sobre la menopausia y otro sobre los comportamientos relacionados con la alimentación en la etapa del climaterio, incluidas las variables sociodemográficas. El análisis de los datos se realizó mediante SPSS 14.0.Resultados: Las mujeres de nuestra muestra tienen conocimientos altos-muy altos en un 74,3% y unos comportamientos que no se correlacionan con el nivel de conocimientos.Conclusiones: Las mujeres conocen qué es lo que deben realizar para mantener una vida saludable, pero a la hora de ponerlo en práctica no lo hacen mayoritariamente. Consideramos necesaria la implantación en los Centros de Salud, de un programa coordinado por el equipo deEnfermería Global Nº 20 Octubre 2010 Página 2salud, dirigido a aplicar los conocimientos que han demostrado poseer las mujeres a los comportamientos diarios, con el objetivo de alcanzar una mayor calidad de vida. Este estudio forma parte de una investigación más amplia realizada sobre los “Conocimientos y comportamientos relacionados con el climaterio de las mujeres de 30-60 años del Área Sanitaria de Vigo” becado por el Fondo de Investigaciones Sanitarias (2007)

Emergent Properties of Tumor Microenvironment in a Real-life Model of Multicell Tumor Spheroids

Multicellular tumor spheroids are an important {\it in vitro} model of the pre-vascular phase of solid tumors, for sizes well below the diagnostic limit: therefore a biophysical model of spheroids has the ability to shed light on the internal workings and organization of tumors at a critical phase of their development. To this end, we have developed a computer program that integrates the behavior of individual cells and their interactions with other cells and the surrounding environment. It is based on a quantitative description of metabolism, growth, proliferation and death of single tumor cells, and on equations that model biochemical and mechanical cell-cell and cell-environment interactions. The program reproduces existing experimental data on spheroids, and yields unique views of their microenvironment. Simulations show complex internal flows and motions of nutrients, metabolites and cells, that are otherwise unobservable with current experimental techniques, and give novel clues on tumor development and strong hints for future therapies.Comment: 20 pages, 10 figures. Accepted for publication in PLOS One. The published version contains links to a supplementary text and three video file

Effectiveness of individualized inhaler technique training on low adherence (LowAd) in ambulatory patients with COPD and asthma

© 2022. This document is made available under the CC-BY 4.0 license http://creativecommons.org/licenses/by /4.0/ This document is the published version of a published work that appeared in final form in npj primary care respiratory medicineTo analyze whether there is improvement in adherence to inhaled treatment in patients with COPD and asthma after an educational intervention based on the teach-to-goal method. This is a prospective, non-randomized, single-group study, with intervention and before-after evaluation. The study population included 120 patients (67 females and 53 males) diagnosed with asthma (70.8%) and COPD (29.1%). The level of adherence (low and optimal) and the noncompliance behavior pattern (erratic, deliberate and unwitting) were determined by the Test of the adherence to Inhalers (TAI). This questionnaire allows you to determine the level of adherence and the types of noncompliance. Low Adherence (LowAd) was defined as a score less than 49 points. All patients received individualized educational inhaler technique intervention (IEITI). Before the IEITI, 67.5% of the patients had LowAd. Following IEITI, on week 24, LowAd was 55% (p = 0.024). Each patient can present one or more types of noncompliance. The most frequent type was forgetting to use the inhaler (erratic), 65.8%. The other types were deliberate: 43.3%, and unwitting: 57.5%. All of them had decreased on the final visit: 51.7% (p = 0.009), 25.8% (p = 0.002), 39.2% (p = 0.002). There were no significant differences in adherence between asthma and COPD patients at the start of the study. The only predicting factor of LowAd was the female gender. An individualized educational intervention, in ambulatory patients with COPD and asthma, in real-world clinical practice conditions, improves adherence to the inhaled treatment

Combined In Silico, In Vivo, and In Vitro Studies Shed Insights into the Acute Inflammatory Response in Middle-Aged Mice

We combined in silico, in vivo, and in vitro studies to gain insights into age-dependent changes in acute inflammation in response to bacterial endotoxin (LPS). Time-course cytokine, chemokine, and NO2-/NO3- data from "middle-aged" (6-8 months old) C57BL/6 mice were used to re-parameterize a mechanistic mathematical model of acute inflammation originally calibrated for "young" (2-3 months old) mice. These studies suggested that macrophages from middle-aged mice are more susceptible to cell death, as well as producing higher levels of pro-inflammatory cytokines, vs. macrophages from young mice. In support of the in silico-derived hypotheses, resident peritoneal cells from endotoxemic middle-aged mice exhibited reduced viability and produced elevated levels of TNF-α, IL-6, IL-10, and KC/CXCL1 as compared to cells from young mice. Our studies demonstrate the utility of a combined in silico, in vivo, and in vitro approach to the study of acute inflammation in shock states, and suggest hypotheses with regard to the changes in the cytokine milieu that accompany aging. © 2013 Namas et al

The effect of S-substitution at the O6-guanine site on the structure and dynamics of a DNA oligomer containing a G:T mismatch

The effect of S-substitution on the O6 guanine site of a 13-mer DNA duplex containing a G:T mismatch is studied using molecular dynamics. The structure, dynamic evolution and hydration of the S-substituted duplex are compared with those of a normal duplex, a duplex with Ssubstitution on guanine, but no mismatch and a duplex with just a G:T mismatch. The S-substituted mismatch leads to cell death rather than repair. One suggestion is that the G:T mismatch recognition protein recognises the S-substituted mismatch (GS:T) as G:T. This leads to a cycle of futile repair ending in DNA breakage and cell death. We find that some structural features of the helix are similar for the duplex with the G:T mismatch and that with the S-substituted mismatch, but differ from the normal duplex, notably the helical twist. These differences arise from the change in the hydrogen-bonding pattern of the base pair. However a marked feature of the S-substituted G:T mismatch duplex is a very large opening. This showed considerable variability. It is suggested that this enlarged opening would lend support to an alternative model of cell death in which the mismatch protein attaches to thioguanine and activates downstream damage-response pathways. Attack on the sulphur by reactive oxygen species, also leading to cell death, would also be aided by the large, variable opening

Rhodococcus opacus B4: a promising bacterium for production of biofuels and biobased chemicals

Bacterial lipids have relevant applications in the production of renewable fuels and biobased oleochemicals. The genus Rhodococcus is one of the most relevant lipid producers due to its capability to accumulate those compounds, mainly triacylglycerols (TAG), when cultivated on different defined substrates, namely sugars, organic acids and hydrocarbons but also on complex carbon sources present in industrial wastes. In this work, the production of storage lipids by Rhodococcus opacus B4 using glucose, acetate and hexadecane is reported for the first time and its productivity compared with Rhodococcus opacus PD630, the best TAG producer bacterium reported. Both strains accumulated mainly TAG from all carbon sources, being influenced by the carbon source itself and by the duration of the accumulation period. R. opacus B4 produced 0.09 and 0.14 g L1 at 24 and 72 h, with hexadecane as carbon source, which was 2 and 3.3 fold higher than the volumetric production obtained by R. opacus PD630. Both strains presented similar fatty acids (FA) profiles in intact cells while in TAG produced fraction, R. opacus B4 revealed a higher variability in fatty acid composition than R. opacus PD630, when both strains were cultivated on hexadecane. The obtained results open new perspectives for the use of R. opacus B4 to produce TAG, in particular using oily (alkane-contaminated) waste and wastewater as cheap raw-materials. Combining TAG production with hydrocarbons degradation is a promising strategy to achieve environmental remediation while producing added value compounds.This work was financially supported by the Portuguese Science Foundation (FCT) and European Social Fund (ESF, POPH-QREN) through the Grant given to A.R. Castro (SFRH/BD/64500/2009), the FCT Strategic Project of UID/BIO/04469/2013 unit and COMPETE 2020 (POCI-01-0145-FEDER-006684) and project RECI/BBB-EBI/0179/2012 (FCOMP-01-0124-FEDER-027462)

Polyfunctional T cell responses in children in early stages of chronic Trypanosoma cruzi infection contrast with monofunctional responses of long-term infected adults

Background: Adults with chronic Trypanosoma cruzi exhibit a poorly functional T cell compartment, characterized by monofunctional (IFN-γ-only secreting) parasite-specific T cells and increased levels of terminally differentiated T cells. It is possible that persistent infection and/or sustained exposure to parasites antigens may lead to a progressive loss of function of the immune T cells. Methodology/Principal Findings: To test this hypothesis, the quality and magnitude of T. cruzi-specific T cell responses were evaluated in T. cruzi-infected children and compared with long-term T. cruzi-infected adults with no evidence of heart failure. The phenotype of CD4+ T cells was also assessed in T. cruzi-infected children and uninfected controls. Simultaneous secretion of IFN-γ and IL-2 measured by ELISPOT assays in response to T. cruzi antigens was prevalent among T. cruzi-infected children. Flow cytometric analysis of co-expression profiles of CD4+ T cells with the ability to produce IFN-γ, TNF-α, or to express the co-stimulatory molecule CD154 in response to T. cruzi showed polyfunctional T cell responses in most T. cruzi-infected children. Monofunctional T cell responses and an absence of CD4+TNF-α+-secreting T cells were observed in T. cruzi-infected adults. A relatively high degree of activation and differentiation of CD4+ T cells was evident in T. cruzi-infected children. Conclusions/Significance: Our observations are compatible with our initial hypothesis that persistent T. cruzi infection promotes eventual exhaustion of immune system, which might contribute to disease progression in long-term infected subjects.Fil: Albareda, María Cecilia. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud. Instituto Nacional de Parasitología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: de Rissio, Ana María. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud. Instituto Nacional de Parasitología; ArgentinaFil: Tomas, Gonzalo. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud. Instituto Nacional de Parasitología; ArgentinaFil: Serjan, Alicia. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Alvarez, María Gabriela. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Viotti, Rodolfo Jorge. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Fichera, Laura Edith. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud. Instituto Nacional de Parasitología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Esteva, Mónica Inés. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud. Instituto Nacional de Parasitología; ArgentinaFil: Potente, Daniel Fernando. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Armenti, Alejandro. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Tarleton, Rick L.. University of Georgia; Estados UnidosFil: Laucella, Susana Adriana. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud. Instituto Nacional de Parasitología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Solitary waves in the Nonlinear Dirac Equation

In the present work, we consider the existence, stability, and dynamics of solitary waves in the nonlinear Dirac equation. We start by introducing the Soler model of self-interacting spinors, and discuss its localized waveforms in one, two, and three spatial dimensions and the equations they satisfy. We present the associated explicit solutions in one dimension and numerically obtain their analogues in higher dimensions. The stability is subsequently discussed from a theoretical perspective and then complemented with numerical computations. Finally, the dynamics of the solutions is explored and compared to its non-relativistic analogue, which is the nonlinear Schr{\"o}dinger equation. A few special topics are also explored, including the discrete variant of the nonlinear Dirac equation and its solitary wave properties, as well as the PT-symmetric variant of the model