Effect of the anisotropy of the cells on the topological properties of two- and tree-dimensional froths

URL: http://www-spht.cea.fr/articles/T00/164 Effet de l'anisotropie des cellules sur les propriétés topologiques des mousses 2D et 3DInternational audienceWe study the effect of the anisotropy of the cells on the topological properties of monodisperse 2D and 3D froths. These froths are built by Voronoï tessellation of actual assemblies of monosize disks (2D) and of many numerical packings of monosize disks (2D) and spheres (3D). We show that topological properties of these froths depend universally on the anisotropy of the cells

Naturally occurring C-terminal splice variants of nuclear receptors

Alternative mRNA splicing in the region encoding the C-terminus of nuclear receptors results in receptor variants lacking the entire ligand-binding domain (LBD), or a part of it, and instead contain a sequence of splice variant-specific C-terminal amino acids. A total of thirteen such splice variants have been shown to occur in vertebrates, and at least nine occur in humans. None of these receptor variants appear to be able to bind endogenous ligands and to induce transcription on promoters containing the response element for the respective canonical receptor variant. Interestingly, ten of these C-terminal splice variants have been shown to display dominant-negative activity on the transactivational properties of their canonical equivalent. Research on most of these splice variants has been limited, and the dominant-negative effect of these receptor variants has only been demonstrated in reporter assays in vitro, using transiently transfected receptors and reporter constructs. Therefore, the in vivo function and relevance of most C-terminal splice variants remains unclear. By reviewing the literature on the human glucocorticoid receptor β-isoform (hGRβ), we show that the dominant-negative effect of hGRβ is well established using more physiologically relevant readouts. The hGR β-isoform may alter gene transcription independent from the canonical receptor and increased hGRβ levels correlate with glucocorticoid resistance and the occurrence of several immune-related diseases. Thus, available data suggests that C-terminal splice variants of nuclear receptors act as dominant-negative inhibitors of receptor-mediated signaling in vivo, and that aberrant expression of these isoforms may be involved in the pathogenesis of a variety of diseases

Field induced stationary state for an accelerated tracer in a bath

Our interest goes to the behavior of a tracer particle, accelerated by a constant and uniform external field, when the energy injected by the field is redistributed through collision to a bath of unaccelerated particles. A non equilibrium steady state is thereby reached. Solutions of a generalized Boltzmann-Lorentz equation are analyzed analytically, in a versatile framework that embeds the majority of tracer-bath interactions discussed in the literature. These results --mostly derived for a one dimensional system-- are successfully confronted to those of three independent numerical simulation methods: a direct iterative solution, Gillespie algorithm, and the Direct Simulation Monte Carlo technique. We work out the diffusion properties as well as the velocity tails: large v, and either large -v, or v in the vicinity of its lower cutoff whenever the velocity distribution is bounded from below. Particular emphasis is put on the cold bath limit, with scatterers at rest, which plays a special role in our model.Comment: 20 pages, 6 figures v3:minor corrections in sec.III and added reference

Analyticity and Integrabiity in the Chiral Potts Model

We study the perturbation theory for the general non-integrable chiral Potts model depending on two chiral angles and a strength parameter and show how the analyticity of the ground state energy and correlation functions dramatically increases when the angles and the strength parameter satisfy the integrability condition. We further specialize to the superintegrable case and verify that a sum rule is obeyed.Comment: 31 pages in harvmac including 9 tables, several misprints eliminate

Simultaneous non-negative matrix factorization for multiple large scale gene expression datasets in toxicology

Non-negative matrix factorization is a useful tool for reducing the dimension of large datasets. This work considers simultaneous non-negative matrix factorization of multiple sources of data. In particular, we perform the first study that involves more than two datasets. We discuss the algorithmic issues required to convert the approach into a practical computational tool and apply the technique to new gene expression data quantifying the molecular changes in four tissue types due to different dosages of an experimental panPPAR agonist in mouse. This study is of interest in toxicology because, whilst PPARs form potential therapeutic targets for diabetes, it is known that they can induce serious side-effects. Our results show that the practical simultaneous non-negative matrix factorization developed here can add value to the data analysis. In particular, we find that factorizing the data as a single object allows us to distinguish between the four tissue types, but does not correctly reproduce the known dosage level groups. Applying our new approach, which treats the four tissue types as providing distinct, but related, datasets, we find that the dosage level groups are respected. The new algorithm then provides separate gene list orderings that can be studied for each tissue type, and compared with the ordering arising from the single factorization. We find that many of our conclusions can be corroborated with known biological behaviour, and others offer new insights into the toxicological effects. Overall, the algorithm shows promise for early detection of toxicity in the drug discovery process

Selective PDE4 subtype inhibition provides new opportunities to intervene in neuroinflammatory versus myelin damaging hallmarks of multiple sclerosis

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by focal inflammatory lesions and prominent demyelination. Even though the currently available therapies are effective in treating the initial stages of disease, they are unable to halt or reverse disease progression into the chronic progressive stage. Thus far, no repair-inducing treatments are available for progressive MS patients. Hence, there is an urgent need for the development of new therapeutic strategies either targeting the destructive immunological demyelination or boosting endogenous repair mechanisms. Using in vitro, ex vivo, and in vivo models, we demonstrate that selective inhibition of phosphodiesterase 4 (PDE4), a family of enzymes that hydrolyzes and inactivates cyclic adenosine monophosphate (cAMP), reduces inflammation and promotes myelin repair. More specifically, we segregated the myelination-promoting and anti-inflammatory effects into a PDE4D- and PDE4B-dependent process respectively. We show that inhibition of PDE4D boosts oligodendrocyte progenitor cells (OPC) differentiation and enhances (re)myelination of both murine OPCs and human iPSC-derived OPCs. In addition, PDE4D inhibition promotes in vivo remyelination in the cuprizone model, which is accompanied by improved spatial memory and reduced visual evoked potential latency times. We further identified that PDE4B-specific inhibition exerts anti-inflammatory effects since it lowers in vitro monocytic nitric oxide (NO) production and improves in vivo neurological scores during the early phase of experimental autoimmune encephalomyelitis (EAE). In contrast to the pan PDE4 inhibitor roflumilast, the therapeutic dose of both the PDE4B-specific inhibitor A33 and the PDE4D-specific inhibitor Gebr32a did not trigger emesis-like side effects in rodents. Finally, we report distinct PDE4D isoform expression patterns in human area postrema neurons and human oligodendroglia lineage cells. Using the CRISPR-Cas9 system, we confirmed that pde4d1/2 and pde4d6 are the key targets to induce OPC differentiation. Collectively, these data demonstrate that gene specific PDE4 inhibitors have potential as novel therapeutic agents for targeting the distinct disease processes of MS

Stearoyl-CoA desaturase-1 impairs the reparative properties of macrophages and microglia in the brain

Failure of remyelination underlies the progressive nature of demyelinating diseases such as multiple sclerosis. Macrophages and microglia are crucially involved in the formation and repair of demyelinated lesions. Here we show that myelin uptake temporarily skewed these phagocytes toward a disease-resolving phenotype, while sustained intracellular accumulation of myelin induced a lesion-promoting phenotype. This phenotypic shift was controlled by stearoyl-CoA desaturase-1 (SCD1), an enzyme responsible for the desaturation of saturated fatty acids. Monounsaturated fatty acids generated by SCD1 reduced the surface abundance of the cholesterol efflux transporter ABCA1, which in turn promoted lipid accumulation and induced an inflammatory phagocyte phenotype. Pharmacological inhibition or phagocyte-specific deficiency of Scd1 accelerated remyelination ex vivo and in vivo. These findings identify SCD1 as a novel therapeutic target to promote remyelination

PPARα: energy combustion, hypolipidemia, inflammation and cancer

The peroxisome proliferator-activated receptor α (PPARα, or NR1C1) is a nuclear hormone receptor activated by a structurally diverse array of synthetic chemicals known as peroxisome proliferators. Endogenous activation of PPARα in liver has also been observed in certain gene knockout mouse models of lipid metabolism, implying the existence of enzymes that either generate (synthesize) or degrade endogenous PPARα agonists. For example, substrates involved in fatty acid oxidation can function as PPARα ligands. PPARα serves as a xenobiotic and lipid sensor to regulate energy combustion, hepatic steatosis, lipoprotein synthesis, inflammation and liver cancer. Mainly, PPARα modulates the activities of all three fatty acid oxidation systems, namely mitochondrial and peroxisomal β-oxidation and microsomal ω-oxidation, and thus plays a key role in energy expenditure. Sustained activation of PPARα by either exogenous or endogenous agonists leads to the development of hepatocellular carcinoma resulting from sustained oxidative and possibly endoplasmic reticulum stress and liver cell proliferation. PPARα requires transcription coactivator PPAR-binding protein (PBP)/mediator subunit 1(MED1) for its transcriptional activity

De-Novo Identification of PPARγ/RXR Binding Sites and Direct Targets during Adipogenesis

BACKGROUND: The pathophysiology of obesity and type 2 diabetes mellitus is associated with abnormalities in endocrine signaling in adipose tissue and one of the key signaling affectors operative in these disorders is the nuclear hormone transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma). PPARgamma has pleiotropic functions affecting a wide range of fundamental biological processes including the regulation of genes that modulate insulin sensitivity, adipocyte differentiation, inflammation and atherosclerosis. To date, only a limited number of direct targets for PPARgamma have been identified through research using the well established pre-adipogenic cell line, 3T3-L1. In order to obtain a genome-wide view of PPARgamma binding sites, we applied the pair end-tagging technology (ChIP-PET) to map PPARgamma binding sites in 3T3-L1 preadipocyte cells. METHODOLOGY/PRINCIPAL FINDINGS: Coupling gene expression profile analysis with ChIP-PET, we identified in a genome-wide manner over 7700 DNA binding sites of the transcription factor PPARgamma and its heterodimeric partner RXR during the course of adipocyte differentiation. Our validation studies prove that the identified sites are bona fide binding sites for both PPARgamma and RXR and that they are functionally capable of driving PPARgamma specific transcription. Our results strongly indicate that PPARgamma is the predominant heterodimerization partner for RXR during late stages of adipocyte differentiation. Additionally, we find that PPARgamma/RXR association is enriched within the proximity of the 5' region of the transcription start site and this association is significantly associated with transcriptional up-regulation of genes involved in fatty acid and lipid metabolism confirming the role of PPARgamma as the master transcriptional regulator of adipogenesis. Evolutionary conservation analysis of these binding sites is greater when adjacent to up-regulated genes than down-regulated genes, suggesting the primordial function of PPARgamma/RXR is in the induction of genes. Our functional validations resulted in identifying novel PPARgamma direct targets that have not been previously reported to promote adipogenic differentiation. CONCLUSIONS/SIGNIFICANCE: We have identified in a genome-wide manner the binding sites of PPARgamma and RXR during the course of adipogenic differentiation in 3T3L1 cells, and provide an important resource for the study of PPARgamma function in the context of adipocyte differentiation