Search

Abstract SETD8 is a methyltransferase that is overexpressed in several cancers, which monomethylates H4K20 as well as other non-histone targets such as PCNA or p53. We here report novel SETD8 inhibitors, which were discovered while trying to identify chemicals that prevent 53BP1 foci formation, an event mediated by H4K20 methylation. Consistent with previous reports, SETD8 inhibitors induce p53 expression, although they are equally toxic for p53 proficient or deficient cells. Thermal stability proteomics revealed that the compounds had a particular impact on nucleoli, which was confirmed by fluorescent and electron microscopy. Similarly, Setd8 deletion generated nucleolar stress and impaired ribosome biogenesis, supporting that this was an on-target effect of SETD8 inhibitors. Furthermore, a genome-wide CRISPR screen identified an enrichment of nucleolar factors among those modulating the toxicity of SETD8 inhibitors. Accordingly, the toxicity of SETD8 inhibition correlated with MYC or mTOR activity, key regulators of ribosome biogenesis. Together, our study provides a new class of SETD8 inhibitors and a novel biomarker to identify tumors most likely to respond to this therapy.

Este artículo analiza el proceso de negociación del Acuerdo de Libre Comercio MERCOSUR-Singapur y explica la dinámica e intensidad de las relaciones comerciales inter-regionales durante el período 2001-2023. Para este propósito, el estudio empleó una investigación de enfoque empírico, apoyada en métodos cualitativos y cuantitativos. Con base en la revisión documental y el cálculo de indicadores de comercio, concluye –entre otras cosas– que el Acuerdo de Libre Comercio MERCOSUR-Singapur es un hito dentro del inter-regionalismo MERCOSUR-ASEAN, alcanzado por el liderazgo de Paraguay en las negociaciones, y que tanto la actual posición como la dinámica e intensidad comercial MERCOSUR-Singapur están determinadas por los intercambios bilaterales con Brasil.

El discurso matemático escolar se da con la intención de comunicar conceptos abstractos. La metáfora, en su dimensión cognitiva, es un recurso lingüístico que genera un fenómeno mental en el interlocutor a través del cual el cerebro trata de conectar fenómenos concretos con conceptos abstractos. Este recurso lingüístico ayuda al estudiante en la construcción de conocimiento matemático. No se puede asegurar que las eventuales metáforas que aparecen en los libros de texto sean usadas con la misma intención del profesor en su clase, aunque, en principio, las dos fuentes, convergen en la intencionalidad de comunicar un concepto matemático abstracto. Este artículo muestra los resultados de una investigación cualitativa, acerca de las metáforas relacionadas con los números enteros negativos en el discurso escrito en los libros de texto de algunas editoriales. Las conclusiones indican que en los libros analizados se detectan metáforas conceptuales, principalmente ontológicas y orientacionales.

Abstract Protein methylation is an important modification beyond epigenetics. However, systems analyses of protein methylation lag behind compared to other modifications. Recently, thermal stability analyses have been developed which provide a proxy of a protein functional status. Here, we show that molecular and functional events closely linked to protein methylation can be revealed by the analysis of thermal stability. Using mouse embryonic stem cells as a model, we show that Prmt5 regulates mRNA binding proteins that are enriched in intrinsically disordered regions and involved in liquid-liquid phase separation mechanisms, including the formation of stress granules. Moreover, we reveal a non-canonical function of Ezh2 in mitotic chromosomes and the perichromosomal layer, and identify Mki67 as a putative Ezh2 substrate. Our approach provides an opportunity to systematically explore protein methylation function and represents a rich resource for understanding its role in pluripotency.

Parte de la literatura especializada ubica el inicio del proceso de integración latinoamericano en la segunda mitad del siglo XX, concretamente desde la institución de la Asociación Latinoamericana de Libre Comercio (ALALC) con el Tratado de Montevideo de 1960 (TM-60). También suele argumentarse que este fenómeno ha sido una emulación de otras experiencias integradoras, como la europea. Este artículo, en general, intenta demostrar que la integración latinoamericana es un proceso con larga historia y motivos propios, no nacido a la luz de la integración europea. Para explicarlo, toma como caso de estudio particular a la Comunidad Andina (CAN), a fin de analizar la continuidad histórica de ideales y proyectos de integración promovidos desde el siglo XIX, con raíces identitarias determinantes. Al efecto, se realizó una investigación documental-descriptiva, enmarcada dentro de enfoques teóricos sobre: construcción de regiones, tendencias incidentes en la regionalización y dificultades históricas concurrentes tanto en la construcción del Estado como en la segmentación territorial de América Latina. Entre sus hallazgos se encuentra la identificación de fuerzas inside-out y outside-in que reflejan tal continuidad histórica de la integración en el regionalismo andino, como sub-óptimo del proyecto original.

Cardiac rhabdomyoma (CRHM) is the principal cardiac tumor in children and is most often associated with tuberous sclerosis complex (TSC). Mutations in the TSC1 and TSC2 genes cause the overactivation of the mammalian Target of Rapamycin (mTOR). This protein family is responsible for abnormal cell proliferation leading to the formation of CRHMs and hamartomas in other organs. Despite the tendency for spontaneous regression, some CRHMs can cause heart failure and intractable arrhythmias, requiring surgical resection. In recent years, the use of everolimus and sirolimus (mTOR inhibitors) in the treatment of CRHMs has been reported. We report two cases of neonates with giant rhabdomyomas, with hemodynamic repercussions treated with low-dose everolimus (4.5 mg/m2/week). In both cases, we obtained an approximate decrease of 50% in the total area of the mass after three weeks of treatment. Despite rebound growth after stopping the drug, we were able to evidence that the use of low doses of everolimus immediately after birth is effective and safe in the treatment of giant CRHMs, avoiding surgical resection of the tumor and associated morbidity and mortality.

We describe two fatal cases of COVID-19 in which Rhizopus microsporus and Lichtheimia corymbifera were cultured from endotracheal aspirate samples. Both patients had no underlying comorbidities other than obesity. Despite antifungal therapy, both cases developed septic shock and progressive refractory hypoxemia without evidence of other underlying infections. It is unclear whether isolation of these fungal organisms represents invasive disease or corresponds to an epiphenomenon of critical illness. Yet, patients suffering from COVID-19 may be at risk of superinfection from a broader range of fungal organisms than previously thought.

ABSTRACT Background: Recent changes to the diagnostic criteria for multiple sclerosis (MS) and new medications have had a major impact on the way in which specialists manage the disease. Objective: To investigate factors considered by Brazilian neurologists in managing MS, and to identify how these contribute to diagnosis and treatment. Methods: Potential participants were selected by a steering committee (MS experts who developed this survey). Only MS specialists were included in the study (neurologists who had completed a neuroimmunology fellowship or who were treating more than 30 MS patients). Links to the online questionnaire were distributed between March 2019 and January 2020. This questionnaire was composed of sections with hypothetical MS scenarios. Results: Neurologists from 13 Brazilian states responded to the survey (n = 94). In the clinically isolated syndrome (CIS) scenario, the respondents agreed to treat patients with a high risk of MS diagnosis, whereas in the radiologically isolated syndrome (RIS) half of the respondents opted not to treat, even among high-risk patients. In cases of low-activity relapsing-remitting MS (RRMS), the choice of treatment was distributed among interferon beta, glatiramer acetate and teriflunomide, which were changed to fingolimod and natalizumab, as RRMS severity increased. The topics in which disagreement was found included practices regarding use of disease-modifying therapy (DMT) for pregnant patients and the washout period required for some DMTs. Conclusions: This study enabled identification of areas of agreement and disagreement about MS treatment among Brazilian neurologists, which can be used to update future protocols and improve patient management.

One of the worst consequences of armed conflict is the displacement of people from conflict areas in search of safety. These events generate serious effects on the mental health of the population and deteriorate the social fabric. The main objective of this article is to understand the mental health problems suffered by those displaced by the conflict in Colombia from the perspective of the integral restitution of victims. The main conclusion is that mental health care for displaced persons is an integral process that involves not only clinical factors, but also social, economic and cultural factors that, together, create the conditions for them to overcome the trauma suffered during the process of forced displacement.

El artículo se enmarca en la discusión sobre los problemas de la reforma de las empresas estatales en las economías centralmente planificadas, específicamente en el caso de Cuba. Algunos de los mayores obstáculos para que las empresas mejoren su desempeño y cumplan con su rol en el sistema económico se relacionan con la multiplicidad de objetivos que se les impone centralmente y el ejercicio de funciones monetarias y fiscales ajenas a estas entidades. Para solucionarlo se proponen ideas para una hoja de ruta que comienza por una nueva clasificación de las empresas estatales cubanas a partir de considerar una función de optimización diferente. No obstante, se apunta que el éxito de esta propuesta depende de otras reformas estructurales acompañantes. This paper addresses the reform of state-owned enterprises in centrally planned economies, specifically the case of Cuba. Some of the major obstacles that hinder restructuring to improve firm performance and the fulfilling of their role in the economic system have to do with the fact that those entities are commanded to play monetary and fiscal functions that go well beyond the role of enterprises in economic systems. This paper proposes first ideas for a road map starting with a new way to classify Cuban state companies through their optimisation function. However, the success of such transformation is contingent on other accompanying structural reforms.

PurposeInterferon beta receptor 2 subunit (IFNAR2) can be produced as a transmembrane protein, but also as a soluble form (sIFNAR2) generated by alternative splicing or proteolytic cleavage, which has both agonist and antagonist activities for IFN-β. However, its role regarding the clinical response to IFN-β for relapsing-remitting multiple sclerosis (RRMS) is unknown. We aim to evaluate the in vitro short-term effects and after 6 and 12 months of IFN-β therapy on sIFNAR2 production and their association with the clinical response in MS patients.MethodsNinety-four RRMS patients were included and evaluated at baseline, 6 and 12 months from treatment onset. A subset of 41 patients were classified as responders and non-responders to IFN-β therapy. sIFNAR2 serum levels were measured by ELISA. mRNA expression for IFNAR1, IFNAR2 splice variants, MxA and proteases were assessed by RT-PCR. The short-term effect was evaluated in PBMC from RRMS patients after IFN-β stimulation in vitro.ResultsProtein and mRNA levels of sIFNAR2 increased after IFN-β treatment. According to the clinical response, only non-responders increased sIFNAR2 significantly at both protein and mRNA levels. sIFNAR2 gene expression correlated with the transmembrane isoform expression and was 2.3-fold higher. While MxA gene expression increased significantly after treatment, IFNAR1 and IFNAR2 only slightly increased. After short-term IFN-β in vitro induction of PBMC, 6/7 patients increased the sIFNAR2 expression.ConclusionsIFN-β administration induces the production of sIFNAR2 in RRMS and higher levels might be associated to the reduction of therapeutic response. Thus, levels of sIFNAR2 could be monitored to optimize an effective response to IFN-β therapy.

Este artículo muestra los resultados de una investigación de tipo cualitativo-interpretativo en la cual se indaga sobre el discurso de dos docentes, con el fin de caracterizar el tipo de lenguaje metafórico utilizado en el aula para la enseñanza de los números racionales y la posible divergencia entre este lenguaje y el entendimiento de los estudiantes, causada por las expresiones metafóricas que utiliza el profesor en lenguaje no formal para explicar este tema a estudiantes de grado séptimo. Para el análisis del lenguaje metafórico de los docentes, se tiene en cuenta la teoría de la metáfora conceptual que aparece en Lakoff y Johnson, (1995).

Purpose: Breast arterial calcifications (BAC) have been associated with cardiovascular diseases. We aimed to examine whether the presence of BAC could predict the development of cardiovascular events in the very long term, as evidence has suggested. Patients and Methods: We conducted a 23-year follow-up retrospective cohort study considering women specifically studied for breast cancer. After reviewing the mammograms of 1759 women, we selected 128 patients with BAC and an equal number of women without BAC. Results: Women with BAC had higher relative risk (RR) for cardiovascular events, globally 1.66 (95% CI): 1.31–2.10 vs. 0.53 (0.39–0.72), and individually for ischemic heart disease 3.25 (1.53–6.90) vs. 0.85 (0.77–0.94), hypertensive heart disease 2.85 (1.59–5.09) vs. 0.79 (0.69–0.89), valvular heart disease 2.19 (1.28–3.75) vs. 0.83 (0.73–0.94), congestive heart failure 2.06 (1.19–3.56) vs. 0.85 (0.75–0.96), peripheral vascular disease 2.8 (1.42–5.52) vs. 0.85 (0.76–0.94), atrial fibrillation 1.83 (1.09–3.08) vs. 0.86 (0.76–0.98), and lacunar infarction 2.23 (1.21–4.09) vs. 0.86 (0.77–0.96). Cox’s multivariate analysis, also considering classical risk factors, indicated that this BAC was significantly and independently associated with survival (both cardiovascular event-free and specific survival; 1.94 (1.38–2.73) and 6.6 (2.4–18.4)). Conclusions: Our data confirm the strong association of BAC on mammograms and the development cardiovascular events, but also evidence the association of BAC with cardiovascular event-free and specific survival.

Background Globally, critical illness results in millions of deaths every year. Although many of these deaths are potentially preventable, the basic, life-saving care of critically ill patients are often overlooked in health systems. Essential Emergency and Critical Care (EECC) has been devised as the care that should be provided to all critically ill patients in all hospitals in the world. EECC includes the effective care of low cost and low complexity for the identification and treatment of critically ill patients across all medical specialties. This study aimed to specify the content of EECC and additionally, given the surge of critical illness in the ongoing pandemic, the essential diagnosis-specific care for critically ill patients with COVID-19.Methods In a Delphi process, consensus (>90% agreement) was sought from a diverse panel of global clinical experts. The panel iteratively rated proposed treatments and actions based on previous guidelines and the WHO/ICRC’s Basic Emergency Care. The output from the Delphi was adapted iteratively with specialist reviewers into a coherent and feasible package of clinical processes plus a list of hospital readiness requirements.Results The 269 experts in the Delphi panel had clinical experience in different acute medical specialties from 59 countries and from all resource settings. The agreed EECC package contains 40 clinical processes and 67 requirements, plus additions specific for COVID-19.Conclusion The study has specified the content of care that should be provided to all critically ill patients. Implementing EECC could be an effective strategy for policy makers to reduce preventable deaths worldwide.

Overview: We assessed the role of age and disease activity as new factors contributing to establish the risk of progressive multifocal leucoencephalopathy in multiple sclerosis patients treated with natalizumab in 36 University Hospitals in Europe. We performed the study in 1,307 multiple sclerosis patients (70.8% anti-John Cunninghan virus positive antibodies) treated with natalizumab for a median time of 3.28 years. Epidemiological, clinical, and laboratory variables were collected. Lipid-specific IgM oligoclonal band status was available in 277 patients. Factors associated with progressive multifocal leucoencephalopathy onset were explored by uni- and multivariate logistic regression.Results: Thirty-five patients developed progressive multifocal leucoencephalopathy. The multivariate analysis identified anti-John Cunninghan virus antibody indices and relapse rate as the best predictors for the onset of this serious opportunistic infection in the whole cohort. They allowed to stratify progressive multifocal leucoencephalopathy risk before natalizumab initiation in individual patients [area under the curve (AUC) = 0.85]. The risk ranged from 0.5, to 1/50 in the opposite case. In patients with lipid-specific IgM oligoclonal bands assessment, age at natalizumab onset, anti-John Cunninghan virus antibody indices, and lipid-specific IgM oligoclonal band status predicted progressive multifocal leucoencephalopathy risk (AUC = 0.92). The absence of lipid-specific IgM oligoclonal bands was the best individual predictor (OR = 40.94). The individual risk ranged from

Every housing should fulfill safety, comfort and durability standards, even more when due to climate change disasters occur more often than ever. In Chile, construction standards can be found in the General Urban Planning and Construction Ordinance (OGUC), whose update will include elements for risk management in order to decrease vulnerability. In this study, thermal, mechanic, fire resistant and acoustic isolation standards where evaluated in 5 thermic zones. This information allowed the creation of manufacturing, installation, technical specification manuals, and a bill that regulates emergency housing and transient settlements standards. This experience allowed a critical analysis of the compliance with standards for social housing and wood building, which does not account, for example, for smoke opacity and toxicity, thermal-acoustic insulators and fire resistance: less harmful preservatives or coatings with sustainability in mind. The existence of the ordinance (OGUC) does not imply compliance of energy efficiency, seismic and fire resistance standards simultaneously in practice, as many housing projects do not consider a final reception of work. Multi-criteria discrimination analyzes may help to make design decisions in wood constructions.

ATR kinase is required for meiosis in non-mammalian model organisms. Here the authors demonstrate, using a hypomorphic Atr mutation and chemical inhibition, that ATR is also essential for male meiosis in mouse, regulating meiotic recombination and synapsis.

Imbalance in the oxidative status in neurons, along with mitochondrial damage, are common characteristics in some neurodegenerative diseases. The maintenance in energy production is crucial to face and recover from oxidative damage, and the preservation of different sources of energy production is essential to preserve neuronal function. Fingolimod phosphate is a drug with neuroprotective and antioxidant actions, used in the treatment of multiple sclerosis. This work was performed in a model of oxidative damage on neuronal cell cultures exposed to menadione in the presence or absence of fingolimod phosphate. We studied the mitochondrial function, antioxidant enzymes, protein nitrosylation, and several pathways related with glucose metabolism and glycolytic and pentose phosphate in neuronal cells cultures. Our results showed that menadione produces a decrease in mitochondrial function, an imbalance in antioxidant enzymes, and an increase in nitrosylated proteins with a decrease in glycolysis and glucose-6-phosphate dehydrogenase. All these effects were counteracted when fingolimod phosphate was present in the incubation media. These effects were mediated, at least in part, by the interaction of this drug with its specific S1P receptors. These actions would make this drug a potential tool in the treatment of neurodegenerative processes, either to slow progression or alleviate symptoms.

Currently available treatments for secondary progressive multiple sclerosis(SPMS) have limited efficacy and/or safety concerns. Adipose-mesenchymal derived stem cells(AdMSCs) represent a promising option and can be readily obtained using minimally invasive procedures.In this triple-blind, placebo-controlled study, cell samples were obtained from consenting patients by lipectomy and subsequently expanded. Patients were randomized to a single infusion of placebo, low-dose(1x106cells/kg) or high-dose(4x106cells/kg) autologous AdMSC product and followed for 12 months. Safety was monitored recording adverse events, laboratory parameters, vital signs and spirometry. Expanded disability status score (EDSS), magnetic-resonance-imaging, and other measures of possible treatment effects were also recorded.Thirty-four patients underwent lipectomy for AdMSCs collection, were randomized and thirty were infused (11 placebo, 10 low-dose and 9 high-dose); 4 randomized patients were not infused because of karyotype abnormalities in the cell product. Only one serious adverse event was observed in the treatment arms (urinary infection, considered not related to study treatment). No other safety parameters showed changes. Measures of treatment effect showed an inconclusive trend of efficacy.Infusion of autologous AdMSCs is safe and feasible in patients with SPMS. Larger studies and probably treatment at earlier phases would be needed to investigate the potential therapeutic benefit of this technique.

In the fission yeast Schizosaccharomyces pombe the prevailing approach for gene manipulations is based on homologous recombination of a PCR product that contains genomic target sequences and a selectable marker. The CRISPR/Cas9 system has recently been implemented in fission yeast, which allows for seamless genome editing without integration of a selection marker or leaving any other genomic ‘scars’. The published method involves manual design of the single guide RNA (sgRNA), and digestion of a large plasmid with a problematic restriction enzyme to clone the sgRNA. To increase the efficiency of this approach, we have established and optimized a PCR-based system to clone the sgRNA without restriction enzymes into a plasmid with a dominant natMX6 (nourseothricin) selection marker. We also provide a web-tool, CRISPR4P, to support the design of the sgRNAs and the primers required for the entire process of seamless DNA deletion. Moreover, we report the preparation of G1-synchronized and cryopreserved S. pombe cells, which greatly increases the efficiency and speed for transformations, and may also facilitate standard gene manipulations. Applying this optimized CRISPR/Cas9-based approach, we have successfully deleted over 80 different non-coding RNA genes, which are generally lowly expressed, and have inserted 7 point mutations in 4 different genomic regions.

Se describen dos casos de drenaje venoso pulmonar anómalo parcial del pulmón izquierdo a la vena vertical, la cual drena a su vez a la vena innominada, en dos niños de 6 y 8 años respectivamente. Se exponen el cuadro clínico, los hallazgos del cateterismo, la evolución clínica y el resultado postquirúrgico; adicionalmente, se hace una revisión de la literatura.

The Anaphase-promoting complex/cyclosome (APC/C) cofactor Cdh1 modulates cell proliferation by targeting multiple cell-cycle regulators for ubiquitin-dependent degradation. Lack of Cdh1 results in structural and numerical chromosome aberrations, a hallmark of genomic instability. By using a proteomic approach in Cdh1-null cells and mouse tissues, we have identified kinesin Eg5 and topoisomerase 2α as Cdh1 targets involved in the maintenance of genomic stability. These proteins are ubiquitinated and degraded through specific KEN and D boxes in a Cdh1-dependent manner. Whereas Cdh1-null cells display partial resistance to Eg5 inhibitors such as monastrol, lack of Cdh1 results in a dramatic sensitivity to Top2α poisons as a consequence of increased levels of trapped Top2α-DNA complexes. Chemical inhibition of the APC/C in cancer cells results in increased sensitivity to Top2α poisons. This work identifies in vivo targets of the mammalian APC/C-Cdh1 complex and reveals synthetic lethal interactions of relevance in anticancer treatments.

Treatment satisfaction in patients with relapsing-remitting multiple sclerosis (RRMS) may impact adherence and thus clinical outcomes. The objective of this study was to measure the satisfaction of patients with RRMS with injectable disease-modifying therapies (DMTs) and to evaluate the factors associated with treatment satisfaction.In this observational retrospective study conducted in the neurology departments of 35 hospitals throughout Spain, demographic data, disease characteristics, and information on treatment with injectable DMTs were collected at a single scheduled visit. Treatment satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM), version 1.4. Patients also answered complementary questions about the factors that might affect treatment satisfaction. The data collected were analyzed descriptively. A regression model was used to explore the factors associated with treatment satisfaction.The study included 445 patients (mean±SD age, 41±10.2 years; two-thirds women). The percentages treated with each DMT were Avonex 28.5%, Rebif 44 μg 24.5%, Copaxone 22.5%, Betaferon 13.0%, Rebif22 μg 8.3% and Extavia 3.1%. The mean±SD overall satisfaction according to the TSQM was 68.8±18.6 and the highest overall satisfaction was reported for Rebif 22 μg (72.4±20.3) and the lowest for Extavia (61.7±23.7). In the regression analysis, rehabilitation, interference with social life, pain on injection and number of MS treatments received were significantly associated with a decrease in overall TSMQ score. A small but significant negative correlation was found between EDSS scores and TSMQ scores (rho = -0.11, p = 0.02) and effectiveness (rho = -0.17, p

In the fission yeast Schizosaccharomyces pombe the prevailing approach for gene manipulations is based on homologous recombination of a PCR product that contains genomic target sequences and a selectable marker. The CRISPR/Cas9 system has recently been implemented in fission yeast, which allows for seamless genome editing without integration of a selection marker or leaving any other genomic ‘scars’. The published method involves manual design of the single guide RNA (sgRNA), and digestion of a large plasmid with a problematic restriction enzyme to clone the sgRNA. To increase the efficiency of this approach, we have established and optimized a PCR-based system to clone the sgRNA without restriction enzymes into a plasmid with a dominant natMX6 (nourseothricin) selection marker. We also provide a web-tool, CRISPR4P, to support the design of the sgRNAs and the primers required for the entire process of seamless DNA deletion. Moreover, we report the preparation of G1-synchronized and cryopreserved S. pombe cells, which greatly increases the efficiency and speed for transformations, and may also facilitate standard gene manipulations. Applying this optimized CRISPR/Cas9-based approach, we have successfully deleted over 80 different non-coding RNA genes, which are generally lowly expressed, and have inserted 7 point mutations in 4 different genomic regions.

Para los mayas, a diferencia de Occidente, la matemática tiene un significado que sobrepasa los numerales y las operaciones entre ellos. Según su cosmovisión, la Deidad, la creadora del universo, es soberana en cuanto al cálculo matemático (Cabrera, 1992). La matemática maya ofrece la posibilidad de realizar las operaciones aritméticas de suma, resta, multiplicación, división y cálculo de raíces de forma sencilla, dado que la cultura maya logró sintetizar la cantidad mediante tres símbolos y logró sintetizar el valor con el sistema posicional en base veinte (Calderón, 1966). Se pretende en este artículo hacer un reconocimiento de los numerales mayas, su concepción metafórica y algunas operaciones aritméticas.

La idea esencial es que a la planificación estratégica territorial, como proceso complejo, han de incorporarse estudios que propicien la identificación de los factores del desarrollo con el fin de lograr una relación directa entre éstos y los objetivos estratégicos. Esta relación ha de favorecer los cambios estructurales implícitos en los procesos de desarrollo. Desde el punto de vista teórico se aporta una definición de factores del desarrollo y, sobre esta base, se fundamenta un procedimiento metodológico para su identificación mediante el uso de las técnicas de análisis regional, métodos de análisis estructural y de expertos, éstos últimos para el estudio de la relación objetivos estratégicos-factores del desarrollo. La propuesta constituye un instrumento para el perfeccionamiento de la gestión y planificación estratégicas a escala local.

La leucemia aguda promielocítica (LAP) se caracteriza por la presencia de la translocación recíproca t (15;17) que tiene como resultado la formación del gen híbrido PML-RARa . Como la LAP se considera una emergencia hematológica y además tiene hoy en día un tratamiento muy específico con ácido retinoico (ATRA), es muy importante hacer un diagnóstico rápido y preciso, que en muchos casos permite incluso salvar la vida del paciente. En la actualidad se han desarrollado métodos de RT-PCR para detectar el gen híbrido PML-RARa . Estas técnicas moleculares han sido extremadamente útiles en el diagnóstico de esta entidad. En este trabajo presentamos los resultados preliminares del diagnóstico molecular en 38 pacientes con LAP. En 36 pacientes se demostró la presencia del gen híbrido y 2 fueron negativos. Del total de enfermos con resultados positivos, 19 (55 %) fueron bcr 1, 2 (5 %) fueron bcr 2 y 14 (40 %) fueron bcr 3. Todos los pacientes con resultados positivos respondieron al tratamiento con ATRA. En 1 de los 2 pacientes con resultados negativos se demostró la presencia de la t(11;17). Ninguno de estos 2 enfermos respondió al tratamiento con ATRAAcute promyelocytic leukemia (APL) is characterized by the reciprocal translocation t(15; 17) that results in fusion gene PML-RARa formation. As APL is considered to be an hematological emergency and also is given a very specific treatment with retinoic acid (ATRA), then it is very important to diagnose quickly and accurately which makes it possible in many cases to save the patient's life. At present RT- PCR methods have been developed to detect PML-RARa gen. These molecular techniques have been extremely useful in diagnosing this entity. This paper sets forth the preliminary results of molecular diagnoses of APL in 38 patients. 36 cases presented the fusion gene and 2 did not. Of the total number of positive patients, 19(55%) were bcr 1, 2 (5%) were bcr 2 and 14(40%) bcr 3. All the patients with positive results were responsive to treatment with ATRA. One of the two patients with negative results showed the existence of t (11; 17). These two patients did not respond to treatment with ATRA

BackgroundHuman endogenous retroviruses (HERVs) are repetitive sequences derived from ancestral germ-line infections by exogenous retroviruses and different HERV families have been integrated in the genome. HERV-Fc1 in chromosome X has been previously associated with multiple sclerosis (MS) in Northern European populations. Additionally, HERV-Fc1 RNA levels of expression have been found increased in plasma of MS patients with active disease. Considering the North-South latitude gradient in MS prevalence, we aimed to evaluate the role of HERV-Fc1on MS risk in three independent Spanish cohorts.MethodsA single nucleotide polymorphism near HERV-Fc1, rs391745, was genotyped by Taqman chemistry in a total of 2473 MS patients and 3031 ethnically matched controls, consecutively recruited from: Northern (569 patients and 980 controls), Central (883 patients and 692 controls) and Southern (1021 patients and 1359 controls) Spain. Our results were pooled in a meta-analysis with previously published data.ResultsSignificant associations of the HERV-Fc1 polymorphism with MS were observed in two Spanish cohorts and the combined meta-analysis with previous data yielded a significant association [rs391745 C-allele carriers: pM-H = 0.0005; ORM-H (95% CI) = 1.27 (1.11-1.45)]. Concordantly to previous findings, when the analysis was restricted to relapsing remitting and secondary progressive MS samples, a slight enhancement in the strength of the association was observed [pM-H = 0.0003, ORM-H (95% CI) = 1.32 (1.14-1.53)].ConclusionAssociation of the HERV-Fc1 polymorphism rs391745 with bout-onset MS susceptibility was confirmed in Southern European cohorts.

Polycomb group (PcG) proteins are transcriptional repressors of genes involved in development and differentiation, and also maintain repression of key genes involved in the cell cycle, indirectly regulating cell proliferation. The human SCML2 gene, a mammalian homologue of the Drosophila PcG protein SCM, encodes two protein isoforms: SCML2A that is bound to chromatin and SCML2B that is predominantly nucleoplasmic. Here, we purified SCML2B and found that it forms a stable complex with CDK/CYCLIN/p21 and p27, enhancing the inhibitory effect of p21/p27. SCML2B participates in the G1/S checkpoint by stabilizing p21 and favoring its interaction with CDK2/CYCE, resulting in decreased kinase activity and inhibited progression through G1. In turn, CDK/CYCLIN complexes phosphorylate SCML2, and the interaction of SCML2B with CDK2 is regulated through the cell cycle. These findings highlight a direct crosstalk between the Polycomb system of cellular memory and the cell-cycle machinery in mammals.

CD6 has recently been identified and validated as risk gene for multiple sclerosis (MS), based on the association of a single nucleotide polymorphism (SNP), rs17824933, located in intron 1. CD6 is a cell surface scavenger receptor involved in T-cell activation and proliferation, as well as in thymocyte differentiation. In this study, we performed a haptag SNP screen of the CD6 gene locus using a total of thirteen tagging SNPs, of which three were non-synonymous SNPs, and replicated the recently reported GWAS SNP rs650258 in a Spanish-Basque collection of 814 controls and 823 cases. Validation of the six most strongly associated SNPs was performed in an independent collection of 2265 MS patients and 2600 healthy controls. We identified association of haplotypes composed of two non-synonymous SNPs [rs11230563 (R225W) and rs2074225 (A257V)] in the 2(nd) SRCR domain with susceptibility to MS (P max(T) permutation = 1×10(-4)). The effect of these haplotypes on CD6 surface expression and cytokine secretion was also tested. The analysis showed significantly different CD6 expression patterns in the distinct cell subsets, i.e. - CD4(+) naïve cells, P = 0.0001; CD8(+) naïve cells, P

BackgroundAdherence to interferon β-1b (INFβ-1b) therapy is essential to maximize the beneficial effects of treatment in multiple sclerosis (MS). For that reason, the main objectives of this study are to assess adherence to INFβ-1b in patients suffering from MS in Spain, and to identify the factors responsible for adherence in routine clinical practice.Methodology/principal findingsThis was an observational, retrospective, cross-sectional study including 120 Spanish patients with MS under INFβ-1b treatment. Therapeutic adherence was assessed with Morisky-Green test and with the percentage of doses received. The proportion of adherent patients assessed by Morisky-Green test was 68.3%, being indicative of poor adherence. Nevertheless, the percentage of doses received, which was based on the number of injected medication, was 94.3%. The main reason for missing INFβ-1b injections was forgetting some of the administrations (64%). Therefore, interventions that diminish forgetfulness might have a positive effect in the proportion of adherent patients and in the percentage of doses received. In addition, age and comorbidities had a significant effect in the number of doses injected per month, and should be considered in the management of adherence in MS patients.Conclusion/significanceAmong all the available methods for assessing adherence, the overall consumption of the intended dose has to be considered when addressing adherence.

Multiple Sclerosis (MS) is the most common progressive and disabling neurological condition affecting young adults in the world today. From a genetic point of view, MS is a complex disorder resulting from the combination of genetic and non-genetic factors. We aimed to identify previously unidentified loci conducting a new GWAS of Multiple Sclerosis (MS) in a sample of 296 MS cases and 801 controls from the Spanish population. Meta-analysis of our data in combination with previous GWAS was done. A total of 17 GWAS-significant SNPs, corresponding to three different loci were identified:HLA, IL2RA, and 5p13.1. All three have been previously reported as GWAS-significant. We confirmed our observation in 5p13.1 for rs9292777 using two additional independent Spanish samples to make a total of 4912 MS cases and 7498 controls (ORpooled = 0.84; 95%CI: 0.80-0.89; p = 1.36 × 10-9). This SNP differs from the one reported within this locus in a recent GWAS. Although it is unclear whether both signals are tapping the same genetic association, it seems clear that this locus plays an important role in the pathogenesis of MS.

The human leukocyte antigen (HLA) DRB1*1501 has been consistently associated with multiple sclerosis (MS) in nearly all populations tested. This points to a specific antigen presentation as the pathogenic mechanism though this does not fully explain the disease association. The identification of expression quantitative trait loci (eQTL) for genes in the HLA locus poses the question of the role of gene expression in MS susceptibility. We analyzed the eQTLs in the HLA region with respect to MS-associated HLA-variants obtained from genome-wide association studies (GWAS). We found that the Tag of DRB1*1501, rs3135388 A allele, correlated with high expression of DRB1, DRB5 and DQB1 genes in a Caucasian population. In quantitative terms, the MS-risk AA genotype carriers of rs3135388 were associated with 15.7-, 5.2- and 8.3-fold higher expression of DQB1, DRB5 and DRB1, respectively, than the non-risk GG carriers. The haplotype analysis of expression-associated variants in a Spanish MS cohort revealed that high expression of DRB1 and DQB1 alone did not contribute to the disease. However, in Caucasian, Asian and African American populations, the DRB1*1501 allele was always highly expressed. In other immune related diseases such as type 1 diabetes, inflammatory bowel disease, ulcerative colitis, asthma and IgA deficiency, the best GWAS-associated HLA SNPs were also eQTLs for different HLA Class II genes. Our data suggest that the DR/DQ expression levels, together with specific structural properties of alleles, seem to be the causal effect in MS and in other immunopathologies rather than specific antigen presentation alone.

The TNF-related apoptosis inducing ligand (TRAIL)/TRAIL receptor system participates in crucial steps in immune cell activation or differentiation. It is able to inhibit proliferation and activation of T cells and to induce apoptosis of neurons and oligodendrocytes, and seems to be implicated in autoimmune diseases. Thus, TRAIL and TRAIL receptor genes are potential candidates for involvement in susceptibility to multiple sclerosis (MS). To test whether single-nucleotide polymorphisms (SNPs) in the human genes encoding TRAIL, TRAILR-1, TRAILR-2, TRAILR-3 and TRAILR-4 are associated with MS susceptibility, we performed a candidate gene case-control study in the Spanish population. 59 SNPs in the TRAIL and TRAIL receptor genes were analysed in 628 MS patients and 660 controls, and validated in an additional cohort of 295 MS patients and 233 controls. Despite none of the SNPs withstood the highly conservative Bonferroni correction, three SNPs showing uncorrected p values

The design, implementation, and test of a real-time flexible 2×2 (Multiple Input Multiple Output-Orthogonal Frequency Division Multiplexing) MIMO-OFDM IEEE 802.16 prototype are presented. For the design, a channel measurement campaign on the 3.5 GHz band has been carried out, focusing on outdoor-indoor scenarios. The analysis of measured channels showed that higher capacity can be achieved in case of obstructed scenarios and that (Channel Distribution Information at the Transmitter) CDIT capacity is close to (Channel State Information at the Transmitter) CSIT with much lower complexity and requirements in terms of channel estimation and feedback. The baseband prototype used an (Field Programmable Gate Array) FPGA where enhanced signal processing algorithms are implemented in order to improve system performance. We have shown that for MIMO-OFDM systems, extra signal processing such as enhanced joint channel and frequency offset estimation is needed to obtain a good performance and approach in practice the theoretical capacity improvements.

BACKGROUND: IL-2 receptor (IL2R) alpha is the specific component of the high affinity IL2R system involved in the immune response and in the control of autoimmunity. METHODS AND RESULTS: Here we perform a replication and fine mapping of the IL2RA gene region analyzing 3 SNPs previously associated with multiple sclerosis (MS) and 5 SNPs associated with type 1 diabetes (T1D) in a collection of 798 MS patients and 927 matched Caucasian controls from the south of Spain. We observed association with MS in 6 of 8 SNPs. The rs1570538, at the 3'- UTR extreme of the gene, previously reported to have a weak association with MS, is replicated here (P = 0.032). The most associated T1D SNP (rs41295061) was not associated with MS in the present study. However, the rs35285258, belonging to another independent group of SNPs associated with T1D, showed the maximal association in this study but different risk allele. We replicated the association of only one (rs2104286) of the two IL2RA SNPs identified in the recently performed genome-wide association study of MS. CONCLUSIONS: These findings confirm and extend the association of this gene with MS and reveal a genetic heterogeneity of the associated polymorphisms and risk alleles between MS and T1D suggesting different immunopathological roles of IL2RA in these two diseases.

A pesar de que hoy menos que ayer exista acuerdo sobre el contenido significativo de la expresión sociedad civil, hoy, quizás más que ayer, amparados a esa noción, o enarbolando esa bandera, impugnadores, reformadores o dirigentes de diverso orden y signo, se sienten bien escudados al evocar o al invocar esas palabras. En sus diversas y sucesivas formulaciones, la noción de sociedad civil ha enfrentado una concepción de civilidad polémica a las prácticas y a las representaciones del poder predominantes en su momento histórico: 1) la de contractualidad social y autofundante a la legitimidad sagrada del poder defendida sobre todo por los teóricos absolutistas de la pre-modernidad; 2) la de una civilidad fundada en la persuasión, el arreglo y el consenso frente al recurso a la violencia y a la lucha armada; 3) la de la irreductibilidad de la vida social y cultural frente a las tentativas de control y de subordinación por parte de un poder central, monopolizador de la iniciativa y del quehacer político.

El Análisis de Cluster, junto con el Análisis de Componentes Principales, es un método de gran interés en Sociología dentro de la perspectiva que se puede llamar de descripciones densas. Además su aplicación es más fecunda cuando se realiza complementariamente al Análisis de Componentes. En el artículo se da cuenta del proceso y del diseño de su realización sin entrar en los aspectos matemáticos. Así, se trata en él de la preparación del método, de losprocedimientos y criterios de elección del número de clusters y de las formas de validación del mismo. La insistencia en la validación proviene de que aún siendo un método fecundo de agregación, es muy sensible, sin embargo, a las variaciones que puede tener su preparación y a los criterios de selección de grupos.