TWEAK affects keratinocyte G2/M growth arrest and induces apoptosis through the translocation of the AIF protein to the nucleus

The soluble TNF-like weak inducer of apoptosis (TWEAK, TNFSF12) binds to the fibroblast growth factor-inducible 14 receptor (FN14, TNFRSF12A) on the cell membrane and induces multiple biological responses, such as proliferation, migration, differentiation, angiogenesis and apoptosis. Previous reports show that TWEAK, which does not contain a death domain in its cytoplasmic tail, induces the apoptosis of tumor cell lines through the induction of TNFα secretion. TWEAK induces apoptosis in human keratinocytes. Our experiments clearly demonstrate that TWEAK does not induce the secretion of TNFα or TRAIL proteins. The use of specific inhibitors and the absence of procaspase-3 cleavage suggest that the apoptosis of keratinocytes follows a caspase- and cathepsin B-independent pathway. Further investigation showed that TWEAK induces a decrease in the mitochondrial membrane potential of keratinocytes. Confocal microscopy showed that TWEAK induces the cleavage and the translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus, thus initiating caspase-independent apoptosis. Moreover, TWEAK induces FOXO3 and GADD45 expression, cdc2 phosphorylation and cdc2 and cyclinB1 degradation, resulting in the arrest of cell growth at the G2/M phase. Finally, we report that TWEAK and FN14 are normally expressed in the basal layer of the physiological epidermis and are greatly enhanced in benign (psoriasis) and malignant (squamous cell carcinoma) skin pathologies that are characterized by an inflammatory component. TWEAK might play an essential role in skin homeostasis and pathology.     

Notch signaling: a mediator of beta-cell de-differentiation in diabetes?

Cytokines are mediators of pancreatic beta-cell dysfunction and death in type 1 diabetes mellitus. Microarray analyses of insulin-producing cells exposed to interleukin-1beta+interferon-gamma showed decreased expression of genes related to beta-cell-differentiated functions and increased expression of members of the Notch signaling pathway. Re-expression of this developmental pathway may contribute for loss-of-function of beta-cells exposed to an autoimmune attack. In this study, we show that rat primary beta-cells exposed to cytokines up-regulate several Notch receptors and ligands, and the target gene Hes1. Transfection of insulin-producing INS-1E cells and primary rat beta-cells with a constitutively active form of the Notch receptor down-regulated Pdx1 and insulin expression in INS-1E cells but not in primary beta-cells. Thus, activation of the Notch pathway inhibits differentiated functions in dividing but not in terminally differentiated beta-cells.     

The Arabidopsis TONNEAU2 gene encodes a putative novel protein phosphatase 2A regulatory subunit essential for the control of the cortical cytoskeleton

In Arabidopsis ton2 mutants, abnormalities of the cortical microtubular cytoskeleton, such as disorganization of the interphase microtubule array and lack of the preprophase band before mitosis, markedly affect cell shape and arrangement as well as overall plant morphology. We present the molecular isolation of the TON2 gene, which is highly conserved in higher plants and has a vertebrate homolog of unknown function. It encodes a protein similar in its C-terminal part to B" regulatory subunits of type 2A protein phosphatases (PP2As). We show that the TON2 protein interacts with an Arabidopsis type A subunit of PP2A in the yeast two-hybrid system and thus likely defines a novel subclass of PP2A subunits that are possibly involved in the control of cytoskeletal structures in plants.     

Bacterial cell wall macroamphiphiles: Pathogen-/microbe-associated molecular patterns detected by mammalian innate immune system

Innate immune system is the first line of host defense against invading microorganisms. It relies on a limited number of germline-encoded pattern recognition receptors that recognize conserved molecular structures of microbes, referred to as pathogen-/microbe-associated molecular patterns (PAMPs/MAMPs). Bacterial cell wall macroamphiphiles, namely Gram-negative bacteria lipopolysaccharide (LPS), Gram-positive bacteria lipoteichoic acid (LTA), lipoproteins and mycobacterial lipoglycans, are important molecules for the physiology of bacteria and evidently meet PAMP/MAMP criteria. They are well suited to innate immune recognition and constitute non-self signatures detected by the innate immune system to signal the presence of an infective agent. They are notably recognized via their lipid anchor by Toll-like receptors (TLRs) 4 or 2. Here, we review our current knowledge of the molecular bases of macroamphiphile recognition by TLRs, with a special emphasis on mycobacterial lipoglycan detection by TLR2.     

Therapeutic Use of a Selective S1P1 Receptor Modulator Ponesimod in Autoimmune Diabetes

In the present study, we investigated the therapeutic potential of a selective S1P₁ receptor modulator, ponesimod, to protect and reverse autoimmune diabetes in non-obese diabetic (NOD) mice. Ponesimod was administered orally to NOD mice starting at 6, 10, 13 and 16 weeks of age up to 35 weeks of age or to NOD mice showing recent onset diabetes. Peripheral blood and spleen B and T cell counts were significantly reduced after ponesimod administration. In pancreatic lymph nodes, B lymphocytes were increased and expressed a transitional 1-like phenotype. Chronic oral ponesimod treatment efficiently prevented autoimmune diabetes in 6, 10 and 16 week-old pre-diabetic NOD mice. Treatment withdrawal led to synchronized disease relapse. Ponesimod did not inhibit the differentiation of autoreactive T cells as assessed by adoptive transfer of lymphocytes from treated disease-free NOD mice. In addition, it did not affect the migration, proliferation and activation of transgenic BDC2.5 cells into the target tissue. However, ponesimod inhibited spreading of the T cell responses to islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP). Treatment of diabetic NOD mice with ponesimod induced disease remission. However, here again, upon treatment cessation, the disease rapidly recurred. This recurrence was effectively prevented by combination treatment with a CD3 antibody leading to the restoration of self-tolerance. In conclusion, treatment with a selective S1P₁ modulator in combination with CD3 antibody represents a promising therapeutic approach for the treatment of autoimmune diabetes.     

Lactic acid production from hemicellulosic hydrolyzate by cells of <Emphasis Type="Italic">Lactobacillus bifermentans</Emphasis> immobilized in Ca-alginate using response surface methodology

Consumption of hexoses/pentoses and production of lactic acid by Lactobacillus bifermentans were investigated in optimized culture medium and hemicellulosic hydrolyzates. The hydrolyzate used had the following composition (expressed in gL⁻¹): xylose 50 ± 5 gL⁻¹; glucose 18 ± 3 gL⁻¹; arabinose 29 ± 5 gL⁻¹. The immobilization experiments were conducted with microbial cells entrapped in calcium alginate beads. The results indicate that maximum concentrations of lactic acid were produced after 54 h of fermentation. All glucose and arabinose in wheat bran hydrolyzate were consumed during fermentation. Only xylose was not completely consumed. The substrate consumption rate was 3.2 gh⁻¹, 1.9 gh⁻¹, 1.6 gh⁻¹ respectively for glucose, arabinose, and xylose. The optimized culture condition gave a lactic acid concentration and metabolic yield of 62.77 gL⁻¹ and 0.83 gg⁻¹. These parameters improved to 41.3 gL⁻¹ and 0.47 gg⁻¹ respectively, when cell free was used.     

An ecological paradox: More woodland predators and less artificial nest predation in landscapes colonized by noisy miners

Many passerine bird populations, particularly those that have open‐cup nests, are in decline in agricultural landscapes. Current theory suggests that an increase in habitat generalist predators in response to landscape change is partially responsible for these declines. However, empirical tests have failed to reach a consensus on how and through what mechanisms landscape change affects nest predation. We tested one hypothesis, the Additive Predation Model, with an artificial nest experiment in fragmented landscapes in southern Queensland, Australia. We employed structural equation modelling of the influence of the relative density of woodland and habitat generalist predators and landscape features at the nest, site, patch and landscape scales on the probability of nest predation. We found little support for the Additive Predation Model, with no significant influence of the density of woodland predators on the probability of nest predation, although landscape features at different spatial scales were important. Within woodlands fragmented by agriculture in eastern Australia, the presence of noisy miner colonies appears to influence ecological processes important for nest predation such that the Additive Predation Model does not hold. In the absence of colonies of the aggressive native bird, the noisy miner, the influence of woodland predators on the risk of artificial nest predation was low compared with that of habitat generalist predators. Outside noisy miner colonies, we found significant edge effects with greater predation rates for artificial nests within woodland patches located closer to the agricultural matrix. Furthermore, the density of habitat generalist predators increased with the extent of irrigated land‐use, suggesting that in the absence of noisy miner colonies, nest predation increases with land‐use intensity at the landscape scale.