Endogenous opioids seem to play a critical role in the regulation of mood states. For example, there is accumulating evidence that stimulation of -opioid receptors, upon which the endogenous opioid dynorphin acts, can produce depressivelike behaviors in laboratory animals. Here we examined whether systemic administration of salvinorin A (SalvA), a potent and highly selective -opioid agonist, would produce depressivelike effects in the forced swim test (FST) and intracranial selfstimulation (ICSS) test, which are behavioral models often used to study depression in rats. We extracted, isolated, and purified SalvA from Salvia divinorum plant leaves and examined its effects on behavior in the FST and ICSS test across a range of doses (0.125-2.0 mg/kg) after systemic (intraperitoneal) administration. SalvA dose dependently increased immobility in the FST, an effect opposite to that of standard antidepressant drugs. Doses of SalvA that produced these effects in the FST did not affect locomotor activity in an open field. Furthermore, SalvA dose dependently elevated ICSS thresholds, an effect similar to that produced by treatments that cause depressive symptoms in humans. At a dose that caused the depressivelike effects in both the FST and ICSS assays, SalvA decreased extracellular concentrations of dopamine (DA) within the nucleus accumbens (NAc), a critical component of brain reward circuitry, without affecting extracellular concentrations of serotonin (5-HT). These data provide additional support for the hypothesis that stimulation of brain -opioid receptors triggers depressive-like signs in rats and raise the possibility that decreases in extracellular concentrations of DA within the NAc contribute to these effects.Although much research on depression has focused on brain norepinephrine and serotonin (5-HT) systems, there is substantial evidence that other systems have important roles in the neurobiology of mood and affective disorders. For example, the mesolimbic dopamine (DA) systemwhich projects from the ventral tegmental area to the nucleus accumbens (NAc)-contributes importantly to the hedonic (rewarding) effects of food, sexual behavior, and addictive drugs (see Wise, 1998;Nestler and Carlezon, 2005). It has been proposed that disruption of DA function within the NAc causes anhedonia (reduced ability to experience reward) (Wise, 1982), a hallmark sign of clinical depression. The mesolimbic DA system is modulated by noradrenergic and serotonergic inputs (Pasquier et al., 1977), as well as endogenous opioid peptides (Devine et al., 1993;Shippenberg and Rea, 1997;Svingos et al., 1999). Agents that selectively affect the function of -opioid receptors cause profound alterations in mood in humans (Pfeiffer et al., 1986;Roth et al., 2002) and motivated behaviors in laboratory animals (Shippenberg and Herz, 1987;Todtenkopf et al., 2004), suggesting that manipulations targeting brain -opioid systems might be useful in the study and treatment of depressive disorders.

Synthetic protocols and circular dichroism (CD) spectra are reported for a series of oligomers of (R,R)-trans-2-aminocyclopentanecarboxylic acid (trans-ACPC). The two longest oligomers, a hexamer and an octamer, have also been examined crystallographically. Both crystal structures show that the β-peptide backbone adopts a regular helix that is defined by a series of interwoven 12-membered ring hydrogen bonds (“12-helix”). Each hydrogen bond links a carbonyl oxygen to an amide proton three residues toward the C-terminus. CD data suggest that the conformational preference of trans-ACPC oligomers in methanol is strongly length-dependent, which implies that 12-helix formation is a cooperative process, as seen for the α-helix formed by conventional peptides. Previous work has established that oligomers and polymers of β-amino acids can adopt helical conformations, but the 12-helix is an unprecedented β-peptide secondary structure.

The thermodynamically less stable form of galactose-galactofuranose (Galf)-is essential for the viability of several pathogenic species of bacteria and protozoa but absent in this form in mammals, so the biochemical pathways by which Galf-containing glycans are assembled and catabolysed are attractive sites for drug action. This potential has led to increasing interest in the synthesis of molecules containing Galf residues, their subsequent use in studies directed towards understanding the enzymes that process these residues and the identification of potential inhibitors of these pathways. Major achievements of the past several years have included an in-depth understanding of the mechanism of UDP-galactopyranose mutase (UGM), the enzyme that produces UDP-Galf, which is the donor species for galactofuranosyltransferases. A number of methods for the synthesis of galactofuranosides have also been developed, and practitioners in the field now have many options for the initiation of a synthesis of glycoconjugates containing either alpha- or beta-Galf residues. UDP-Galf has also been prepared by a number of approaches, and it appears that a chemoenzymatic approach is currently the most viable method for producing multi-milligram amounts of this important intermediate. Recent advances both in the understanding of the mechanism of UGM and in the synthesis of galactofuranose and its derivatives are highlighted in this review.

Bacterial capsules are surface layers made of long-chain polysaccharides. They are anchored to the outer membrane of many Gram-negative bacteria, including pathogens such as Escherichia coli , Neisseria meningitidis , Haemophilus influenzae , and Pasteurella multocida . Capsules protect pathogens from host defenses including complement-mediated killing and phagocytosis and therefore represent a major virulence factor. Capsular polysaccharides are synthesized by enzymes located in the inner (cytoplasmic) membrane and are then translocated to the cell surface. Whereas the enzymes that synthesize the polysaccharides have been studied in detail, the structure and biosynthesis of the anchoring elements have not been definitively resolved. Here we determine the structure of the glycolipid attached to the reducing terminus of the polysialic acid capsular polysaccharides from E. coli K1 and N. meningitidis group B and the heparosan-like capsular polysaccharide from E. coli K5. All possess the same unique glycolipid terminus consisting of a lyso-phosphatidylglycerol moiety with a β-linked poly-(3-deoxy- d - manno -oct-2-ulosonic acid) (poly-Kdo) linker attached to the reducing terminus of the capsular polysaccharide.

No abstract

No abstract

No abstract

Background: GlfT2 is a bifunctional galactofuranosyltransferase essential for mycobacterial cell wall biosynthesis. Results: Crystal structures of free and UDP-bound GlfT2, along with mutagenesis and kinetic studies, reveal novel details underlying substrate binding and catalysis. Conclusion:The homotetrameric architecture, distinctive nucleotide-binding site, and unprecedented structural features underlying the bifunctional polymerase activity of GlfT2 are revealed. Significance: Novel insights into polymerizing glycosyltransferases and the design of anti-mycobacterial therapeutics are obtained.