Genetic variation in DLG5 is associated with inflammatory bowel disease

Crohn disease and ulcerative colitis are two subphenotypes of inflammatory bowel disease (IBD), a complex disorder resulting from gene-environment interaction. We refined our previously defined linkage region for IBD on chromosome 10q23 and used positional cloning to identify genetic variants in DLG5 associated with IBD. DLG5 encodes a scaffolding protein involved in the maintenance of epithelial integrity. We identified two distinct haplotypes with a replicable distortion in transmission (P = 0.000023 and P = 0.004 for association with IBD, P = 0.00012 and P = 0.04 for association with Crohn disease). One of the risk-associated DLG5 haplotypes is distinguished from the common haplotype by a nonsynonymous single-nucleotide polymorphism 113G-->A, resulting in the amino acid substitution R30Q in the DUF622 domain of DLG5. This mutation probably impedes scaffolding of DLG5. We stratified the study sample according to the presence of risk-associated CARD15 variants to study potential gene-gene interaction. We found a significant difference in association of the 113A DLG5 variant with Crohn disease in affected individuals carrying the risk-associated CARD15 alleles versus those carrying non-risk-associated CARD15 alleles. This is suggestive of a complex pattern of gene-gene interaction between DLG5 and CARD15, reflecting the complex nature of polygenic diseases. Further functional studies will evaluate the biological significance of DLG5 variants.     

Genome-wide survey of protein kinases required for cell cycle progression

Cycles of protein phosphorylation are fundamental in regulating the progression of the eukaryotic cell through its division cycle. Here we test the complement of Drosophila protein kinases (kinome) for cell cycle functions after gene silencing by RNA-mediated interference. We observed cell cycle dysfunction upon downregulation of 80 out of 228 protein kinases, including most kinases that are known to regulate the division cycle. We find new enzymes with cell cycle functions; some of these have family members already known to phosphorylate microtubules, actin or their associated proteins. Additionally, depletion of several signalling kinases leads to specific mitotic aberrations, suggesting novel roles for familiar enzymes. The survey reveals the inter-digitation of systems that monitor cellular physiology, cell size, cellular stress and signalling processes with the basic cell cycle regulatory machinery.     

Partial quantum information

Information--be it classical or quantum--is measured by the amount of communication needed to convey it. In the classical case, if the receiver has some prior information about the messages being conveyed, less communication is needed. Here we explore the concept of prior quantum information: given an unknown quantum state distributed over two systems, we determine how much quantum communication is needed to transfer the full state to one system. This communication measures the partial information one system needs, conditioned on its prior information. We find that it is given by the conditional entropy--a quantity that was known previously, but lacked an operational meaning. In the classical case, partial information must always be positive, but we find that in the quantum world this physical quantity can be negative. If the partial information is positive, its sender needs to communicate this number of quantum bits to the receiver; if it is negative, then sender and receiver instead gain the corresponding potential for future quantum communication. We introduce a protocol that we term 'quantum state merging' which optimally transfers partial information. We show how it enables a systematic understanding of quantum network theory, and discuss several important applications including distributed compression, noiseless coding with side information, multiple access channels and assisted entanglement distillation.     

Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections

CD1d-restricted natural killer T (NKT) cells are innate-like lymphocytes that express a conserved T-cell receptor and contribute to host defence against various microbial pathogens. However, their target lipid antigens have remained elusive. Here we report evidence for microbial, antigen-specific activation of NKT cells against Gram-negative, lipopolysaccharide (LPS)-negative alpha-Proteobacteria such as Ehrlichia muris and Sphingomonas capsulata. We have identified glycosylceramides from the cell wall of Sphingomonas that serve as direct targets for mouse and human NKT cells, controlling both septic shock reaction and bacterial clearance in infected mice. In contrast, Gram-negative, LPS-positive Salmonella typhimurium activates NKT cells through the recognition of an endogenous lysosomal glycosphingolipid, iGb3, presented by LPS-activated dendritic cells. These findings identify two novel antigenic targets of NKT cells in antimicrobial defence, and show that glycosylceramides are an alternative to LPS for innate recognition of the Gram-negative, LPS-negative bacterial cell wall.     

A novel ubiquitin ligase is deficient in Fanconi anemia

Fanconi anemia is a recessively inherited disease characterized by congenital defects, bone marrow failure and cancer susceptibility. Cells from individuals with Fanconi anemia are highly sensitive to DNA-crosslinking drugs, such as mitomycin C (MMC). Fanconi anemia proteins function in a DNA damage response pathway involving breast cancer susceptibility gene products, BRCA1 and BRCA2 (refs. 1,2). A key step in this pathway is monoubiquitination of FANCD2, resulting in the redistribution of FANCD2 to nuclear foci containing BRCA1 (ref. 3). The underlying mechanism is unclear because the five Fanconi anemia proteins known to be required for this ubiquitination have no recognizable ubiquitin ligase motifs. Here we report a new component of a Fanconi anemia protein complex, called PHF9, which possesses E3 ubiquitin ligase activity in vitro and is essential for FANCD2 monoubiquitination in vivo. Because PHF9 is defective in a cell line derived from an individual with Fanconi anemia, we conclude that PHF9 (also called FANCL) represents a novel Fanconi anemia complementation group (FA-L). Our data suggest that PHF9 has a crucial role in the Fanconi anemia pathway as the likely catalytic subunit required for monoubiquitination of FANCD2.     

Shiverer peripheral myelin contains P2

Myelin-deficient mutant mice, such as shiverer, can provide information about the normal mechanisms involved in myelination. The shiverer mouse carries a recessive, autosomal mutation resulting in an extreme deficiency in central myelin, and the small amount of myelin present is poorly compacted; the peripheral myelin, however, appears essentially normal. As the amount of myelin basic protein (P1) in both central and peripheral nervous system myelin is extremely low in shiverer, it is possible that P1 is essential for the normal formation and compaction of central myelin, but not of peripheral myelin. Some other protein would then be responsible for the formation of compact peripheral myelin in shiverer. Peripheral myelin contains another basic protein, designated P2, which could be a possible candidate for this role. Kirschner and Ganser, however, using SDS-polyacrylamide gel electrophoresis, reported that P2, as well as P1, is absent from shiverer sciatic nerve. This is an important observation if correct, because it not only excludes the possibility that P2 is required for compaction but also makes it less likely that the deficiency in P1 is the primary defect in shiverer. As P2 in rat and mouse has frequently been confused with another small basic protein (related to P1) in SDS-polyacrylamide gels, it seemed worthwhile to reassess this aspect of the Kirschner and Ganser observations. Immunohistochemistry and immunoblotting have been used here to show unambiguously that P2 is present in shiverer peripheral myelin.     

Reshaping human antibodies for therapy

A human IgGI antibody has been reshaped for serotherapy in humans by introducing the six hypervariable regions from the heavy- and light-chain variable domains of a rat antibody directed against human lymphocytes. The reshaped human antibody is as effective as the rat antibody in complement and is more effective in cell-mediated lysis of human lymphocytes.     

Retinal ganglion cells lose response to laminin with maturation

The decisive role played by adhesive interactions between neuronal processes and the culture substrate in determining the form and extent of neurite outgrowth in vitro has greatly influenced ideas about the mechanisms of axonal growth and guidance in the vertebrate nervous system. These studies have also helped to identify adhesive molecules that might be involved in guiding axonal growth in vivo. One candidate molecule is laminin, a major glycoprotein of basal laminae which has been shown to induce a wide variety of embryonic neurones to extend neurites in culture. Moreover, laminin is found in large amounts in injured nerves that can successfully regenerate but is absent from nerves where regeneration fails. However, it is unclear to what extent the mechanisms that regulate axonal regeneration also operate in the embryo when axon outgrowth is initiated. Here we have examined the substrate requirements for neurite outgrowth in vitro by chick embryo retinal ganglion cells, the only cells in the retina to send axons to the brain. We show that while retinal ganglion cells from embryonic day 6 (E6) chicks extend profuse neurites on laminin, those from E11 do not, although they retain the ability to extend neurites on astrocytes via a laminin-independent mechanism. This represents the first evidence that central nervous system neurones may undergo a change in their substrate requirements for neurite outgrowth as they mature.