A Poglut1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss

Skeletal muscle regeneration by muscle satellite cells is a physiological mechanism activated upon muscle damage and regulated by Notch signaling. In a family with autosomal recessive limbgirdle muscular dystrophy, we identified a missense mutation in POGLUT1 (protein O-glucosyltransferase 1), an enzyme involved in Notch posttranslational modification and function. In vitro and in vivo experiments demonstrated that the mutation reduces Oglucosyltransferase activity on Notch and impairs muscle development. Muscles from patients revealed decreased Notch signaling, dramatic reduction in satellite cell pool and a muscle-specific adystroglycan hypoglycosylation not present in patients’ fibroblasts. Primary myoblasts from patients showed slow proliferation, facilitated differentiation, and a decreased pool of quiescent PAX7+ cells. A robust rescue of the myogenesis was demonstrated by increasing Notch signaling. None of these alterations were found in muscles from secondary dystroglycanopathy patients. These data suggest that a key pathomechanism for this novel form of muscular dystrophy is Notch-dependent loss of satellite cells.Junta de Andalucía PI-0017-201

Finding the "Dark Matter'' in Human and Yeast Protein Network Prediction and Modelling

Accurate modelling of biological systems requires a deeper and more complete knowledge about the molecular components and their functional associations than we currently have. Traditionally, new knowledge on protein associations generated by experiments has played a central role in systems modelling, in contrast to generally less trusted bio-computational predictions. However, we will not achieve realistic modelling of complex molecular systems if the current experimental designs lead to biased screenings of real protein networks and leave large, functionally important areas poorly characterised. To assess the likelihood of this, we have built comprehensive network models of the yeast and human proteomes by using a meta-statistical integration of diverse computationally predicted protein association datasets. We have compared these predicted networks against combined experimental datasets from seven biological resources at different level of statistical significance. These eukaryotic predicted networks resemble all the topological and noise features of the experimentally inferred networks in both species, and we also show that this observation is not due to random behaviour. In addition, the topology of the predicted networks contains information on true protein associations, beyond the constitutive first order binary predictions. We also observe that most of the reliable predicted protein associations are experimentally uncharacterised in our models, constituting the hidden or "dark matter'' of networks by analogy to astronomical systems. Some of this dark matter shows enrichment of particular functions and contains key functional elements of protein networks, such as hubs associated with important functional areas like the regulation of Ras protein signal transduction in human cells. Thus, characterising this large and functionally important dark matter, elusive to established experimental designs, may be crucial for modelling biological systems. In any case, these predictions provide a valuable guide to these experimentally elusive regions

The morphology of CLL revisited: the clinical significance of prolymphocytes and correlations with prognostic/molecular markers in the LRF CLL4 trial

Historically, an increase in the percentage and number of circulating prolymphocytes in chronic lymphocytic leukaemia (CLL) has been associated with strong expression of surface immunoglobulin, trisomy 12 and a poor outcome. This study re-examines the biological and clinical significance of increased peripheral blood prolymphocytes in 508 patients at entry into the randomized UK Leukaemia Research Fund CLL4 trial. It also investigates the associations between increased prolymphocytes and a comprehensive array of biomarkers. 270 patients (53%) had <5% prolymphocytes, 167 (33%) had 5-9%, 60 (12%) had 10-14% and 11 (2%) had ?15% prolymphocytes. We show that a higher proportion of prolymphocytes (?10%) was independently associated with NOTCH1 mutations (P = 0·006), absence of 13q deletion (P = 0·001), high CD38 expression (P = 0·02) and unmutated IGHV genes (P = 0·01). Deaths due to Richter syndrome were significantly more common amongst patients who had ?10% vs <10% prolymphocytes (13% vs 2%) respectively (P < 0·0001). ?10% prolymphocytes was also associated with a shorter progression-free survival (Hazard ratio [HR] 1·50 [95% confidence interval [CI]: 1·16-1·93], P = 0·002) and overall survival (HR 1·99 [95% CI: 1·53-2·59], P < 0·0001). Our data support the routine examination of blood films in CLL and suggest that a finding of an increased proportion of prolymphocytes may be a trigger for further evaluation of clinical and laboratory features of progressive disease

Design and validation of a tool to assess motor coordination in primary

La coordinación motriz es un proceso evolutivo complejo de adquisición progresiva. La edad óptima para la adquisición de esos procesos coordinativos es de 6 a 11 años (Educación Primaria). El objetivo del presente estudio es diseñar y validar un instrumento que permita evaluar el nivel de coordinación motriz del alumnado Método: Los sujetos son alumnado de Primaria en centros públicos. Muestreo por conveniencia, con una muestra total de 2512 sujetos. Instrumento: Test cualitativo de observación y evaluación objetiva de la ejecución de la habilidad desarrollada en 7 tareas. Resultados: La Consistencia interna (Alfa de Cronbach 0.827), estabilidad temporal (coeficiente correlación: 0.99) y concordancia inter-observadores (coeficiente correlación: 0.95). La validez se comprobó mediante la opinión intuitiva de expertos, siendo la opinión mayoritariamente favorable. Conclusión: El test 3JS es un instrumento fiable, válido y eficaz para medir el desarrollo de la coordinación motriz en el alumnado de 6 a 12 añosMotor coordination is a complex evolutionary process which is gradually acquired. The optimum age for the achievement of these coordination processes is between 6 and 11 years old (Primary Education). The aim of this study is to design and validate a tool which will allow assessing the motor coordination level of the students. Method: Subjects and Sample. Students from Primary Education public schools. ‘Convenience’ sampling, with a total of 2512 subjects. Tool: Qualitative observation test and objective evaluation of the implementation of the abilities developed in 7 tasks. Results: Reliability: Internal Consistency (Cronbach Alpha 0.827), test-retest reliability (correlation coefficient; 0.99) and inter-observer agreement (correlation coefficient; 0.95). Validity has been verified by the experts’ intuitive perception, issuing a largely favourable opinion. Conclusion: The 3JS test is a reliable, valid and effective tool for measuring the motor coordination development in students between 6 and 12 years ol

Muros de escollera en urbanizaciones

The uneven and slopes terrain force us to intervene with rigid or flexible containment structures. Containment structures tend to be mostly of reinforced concrete or steel sheet piling. For some time, the use of stone jetties as containment structures and permanent stabilization in housing estates is being imposed. This type of structure has been used successfully in slopes of roads and jetties on port. When moving it to suburbia has disparaged some aspects, both design and calculation, not taking into account actions in risk areas, or eliminating essential components as filters and drain components. This document analyzes the work of intervention in two works affected in Motril (Granada, Spain) and Almeria (Spain), where the breakwaters were utilized, reaching recidivism in one of them. Guide for the design and construction of breakwaters in roadworks from the Ministry of Public Works in 1998, revised in 2006, [3] is a valuable document but requires a Decalogue of specific instructions for use in works of urbanization, in general of lower volume, and with the largest number of meetings of surfaces. Three-dimensionality is usually an important factor to take into account.Los desniveles y pendientes del terreno nos obligan a intervenir mediante estructuras de contención, rígidas o flexibles. Las estructuras de contención suelen ser en su mayor parte de hormigón armado o tablestacas metálicas. Desde hace algún tiempo se está imponiendo la utilización de escolleras de piedra como estructuras de contención y estabilización permanentes en urbanizaciones. Este tipo de estructuras ya habían sido usadas con éxito en taludes de carreteras y espigones de puerto. Al trasladarse a las urbanizaciones se ha menospreciado algunos aspectos, tanto de diseño y cálculo, no teniendo en cuenta las acciones sísmicas en zonas de riesgo como Motril, o eliminando componentes esenciales como filtros y drenajes. El presente documento analiza los trabajos de intervención realizados en dos obras siniestradas en Motril y Almería (España), donde se utilizaron las escolleras, uno de ellos incluso reincidente. La Guía para el diseño y construcción de escolleras en obras de carreteras del Ministerio de Fomento de 1998, revisada en 2006, es un valioso documento pero precisa de un decálogo de instrucciones precisas para su uso en obras de urbanización, en general de menor volumen, y con mayor número de encuentros de superficies. La tridimensionalidad suele ser un factor importante a tener en cuenta

Design of a case management model for people with chronic disease (Heart Failure and COPD). Phase I: modeling and identification of the main components of the intervention through their actors: patients and professionals (DELTA-ICE-PRO Study

Background Chronic diseases account for nearly 60% of deaths around the world. The extent of this silent epidemic has not met determined responses in governments, policies or professionals in order to transform old Health Care Systems, configured for acute diseases. There is a large list of research about alternative models for people with chronic conditions, many of them with an advanced practice nurse as a key provider, as case management. But some methodological concerns raise, above all, the design of the intervention (intensity, frequency, components, etc). Methods/Design Objectives: General: To develop the first and second phases (theorization and modeling) for designing a multifaceted case-management intervention in people with chronic conditions (COPD and heart failure) and their caregivers. Specific aims: 1) To identify key events in people living with chronic disease and their relation with the Health Care System, from their point of view. 2) To know the coping mechanisms developed by patients and their caregivers along the story with the disease. 3) To know the information processing and its utilization in their interactions with health care providers. 4) To detect potential unmet needs and the ways deployed by patients and their caregivers to resolve them. 5) To obtain a description from patients and caregivers, about their itineraries along the Health Care System, in terms of continuity, accessibility and comprehensiveness of care. 6) To build up a list of promising case-management interventions in patients with Heart Failure and COPD with this information in order to frame it into theoretical models for its reproducibility and conceptualization. 7) To undergo this list to expert judgment to assess its feasibility and pertinence in the Andalusian Health Care. Design: Qualitative research with two phases: For the first five objectives, a qualitative technique with biographic stories will be developed and, for the remaining objectives, an expert consensus through Delphi technique, on the possible interventions yielded from the first phase. The study will be developed in the provinces of Almería, Málaga and Granada in the Southern Spain, from patients included in the Andalusian Health Care Service database with the diagnosis of COPD or Heart Failure, with the collaboration of case manager nurses and general practitioners for the assessment of their suitability to inclusion criteria. Patients and caregivers will be interviewed in their homes or their Health Centers, with their family or their case manager nurse as mediator. Discussion First of a series of studies intended to design a case-management service for people with heart failure and COPD, in the Andalusian Health Care System, where case management has been implemented since 2002. Accordingly with the steps of a theoretical model for complex interventions, in this study, theorization and intervention modeling phases will be developed.This research was carried out with the support of one research grant, awarded by the Regional Health Ministry of Andalusia (Exp. 0222/2008

Update on Dihydropteroate Synthase (DHPS) Mutations in Pneumocystis jirovecii

A Pneumocystis jirovecii is one of the most important microorganisms that cause pneumonia in immunosupressed individuals. The guideline for treatment and prophylaxis of Pneumocystis pneumonia (PcP) is the use of a combination of sulfa drug-containing trimethroprim and sulfamethoxazole. In the absence of a reliable method to culture Pneumocystis, molecular techniques have been developed to detect mutations in the dihydropteroate synthase gene, the target of sulfa drugs, where mutations are related to sulfa resistance in other microorganisms. The presence of dihydropteroate synthase (DHPS) mutations has been described at codon 55 and 57 and found almost around the world. In the current work, we analyzed the most common methods to identify these mutations, their geographical distribution around the world, and their clinical implications. In addition, we describe new emerging DHPS mutations. Other aspects, such as the possibility of transmitting Pneumocystis mutated organisms between susceptible patients is also described, as well as a brief summary of approaches to study these mutations in a heterologous expression system

Fast Biofilm Penetration and Anti-PAO1 Activity of Nebulized Azithromycin in Nanoarchaeosomes

Azithromycin (AZ) is a broad-spectrum antibiotic with anti-inflammatory and antiquorum sensing activity against biofilm forming bacteria such as Pseudomonas aeruginosa. AZ administered by oral or parenteral routes, however, neither efficiently accesses nor remains in therapeutic doses inside pulmonary biofilm depths. Instead, inhaled nanocarriers loaded with AZ may revert the problem of low accessibility and permanence of AZ into biofilms, enhancing its antimicrobial activity. The first inhalable nanovesicle formulation of AZ, nanoarchaeosome-AZ (nanoARC-AZ), is here presented. NanoARC prepared with total polar archaeolipids (TPAs), rich in 2,3-di-O-phytanyl-sn-glycero-1-phospho-(3′-sn-glycerol-1′-methylphosphate) (PGP-Me) from Halorubrum tebenquichense archaebacteria, consisted of ∼180 nm-diameter nanovesicles, loaded with 0.28 w/w AZ/TPA. NanoARC-AZ displayed lower minimal inhibitory concentration and minimal bactericidal concentration, higher preformed biofilm disruptive, and anti-PAO1 activity in biofilms than AZ. NanoARC penetrated and disrupted the structure of the PAO1 biofilm within only 1 h. Two milliliters of 15 μg/mL AZ nanoARC-AZ nebulized for 5 min rendered AZ doses compatible with in vitro antibacterial activity. The strong association between AZ and the nanoARC bilayer, combined with electrostatic attraction and trapping into perpendicular methyl groups of archaeolipids, as determined by Laurdan fluorescence anisotropy, generalized polarization, and small-angle X-ray scattering, was critical to stabilize during storage and endure shear forces of nebulization. NanoARC-AZ was noncytotoxic on A549 cells and human THP-1-derived macrophages, deserving further preclinical exploration as enhancers of AZ anti-PAO1 activity.Fil: Altube, María Julia. Universidad Nacional de Quilmes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Martínez, Melina María Belén. Universidad Nacional de Quilmes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Malheiros, Barbara. Universidade de Sao Paulo; BrasilFil: Maffía, Paulo C.. Universidad Nacional de Quilmes; ArgentinaFil: Barbosa, Leandro R. S.. Universidade de Sao Paulo; BrasilFil: Morilla, María José. Universidad Nacional de Quilmes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Romero, Eder Lilia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; Argentin

Intelligence architecture to detect patterns in scanned documents

La Inteligencia Artificial (en adelante IA) puede ser útil para aumentar la eficiencia en el abordaje de los casos que los Poderes Judiciales deben resolver. Sin embargo, los sistemas judiciales en países de Latinoamérica cuentan con ciertos desafíos para la aplicación de sistemas de IA que deben ser superados si se desea aprovechar los beneficios de la automatización inteligente. Los documentos, a lo largo de su ciclo de vida, suelen estar sujetos a escaneos, impresiones y retrabajos en ambos sentidos. En esta presentación se propone una forma alternativa a la de los reconocedores ópticos de caracteres (OCR), basada en IA aplicada a la detección de patrones en imágenes, que puede contribuir a paliar las dificultades mencionadas; no sólo en el ámbito del caso de estudio aplicado, sino en muy diversos dominios de sistemas de gestión de documentos públicos en la región.Artificial Intelligence (AI hereinafter) can be useful to increase efficiency in dealing with cases that the Judiciary must resolve. However, judicial systems in Latin American countries have certain challenges for the application of AI systems that must be overcome if the benefits of intelligent automation are to be exploited. Documents, throughout their life cycle, are often subject to scanning, printing and reworking in both directions. In this paper we propose an alternative way to OCR, based on AI applied to image pattern detection, which can contribute to alleviate the difficulties mentioned above, not only in the applied case study, but also in many different domains of public document management systems in the regionSociedad Argentina de Informática e Investigación Operativ

Effect of partial preferential orientation and distortions in octahedral clusters on the photoluminescence properties of FeWO4 nanocrystals

This communication is a report of our initial research to obtain iron tungstate (FeWO4) nanocrystals by the microwave-hydrothermal method at 170 degrees C for 45 min. X-ray diffraction patterns showed that the FeWO4 nanocrystals prepared with polyethylene glycol-200 have a partial preferential orientation in the (011) plane in relation to other nanocrystals prepared with sodium bis(2-ethylhexyl) sulfosuccinate and water. Rietveld refinement data indicates that all nanocrystals are monophasic with wolframite-type monoclinic structures and exhibit different distortions on octahedral [FeO6]/[WO6] clusters. High resolution transmission electron microcopy revealed an oriented attachment mechanism for the growth of aggregated FeWO4 nanocrystals. Finally, we observed that the photoluminescence properties of these nanocrystals are affected by partial preferential orientation in the (011) plane and distortions on [FeO6]/[WO6] clusters.Brazilian research financing institution FAPESPBrazilian research financing institution: FAPESP [2009/53189-8, 2009/50303-4]Brazilian research financing institution: CNPq [159710/2011-1]Brazilian research financing institution: CNPqBrazilian research financing institution: CAPESBrazilian research financing institution: CAPE