Statistical Model Checking of e-Motions Domain-Specific Modeling Languages

Domain experts may use novel tools that allow them to de- sign and model their systems in a notation very close to the domain problem. However, the use of tools for the statistical analysis of stochas- tic systems requires software engineers to carefully specify such systems in low level and specific languages. In this work we line up both sce- narios, specific domain modeling and statistical analysis. Specifically, we have extended the e-Motions system, a framework to develop real-time domain-specific languages where the behavior is specified in a natural way by in-place transformation rules, to support the statistical analysis of systems defined using it. We discuss how restricted e-Motions sys- tems are used to produce Maude corresponding specifications, using a model transformation from e-Motions to Maude, which comply with the restrictions of the VeStA tool, and which can therefore be used to per- form statistical analysis on the stochastic systems thus generated. We illustrate our approach with a very simple messaging distributed system.Universidad de Málaga Campus de Excelencia Internacional Andalucía Tech. Research Project TIN2014-52034-R an

Planar Chirality: A Mine for Catalysis and Structure Discovery

[EN] Planar chirality is one of the most fascinating expressions of chirality, which is exploited by nature to lock three-dimensional chiral conformations and, more recently, by chemists to create new chiral reagents, catalysts, and functional organic materials. Nevertheless, the shortage of procedures able to induce and secure asymmetry during the generation of these unique chiral entities has dissuaded chemists from exploiting their structural properties. This Minireview intends to illustrate the limited but remarkable catalytic methods that have been reported for the production of planar chirality in strained molecules and serve as a source of inspiration for the development of new unconventional procedures, which are expected to appear in the near future.We thank the University of the Basque Country UPV/EHU (UFIQOSYC 11/22), the Basque Government (grant IT-1236-19) and Ministerio de Ciencia e Innovation (grant PID2019-109633GB-C21), Spain, for their continuous financial support

Desarrollo de software para sistemas de tiempo real basado en UML. Un enfoque formal basado en metamodelado

El presente trabajo propone una metodología de desarrollo de sistemas de tiempo real que hace un énfasis especial en la consideración de los requisitos no funcionales característicos de este tipo de sistema como los requisitos temporales, la concurrencia, la asignación de prioridades o la interacción con dispositivos físicos. La metodología toma elementos de otras ya existentes, como SOMT y OCTOPUS y propone mecanismos propios para solventar parcialmente problemas como el paso del modelo de objetos al modelo de proceso y la asignación de prioridades. La metodología se divide en cuatro fases divididas en dos áreas distintas, la de los aspectos funcionales y los no funcionales. Durante toda la metodología se usa orientación objetivo y UML. Para aprovechar las ventajas de los métodos formales, como simulación, validación y generación de códigos se propone una semántica formal para parte de los aspectos dinámicos de UML, concretamente las acciones y las máquinas de estados. La semántica propuesta se basa en metamodelado y en el lenguaje MML. En ellas se distingue entre los la sintaxis abstracta y el dominio semántico. Los elementos válidos de ambos conjuntos se definen mediante diagramas de clases, de los que han de ser instancias válidas, y restricciones expresadas en el lenguaje funcional OCL. Los elementos de ambos conjuntos están relacionados entre si a través de la semántica, que implica una relación de uno (en la sintaxis abstracta, el extremo "OF") a muchos (en el dominio semántico, el extremo "instances").Con este esquema, se ha definido una semántica para acciones y ejecuciones, con una jerarquía de clases para los diferentes tipos de acciones y ejecuciones, En el primer nivel de esa jerarquía se distinguen acciones primitivas y compuestas. Una acción se define como un procedimiento computacional que modifica el estado de un elemento del sistema

Tratamiento

Los objetivos del tratamiento del paciente con EPOC son: aliviar los síntomas, mejorar la calidad de vida, la tolerancia al ejercicio, evitar la progresión de la enfermedad, prevenir las complicaciones y aumentar la supervivencia. Los principales pilares de este tratamiento son: evitar la exposición a factores de riesgo (tabaco, tóxicos ambientales...), el tratamiento broncodilatador y antiinflamatorio, la oxigenoterapia, la rehabilitación y algunas medias generales orientadas a mejorar la calidad de vida y la prevención de reagudizaciones. De todas ellas, únicamente el abandono del tabaquismo y la oxigenoterapia, en los casos indicados, han demostrado aumentar la expectativa de vida de los pacientes

Interactive Data Exploration of Distributed Raw Files: A Systematic Mapping Study

When exploring big amounts of data without a clear target, providing an interactive experience becomes really dif cult, since this tentative inspection usually defeats any early decision on data structures or indexing strategies. This is also true in the physics domain, speci cally in high-energy physics, where the huge volume of data generated by the detectors are normally explored via C++ code using batch processing, which introduces a considerable latency. An interactive tool, when integrated into the existing data management systems, can add a great value to the usability of these platforms. Here, we intend to review the current state-of-the-art of interactive data exploration, aiming at satisfying three requirements: access to raw data les, stored in a distributed environment, and with a reasonably low latency. This paper follows the guidelines for systematic mapping studies, which is well suited for gathering and classifying available studies.We summarize the results after classifying the 242 papers that passed our inclusion criteria. While there are many proposed solutions that tackle the problem in different manners, there is little evidence available about their implementation in practice. Almost all of the solutions found by this paper cover a subset of our requirements, with only one partially satisfying the three. The solutions for data exploration abound. It is an active research area and, considering the continuous growth of data volume and variety, is only to become harder. There is a niche for research on a solution that covers our requirements, and the required building blocks are there

Myogenic Precursors from iPS Cells for Skeletal Muscle Cell Replacement Therapy.

The use of adult myogenic stem cells as a cell therapy for skeletal muscle regeneration has been attempted for decades, with only moderate success. Myogenic progenitors (MP) made from induced pluripotent stem cells (iPSCs) are promising candidates for stem cell therapy to regenerate skeletal muscle since they allow allogenic transplantation, can be produced in large quantities, and, as compared to adult myoblasts, present more embryonic-like features and more proliferative capacity in vitro, which indicates a potential for more self-renewal and regenerative capacity in vivo. Different approaches have been described to make myogenic progenitors either by gene overexpression or by directed differentiation through culture conditions, and several myopathies have already been modeled using iPSC-MP. However, even though results in animal models have shown improvement from previous work with isolated adult myoblasts, major challenges regarding host response have to be addressed and clinically relevant transplantation protocols are lacking. Despite these challenges we are closer than we think to bringing iPSC-MP towards clinical use for treating human muscle disease and sporting injuries

Proteomic Analysis of Human iPSC-Derived Neural Stem Cells and Motor Neurons Identifies Proteasome Structural Alterations

Altres ajuts: Fundació La Marató de TV3 (20172110/FBG309768)Background: Proteins targeted by the ubiquitin proteasome system (UPS) are identified for degradation by the proteasome, which has been implicated in the development of neurodegenerative diseases. Major histocompatibility complex (MHC) molecules present peptides broken down by the proteasome and are involved in neuronal plasticity, regulating the synapse number and axon regeneration in the central or peripheral nervous system during development and in brain diseases. The mechanisms governing these effects are mostly unknown, but evidence from different compartments of the cerebral cortex indicates the presence of immune-like MHC receptors in the central nervous system. Methods: We used human induced pluripotent stem cells (iPSCs) differentiated into neural stem cells and then into motor neurons as a developmental model to better understand the structure of the proteasome in developing motor neurons. We performed a proteomic analysis of starting human skin fibroblasts, their matching iPSCs, differentiated neural stem cells and motor neurons that highlighted significant differences in the constitutive proteasome and immunoproteasome subunits during development toward motor neurons from iPSCs. Results: The proteomic analysis showed that the catalytic proteasome subunits expressed in fibroblasts differed from those in the neural stem cells and motor neurons. Western blot analysis confirmed the proteomic data, particularly the decreased expression of the β5i (PSMB8) subunit immunoproteasome in MNs compared to HFFs and increased β5 (PSMB5) in MNs compared to HFFs. Conclusion: The constitutive proteasome subunits are upregulated in iPSCs and NSCs from HFFs. Immunoproteasome subunit β5i expression is higher in MNs than NSCs; however, overall, there is more of a constitutive proteasome structure in MNs when comparing HFFs to MNs. The proteasome composition may have implications for motor neuron development and neurodevelopmental diseases that warrant further investigation

Two novel ligand-independent variants of the VEGFR-1 receptor are expressed in human testis and spermatozoa, one of them with the ability to activate SRC proto-oncogene tyrosine kinases

SRC activation; Fertility; Mature testisActivación de SRC; Fertilidad; Testículo maduroActivació SRC; Fertilitat; Testicle madurThe vascular endothelial growth factor receptor 1 (VEGFR-1) family of receptors is preferentially expressed in endothelial cells, with the full-length and mostly the soluble (sVEGFR-1) isoforms being the most expressed ones. Surprisingly, cancer cells (MDA-MB-231) express, instead, alternative intracellular VEGFR-1 variants. We wondered if these variants, that are no longer dependent on ligands for activation, were expressed in a physiological context, specifically in spermatogenic cells, and whether their expression was maintained in spermatozoa and required for human fertility. By interrogating a human library of mature testis cDNA, we characterized two new truncated intracellular variants different from the ones previously described in cancer cells. The new isoforms were transcribed from alternative transcription start sites (aTSS) located respectively in intron-19 (i19VEGFR-1) and intron-28 (i28VEGFR-1) of the VEGFR-1 gene (GenBank accession numbers JF509744 and JF509745) and expressed in mature testis and spermatozoa. In this paper, we describe the characterization of these isoforms by RT-PCR, northern blot, and western blot, their preferential expression in human mature testis and spermatozoa, and the elements that punctuate their proximal promoters and suggest cues for their expression in spermatogenic cells. Mechanistically, we show that i19VEGFR-1 has a strong ability to phosphorylate and activate SRC proto-oncogene non-receptor tyrosine kinases and a significant bias toward a decrease in expression in patients considered infertile by WHO criteria.This study was supported by the University of Barcelona, MINECO project grant BFU2014-54467-P

Exploiting endocytosis for transfection of mRNA for cytoplasmatic delivery using cationic gold nanoparticles

Gene therapeutics; Gold nanoparticles; SafetyTerapia génica; Nanopartículas de oro; SeguridadTeràpia gènica; Nanopartícules d'or; SeguretatIntroduction: Gene therapy holds promise to cure various diseases at the fundamental level. For that, efficient carriers are needed for successful gene delivery. Synthetic ‘non-viral’ vectors, as cationic polymers, are quickly gaining popularity as efficient vectors for transmitting genes. However, they suffer from high toxicity associated with the permeation and poration of the cell membrane. This toxic aspect can be eliminated by nanoconjugation. Still, results suggest that optimising the oligonucleotide complexation, ultimately determined by the size and charge of the nanovector, is not the only barrier to efficient gene delivery. Methods: We herein develop a comprehensive nanovector catalogue comprising different sizes of Au NPs functionalized with two different cationic molecules and further loaded with mRNA for its delivery inside the cell. Results and Discussion: Tested nanovectors showed safe and sustained transfection efficiencies over 7 days, where 50 nm Au NPs displayed the highest transfection rates. Remarkably, protein expression was increased when nanovector transfection was performed combined with chloroquine. Cytotoxicity and risk assessment demonstrated that nanovectors are safe, ascribed to lesser cellular damage due to their internalization and delivery via endocytosis. Obtained results may pave the way to design advanced and efficient gene therapies for safely transferring oligonucleotides.We acknowledge financial support from the Spanish Ministerio de Ciencia, Innovación y Universidades (MCIU) (RTI2018-099965-B-I00, AEI/FEDER,UE) proyectos de I+D+i de programación conjunta internacional MCIN/AEI (CONCORD, PCI2019-103436) cofunded by the European Union and Generalitat de Catalunya (2017-SGR-1431). ICN2 is supported by the Severo Ochoa program from Spanish MINECO (SEV-2017-0706) and is funded by the CERCA Programme/Generalitat de Catalunya