An actively accreting massive black hole in the dwarf starburst galaxy Henize 2-10

Supermassive black holes are now thought to lie at the heart of every giant galaxy with a spheroidal component, including our own Milky Way. The birth and growth of the first 'seed' black holes in the earlier Universe, however, is observationally unconstrained and we are only beginning to piece together a scenario for their subsequent evolution. Here we report that the nearby dwarf starburst galaxy Henize?2-10 (refs 5 and 6) contains a compact radio source at the dynamical centre of the galaxy that is spatially coincident with a hard X-ray source. From these observations, we conclude that Henize?2-10 harbours an actively accreting central black hole with a mass of approximately one million solar masses. This nearby dwarf galaxy, simultaneously hosting a massive black hole and an extreme burst of star formation, is analogous in many ways to galaxies in the infant Universe during the early stages of black-hole growth and galaxy mass assembly. Our results confirm that nearby star-forming dwarf galaxies can indeed form massive black holes, and that by implication so can their primordial counterparts. Moreover, the lack of a substantial spheroidal component in Henize?2-10 indicates that supermassive black-hole growth may precede the build-up of galaxy spheroids.     

Altered chloride ion channel kinetics associated with the delta F508 cystic fibrosis mutation.

Cystic fibrosis is associated with a defect in epithelial chloride ion transport which is caused by mutations in a membrane protein called CFTR (cystic fibrosis transmembrane conductance regulator). Heterologous expression of CFTR produces cyclicAMP-sensitive Cl(-)-channel activity. Deletion of phenylalanine at amino-acid position 508 in CFTR (delta F508 CFTR) is the most common mutation in cystic fibrosis. It has been proposed that this mutation prevents glycoprotein maturation and its transport to its normal cellular location. We have expressed both CFTR and delta F508 CFTR in Vero cells using recombinant vaccinia virus. Although far less delta F508 CFTR reached the plasma membrane than normal CFTR, sufficient delta F508 CFTR was expressed at the plasma membrane to permit functional analysis. delta F508 CFTR expression induced a reduced activity of the cAMP-activated Cl- channel, with conductance, anion selectivity and open-time kinetics similar to those of CFTR, but with much greater closed times, resulting in a large decrease of open probability. The delta F508 mutation thus seems to have two major consequences, an abnormal translocation of the CFTR protein which limits membrane insertion, and an abnormal function in mediating Cl- transport.     

Synthesis in E. coli of alpha 1-antitrypsin variants of therapeutic potential for emphysema and thrombosis

The primary function of alpha 1-antitrypsin (alpha 1-AT), an antiprotease produced by the liver, is the inhibition of neutrophil elastase, a protease capable of hydrolysing most connective tissue components. The importance of alpha 1-AT is demonstrated by the high incidence of early-onset emphysema in individuals with hereditary alpha 1-AT deficiency (Type PiZZ), in whom serum levels of alpha 1-AT are 10-20% of normal. Oxidants in tobacco smoke can inactivate alpha 1-AT in vitro, and studies have shown that alpha 1-AT from the lungs of individuals who smoke cigarettes may also be partially inactivated, perhaps explaining the high incidence of emphysema associated with cigarette smoking. Oxidative inactivation is probably due to modification of the Met residue (Met358) at the P1 subsite position of the elastase binding site of the protein. To study the possibility of modulating the biological properties of alpha 1-AT, we have introduced selected sequence modifications at the reactive site by in vitro mutation of a cloned alpha 1-AT complementary DNA. We describe here the characterization of two alpha 1-AT analogues produced in Escherichia coli. The first, alpha 1-AT(Met385----Val), is not only fully active as an elastase inhibitor but is also resistant to oxidative inactivation. The other, alpha 1-AT(Met358----Arg), no longer inhibits elastase but is an efficient thrombin inhibitor. The active site of the latter is identical to that of the alpha 1-AT (Pittsburgh) variant, which was associated with a fatal bleeding disorder.     

A plant pathogen virulence factor inhibits the eukaryotic proteasome by a novel mechanism

Pathogenic bacteria often use effector molecules to increase virulence. In most cases, the mode of action of effectors remains unknown. Strains of Pseudomonas syringae pv. syringae (Pss) secrete syringolin A (SylA), a product of a mixed non-ribosomal peptide/polyketide synthetase, in planta. Here we identify SylA as a virulence factor because a SylA-negative mutant in Pss strain B728a obtained by gene disruption was markedly less virulent on its host, Phaseolus vulgaris (bean). We show that SylA irreversibly inhibits all three catalytic activities of eukaryotic proteasomes, thus adding proteasome inhibition to the repertoire of modes of action of virulence factors. The crystal structure of the yeast proteasome in complex with SylA revealed a novel mechanism of covalent binding to the catalytic subunits. Thus, SylA defines a new class of proteasome inhibitors that includes glidobactin A (GlbA), a structurally related compound from an unknown species of the order Burkholderiales, for which we demonstrate a similar proteasome inhibition mechanism. As proteasome inhibitors are a promising class of anti-tumour agents, the discovery of a novel family of inhibitory natural products, which we refer to as syrbactins, may also have implications for the development of anti-cancer drugs. Homologues of SylA and GlbA synthetase genes are found in some other pathogenic bacteria, including the human pathogen Burkholderia pseudomallei, the causative agent of melioidosis. It is thus possible that these bacteria are capable of producing proteasome inhibitors of the syrbactin class.     

Positional cloning of a novel gene influencing asthma from chromosome 2q14

Asthma is a common disease in children and young adults. Four separate reports have linked asthma and related phenotypes to an ill-defined interval between 2q14 and 2q32 (refs. 1-4), and two mouse genome screens have linked bronchial hyper-responsiveness to the region homologous to 2q14 (refs. 5,6). We found and replicated association between asthma and the D2S308 microsatellite, 800 kb distal to the IL1 cluster on 2q14. We sequenced the surrounding region and constructed a comprehensive, high-density, single-nucleotide polymorphism (SNP) linkage disequilibrium (LD) map. SNP association was limited to the initial exons of a solitary gene of 3.6 kb (DPP10), which extends over 1 Mb of genomic DNA. DPP10 encodes a homolog of dipeptidyl peptidases (DPPs) that cleave terminal dipeptides from cytokines and chemokines, and it presents a potential new target for asthma therapy.     

Ferroelectric relaxor as a critical state

After revisiting models for the ferroelectric relaxors,we notice that the models can be classified into two categories.One group models are directly based upon the compositional fluctuations,such as Smolenskii's theory and SRBRF model.The other models are experimental phenomenon oriented,such as macro-micro domain crossover and superparaelectric state. The later explanations imply that the ferroelectric relaxor is in a critical state.The unusual field induced phase transition in ferroelectric relaxor also s...     

Activated human monocytes express the c-sis proto-oncogene and release a mediator showing PDGF-like activity

Current ideas about the mechanism of wound healing and the pathogenesis of atherosclerosis, pulmonary fibrosis and hepatic fibrosis suggest a central role for the mononuclear phagocyte in attracting and/or stimulating the proliferation of mesenchymal cells. We demonstrate here that activated human blood monocytes, but not resting monocytes, release a mediator that attracts smooth muscle cells and cooperates with other mediators to stimulate fibroblast proliferation. This mediator is very similar to platelet-derived growth factor (PDGF): its chromatographic properties and chemical stability are similar to those of PDGF, it competes with 125I-PDGF for binding to fibroblasts and it immunoprecipitates with anti-PDGF antibodies. In parallel, stimulated monocytes, but not resting monocytes, express the c-sis proto-oncogene, a gene coding for one of the PDGF chains, consistent with the concept that expression of the c-sis proto-oncogene may be involved in the ability of mononuclear phagocytes to modulate the accumulation of mesenchymal cells.