Imbalance of p75(NTR)/TrkB protein expression in Huntington's disease: Implication for neuroprotective therapies

Neuroprotective therapies based on brain-derived neurotrophic factor (BDNF) administration have been proposed for Huntington's disease (HD) treatment. However, our group has recently reported reduced levels of TrkB in HD mouse models and HD human brain suggesting that besides a decrease on BDNF levels a reduction of TrkB expression could also contribute to diminished neurotrophic support in HD. BDNF can also bind to p75 neurotrophin receptor (p75(NTR)) modulating TrkB signaling. Therefore, in this study we have analyzed the levels of p75(NTR) in several HD models, as well as in HD human brain. Our data demonstrates a p75(NTR)/TrkB imbalance in the striatum of two different HD mouse models, Hdh(Q111/111) homozygous knockin mice and R6/1 mice that was also manifested in the putamen of HD patients. The imbalance between TrkB and p75(NTR) levels in a HD cellular model did not affect BDNF-mediated TrkB activation of prosurvival pathways but induced activation of apoptotic cascades as demonstrated by increased JNK phosphorylation. Moreover, BDNF failed to protect mutant huntingtin striatal cells transfected with p75(NTR) against NMDA-mediated excitotoxicity, which was associated with decreased Akt phosphorylation. Interestingly, lack of Akt activation following BDNF and NMDA treatment correlated with increased PP1 levels. Accordingly, pharmacological inhibition of PP1 by okadaic acid (OA) prevented mutant huntingtin striatal cell death induced by NMDA and BDNF. Altogether, our findings demonstrate that the p75(NTR)/TrkB imbalance induced by mutant huntingtin in striatal cells associated with the aberrant activity of PP1 disturbs BDNF neuroprotection likely contributing to increasing striatal vulnerability in HD. On the basis of this data we hypothesize that normalization of p75(NTR) and/or TrkB expression or their signaling will improve BDNF neuroprotective therapies in HD. Cell Death and Disease (2013) 4, e595; doi:10.1038/cddis.2013.116; published online 18 April 201

LU Factorization of Non-standard Forms and Direct Multiresolution Solvers

AbstractIn this paper we introduce the multiresolution LU factorization of non-standard forms (NS-forms) and develop fastdirect multiresolutionmethods for solving systems of linear algebraic equations arising in elliptic problems.The NS-form has been shown to provide a sparse representation for a wide class of operators, including those arising in strictly elliptic problems. For example, Green's functions of such operators (which are ordinarily represented by dense matrices, e.g., of sizeNbyN) may be represented by −log ϵ·Ncoefficients, where ϵ is the desired accuracy.The NS-form is not an ordinary[fn9] matrix representation and the usual operations such as multiplication of a vector by the NS-form are different from the standard matrix–vector multiplication. We show that (up to a fixed but arbitrary accuracy) the sparsity of the LU factorization is maintained on any finite number of scales for self-adjoint strictly elliptic operators and their inverses. Moreover, the condition number of matrices for which we compute the usual LU factorization at different scales isO(1). The direct multiresolution solver presents, therefore, an alternative to a multigrid approach and may be interpreted as a multigrid method with a single V-cycle.For self-adjoint strictly elliptic operators the multiresolution LU factorization requires onlyO((−log ϵ)2·N) operations. Combined withO(N) procedures of multiresolution forward and back substitutions, it yields a fast direct multiresolution solver. We also describe direct methods for solving matrix equations and demonstrate how to construct the inverse inO(N) operations (up to a fixed but arbitrary accuracy). We present several numerical examples which illustrate the algorithms developed in the paper. Finally, we outline several directions for generalization of our algorithms. In particular, we note that the multidimensional versions of the multiresolution LU factorization maintain sparsity, unlike the usual LU factorization

String-based Multi-adjoint Lattices for Tracing Fuzzy Logic Computations

Classically, most programming languages use in a predefined way thenotion of “string” as an standard data structure for a comfortable management of arbitrary sequences of characters. However, in this paper we assign a different role to this concept: here we are concerned with fuzzy logic programming, a somehow recent paradigm trying to introduce fuzzy logic into logic programming. In this setting, the mathematical concept of multi-adjoint lattice has been successfully exploited into the so-called Multi-adjoint Logic Programming approach, MALP in brief, for modeling flexible notions of truth-degrees beyond the simpler case of true and false. Our main goal points out not only our formal proof verifying that stringbased lattices accomplish with the so-called multi-adjoint property (as well as its Cartesian product with similar structures), but also its correspondence with interesting debugging tasks into the FLOPER system (from “Fuzzy LOgic Programming Environment for Research”) developed in our research group

TRPC Channels in the SOCE Scenario

Transient receptor potential (TRP) proteins form non-selective Ca2+ permeable channels that contribute to the modulation of a number of physiological functions in a variety of cell types. Since the identification of TRP proteins in Drosophila, it is well known that these channels are activated by stimuli that induce PIP2 hydrolysis. The canonical TRP (TRPC) channels have long been suggested to be constituents of the store-operated Ca2+ (SOC) channels; however, none of the TRPC channels generate Ca2+ currents that resemble ICRAC. STIM1 and Orai1 have been identified as the components of the Ca2+ release-activated Ca2+ (CRAC) channels and there is a body of evidence supporting that STIM1 is able to gate Orai1 and TRPC1 in order to mediate non-selective cation currents named ISOC. STIM1 has been found to interact to and activate Orai1 and TRPC1 by different mechanisms and the involvement of TRPC1 in store-operated Ca2+ entry requires both STIM1 and Orai1. In addition to the participation of TRPC1 in the ISOC currents, TRPC1 and other TRPC proteins might play a relevant role modulating Orai1 channel function. This review summarizes the functional role of TRPC channels in the STIM1–Orai1 scenario.Junta de Extremadura Consejería de Economía e Infraestructura-FEDER Grant IB16046 y GR18061Junta de Extremadura TA18011 y TA18054Ministerio de Ciencia, Innovación y Universidade

TRPC6 channels are required for proliferation, migration and invasion of breast cancer cell lines by modulation of Orai1 and Orai3 surface exposure

Transient receptor potential channels convey signaling information from a number of stimuli to a wide variety of cellular functions, mainly by inducing changes in cytosolic Ca2+ concentration. Different members of the TRPC, TRPM and TRPV subfamilies have been reported to play a role in tumorigenesis. Here we show that the estrogen receptor positive and triple negative breast cancer cell lines, MCF7 and MDA-MB-231, respectively, exhibit enhanced expression of the TRPC6 channel as compared to the non-tumoral MCF10A cell line. In vitro TRPC6 knockdown using shRNA impaired MCF7 and MDA-MB-231 cell proliferation, migration and invasion detected by BrdU incorporation, wound healing and Boyden chamber assays, respectively. Using RNAi-mediated TRPC6 silencing as well as overexpression of the pore-dead dominant-negative TRPC6 mutant we have found that TRPC6 plays a relevant role in the activation of store-operated Ca2+ entry in the breast cancer cell lines but not in non-tumoral breast cells. Finally, we have found that TRPC6 interacts with Orai1 and Orai3 in MCF7 and MDA-MB-231 cells and is required for the translocation of Orai1 and Orai3 to the plasma membrane in MDA-MB-231 and MCF7 cells, respectively, upon Ca2+ store depletion. These findings introduce a novel mechanism for the modulation of Ca2+ influx and the development of different cancer hallmarks in breast cancer cells

Acute-on-chronic liver failure in cirrhosis

The definition of acute-on-chronic liver failure (ACLF) remains contested. In Europe and North America, the term is generally applied according to the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) Consortium guidelines, which defines this condition as a syndrome that develops in patients with cirrhosis and is characterized by acute decompensation, organ failure and high short-term mortality. One-third of patients who are hospitalized for acute decompensation present with ACLF at admission or develop the syndrome during hospitalization. ACLF frequently occurs in a closed temporal relationship to a precipitating event, such as bacterial infection or acute alcoholic, drug-induced or viral hepatitis. However, no precipitating event can be identified in approximately 40% of patients. The mechanisms of ACLF involve systemic inflammation due to infections, acute liver damage and, in cases without precipitating events, probably intestinal translocation of bacteria or bacterial products. ACLF is graded into three stages (ACLF grades 1–3) on the basis of the number of organ failures, with higher grades associated with increased mortality. Liver and renal failures are the most common organ failures, followed by coagulation, brain, circulatory and respiratory failure. The 28-day mortality rate associated with ACLF is 30%. Depending on the grade, ACLF can be reversed using standard therapy in only 16–51% of patients, leaving a considerable proportion of patients with ACLF that remains steady or progresses. Liver transplantation in selected patients with ACLF grade 2 and ACLF grade 3 increases the 6-month survival from 10% to 80%

Acute-on-Chronic Liver Failure: Definition, Diagnosis, and Clinical Characteristics

Acute-on-chronic liver failure (ACLF) is a recently recognized syndrome in cirrhosis characterized by acute decompensation (AD), organ failure(s), and high short-term mortality. Organ failure(s) is defined by the Chronic Liver Failure-Sequential Organ Failure (CLIF-SOFA) score or by its simplified version Chronic Liver Failure-Organ Failure Assessment (CLIF-OF) score. They include six types of organ failure: liver, renal, coagulation, cerebral, respiratory, and circulatory. One third of patients hospitalized with AD present with ACLF at admission or develop ACLF during hospitalization. Acute-on-chronic liver failure frequently occurs in a closed relationship to a precipitating event. According to the number of organ failures, ACLF is graded into three stages: ACLF-1 = single renal failure or single nonrenal organ failure if associated with renal dysfunction and/or cerebral dysfunction; ACLF-2 = two organ failures; and ACLF-3 = three to six organ failures, with increasing 28-day mortality rate (from 23%–74%). Acute-on-chronic liver failure may develop at any phase during the clinical course of the disease. Patients without prior AD develop a severe form of ACLF

Higher education and unemployment in Europe : an analysis of the academic subject and national effects

This paper examines the impact of an academic degree and field of study on short and long-term unemployment across Europe (EU15). Labour Force Survey (LFS) data on over half a million individuals are utilised for that purpose. The harmonized LFS classification of level of education and field of study overcomes past problems of comparability across Europe. The study analyses (i) the effect of an academic degree at a European level, (ii) the specific effect of 14 academic subjects and (iii) country specific effects. The results indicate that an academic degree is more effective on reducing the likelihood of short-term than long-term unemployment. This general pattern even though it is observed for most of the academic subjects its levels show significant variation across disciplines and countries

Genetic characterization of the Canaria bovine breed using microsatellites: preliminary study

Two sub populations of the Canaria breed of cattle located in the islands of Gran Canaria and Tenerife were genetically studied. Six microsatellites markers have been analyzed in a total of 35 individuals distributed in different non related herds. All the analyzed markers were polymorphic, the number of alleles varied between two and eleven per locus. The variability, heterozigosity per locus and over all mean were estimated by mean of calculation the allelic frequencies. These results are indicative of the genetic variability present; although it is indispensable to enlarge the number of loci with the purpose of defining with more precision the situation of the breed