Phosphatidylinositol 3-kinase C2 alpha is essential for ATP-dependent priming of neurosecretory granule exocytosis

Neurotransmitter release and hormonal secretion are highly regulated processes culminating in the calcium-dependent fusion of secretory vesicles with the plasma membrane. Here, we have identified a role for phosphatidylinositol 3-kinase C2 alpha (PI3K-C2 alpha) and its main catalytic product, PtdIns3P, in regulated exocytosis. In neuroendocrine cells, PI3K-C2 alpha is present on a subpopulation of mature secretory granules. Impairment of PI3K-C2 alpha function specifically inhibits the ATP-dependent priming phase of exocytosis. Overexpression of wild-type PI3K-C2 alpha enhanced secretion, whereas transfection of PC12 cells with a catalytically inactive PI3K-C2 alpha mutant or a 2xFYVE domain sequestering PtdIns3P abolished secretion. Based on these results, we propose that production of PtdIns3P by PI3K-C2 alpha is required for acquisition of fusion competence in neurosecretion.

Psychophysiological responses to pain identify reproducible human clusters

Pain is a ubiquitous yet highly variable experience. The psychophysiological and genetic factors responsible for this variability remain unresolved. We hypothesised the existence of distinct human pain clusters (PCs) composed of distinct psychophysiological and genetic profiles coupled with differences in the perception and the brain processing of pain. We studied 120 healthy subjects in whom the baseline personality and anxiety traits and the serotonin transporter-linked polymorphic region (5-HTTLPR) genotype were measured. Real-time autonomic nervous system parameters and serum cortisol were measured at baseline and after standardised visceral and somatic pain stimuli. Brain processing reactions to visceral pain were studied in 29 subjects using functional magnetic resonance imaging (fMRI). The reproducibility of the psychophysiological responses to pain was assessed at 1 year. In group analysis, visceral and somatic pain caused an expected increase in sympathetic and cortisol responses and activated the pain matrix according to fMRI studies. However, using cluster analysis, we found 2 reproducible PCs: at baseline, PC1 had higher neuroticism/anxiety scores (P ≤ 0.01); greater sympathetic tone (P < 0.05); and higher cortisol levels (P ≤ 0.001). During pain, less stimulus was tolerated (P ≤ 0.01), and there was an increase in parasympathetic tone (P ≤ 0.05). The 5-HTTLPR short allele was over-represented (P ≤ 0.005). PC2 had the converse profile at baseline and during pain. Brain activity differed (P ≤ 0.001); greater activity occurred in the left frontal cortex in PC1, whereas PC2 showed greater activity in the right medial/frontal cortex and right anterior insula. In health, 2 distinct reproducible PCs exist in humans. In the future, PC characterization may help to identify subjects at risk for developing chronic pain and may reduce variability in brain imaging studies. © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

El daño y el nexo causal en la perdida de oportunidad

El presente escrito se ocupa de estudiar el nexo de causalidad como elemento estructural de la responsabilidad cuando éste es difuso. Para ello, se pretende abordar la pérdida de la oportunidad como una teoría especial de causalidad que tiene lugar cuando el nexo causal no resulta claro, lo cual contradice la tesis preponderante de la doctrina y la jurisprudencia tradicional según la cual, la pérdida de la oportunidad es un criterio autónomo del daño. En su contenido se realiza una explicación del por qué se entiende la pérdida de la oportunidad como una teoría especial de causalidad y no como un criterio autónomo de daño, haciendo énfasis en el elemento de certeza que caracteriza al daño. Posteriormente, se advierte del tratamiento que la jurisprudencia le ha dado a la pérdida de la oportunidad. A su turno, el presente documento, indica la naturaleza jurídica de la pérdida de la oportunidad, afirmando que es una inferencia lógica que realiza el juez y no un hecho que altere el estado de las cosas como si sucede con el daño. Finalmente, se aborda la prueba de la teoría de la pérdida de la oportunidad mediante un cálculo de probabilidades y se identifican los pasos para realizar una adecuada reparación integral.

Analisi delle prestazioni di un sistema di accumulo termico

Analisi termofluidodinamica di un accumulatore di calore che utilizza materiali a cambiamento di fase (PCM). I campi di velocità, di temperatura e di titolo, in regime termico non stazionario, relativi al singolo canale, vengono calcolati con un programma basato sul metodo dei volumi finiti, scritto in ambiente di lavoro Matlab. Vengono proposte diverse ottimizzazioni delle performance di accumulo termico, basate su un algoritmo genetico. Le ottimizzazioni sono fatte sia con differenti tipi di parametri di valutazione, sia con differenti gradi del polinomio che descrive la parete del canale; per ogni ottimizzazione l’algoritmo genetico è stato, quindi, utilizzato per determinare i parametri geometrici del canale ottimali. A partire dai risultati ottenuti dalle ottimizzazioni, vengono poi analizzate le prestazioni di canali della stessa geometria, ai quali viene aggiunta un’intelaiatura metallica. Vengono, infine, mostrati i risultati delle simulazioni numeriche fatte.