Time-parallel iterative solvers for parabolic evolution equations

We present original time-parallel algorithms for the solution of the implicit Euler discretization of general linear parabolic evolution equations with time-dependent self-adjoint spatial operators. Motivated by the inf-sup theory of parabolic problems, we show that the standard nonsymmetric time-global system can be equivalently reformulated as an original symmetric saddle-point system that remains inf-sup stable with respect to the same natural parabolic norms. We then propose and analyse an efficient and readily implementable parallel-in-time preconditioner to be used with an inexact Uzawa method. The proposed preconditioner is non-intrusive and easy to implement in practice, and also features the key theoretical advantages of robust spectral bounds, leading to convergence rates that are independent of the number of time-steps, final time, or spatial mesh sizes, and also a theoretical parallel complexity that grows only logarithmically with respect to the number of time-steps. Numerical experiments with large-scale parallel computations show the effectiveness of the method, along with its good weak and strong scaling properties

Essential Oils as Feed AdditivesFuture Perspectives

The inconsistency of phytogenic feed additives' (PFA) effects on the livestock industry poses a risk for their use as a replacement for antibiotic growth promoters. The livestock market is being encouraged to use natural growth promotors, but information is limited about the PFA mode of action. The aim of this paper is to present the complexity of compounds present in essential oils (EOs) and factors that influence biological effects of PFA. In this paper, we highlight various controls and optimization parameters that influence the processes for the standardization of these products. The chemical composition of EOs depends on plant genetics, growth conditions, development stage at harvest, and processes of extracting active compounds. Their biological effects are further influenced by the interaction of phytochemicals and their bioavailability in the gastrointestinal tract of animals. PFA effects on animal health and production are also complex due to various EO antibiotic, antioxidant, anti-quorum sensing, anti-inflammatory, and digestive fluids stimulating activities. Research must focus on reliable methods to identify and control the quality and effects of EOs. In this study, we focused on available microencapsulation techniques of EOs to increase the bioavailability of active compounds, as well as their application in the animal feed additive industry

Efekti fitogenog aditiva na histomorfometrijske karakteristike creva kod odlučene prasadi supklinički prirodno inficirane bakterijom lawsonia intracellularis

Proliferative enteropathy, also known as proliferative ileitis, is considered to be one of the most economically important diseases in pig production worldwide. The estimated losses per affected growing pig usually range from US $1 to$5. The disease is caused by Lawsonia intrawellularis, a Gram-negative, obligately intracellular bacterium. Control of the disease can be achieved with the use of vaccines or antibiotics. Recently there has been an increase in the efforts in the control of certain pathologies of the digestive system with phytogenic additives. The aim of this work was to assess the effects of a phytogenic additive on the histomorphometric characteristics of the intestines in weaned pigs with a subclinical infection with L. intracellularis acquired spontaneously. Histomorphometry analysis showed that crypt depth was significantly shorter (P <0.05), and the villus-height-to-crypt-depth ratio (P<0.05) significantly greater in the treatment group than the control. This improvement in the histological parameters of the intestine, considered to be indicators of its health, proved the positive effect of the tested additive on the digestive system in pigs.Proliferativna enteropatija poznata kao i proliferativni ileitis smatra se jednom od ekonomski najznačajnih bolesti u svinjarskoj proizvodnji širom sveta. Procenjeni gubici po obolelom tovljeniku obično se kreću od 1 do 5 američkih dolara. Uzročnik ovog oboljenja je Lawsonia intracellularis, gram negativna obligatna intracelularna bakterija. Kontrola ovog oboljenja ostvaruje se primenom vakcinacije ili antibiotika. U poslednje vreme sve je češća primena fi togenih aditiva u cilju kontolisanja određenih patoloških stanja digestivnog trakta. Cilj ovog rada bio je da se ustanove efekti fi togenog aditiva na histomorfometrijske karakteristike creva kod odlučenih prasadi supklinički prirodno infi ciranih L. intracellularis. Histomorfometrijska analiza pokazala je da su kripte bile značajno (P<0,05) pliće, a količnik visine vilusa i dubine kripti značajno veći (P<0,05) u tretiranoj grupi prasadi nego u kontroli. Ovo poboljšanje histoloških parametara creva, koje se smatraju indikatorima njegovog zdravlja, dokaz je pozitivnog efekta ispitivanog aditiva na digestivni sistem svinja

Genotoxicity of triiodothyronine: effects on salmonella typhimurium ta100 and human lymphocytes in vitro

There is increasing evidence that substances which are normally present in human or animal bodies may, under the certain circumstances, exhibit deleterious effects on genetic material, therefore acting as endogenous mutagenic agents. Since hormones represent one of the best studied endogenous mutagens, some research focused on the possible role of thyroid hormone in mutagenesis and carcinogenesis. Indeed, thyroid hormones accelerate aerobic metabolism and production of reactive oxygen species (ROS) and, therefore, may exhibit mutagenic effects in various test systems on mammalian cells. However, possible mutagenic effects on prokaryotic DNA has not been investigated so far. Hence, the aim of this research was to compare the sensitivity of TA 100 Salmonella typhimurium with and without metabolic activation with S9 fraction, and human lymphocytes to possible genotoxic effects of triiodothyronine (T-3). Therefore, we used the reverse mutation assay on S. typhimurium (Ames test) and in vitro Comet assay in isolated peripheral blood human lymphocytes. In both tests-systems a broad spectrum of T-3 concentrations was applied. The obtained results showed absence of genotoxic effects of T-3 in bacterial reverse mutation assay and very profound genotoxic effects in human lymphocytes at concentrations higher than 15 mu M. We only observed cytotoxic effects in bacterial system at very high T-3 concentrations (300 and 500 mu M). In conclusion, T-3 was unable to increase the level of reverse mutations in Ames test both with and without S9 mix. Therefore, it seems that ROS production in mitochondria may be the primary cause of DNA damage caused by T-3 in mammalian cells

A cross-disciplinary approach to understanding neural stem cells in development and disease

© 2010. Published by The Company of Biologists LtdThe Company of Biologists recently launched a new series of workshops aimed at bringing together scientists with different backgrounds to discuss cutting edge research in emerging and cross-disciplinary areas of biology. The first workshop was held at Wilton Park, Sussex, UK, and the chosen theme was ‘Neural Stem Cells in Development and Disease’, which is indeed a hot topic, not only because of the potential use of neural stem cells in cell replacement therapies to treat neurodegenerative diseases, but also because alterations in their behaviour can, in certain cases, lie at the origin of brain tumours and other diseases.Work in D.H.’s laboratory is supported by Fundação Ciência e Tecnologia and Fundação Champalimaud Neuroscience Program. Work in L.B.-C’s laboratory is supported by the CNRS, the French National Research Agency (ANR), the Medical Research Foundation (FRM), the Paris School of Neuroscience (ENP), the PIME program, the Schlumberger Association for Education and Research (FSER), and the European 7th Framework Program (IP NeuroXsys)

The Tripartite Motif Protein MADD-2 Functions with the Receptor UNC-40 (DCC) in Netrin-Mediated Axon Attraction and Branching

Neurons innervate multiple targets by sprouting axon branches from a primary axon shaft. We show here that the ventral guidance factor unc-6 (Netrin), its receptor unc-40 (DCC), and the gene madd-2 stimulate ventral axon branching in C. elegans chemosensory and mechanosensory neurons. madd-2 also promotes attractive axon guidance to UNC-6 and assists unc-6- and unc-40-dependent ventral recruitment of the actin regulator MIG-10 in nascent axons. MADD-2 is a tripartite motif protein related to MID-1, the causative gene for the human developmental disorder Opitz syndrome. MADD-2 and UNC-40 proteins preferentially localize to a ventral axon branch that requires their function; genetic results indicate that MADD-2 potentiates UNC-40 activity. Our results identify MADD-2 as an UNC-40 cofactor in axon attraction and branching, paralleling the role of UNC-5 in repulsion, and provide evidence that targeting of a guidance factor to specific axonal branches can confer differential responsiveness to guidance cues.National Institutes of Health (U.S.) (Grant number GM0680678

TRIM32 Regulates Skeletal Muscle Stem Cell Differentiation and Is Necessary for Normal Adult Muscle Regeneration

Limb girdle muscular dystrophy type 2H (LGMD2H) is an inherited autosomal recessive disease of skeletal muscle caused by a mutation in the TRIM32 gene. Currently its pathogenesis is entirely unclear. Typically the regeneration process of adult skeletal muscle during growth or following injury is controlled by a tissue specific stem cell population termed satellite cells. Given that TRIM32 regulates the fate of mammalian neural progenitor cells through controlling their differentiation, we asked whether TRIM32 could also be essential for the regulation of myogenic stem cells. Here we demonstrate for the first time that TRIM32 is expressed in the skeletal muscle stem cell lineage of adult mice, and that in the absence of TRIM32, myogenic differentiation is disrupted. Moreover, we show that the ubiquitin ligase TRIM32 controls this process through the regulation of c-Myc, a similar mechanism to that previously observed in neural progenitors. Importantly we show that loss of TRIM32 function induces a LGMD2H-like phenotype and strongly affects muscle regeneration in vivo. Our studies implicate that the loss of TRIM32 results in dysfunctional muscle stem cells which could contribute to the development of LGMD2H

miRNA-Dependent Translational Repression in the Drosophila Ovary

Background: The Drosophila ovary is a tissue rich in post-transcriptional regulation of gene expression. Many of the regulatory factors are proteins identified via genetic screens. The more recent discovery of microRNAs, which in other animals and tissues appear to regulate translation of a large fraction of all mRNAs, raised the possibility that they too might act during oogenesis. However, there has been no direct demonstration of microRNA-dependent translational repression in the ovary. Methodology/Principal Findings: Here, quantitative analyses of transcript and protein levels of transgenes with or without synthetic miR-312 binding sites show that the binding sites do confer translational repression. This effect is dependent on the ability of the cells to produce microRNAs. By comparison with microRNA-dependent translational repression in other cell types, the regulated mRNAs and the protein factors that mediate repression were expected to be enriched in sponge bodies, subcellular structures with extensive similarities to the P bodies found in other cells. However, no such enrichment was observed. Conclusions/Significance: Our results reveal the variety of post-transcriptional regulatory mechanisms that operate in the Drosophila ovary, and have implications for the mechanisms of miRNA-dependent translational control used in the ovary.This work was supported in part by NIH grant GM54409 and in part by Research Grant No. 1-FY08-445. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Cellular and Molecular Biolog

SMARCA2-deficiency confers sensitivity to targeted inhibition of SMARCA4 in esophageal squamous cell carcinoma cell lines

SMARCA4/BRG1 and SMARCA2/BRM, the two mutually exclusive catalytic subunits of the BAF complex, display a well-established synthetic lethal relationship in SMARCA4-deficient cancers. Using CRISPR-Cas9 screening, we identify SMARCA4 as a novel dependency in SMARCA2-deficient esophageal squamous cell carcinoma (ESCC) models, reciprocal to the known synthetic lethal interaction. Restoration of SMARCA2 expression alleviates the dependency on SMARCA4, while engineered loss of SMARCA2 renders ESCC models vulnerable to concomitant depletion of SMARCA4. Dependency on SMARCA4 is linked to its ATPase activity, but not to bromodomain function. We highlight the relevance of SMARCA4 as a drug target in esophageal cancer using an engineered ESCC cell model harboring a SMARCA4 allele amenable to targeted proteolysis and identify SMARCA4-dependent cell models with low or absent SMARCA2 expression from additional tumor types. These findings expand the concept of SMARCA2/SMARCA4 paralog dependency and suggest that pharmacological inhibition of SMARCA4 represents a novel therapeutic opportunity for SMARCA2-deficient cancers