Wnt/β-catenin signaling stimulates the expression and synaptic clustering of the autism-associated Neuroligin 3 gene

Indexación: Scopus.Synaptic abnormalities have been described in individuals with autism spectrum disorders (ASD). The cell-adhesion molecule Neuroligin-3 (Nlgn3) has an essential role in the function and maturation of synapses and NLGN3 ASD-associated mutations disrupt hippocampal and cortical function. Here we show that Wnt/β-catenin signaling increases Nlgn3 mRNA and protein levels in HT22 mouse hippocampal cells and primary cultures of rat hippocampal neurons. We characterized the activity of mouse and rat Nlgn3 promoter constructs containing conserved putative T-cell factor/lymphoid enhancing factor (TCF/LEF)-binding elements (TBE) and found that their activity is significantly augmented in Wnt/β-catenin cell reporter assays. Chromatin immunoprecipitation (ChIP) assays and site-directed mutagenesis experiments revealed that endogenous β-catenin binds to novel TBE consensus sequences in the Nlgn3 promoter. Moreover, activation of the signaling cascade increased Nlgn3 clustering and co-localization with the scaffold PSD-95 protein in dendritic processes of primary neurons. Our results directly link Wnt/β-catenin signaling to the transcription of the Nlgn3 gene and support a functional role for the signaling pathway in the dysregulation of excitatory/inhibitory neuronal activity, as is observed in animal models of ASD.https://www.nature.com/articles/s41398-018-0093-y.pd

Comparative pan-genome analysis of Piscirickettsia salmonis reveals genomic divergences within genogroups

Indexación: Scopus.Piscirickettsia salmonis is the etiological agent of salmonid rickettsial septicemia, a disease that seriously affects the salmonid industry. Despite efforts to genomically characterize P. salmonis, functional information on the life cycle, pathogenesis mechanisms, diagnosis, treatment, and control of this fish pathogen remain lacking. To address this knowledge gap, the present study conducted an in silico pan-genome analysis of 19 P. salmonis strains from distinct geographic locations and genogroups. Results revealed an expected open pan-genome of 3,463 genes and a core-genome of 1,732 genes. Two marked genogroups were identified, as confirmed by phylogenetic and phylogenomic relationships to the LF-89 and EM-90 reference strains, as well as by assessments of genomic structures. Different structural configurations were found for the six identified copies of the ribosomal operon in the P. salmonis genome, indicating translocation throughout the genetic material. Chromosomal divergences in genomic localization and quantity of genetic cassettes were also found for the Dot/Icm type IVB secretion system. To determine divergences between core-genomes, additional pan-genome descriptions were compiled for the so-termed LF and EM genogroups. Open pan-genomes composed of 2,924 and 2,778 genes and core-genomes composed of 2,170 and 2,228 genes were respectively found for the LF and EM genogroups. The core-genomes were functionally annotated using the Gene Ontology, KEGG, and Virulence Factor databases, revealing the presence of several shared groups of genes related to basic function of intracellular survival and bacterial pathogenesis. Additionally, the specific pan-genomes for the LF and EM genogroups were defined, resulting in the identification of 148 and 273 exclusive proteins, respectively. Notably, specific virulence factors linked to adherence, colonization, invasion factors, and endotoxins were established. The obtained data suggest that these genes could be directly associated with inter-genogroup differences in pathogenesis and host-pathogen interactions, information that could be useful in designing novel strategies for diagnosing and controlling P. salmonis infection. © 2017 Nourdin-Galindo, Sánchez, Molina, Espinoza-Rojas, Oliver, Ruiz, Vargas-Chacoff, Cárcamo, Figueroa, Mancilla, Maracaja-Coutinho and Yañez.https://www.frontiersin.org/articles/10.3389/fcimb.2017.00459/ful

Modeling of Mechanosensing Mechanisms Reveals Distinct Cell Migration Modes to Emerge From Combinations of Substrate Stiffness and Adhesion Receptor–Ligand Affinity

Mesenchymal cell migration is an integral process in development and healing. The process is regulated by both mechanical and biochemical properties. Mechanical properties of the environment are sensed through mechanosensing, which consists of molecular responses mediated by mechanical signals. We developed a computational model of a deformable 3D cell on a flat substrate using discrete element modeling. The cell is polarized in a single direction and thus moves along the long axis of the substrate. By modeling discrete focal adhesions and stress fibers, we implement two mechanosensing mechanisms: focal adhesion stabilization by force and stress fiber strengthening upon contraction stalling. Two substrate-associated properties, substrate (ligand) stiffness and adhesion receptor–ligand affinity (in the form of focal adhesion disassembly rate), were varied for different model setups in which the mechanosensing mechanisms are set as active or inactive. Cell displacement, focal adhesion number, and cellular traction were quantified and tracked in time. We found that varying substrate stiffness (a mechanical property) and adhesion receptor–ligand affinity (a biochemical property) simultaneously dictate the mode in which cells migrate; cells either move in a smooth manner reminiscent of keratocytes or in a cyclical manner reminiscent of epithelial cells. Mechanosensing mechanisms are responsible for the range of conditions in which a cell adopts a particular migration mode. Stress fiber strengthening, specifically, is responsible for cyclical migration due to build-up of enough force to elicit rupture of focal adhesions and retraction of the cellular rear. Together, both mechanisms explain bimodal dependence of cell migration on substrate stiffness observed in the literature

Energy damage index based on capacity and response spectra

Non-linear dynamic analysis and the damage index of Park-Ang have been often used to assess expected seismic damage to a structure. Depending on the size of the structure and the duration of the record, the computational effort in dynamic analyses is usually high. In this research, a new damage index is proposed based on nonlinear static analysis. The damage index is a linear combination of two energy functions: (1) the strain energy associated with the stiffness variation and the ductility of the structure, and (2) the dissipated energy associated with hysteretic cycles. These two energy functions are obtained from the capacity curve of the structure and from the energy balance with the spectral acceleration. To show the ability of the index to represent damage, low-rise steel buildings were studied under the seismic actions that are expected in Mexico City. The results obtained with the new method show good agreement with those calculated by means of dynamic analyses using the Park-Ang damage index. On average, the Park-Ang damage index is well-fitted by the combination of 62% of the strain energy and 38% of the energy dissipated by hysteresis. Moreover, the new damage index can link damage to certain characteristics of seismic actions, such as their intensity and duration. Therefore, the new approach results in a practical, powerful tool for estimating seismic damage in buildings, especially as probabilistic approaches require massive computations.This research was partially funded by the Ministry of Economy and Competitiveness (MINECO) of the Spanish Government and by the European Regional Development Fund (ERDF) of the European Union (EU) through projects referenced as: CGL2011-23621 and CGL2015-65913-P (MINECO/FEDER, UE). The first author holds PhD fellowships from the Universidad Juarez Autonoma de Tabasco (UJAT) and from the ‘Programa de Mejoramiento del Profesorado, Mexico (PROMEP)’.Peer ReviewedPostprint (author's final draft

New bounds for the free energy of directed polymers in dimension 1+1 and 1+2

We study the free energy of the directed polymer in random environment in dimension 1+1 and 1+2. For dimension 1, we improve the statement of Comets and Vargas concerning very strong disorder by giving sharp estimates on the free energy at high temperature. In dimension 2, we prove that very strong disorder holds at all temperatures, thus solving a long standing conjecture in the field.Comment: 31 pages, 4 figures, final version, accepted for publication in Communications in Mathematical Physic

Probabilistic seismic damage assessment of reinforced concrete buildings considering directionality effects

This is an Accepted Manuscript of an article published by Taylor & Francis Group in Structure and Infrastructure Engineering on 2018, available online at: http://www.tandfonline.com/10.1080/15732479.2017.1385089Most of buildings and structures are usually projected according to two main axes. However, the geographical position of these buildings varies randomly. Such random distributions of the azimuthal positions of structures, in most of the cities, generally, are not accounted for when assessing their seismic risk; certainly, the direction of the seismic loads is another highly random variable. Moreover, an additional important source of uncertainty is related to the structural response, mainly due to the random character of the mechanical properties. There is a consensus that uncertainties must be considered for adequately assessing the seismic risk of structures, but these directionality effects have not been deeply explored so far. In this article, the influence of the high uncertainty involved in these input variables on the expected seismic damage is analysed. Thus, an actual earthquake, which affected the southern part of Spain, is studied. Notably, damages on a group of affected buildings, located close to the epicentre, are analysed and discussed in detail. The results show that the influence of the random azimuthal position of structures is an important source of uncertainty and that it should be taken into account when estimating the expected seismic risk in urban areas.Peer ReviewedPostprint (author's final draft

Inmovilización fotocatalítca de nanopartículas de TiO2 sobre películas de polietileno de baja densidad y su aplicación como superficies autolimpiantes fotoinducidas

Los procesos fotocatalíticos sobre TiO2 han emergido como una alternativa promisoria para ser aplicados como superficies autolimpiantes y antimicrobianas foto-inducidas

Modeling the Subsurface Structure of Sunspots

While sunspots are easily observed at the solar surface, determining their subsurface structure is not trivial. There are two main hypotheses for the subsurface structure of sunspots: the monolithic model and the cluster model. Local helioseismology is the only means by which we can investigate subphotospheric structure. However, as current linear inversion techniques do not yet allow helioseismology to probe the internal structure with sufficient confidence to distinguish between the monolith and cluster models, the development of physically realistic sunspot models are a priority for helioseismologists. This is because they are not only important indicators of the variety of physical effects that may influence helioseismic inferences in active regions, but they also enable detailed assessments of the validity of helioseismic interpretations through numerical forward modeling. In this paper, we provide a critical review of the existing sunspot models and an overview of numerical methods employed to model wave propagation through model sunspots. We then carry out an helioseismic analysis of the sunspot in Active Region 9787 and address the serious inconsistencies uncovered by \citeauthor{gizonetal2009}~(\citeyear{gizonetal2009,gizonetal2009a}). We find that this sunspot is most probably associated with a shallow, positive wave-speed perturbation (unlike the traditional two-layer model) and that travel-time measurements are consistent with a horizontal outflow in the surrounding moat.Comment: 73 pages, 19 figures, accepted by Solar Physic