Regulation of 5-HT1A receptor function in brain following agonist or antidepressant administration

Adaptive changes in the serotonergic system are generally believed to underlie the therapeutic effectiveness of the azapirone anxiolytics and a variety of antidepressant drugs. The serotonin-1A (5-HT(1A)) receptor has been implicated in affective disorders. Thus, studies of the regulation of 5-HT(1A) receptor function may have important implications for our understanding the role of this receptor in the mechanism of action of these therapeutic agents. This review focuses on the regulation of central 5-HT(1A) receptor function following administration of 5-HT(1A) receptor agonists or antidepressant drugs expected to increase the synaptic concentration of the neurotransmitter 5-HT. The majority of evidence supports regional differences in the regulation of central 5-HT(1A) receptor function following repeated agonist or antidepressant administration, which may be due to differences in processes involved in desensitization of the receptor at the cellular level. Region-specific differences in the regulation of 5-HT(1A) receptor function may be based on compensatory changes distal to the receptor, such as regulatory changes at the level of effector (e.g. adenylyl cyclase or ion channel), or at the level of the G protein such as changes in G protein expression, or phosphorylation of the G protein. It may be that the increase in serotonin neurotransmission, due to somatodendritic autoreceptor desensitization following agonist or antidepressant treatment, to normo-sensitive 5-HT(1A) receptors in certain brain regions (e.g. hippocampus or cortex) and to sub-sensitive 5-HT(1A) receptors in other brain regions (e.g. amygdala or hypothalamus) underlies the therapeutic efficacy of these drugs.     

Human herpesvirus 8 infects and replicates in primary cultures of activated B lymphocytes through DC-SIGN

Human herpesvirus 8 (HHV-8) is the etiological agent of Kaposi's sarcoma, primary effusion lymphoma, and some forms of multicentric Castleman's disease. Although latent HHV-8 DNA can be detected in B cells from persons with these cancers, there is little information on the replication of HHV-8 in B cells. Indeed, B cells are relatively resistant to HHV-8 infection in vitro. We have recently shown that DC-SIGN, a C-type lectin first identified on dendritic cells (DC), is an entry receptor for HHV-8 on DC and macrophages. We have also demonstrated previously that B lymphocytes from peripheral blood and tonsils express DC-SIGN and that this expression increases after B-cell activation. Here we show that activated blood and tonsillar B cells can be productively infected with HHV-8, as measured by an increase in viral DNA, the expression of viral lytic and latency proteins, and the production of infectious virus. The infection of B cells with HHV-8 was blocked by the pretreatment of the cells with antibody specific for DC-SIGN or with mannan but not antibody specific for xCT, a cystine/glutamate exchange transporter that has been implicated in HHV-8 fusion to cells. The infection of B cells with HHV-8 resulted in increased expression of DC-SIGN and a decrease in the expression of CD20 and major histocompatibility complex class I. HHV-8 could also infect and replicate in B-cell lines transduced to express full-length DC-SIGN but not in B-cell lines transduced to express DC-SIGN lacking the transmembrane domain, demonstrating that the entry of HHV-8 into B cells is related to DC-SIGN-mediated endocytosis. The role of endocytosis in viral entry into activated B cells was confirmed by blocking HHV-8 infection with endocytic pathway inhibitors. Thus, the expression of DC-SIGN is essential for productive HHV-8 infection of and replication in B cells.     

Clostridiolysin S,a Post-translationally Modified Biotoxin from Clostridium botulinum

Through elaboration of its botulinum toxins, Clostridium botulinum produces clinical syndromes of infant botulism, wound botulism, and other invasive infections. Using comparative genomic analysis, an orphan nine-gene cluster was identified in C. botulinum and the related foodborne pathogen Clostridium sporogenes that resembled the biosynthetic machinery for streptolysin S, a key virulence factor from group A Streptococcus responsible for its hallmark β-hemolytic phenotype. Genetic complementation, in vitro reconstitution, mass spectral analysis, and plasmid intergrational mutagenesis demonstrate that the streptolysin S-like gene cluster from Clostridium sp. is responsible for the biogenesis of a novel post-translationally modified hemolytic toxin, clostridiolysin S.     

The group B streptococcal sialic acid O-acetyltransferase is encoded by neuD, a conserved component of bacterial sialic acid biosynthetic gene clusters

Nearly two dozen microbial pathogens have surface polysaccharides or lipo-oligosaccharides that contain sialic acid (Sia), and several Sia-dependent virulence mechanisms are known to enhance bacterial survival or result in host tissue injury. Some pathogens are also known to O-acetylate their Sias, although the role of this modification in pathogenesis remains unclear. We report that neuD, a gene located within the Group B Streptococcus (GBS) Sia biosynthetic gene cluster, encodes a Sia O-acetyltransferase that is itself required for capsular polysaccharide (CPS) sialylation. Homology modeling and site-directed mutagenesis identified Lys-123 as a critical residue for Sia O-acetyltransferase activity. Moreover, a single nucleotide polymorphism in neuD can determine whether GBS displays a "high" or "low" Sia O-acetylation phenotype. Complementation analysis revealed that Escherichia coli K1 NeuD also functions as a Sia O-acetyltransferase in GBS. In fact, NeuD homologs are commonly found within Sia biosynthetic gene clusters. A bioinformatic approach identified 18 bacterial species with a Sia biosynthetic gene cluster that included neuD. Included in this list are the sialylated human pathogens Legionella pneumophila, Vibrio parahemeolyticus, Pseudomonas aeruginosa, and Campylobacter jejuni, as well as an additional 12 bacterial species never before analyzed for Sia expression. Phylogenetic analysis shows that NeuD homologs of sialylated pathogens share a common evolutionary lineage distinct from the poly-Sia O-acetyltransferase of E. coli K1. These studies define a molecular genetic approach for the selective elimination of GBS Sia O-acetylation without concurrent loss of sialylation, a key to further studies addressing the role(s) of this modification in bacterial virulence.     

The Pore-Forming Toxin β hemolysin/cytolysin Triggers p38 MAPK-Dependent IL-10 Production in Macrophages and Inhibits Innate Immunity

Group B Streptococcus (GBS) is a leading cause of invasive bacterial infections in human newborns and immune-compromised adults. The pore-forming toxin (PFT) β hemolysin/cytolysin (βh/c) is a major virulence factor for GBS, which is generally attributed to its cytolytic functions. Here we show βh/c has immunomodulatory properties on macrophages at sub-lytic concentrations. βh/c-mediated activation of p38 MAPK drives expression of the anti-inflammatory and immunosuppressive cytokine IL-10, and inhibits both IL-12 and NOS2 expression in GBS-infected macrophages, which are critical factors in host defense. Isogenic mutant bacteria lacking βh/c fail to activate p38-mediated IL-10 production in macrophages and promote increased IL-12 and NOS2 expression. Furthermore, targeted deletion of p38 in macrophages increases resistance to invasive GBS infection in mice, associated with impaired IL-10 induction and increased IL-12 production in vivo. These data suggest p38 MAPK activation by βh/c contributes to evasion of host defense through induction of IL-10 expression and inhibition of macrophage activation, a new mechanism of action for a PFT and a novel anti-inflammatory role for p38 in the pathogenesis of invasive bacterial infection. Our studies suggest p38 MAPK may represent a new therapeutic target to blunt virulence and improve clinical outcome of invasive GBS infection.     

Comparing product category rules from different programs: learned outcomes towards global alignment

Purpose

Product category rules (PCRs) provide category-specific guidance for estimating and reporting product life cycle environmental impacts, typically in the form of environmental product declarations and product carbon footprints. Lack of global harmonization between PCRs or sector guidance documents has led to the development of duplicate PCRs for the same products. Differences in the general requirements (e.g., product category definition, reporting format) and LCA methodology (e.g., system boundaries, inventory analysis, allocation rules, etc.) diminish the comparability of product claims.

Methods

A comparison template was developed to compare PCRs from different global program operators. The goal was to identify the differences between duplicate PCRs from a broad selection of product categories and propose a path toward alignment. We looked at five different product categories: milk/dairy (two PCRs), horticultural products (three PCRs), wood?Cparticleboard (two PCRs), and laundry detergents (four PCRs).

Results and discussion

Disparity between PCRs ranged from broad differences in scope, system boundaries, and impacts addressed (e.g., multi-impact vs. carbon footprint only) to specific differences of technical elements. The differences primarily reflected the different purposes of the PCR (e.g., label/report), the different standards they were based on (e.g., ISO 14025/PAS 2050), the use of different product categorization systems, or simply the result of being developed independently. Differing degrees of specificity and terminology between PCRs allowed for varied interpretation??at times making direct comparison difficult. For many of the differences between PCRs, however, there was no clear rationale why they could not be consistent in the future.

Conclusions

These results were used to outline a general guidance document for global alignment of PCRs which recommends (1) alignment of PCRs for different purposes, (2) provision of guidance for the adoption of aspects of other PCRs, and (3) provision of greater specificity on content. The overall recommendations also suggest collaboration among program operators to facilitate alignment on issues that evolve from independent development.     

Untersuchungen über nekrozönosen und taxozönosen der testacea (protozoa) im zirbenwaldmoor (Obergurgl,Tirol/Austria)

Zusammenfassung In Zirbenwaldmoor, das südwestlich von Obergurgl in 2150–2200 m Seehöhe liegt, wurde im tiefsten Zentralteil ein Bohrkern von 300 cm entnommen.Der torfbildenden Prozeß wurde durch keine mineralische Überschüttung unterbrochen, so daß im gesamten Profil nur reiner Torf zu finden ist. Wohl war aber die Geschwindigkeit des Torfzuwaschses sehr unregelmäßig. Zwischen dem Ende des jüngeren Atlantikums und dem Beginn des älteren Subatlantikums wurde eine fast vollständige Einstellung des Moorwachstums und Austrocknung der Oberfläche festgestellt.Die erste Testaceengemeinschaft wird von den feuchtigkeitsliebenden Arten Hyalosphenia papilio, Amphitrema flavum und Difflugia rubescens dominiert. Mit der Verlandung des damaligen Sees treten diese Arten zurück, die Gattungen Heleopera und Centropyxis erscheinen. Bei der nachfolgenden Austocknung der Oberfläche wurde das Moor für längere Zeit von einem Birkenbestand bewachsen. Die Folge ist ein starker Rückgang von Abundanz und Artenzahl. Nach Wiederbeginn der Torfbildungstätigkeit wird die Individuendichte der Testaceen wieder größer, vor allem aber die der Moorarten Amphitrema flavum und Hyalosphenia papilio. In den subrezenten Schichten läßt eine neue Testaceengemeinschaft mit den dominanten Arten Nebela collaris, Assulina seminulum und Centropyxis aculeata auf eher trockenere Bedingungen bei der Moorbildung schließen. In den rezenten Schichten dominieren Euglypha ciliata, Corythion dubium, Centropyxis aerophila, das Genus Trinema mit T. enchelys und T. lineare sowie das Genus Nebela mit N. collaris und N. tincta. Diese Taxozönose entspricht weitgehend dem Waldmoostyp von Harnisch, welcher für Einzelsphagnete ohne Moorbildung charakteristisch ist.

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Investigations on the Testacean Nekrocoenoses and Taxocoenoses in the Zirbenwaldmoor (Obergurgl, Tyrol/Austria).The present paper deals with Testacean distribution in a peat profile (0–300 cm) and in recent samples from a subalpine bog near the timberline. The succession of the Testacean nekrocoenoses was studied as well as the taxocoenoses. This study based on phytocoenological and palaeoecological investigations designed to obtain data on stratigraphy of peat profiles, on reconstruction of the peat-forming communities and on pollen analyses, which were carried out by Bortenschlager (1979, 1972) and Rybníek & Rybníkova (1977).

     

Product category rules alignment workshop, October 4, 2011 in Chicago, IL, USA

Purpose  

A workshop on Product Category Rule (PCR) alignment was organized by the American Center for LCA PCR Committee. PCR alignment refers to the process of assuring that PCRs (rules for developing LCA-based claims like EPDs) developed by different parties are consistent within product categories.     

Preservation of Metabolic Flexibility in Skeletal Muscle by a Combined Use of n-3 PUFA and Rosiglitazone in Dietary Obese Mice

Insulin resistance, the key defect in type 2 diabetes (T2D), is associated with a low capacity to adapt fuel oxidation to fuel availability, i.e., metabolic inflexibility. This, in turn, contributes to a further damage of insulin signaling. Effectiveness of T2D treatment depends in large part on the improvement of insulin sensitivity and metabolic adaptability of the muscle, the main site of whole-body glucose utilization. We have shown previously in mice fed an obesogenic high-fat diet that a combined use of n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) and thiazolidinediones (TZDs), anti-diabetic drugs, preserved metabolic health and synergistically improved muscle insulin sensitivity. We investigated here whether n-3 LC-PUFA could elicit additive beneficial effects on metabolic flexibility when combined with a TZD drug rosiglitazone. Adult male C57BL/6N mice were fed an obesogenic corn oil-based high-fat diet (cHF) for 8 weeks, or randomly assigned to various interventions: cHF with n-3 LC-PUFA concentrate replacing 15% of dietary lipids (cHF+F), cHF with 10 mg rosiglitazone/kg diet (cHF+ROSI), cHF+F+ROSI, or chow-fed. Indirect calorimetry demonstrated superior preservation of metabolic flexibility to carbohydrates in response to the combined intervention. Metabolomic and gene expression analyses in the muscle suggested distinct and complementary effects of the interventions, with n-3 LC-PUFA supporting complete oxidation of fatty acids in mitochondria and the combination with n-3 LC-PUFA and rosiglitazone augmenting insulin sensitivity by the modulation of branched-chain amino acid metabolism. These beneficial metabolic effects were associated with the activation of the switch between glycolytic and oxidative muscle fibers, especially in the cHF+F+ROSI mice. Our results further support the idea that the combined use of n-3 LC-PUFA and TZDs could improve the efficacy of the therapy of obese and diabetic patients.