Calcineurin Controls the Expression of Isoform 4CII of the Plasma Membrane Ca2+ Pump in Neurons *

Abstract The expression of the CII splice variant of the plasma membrane Ca2+ ATPase 4 (PMCA4) was down-regulated in granule neurons when they were cultured under conditions of partial membrane depolarization (25 mm KCl), which are required for long term in vitro survival of the neurons. These conditions, which cause a chronic increase of the resting free Ca2+ concentration in the neurons, have recently been shown to promote up-regulation of the PMCA2, 3, and 1CII isoforms. Whereas the chronic, i.e. >3 days, Ca2+ increase was necessary for the up-regulation of the PMCA1CII, 2, and 3, the down-regulation of the PMCA4CII mRNA was already evident 1–2 h after the start of culturing in 25 mm KCl. The immunosuppressant calcineurin inhibitor FK506 inhibited the down-regulation of the PMCA4CII at both the protein and the mRNA level but did not affect the changes of the other PMCA pumps. Direct evidence for the involvement of calcineurin in the down-regulation of the PMCA4CII was obtained by overexpressing a truncated, constitutively active, and Ca2+-independent form of calcineurin; under these conditions, depolarization was not required for the down-regulation of the PMCA4CII pump. De novosynthesis of (transcription) factors was required for the down-regulation of the PMCA4CII mRNA. Calcineurin, therefore, controls the neuronal transcription of PMCA4CII, a splice variant of the pump isoforms that is found almost exclusively in brain

On the first eigenvalue of the Dirichlet-to-Neumann operator on forms

We study a Dirichlet-to-Neumann eigenvalue problem for differential forms on a compact Riemannian manifold with smooth boundary. This problem is a natural generalization of the classical Steklov problem on functions. We derive a number of upper and lower bounds for the first eigenvalue in several contexts: many of these estimates will be sharp, and for some of them we characterize equality. We also relate these new eigenvalues with those of other operators, like the Hodge Laplacian or the biharmonic Steklov operator.Comment: 26 page

A Reilly formula and eigenvalue estimates for differential forms

We derive a Reilly-type formula for differential p-forms on a compact manifold with boundary and apply it to give a sharp lower bound of the spectrum of the Hodge Laplacian acting on differential forms of an embedded hypersurface of a Riemannian manifold. The equality case of our inequality gives rise to a number of rigidity results, when the geometry of the boundary has special properties and the domain is non-negatively curved. Finally we also obtain, as a by-product of our calculations, an upper bound of the first eigenvalue of the Hodge Laplacian when the ambient manifold supports non-trivial parallel forms.Comment: 22 page

Comprehensive genomic analysis reveals the prognostic role of LRRK2 copy-number variations in human malignancies

Genetic alterations of leucine-rich repeat kinase 2 (LRRK2), one of the most important contributors to familial Parkinson\u2019s disease (PD), have been hypothesized to play a role in cancer development due to demographical and preclinical data. Here, we sought to define the prevalence and prognostic significance of LRRK2 somatic mutations across all types of human malignancies by querying the publicly available online genomic database cBioPortal. Ninety-six different studies with 14,041 cases were included in the analysis, and 761/14,041 (5.4%) showed genetic alterations in LRRK2. Among these, 585 (76.9%) were point mutations, indels or fusions, 168 (22.1%) were copy number variations (CNVs), and 8 (1.0%) showed both types of alterations. One case showed the somatic mutation R1441C. A significant difference in terms of overall survival (OS) was noted between cases harboring somatic LRRK2 whole deletions, amplifications, and CNV-unaltered cases (median OS: 20.09, 57.40, and 106.57 months, respectively; p = 0.0008). These results suggest that both LRRK2 amplifications and whole gene deletions could play a role in cancer development, paving the way for future research in terms of potential treatment with LRRK2 small molecule inhibitors for LRRK2-amplified cases

Palavra de tradutor: reflexões sobre tradução por tradutores brasileiros / The Translator's Word: Reflections on Translation by Brazilian translators

Este livro reúne reflexões acerca de concepções de tradução e do fazer tradutório a partir do ponto de vista de diferentes tradutores brasileiros. São reflexões não sistematizadas, produzidas em momentos históricos diferentes, que cobrem um arco temporal de mais de duzentos anos, do final do século XVIII até os nossos dias. São paratextos e metatextos escritos por tradutores, homens e mulheres, que emolduram abordagens de gêneros textuais diversos: do texto técnico-científico ao de ficção, passando pela literatura infantojuvenil, pela poesia épica e lírica e pelo drama.This book brings together reflections on translation and its practice from the viewpoints of a variety of Brazilian translators. These are non-systematized reflections which were produced in different historical contexts spanning over two hundred years, from the end of the 18th century until the present day. They come from paratexts and meta-texts written by translators, men and women, which offer approaches to diverse textual genres: from technical/scientific writings to fiction, as well as children’s literature, epic and lyrical poetry, and drama

Immune regulation of neurodevelopment at the mother–foetus interface: the case of autism

Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined by deficits in social communication and stereotypical behaviours. ASD’s aetiology remains mostly unclear, because of a complex interaction between genetic and environmental factors. Recently, a strong consensus has developed around ASD’s immune-mediated pathophysiology, which is the subject of this review. For many years, neuroimmunological studies tried to understand ASD as a prototypical antibody- or cell-mediated disease. Other findings indicated the importance of autoimmune mechanisms such as familial and individual autoimmunity, adaptive immune abnormalities and the influence of infections during gestation. However, recent studies have challenged the idea that autism may be a classical autoimmune disease. Modern neurodevelopmental immunology shows the double-edged nature of many immune effectors, which can be either beneficial or detrimental depending on tissue homeostasis, stressors, neurodevelopmental stage, inherited and de novo gene mutations and other variables. Nowadays, mother–child interactions in the prenatal environment appear to be crucial for the occurrence of ASD. Studies of animal maternal–foetal immune interaction are being fruitfully carried out using different combinations of type and timing of infection, of maternal immune response and foetal vulnerability and of resilience factors to hostile events. The derailed neuroimmune crosstalk through the placenta initiates and maintains a chronic foetal neuroglial activation, eventually causing the alteration of neurogenesis, migration, synapse formation and pruning. The importance of pregnancy can also allow early immune interventions, which can significantly reduce the increasing risk of ASD and its heavy social burden

Hydrostatic equilibrium configurations of neutron stars in the f(R,L,T)f(R,\mathcal{L},T) gravity theory

In the present work, we obtain the hydrostatic equilibrium configurations of neutron stars in the recently proposed $f(R,\mathcal{L},T)$ theory of gravity, for which $R$ is the Ricci scalar, $\mathcal{L}$ is the matter lagrangian density, $T$ is the trace of the energy-momentum tensor and $f$ is a function of the argument. This theory emerges in the present literature as a generalized geometry-matter coupling theory of gravity. We derive the Tolman-Oppenheimer-Volkoff-like equation for a particular functional form of the $f(R,\mathcal{L},T)$ function. Our solutions are obtained from realistic equations of state describing matter inside neutron stars. We obtain stable solutions for neutron stars and we show that for some values of the free parameter of the theory it is possible to be in agreement with both NICER and LIGO/Virgo observational data