Inelastic J/psi Photoproduction

Inelastic photoproduction of $J/\psi$ particles at high energies is one of the processes to determine the gluon distribution in the nucleon. We have calculated the QCD radiative corrections to the color-singlet model of this reaction. They are large at moderate photon energies, but decrease with increasing energies. The cross section and the $J/\psi$ energy spectrum are compared with the available fixed-target photoproduction data and predictions are given for the HERA energy range.Comment: 14 pages, latex, 7 uuencoded figure

Fragmentation production of doubly heavy baryons

Baryons with a single heavy quark are being studied experimentally at present. Baryons with two units of heavy flavor will be abundantly produced not only at future colliders, but also at existing facilities. In this paper we study the production via heavy quark fragmentation of baryons containing two heavy quarks at the Tevatron, the LHC, HERA, and the NLC. The production rate is woefully small at HERA and at the NLC, but significant at $pp$ and $p\bar{p}$ machines. We present distributions in various kinematical variables in addition to the integrated cross sections at hadron colliders.Comment: 13 pages, macro package epsfig needed, 6 .eps figure files in a separate uuencoded, compressed and tarred file; complete paper available at http://www.physics.carleton.ca/~mad/papers/paper.p

Structure of the cystathionine γ-synthase MetB from Mycobacterium ulcerans

Cystathionine γ-synthase (CGS) is a transferase that catalyzes the reaction between O 4-succinyl-l-homoserine and l-cysteine to produce l-­cystathionine and succinate. The crystal structure of CGS from M. ulcerans is presented covalently linked to the cofactor pyridoxal phosphate (PLP). A second structure contains PLP as well as a highly ordered HEPES molecule in the active site acting as a pseudo-ligand. This is the first structure ever reported from the pathogen M. ulcerans

Somatic ‘Soluble’ Adenylyl Cyclase Isoforms Are Unaffected in Sacytm1Lex/Sacytm1Lex ‘Knockout’ Mice

BACKGROUND: Mammalian Soluble adenylyl cyclase (sAC, Adcy10, or Sacy) represents a source of the second messenger cAMP distinct from the widely studied, G protein-regulated transmembrane adenylyl cyclases. Genetic deletion of the second through fourth coding exons in Sacy(tm1Lex)/Sacy(tm1Lex) knockout mice results in a male sterile phenotype. The absence of any major somatic phenotype is inconsistent with the variety of somatic functions identified for sAC using pharmacological inhibitors and RNA interference. PRINCIPAL FINDINGS: We now use immunological and molecular biological methods to demonstrate that somatic tissues express a previously unknown isoform of sAC, which utilizes a unique start site, and which 'escapes' the design of the Sacy(tm1Lex) knockout allele. CONCLUSIONS/SIGNIFICANCE: These studies reveal increased complexity at the sAC locus, and they suggest that the known isoforms of sAC play a unique function in male germ cells

KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington's disease patients

The activity of the transcription factor nuclear factor-erythroid 2 p45-derived factor 2 (NRF2) is orchestrated and amplified through enhanced transcription of antioxidant and antiinflammatory target genes. The present study has characterized a triazole-containing inducer of NRF2 and elucidated the mechanism by which this molecule activates NRF2 signaling. In a highly selective manner, the compound covalently modifies a critical stress-sensor cysteine (C151) of the E3 ligase substrate adaptor protein Kelch-like ECH-associated protein 1 (KEAP1), the primary negative regulator of NRF2. We further used this inducer to probe the functional consequences of selective activation of NRF2 signaling in Huntington's disease (HD) mouse and human model systems. Surprisingly, we discovered a muted NRF2 activation response in human HD neural stem cells, which was restored by genetic correction of the disease-causing mutation. In contrast, selective activation of NRF2 signaling potently repressed the release of the proinflammatory cytokine IL-6 in primary mouse HD and WT microglia and astrocytes. Moreover, in primary monocytes from HD patients and healthy subjects, NRF2 induction repressed expression of the proinflammatory cytokines IL-1, IL-6, IL-8, and TNFα. Together, our results demonstrate a multifaceted protective potential of NRF2 signaling in key cell types relevant to HD pathology

Selective Sirt2 inhibition by ligand-induced rearrangement of the active site

Sirtuins are a highly conserved class of NAD+-dependent lysine deacylases. The human isotype Sirt2 has been implicated in the pathogenesis of cancer, inflammation and neurodegeneration, which makes the modulation of Sirt2 activity a promising strategy for pharmaceutical intervention. A rational basis for the development of optimized Sirt2 inhibitors is lacking so far. Here we present high-resolution structures of human Sirt2 in complex with highly selective drug-like inhibitors that show a unique inhibitory mechanism. Potency and the unprecedented Sirt2 selectivity are based on a ligand-induced structural rearrangement of the active site unveiling a yet-unexploited binding pocket. Application of the most potent Sirtuin-rearranging ligand, termed SirReal2, leads to tubulin hyperacetylation in HeLa cells and induces destabilization of the checkpoint protein BubR1, consistent with Sirt2 inhibition in vivo. Our structural insights into this unique mechanism of selective sirtuin inhibition provide the basis for further inhibitor development and selective tools for sirtuin biology

H2r: Identification of evolutionary important residues by means of an entropy based analysis of multiple sequence alignments

BACKGROUND: A multiple sequence alignment (MSA) generated for a protein can be used to characterise residues by means of a statistical analysis of single columns. In addition to the examination of individual positions, the investigation of co-variation of amino acid frequencies offers insights into function and evolution of the protein and residues. RESULTS: We introduce conn(k), a novel parameter for the characterisation of individual residues. For each residue k, conn(k) is the number of most extreme signals of co-evolution. These signals were deduced from a normalised mutual information (MI) value U(k, l) computed for all pairs of residues k, l. We demonstrate that conn(k) is a more robust indicator than an individual MI-value for the prediction of residues most plausibly important for the evolution of a protein. This proposition was inferred by means of statistical methods. It was further confirmed by the analysis of several proteins. A server, which computes conn(k)-values is available at http://www-bioinf.uni-regensburg.de. CONCLUSION: The algorithms H2r, which analyses MSAs and computes conn(k)-values, characterises a specific class of residues. In contrast to strictly conserved ones, these residues possess some flexibility in the composition of side chains. However, their allocation is sensibly balanced with several other positions, as indicated by conn(k)

A Piezoelectric Immunosensor Using Hybrid Self-Assembled Monolayers for Detection of Schistosoma japonicum

BACKGROUND: The parasite Schistosoma japonicum causes schistosomiasis disease, which threatens human life and hampers economic and social development in some Asian countries. An important lesson learned from efforts to reduce the occurrence of schistosomiasis is that the diagnostic approach must be altered as further progress is made towards the control and ultimate elimination of the disease. METHODOLOGY/PRINCIPAL FINDINGS: Using mixed self-assembled monolayer membrane (mixed SAM) technology, a mixture of mercaptopropionic acid (MPA) and mercaptoethanol (ME) was self-assembled on the surface of quartz crystals by gold-sulphur-bonds. Soluble egg antigens (SEA) of S. japonicum were then cross-linked to the quartz crystal using a special coupling agent. As compared with the traditional single self-assembled monolayer immobilization method, S. japonicum antigen (SjAg) immobilization using mixed self-assembled monolayers exhibits much greater immunoreactivity. Under optimal experimental conditions, the detection range is 1:1500 to 1:60 (infected rabbit serum dilution ratios). We measured several infected rabbit serum samples with varying S. japonicum antibody (SjAb) concentrations using both immunosensor and ELISA techniques and then produced a correlation analysis. The correlation coefficients reached 0.973. CONCLUSIONS/SIGNIFICANCE: We have developed a new, simple, sensitive, and reusable piezoelectric immunosensor that directly detects SjAb in the serum. This method may represent an alternative to the current diagnostic methods for S. japonicum infection in the clinical laboratory or for analysis outside the laboratory