The ribonucleotide reductase R1 subunits of herpes simplex virus types 1 and 2 protect cells against TNFα- and FasL-induced apoptosis by interacting with caspase-8

We previously reported that HSV-2 R1, the R1 subunit (ICP10; UL39) of herpes simplex virus type-2 ribonucleotide reductase, protects cells against apoptosis induced by the death receptor (DR) ligands tumor necrosis factor-alpha- (TNFα) and Fas ligand (FasL) by interrupting DR-mediated signaling at, or upstream of, caspase-8 activation. Further investigation of the molecular mechanism underlying HSV-2 R1 protection showed that extracellular-regulated kinase 1/2 (ERK1/2), phosphatidylinositol 3-kinase (PI3-K)/Akt, NF-κB and JNK survival pathways do not play a major role in this antiapoptotic function. Interaction studies revealed that HSV-2 R1 interacted constitutively with caspase-8. The HSV-2 R1 deletion mutant R1(1-834)-GFP and Epstein–Barr virus (EBV) R1, which did not protect against apoptosis induced by DR ligands, did not interact with caspase-8, indicating that interaction is required for protection. HSV-2 R1 impaired caspase-8 activation induced by caspase-8 over-expression, suggesting that interaction between the two proteins prevents caspase-8 dimerization/activation. HSV-2 R1 bound to caspase-8 directly through its prodomain but did not interact with either its caspase domain or Fas-associated death domain protein (FADD). Interaction between HSV-2 R1 and caspase-8 disrupted FADD-caspase-8 binding. We further demonstrated that individually expressed HSV-1 R1 (ICP6) shares, with HSV-2 R1, the ability to bind caspase-8 and to protect cells against DR-induced apoptosis. Finally, as the long-lived Fas protein remained stable during the early period of infection, experiments with the HSV-1 UL39 deletion mutant ICP6∆ showed that HSV-1 R1 could be essential for the protection of HSV-1-infected cells against FasL.     

Surface Water Linkages Regulate Trophic Interactions in a Groundwater Food Web

Groundwaters are increasingly viewed as resource-limited ecosystems in which fluxes of dissolved organic carbon (DOC) from surface water are efficiently mineralized by a consortium of microorganisms which are grazed by invertebrates. We tested for the effect of groundwater recharge on resource supply and trophic interactions by measuring physico-chemistry, microbial activity and biomass, structure of bacterial communities and invertebrate density at three sites intensively recharged with surface water. Comparison of measurements made in recharge and control well clusters at each site showed that groundwater recharge significantly increased fluxes of DOC and phosphate, elevated groundwater temperature, and diminished dissolved oxygen (DO). Microbial biomass and activity were significantly higher in recharge well clusters but stimulation of autochthonous microorganisms was not associated with a major shift in bacterial community structure. Invertebrate assemblages were not significantly more abundant in recharge well clusters and did not show any relationship with microbial biomass and activity. Microbial communities were bottom-up regulated by DOC and nutrient fluxes but trophic interactions between microorganisms and invertebrates were apparently limited by environmental stresses, particularly DO depletion and groundwater warming. Hydrological connectivity is a key factor regulating the function of DOC-based groundwater food webs as it influences both resource availability for microorganisms and environmental stresses which affect energy transfer to invertebrates and top-down control on microorganisms.     

Small RNA sequencing reveals miR-642a-3p as a novel adipocyte-specific microRNA and miR-30 as a key regulator of human adipogenesis

Background  

In severe obesity, as well as in normal development, the growth of adipose tissue is the result of an increase in adipocyte size and numbers, which is underlain by the stimulation of adipogenic differentiation of precursor cells. A better knowledge of the pathways that regulate adipogenesis is therefore essential for an improved understanding of adipose tissue expansion. As microRNAs (miRNAs) have a critical role in many differentiation processes, our study aimed to identify the role of miRNA-mediated gene silencing in the regulation of adipogenic differentiation.     

Wine flavor and aroma

The perception of wine flavor and aroma is the result of a multitude of interactions between a large number of chemical compounds and sensory receptors. Compounds interact and combine and show synergistic (i.e., the presence of one compound enhances the perception of another) and antagonistic (a compound suppresses the perception of another) interactions. The chemical profile of a wine is derived from the grape, the fermentation microflora (in particular the yeast Saccharomyces cerevisiae), secondary microbial fermentations that may occur, and the aging and storage conditions. Grape composition depends on the varietal and clonal genotype of the vine and on the interaction of the genotype and its phenotype with many environmental factors which, in wine terms, are usually grouped under the concept of “terroir” (macro, meso and microclimate, soil, topography). The microflora, and in particular the yeast responsible for fermentation, contributes to wine aroma by several mechanisms: firstly by utilizing grape juice constituents and biotransforming them into aroma- or flavor-impacting components, secondly by producing enzymes that transform neutral grape compounds into flavor-active compounds, and lastly by the de novo synthesis of many flavor-active primary (e.g., ethanol, glycerol, acetic acid, and acetaldehyde) and secondary metabolites (e.g., esters, higher alcohols, fatty acids). This review aims to present an overview of the formation of wine flavor and aroma-active components, including the varietal precursor molecules present in grapes and the chemical compounds produced during alcoholic fermentation by yeast, including compounds directly related to ethanol production or secondary metabolites. The contribution of malolactic fermentation, ageing, and maturation on the aroma and flavor of wine is also discussed.     

Effects of different site preparation treatments on species diversity,composition, and plant traits in <Emphasis Type="Italic">Pinus halepensis</Emphasis> woodlands

Biodiversity maintenance is a key component of Mediterranean forest management, yet studies on the effects of silvicultural treatments on plant diversity are scarce. Our experiment assessed the impact of five different site preparation treatments on the composition, diversity, ecological traits (life-form, pollination mode, leaf morphology, seed dispersal mode), indicator values (shade tolerance, nutrients demand) of the understory vegetation in a mature thinned Pinus halepensis stand in southern France. The treatments—chopping, chopping followed by scarification in one or two directions, prescribed burning, control—were replicated four times and applied on a total of 40 plots. Vegetation relevés were performed on each plot in the first, second and fourth year following treatment applications. Plant diversity, measured by the species richness or Shannon’s index, increased in the non-control treatment plots in the first year but then decreased through time. Vegetation composition differed between treatments, with the chopping treatment exhibiting composition and ecological trait values more comparable to those of control plots than the other treatments. The burning and scarification treatments led to higher abundance of therophytes, plants with malacophyllous leaves and insect-pollinated plants, and shade-intolerant and nutrient-demanding species. However, these changes were transient in time, the shade-intolerant species remained abundant but the ruderal species decreased while the ligneous species increased indicating a gradual return to a forest vegetation composition. For the Mediterranean area, most of the findings were similar to those in temperate forests subjected to the same site preparation treatments.     

Bisphenol A induces otolith malformations during vertebrate embryogenesis

Background  

The plastic monomer and plasticizer bisphenol A (BPA), used for manufacturing polycarbonate plastic and epoxy resins, is produced at over 2.5 million metric tons per year. Concerns have been raised that BPA acts as an endocrine disruptor on both developmental and reproductive processes and a large body of evidence suggests that BPA interferes with estrogen and thyroid hormone signaling. Here, we investigated BPA effects during embryonic development using the zebrafish and Xenopus models.     

Discovery and mechanism of ustekinumab: A human monoclonal antibody targeting interleukin-12 and interleukin-23 for treatment of immune-mediated disorders

Monoclonal antibody (mAb) therapy was first established upon the approval of a mouse antibody for treatment of human acute organ rejection. However, the high incidence of immune response against the mouse mAb restricted therapeutic utility. Development of chimeric, “humanized” and human mAbs broadened therapeutic application to immune-mediated diseases requiring long-term treatment. Indeed, mAb therapeutics targeting soluble cytokines are highly effective in numerous immune-mediated disorders. A recent example is ustekinumab, a first-in-class therapeutic human immunoglobulin (Ig) G₁ kappa mAb that binds to the interleukins (IL)-12 and IL-23, cytokines that modulate lymphocyte function, including T-helper (Th) 1 and Th17 cell subsets. Ustekinumab was generated via recombinant human IL-12 immunization of human Ig (hu-Ig) transgenic mice. Ustekinumab binds to the p40 subunit common to IL-12 and IL-23 and prevents their interaction with the IL-12 receptor β1 subunit of the IL-12 and IL-23 receptor complexes. Ustekinumab is approved for treatment of moderate-to-severe plaque psoriasis and has demonstrated efficacy in Crohn disease and psoriatic arthritis. The clinical characterization of ustekinumab continues to refine our understanding of human immune pathologies and may offer a novel therapeutic option for certain immune-mediated diseases.Key words: ustekinumab, psoriasis, monoclonal antibody, interleukin-12/23p40