The Yersinia enterocolitica effector YopP inhibits host cell signalling by inactivating the protein kinase TAK1 in the IL-1 signalling pathway

The mechanism by which YopP simultaneously inhibits mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB pathways has been elusive. Ectopic expression of YopP inhibits the activity and ubiquitination of a complex consisting of overexpressed TGF-beta-activated kinase 1 (TAK1) and its subunit TAK1-binding protein (TAB)1, but not of MEK kinase 1. YopP, but not the catalytically inactive mutant YopP(C172A), also suppresses basal and interleukin-1-inducible activation of endogenous TAK1, TAB1 and TAB2. YopP does not affect the interaction of TAK1, TAB1 and TAB2 but inhibits autophosphorylation of TAK1 at Thr 187 and phosphorylation of TAB1 at Ser 438. Glutathione S-transferase-tagged YopP (GST-YopP) binds to MAPK kinase (MAPKK)4 and TAB1 but not to TAK1 or TAB2 in vitro. Furthermore, YopP in synergy with a previously described negative regulatory feedback loop inhibits TAK1 by MAPKK6-p38-mediated TAB1 phosphorylation. Taken together, these data strongly suggest that YopP binds to TAB1 and directly inhibits TAK1 activity by affecting constitutive TAK1 and TAB1 ubiquitination that is required for autoactivation of TAK1.     

Discovering functional gene expression patterns in the metabolic network of Escherichia coli with wavelets transforms

Background  

Microarray technology produces gene expression data on a genomic scale for an endless variety of organisms and conditions. However, this vast amount of information needs to be extracted in a reasonable way and funneled into manageable and functionally meaningful patterns. Genes may be reasonably combined using knowledge about their interaction behaviour. On a proteomic level, biochemical research has elucidated an increasingly complete image of the metabolic architecture, especially for less complex organisms like the well studied bacterium Escherichia coli.     

Selecting normalization genes for small diagnostic microarrays

Background  

Normalization of gene expression microarrays carrying thousands of genes is based on assumptions that do not hold for diagnostic microarrays carrying only few genes. Thus, applying standard microarray normalization strategies to diagnostic microarrays causes new normalization problems.     

Gender and post-ischemic recovery of hypertrophied rat hearts

Background

Cardiac mortality in Duchenne muscular dystrophy (DMD) has recently become important, because risk of respiratory failure has been reduced due to widespread use of the respirator. The cardiac involvement is characterized by distinctive electrocardiographic abnormalities or dilated cardiomyopathy, but the pathogenesis has remained obscure. In research on DMD, Golden retriever-based muscular dystrophy (GRMD) has attracted much attention as an animal model because it resembles DMD, but GRMD is very difficult to maintain because of their severe phenotypes. We therefore established a line of dogs with Beagle-based canine X-linked muscular dystrophy in Japan (CXMD_J) and examined the cardiac involvement.

Methods

The cardiac phenotypes of eight CXMD_J and four normal male dogs 2 to 21 months of age were evaluated using electrocardiography, echocardiography, and histopathological examinations.

Results

Increases in the heart rate and decreases in PQ interval compared to a normal littermate were detected in two littermate CXMD_J dogs at 15 months of age or older. Distinct deep Q-waves and increase in Q/R ratios in leads II, III, and aVF were detected by 6–7 months of age in all CXMD_J dogs. In the echocardiogram, one of eight of CXMD_J dogs showed a hyperechoic lesion in the left ventricular posterior wall at 5 months of age, but the rest had not by 6–7 months of age. The left ventricular function in the echocardiogram indicated no abnormality in all CXMD_J dogs by 6–7 months of age. Histopathology revealed myocardial fibrosis, especially in the left ventricular posterobasal wall, in three of eight CXMD_J dogs by 21 months of age.

Conclusion

Cardiac involvement in CXMD_J dogs is milder and has slower progression than that described in GRMD dogs. The distinct deep Q-waves have been ascribed to myocardial fibrosis in the posterobasal region of the left ventricle, but our data showed that they precede the lesion on echocardiogram and histopathology. These findings imply that studies of CXMD_J may reveal not only another causative mechanism of the deep Q-waves but also more information on the pathogenesis in the dystrophin-deficient heart.     

Failure of catecholamines to shift T-cell cytokine responses toward a Th2 profile in patients with rheumatoid arthritis

To further understand the role of neuro-immunological interactions in the pathogenesis of rheumatoid arthritis (RA), we studied the influence of sympathetic neurotransmitters on cytokine production of T cells in patients with RA. T cells were isolated from peripheral blood of RA patients or healthy donors (HDs), and stimulated via CD3 and CD28. Co-incubation was carried out with epinephrine or norepinephrine in concentrations ranging from 10(-5) M to 10(-11) M. Interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, interleukin (IL)-4, and IL-10 were determined in the culture supernatant with enzyme-linked immunosorbent assay. In addition, IFN-gamma and IL-10 were evaluated with intracellular cytokine staining. Furthermore, basal and agonist-induced cAMP levels and catecholamine-induced apoptosis of T cells were measured. Catecholamines inhibited the synthesis of IFN-gamma, TNF-alpha, and IL-10 at a concentration of 10(-5) M. In addition, IFN-gamma release was suppressed by 10(-7) M epinephrine. Lower catecholamine concentrations exerted no significant effect. A reduced IL-4 production upon co-incubation with 10(-5) M epinephrine was observed in RA patients only. The inhibitory effect of catecholamines on IFN-gamma production was lower in RA patients as compared with HDs. In RA patients, a catecholamine-induced shift toward a Th2 (type 2) polarised cytokine profile was abrogated. Evaluation of intracellular cytokines revealed that CD8-positive T cells were accountable for the impaired catecholaminergic control of IFN-gamma production. The highly significant negative correlation between age and catecholamine effects in HDs was not found in RA patients. Basal and stimulated cAMP levels in T-cell subsets and catecholamine-induced apoptosis did not differ between RA patients and HDs. RA patients demonstrate an impaired inhibitory effect of catecholamines on IFN-gamma production together with a failure to induce a shift of T-cell cytokine responses toward a Th2-like profile. Such an unfavorable situation is a perpetuating factor for inflammation.     

Polychlorinated biphenyl-degrading microbial communities in soils and sediments

Recent advances in the degradation of polychlorinated biphenyls (PCBs) have focussed on the use of experimental enrichment cultures to obtain PCB-degrading communities, and the use of culture-independent approaches to characterize natural and experimental PCB-degrading communities and to identify the key members in this process. PCB-degrading communities can be surprisingly diverse. Novel types of composite bacteria-mineral biofilm communities have been described. Community metabolism of PCBs may lead to the formation of protoanemonin, a dead-end product in some instances but, in others, a seemingly productive intermediate. Analysis of isotope fractionation and preferred enantiomer degradation has provided new information on degradation of PCBs in anaerobic settings. The first defined community capable of dehalorespiration of PCBs has been described, and important community members identified. Here, we provide an overview of the current knowledge of aerobic and anaerobic degradation of PCBs in microbial consortia and in the environment, including novel approaches to determine in situ PCB degradation.     

Corticotropin releasing hormone: therapeutic implications and medicinal chemistry developments

Corticotropin releasing hormone (CRH, sometimes known as CRF) is an endogenous 41 amino acid peptide that has been implicated in the onset of pregnancy, the 'fight or flight' response, in addition to a large number of physiological disorders. Recently, medicinal chemists have developed a number of potent and selective compounds that show promise in a vast array of therapeutic uses. Herein we review the current status of research.     

Fibrillin-1 and fibrillin-2 in human embryonic and early fetal development.

The extracellular glycoproteins fibrillin-1 and fibrillin-2 are major components of connective tissue microfibrils. Mutations in the fibrillin-1 and fibrillin-2 genes are responsible for the phenotypical manifestations of Marfan syndrome and congenital contractural arachnodactyly respectively, which emphasizes their essential roles in developmental processes of various tissues. Consistent with this last notion, organ culture experiments have indirectly suggested morphogenic roles for fibrillins in lung and kidney development. In order to contribute to the understanding of the roles of fibrillins in developmental and morphogenetic events, we have investigated the distribution of fibrillin-1 and fibrillin-2 in human embryonic and early fetal tissues between the 5th and the 12th gestational week, i.e. at the beginning of organogenesis. Fibrillin-1 and fibrillin-2 were localized immunohistochemically using specific monoclonal antibodies, mAb 69 and mAb 48, respectively. Both fibrillins are widely distributed in various human anlagen, from early developmental stages. In most embryonic and early fetal human organs such as skin, lung, heart, aorta, central nervous system anlage, nerves, and ganglia, fibrillin-1 and fibrillin-2 follow the same temporo-spatial pattern of distribution. However, in other organs such as kidney, liver, rib anlagen, notochord fibrillin-1 and fibrillin-2 are distributed differentially. The present paper is focused on this aspect. These results suggest different roles for fibrillin-1 and -2 in the development of these structures.     

A new sterigmatocystin-producing Emericella variant from agricultural desert soils

An unusual, sterigmatocystin-producing taxon with characteristics of both Emericella nidulans (anamorph Aspergillus nidulans) and Emericella rugulosa (anamorph Aspergillus rugulovalvus, formerly A. rugulosus) was isolated repeatedly during a mycofloral survey of desert cotton field soils where aflatoxin is a chronic problem. Members of this taxon had ascospores with smooth convex walls like E. nidulans but grew slowly like E. rugulosa; moreover, they were similar to an industrial echinocandin B-producing strain which had been classified as "Aspergillus nidulans var. roseus." These new desert isolates were compared with "A. nidulans var. roseus" and representative wild-type isolates of E. nidulans and E. rugulosa using traditional morphological characters, secondary metabolite profiles of mycelial extracts, and Southern blot analysis of genomic DNA. The desert isolates and "A. nidulans var. roseus shared morphological, physiological and molecular characters with E. rugulosa. These isolates constitute a new non-rugulose variant of E. rugulosa.     

(3)H]-M-MPEP, a potent, subtype-selective radioligand for the metabotropic glutamate receptor subtype 5

The synthesis of a new potent, subtype-selective radioligand [(3)H]-M-MPEP (2-methyl-6-((3-methoxyphenyl)ethynyl)-pyridine) and its in vitro pharmacological characteristics are described. Science Ltd.