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

Collapse Of The G D3+ Esr Fine Structure Throughout The Coherent Temperature Of The Gd-doped Kondo Semiconductor Cef E4 P12

Recent experiments on Gd3+ electron-spin resonance (ESR) in the filled skutterudite Ce1-xGdxFe4P12(x≈0.001), at temperatures where the host resistivity manifests a smooth insulator-metal crossover, provide evidence of the underlying Kondo physics associated with this system. At low temperatures (below T≈160 K), Ce1-xGdxFe4P12 behaves as a Kondo insulator with a relatively large hybridization gap, and the Gd3+ ESR spectra display a fine structure with Lorentzian line shape, typical of insulating media. In this work, based on previous experiments performed by the same group, we argue that the electronic gap may be attributed to the large hybridization present in the coherent regime of a Kondo lattice. Moreover, mean-field calculations suggest that the electron-phonon interaction is fundamental at explaining such hybridization. The resulting electronic structure is strongly temperature dependent, and at T∗≈160K the system undergoes an insulator-to-metal transition induced by the withdrawal of 4f electrons from the Fermi volume, the system becoming metallic and nonmagnetic. The Gd3+ ESR fine structure coalesces into a single Dysonian resonance, as in metals. Our simulations suggest that exchange narrowing via the usual Korringa mechanism is not enough to describe the thermal behavior of the Gd3+ ESR spectra in the entire temperature region (4.2-300 K). We propose that the temperature activated fluctuating valence of the Ce ions is the key ingredient that fully describes this unique temperature dependence of the Gd3+ ESR fine structure. © 2016 American Physical Society.942

New therapies for hepatocellular carcinoma

Hepatocellular carcinoma (HCC), one of the most common cancers worldwide, is often diagnosed at an advanced stage when most potentially curative therapies such as resection, transplantation or percutaneous and transarterial interventions are of limited efficacy. The fact that HCC is resistant to conventional chemotherapy, and is rarely amenable to radiotherapy, leaves this disease with no effective therapeutic options and a very poor prognosis. Therefore, the development of more effective therapeutic tools and strategies is much needed. HCCs are phenotypically and genetically heterogeneous tumors that commonly emerge on a background of chronic liver disease. However, in spite of this heterogeneity recent insights into the biology of HCC suggest that certain signaling pathways and molecular alterations are likely to play essential roles in HCC development by promoting cell growth and survival. The identification of such mechanisms may open new avenues for the prevention and treatment of HCC through the development of targeted therapies. In this review we will describe the new potential therapeutic targets and clinical developments that have emerged from progress in the knowledge of HCC biology, In addition, recent advances in gene therapy and combined cell and gene therapy, together with new radiotherapy techniques and immunotherapy in patients with HCC will be discussed

Hepatocellular carcinoma: updates in pathogenesis, detection and treatment

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and the second most common cause of cancer mortality worldwide [1]. The prognosis of HCC patients is very poor. The rates of HCC incidence and mortality are almost equivalent [2] and have increased across most countries over the past three decades [3]. HCC development is closely associated with the presence of chronic liver disease and cirrhosis, albeit the risk factors underlying this condition vary geographically. Hepatitis B virus (HBV) infection and aflatoxin B1 exposure are predominant risk factors in Asia and Africa, while hepatitis C virus (HCV) infection and alcohol consumption are the main risk factors in Europe, the USA and Japan [3,4,5]. Non-alcoholic fatty liver disease (NAFLD) is currently the most prevalent liver disease worldwide, and approximately 60% of biopsied NAFLD patients have non-alcoholic steatohepatitis (NASH) [3]. Importantly, patients with NASH are at high risk of developing HCC even without presenting established cirrhosis [6]. With widespread HBV vaccination and the advent of direct-acting antiviral drugs for HCV infection, NAFLD and associated conditions such as diabetes and obesity are emerging as major global risk factors for HCC. In view of the dismal prognosis of HCC patients, implementing preventive strategies would be an ideal approach to quell the incidence of the disease. Obvious interventions include advocating HBV vaccination in endemic regions, achieving HCV eradication with direct-acting antivirals, promoting healthy nutrition and weight reduction, improving diabetes control, and avoiding excessive alcohol consumption. Still, the implementation of these measures is not always feasible

Microbiological quality of silage made from by-products of cassava starch extraction and viticulture

This study evaluated silages made with varying proportions of viticulture by-products (VC) and starch extraction from cassava (CSE). It attempted to determine the effects of these proportions on the microbial population, fermentative losses, and chemical composition. The treatments were specified as the proportions of VC in the silage (0 g/kg, 250 g/kg, 500 g/kg, 750 g/kg, and 1000 g/kg). Silages were  evaluated before (0) and after 1, 3, 7, 15, 30, and 60 days of ensiling. The experimental design was completely randomized with five  treatments, six storage times and four replications. The increased level of VC in the silage enhanced its dry matter content, ammonia  nitrogen (NH3-N), and buffering capacity, and reduced organic matter content. Fifteen days after ensiling, additional VC increased the concentration of soluble carbohydrates. The increased level of VC decreased the count of Clostridium spp. and lactic acid bacteria (LAB). The incidence of yeasts and enterobacteria was low in all treatments at all time points. Over time, losses as effluent and gases increased. Use of increasing proportions from VC in silage made with CSE increased the contents of dry matter and soluble carbohydrates and  reduced the fermentative losses of the silage. The increased amount of VC also favoured pH reduction and reduced the proliferation of undesirable yeasts, while increasing the population of LAB

S-Adenosylmethionine: a control switch that regulates liver function

Genome sequence analysis reveals that all organisms synthesize S-adenosylmethionine (AdoMet) and that a large fraction of all genes is AdoMet-dependent methyltransferases. AdoMet-dependent methylation has been shown to be central to many biological processes. Up to 85% of all methylation reactions and as much as 48% of methionine metabolism occur in the liver, which indicates the crucial importance of this organ in the regulation of blood methionine. Of the two mammalian genes (MAT1A, MAT2A) that encode methionine adenosyltransferase (MAT, the enzyme that makes AdoMet), MAT1A is specifically expressed in adult liver. It now appears that growth factors, cytokines, and hormones regulate liver MAT mRNA levels and enzyme activity and that AdoMet should not be viewed only as an intermediate metabolite in methionine catabolism, but also as an intracellular control switch that regulates essential hepatic functions such as regeneration, differentiation, and the sensitivity of this organ to injury. The aim of this review is to integrate these recent findings linking AdoMet with liver growth, differentiation, and injury into a comprehensive model. With the availability of AdoMet as a nutritional supplement and evidence of its beneficial role in various liver diseases, this review offers insight into its mechanism of action

Dried brewers’ grain as a replacement for soybean meal on nutrient digestibility and rumen parameters of cattle

The objective of this study was to determine the effect of replacing soybean meal with dried brewers’ grains (DBG) in intake and digestibility of the nutrients and the ruminal parameters of cattle. Four ruminal cannulated Jersey oxen with initial body weight of 662.7 ± 85.5 kg were distributed in a 4x4 Latin square design. The treatments were levels of 0%, 33%, 66% and 100% DBG replacing soybean meal in the diet. Dry matter (DM) and crude protein (CP) intake were not influenced by the treatments. There were linear increases in ether extract (EE), neutral detergent fibre (NDF) and acid detergent fibre (ADF) intakes because of higher levels of these nutrients in diets with DBG. Non-fibre carbohydrate (NFC) and total digestible nutrient (TDN) intake showed a decreasing linear effect. Dry matter and NFC digestibility decreased linearly with rising DBG levels, while EE, CP, NDF and ADF digestibilities were not affected. Ruminal pH was not influenced by DBG levels in the diet. There was a quadratic effect in ammonia nitrogen (NH3-N) concentration in the rumen, with the maximum occurring at a level of 36.7% DGB. The replacement of soybean meal with DBG in cattle diets did not alter DM intake and ruminal pH, but reduced TDN intake.Keywords: Ammonia nitrogen, by-product, digestibility, intake, p