Cholinergic receptor pathways involved in apoptosis, cell proliferation and neuronal differentiation

Acetylcholine (ACh) has been shown to modulate neuronal differentiation during early development. Both muscarinic and nicotinic acetylcholine receptors (AChRs) regulate a wide variety of physiological responses, including apoptosis, cellular proliferation and neuronal differentiation. However, the intracellular mechanisms underlying these effects of AChR signaling are not fully understood. It is known that activation of AChRs increase cellular proliferation and neurogenesis and that regulation of intracellular calcium through AChRs may underlie the many functions of ACh. Intriguingly, activation of diverse signaling molecules such as Ras-mitogen-activated protein kinase, phosphatidylinositol 3-kinase-Akt, protein kinase C and c-Src is modulated by AChRs. Here we discuss the roles of ACh in neuronal differentiation, cell proliferation and apoptosis. We also discuss the pathways involved in these processes, as well as the effects of novel endogenous AChRs agonists and strategies to enhance neuronal-differentiation of stem and neural progenitor cells. Further understanding of the intracellular mechanisms underlying AChR signaling may provide insights for novel therapeutic strategies, as abnormal AChR activity is present in many diseases

Identification and rejection of pile-up jets at high pseudorapidity with the ATLAS detector

The rejection of forward jets originating from additional proton–proton interactions (pile-up) is crucial for a variety of physics analyses at the LHC, including Standard Model measurements and searches for physics beyond the Standard Model. The identification of such jets is challenging due to the lack of track and vertex information in the pseudorapidity range |η| > 2.5. This paper presents a novel strategy for forward pile-up jet tagging that exploits jet shapes and topological jet correlations in pile-up interactions. Measurements of the per-jet tagging efficiency are presented using a data set of 3.2 fb−1 of proton–proton collisions at a centre-of-mass energy of 13 TeV collected with the ATLAS detector. The fraction of pile-up jets rejected in the range 2.5 < |η| < 4.5 is estimated in simulated events with an average of 22 interactions per bunch-crossing. It increases with jet transverse momentum and, for jets with transverse momentum between 20 and 50 GeV, it ranges between 49% and 67% with an efficiency of 85% for selecting hard-scatter jets. A case study is performed in Higgs boson production via the vector-boson fusion process, showing that these techniques mitigate the background growth due to additional proton–proton interactions, thus enhancing the reach for such signatures

Blind competition on the numerical simulation of steel\u2010fiber\u2010reinforced concrete beams failing in shear

Experimental research has shown the extraordinary potential of the addition of short fibers to cement-based materials by improving significantly the behavior of concrete structures for serviceability and ultimate limit states. Software based on the finite element method has been used for the simulation of the material nonlinear behavior of fiber-reinforced concrete (FRC) structures. The applicability of the existing approaches has often been assessed by simulating experimental tests with structural elements, in general of a small scale, where the parameter values of the material constitutive laws are adjusted for the aimed predicting level, which constitutes an inverse technique of arguable utility for structural design practice. For assessing the predictive performance of these approaches, a blind simulation competition was organized. Two twin T-cross section steel FRC beams, flexurally reinforced with steel bars and without conventional shear reinforcement in the critical shear span, were experimentally tested up to failure. Despite the experimental data provided for the definition of the relevant model parameters, inaccuracies on the load capacity, deflection, and strain at peak load attained 40, 113, and 600%, respectively. Inadequate failure modes and highly different results were estimated with the same commercial software, indicating the need for deeper analysis and understanding of the models and influence of their parameters on their predictive performance.PGC2018-097116-A-I00, Grant/Award Number: MCIU/AEI/FEDER UE; Portuguese Science Foundation (FCT)

Blind competition on the numerical simulation of steel-fiber-reinforced concrete beams failing in shear

La investigación experimental ha demostrado el extraordinario potencial de la adición de fibras cortas a los materiales cementiceos, ya que mejoran significativamente el comportamiento de estructuras de hormigón en los estados límite de servicio y último. Para la simulación del comportamiento no lineal del material en estructuras de hormigón reforzado con fibras se utilizan programas informáticos basados en el método de elementos finitos. Generalmente, las aproximaciones existentes se evalúan en simulaciones de ensayos experimentales de elementos estructurales a pequeña escala, donde los valores de los parámetros de las leyes constitutivas de los materiales se ajustan según el resultado deseado. La utilidad de esta técnica inversa para el diseño estructural es discutible. Precisamente, para evaluar el comportamiento predictivo de dicho enfoque, se organizó una competición a ciegas de simulaciones numéricas. Para ello, se ensayaron hasta rotura, a flexión en tres puntos asimétrica, dos vigas gemelas de hormigón reforzado con fibras de acero de sección en T, reforzadas longitudinalmente con barras de acero y sin cercos en el vano de cortante crítico. A pesar de proporcionar los datos experimentales para la definición de los parámetros mecánicos más relevantes, las simulaciones numéricas dieron resultados dispares en la capacidad de carga, la flecha y la deformación en carga máxima, con variaciones de hasta un 40%, 113% y 600% respectivamente. Además, se obtuvieron modos de fallo y resultados muy diferentes con el mismo programa comercial pero distinto participante, lo que manifiesta la necesidad de un análisis más profundo y de una mejor comprensión de los modelos numéricos y de la influencia de sus parámetros en su capacidad predictiva.Experimental research has shown the extraordinary potential of the addition of short fibers to cement-based materials by improving significantly the behavior of concrete structures for serviceability and ultimate limit states. Software based on the finite element method has been used for the simulation of the material nonlinear behavior of fiber-reinforced concrete (FRC) structures. The applicability of the existing approaches has often been assessed by simulating experimental tests with structural elements, in general of a small scale, where the parameter values of the material constitutive laws are adjusted for the aimed predicting level, which constitutes an inverse technique of arguable utility for structural design practice. For assessing the predictive performance of these approaches, a blind simulation competition was organized. Two twin T-cross section steel FRC beams, flexurally reinforced with steel bars and without conventional shear reinforcement in the critical shear span, were experimentally tested up to failure. Despite the experimental data provided for the definition of the relevant model parameters, inaccuracies on the load capacity, deflection, and strain at peak load attained 40, 113, and 600%, respectively. Inadequate failure modes and highly different results were estimated with the same commercial software, indicating the need for deeper analysis and understanding of the models and influence of their parameters on their predictive performance.Los autores agradecen el apoyo brindado por FCT a través del proyecto ICoSyTec, referencia PTDC/ECICON/27990/2017, y PGC2018-097116-A-I00 (MCIU/AEI/FEDER, UE). Además, expresan su agradecimiento a las empresas Casais, para la producción de las vigas, y CiviTest, para la ejecución de las probetas y los ensayos experimentales de caracterización de las propiedades mecánicas del SFRC y de las armaduras convencionales de la BSC. Por último, pero no menos importante, agradecen el apoyo de la fib en la difusión de la BS

Salicylic acid:old and new implications for the treatment of type 2 diabetes?

Efficacy of salicylic acid as a treatment for diabetes was first established well over a century ago. Antihyperglycaemic effects are thought to include improved peripheral insulin sensitivity and suppression of hepatic glucose production. For most of this period, the molecular mechanisms underlying these effects have been poorly understood and these are still a focus of considerable research, which is reviewed here. Antihyperglycaemic effects are observed only at much higher concentrations than analgesic, antipyretic and antithrombotic properties, suggesting that different targets underlie the antidiabetic aspects of salicylate pharmacology. In the 1950s, antihyperglycaemic responses were linked to mitochondrial uncoupling effects of the drug. Then at the beginning of this century, antihyperglycaemic effects were linked to anti-inflammatory effects of the drug on NF-κB signalling. More recently, new work suggests that direct activation of AMPK may contribute to antihyperglycaemic/antihyperlipidemic actions of salicylates. Better understanding of the mechanism of salicylate’s anthyperglycaemic effects may ultimately accelerate the development of new drugs for human use