Variants located upstream of CHRNB4 on chromosome 15q25.1 are associated with age at onset of daily smoking and habitual smoking

Several genome-wide association and candidate gene studies have linked chromosome 15q24-q25.1 (a region including the CHRNA5-CHRNA3-CHRNB4 gene cluster) with alcohol dependence, nicotine dependence and smoking-related illnesses such as lung cancer and chronic obstructive pulmonary disease. To further examine the impact of these genes on the development of substance use disorders, we tested whether variants within and flanking the CHRNA5-CHRNA3-CHRNB4 gene cluster affect the transition to daily smoking (individuals who smoked cigarettes 4 or more days per week) in a cross sectional sample of adolescents and young adults from the COGA (Collaborative Study of the Genetics of Alcoholism) families. Subjects were recruited from families affected with alcoholism (either as a first or second degree relative) and the comparison families. Participants completed the SSAGA interview, a comprehensive assessment of alcohol and other substance use and related behaviors. Using the Quantitative trait disequilibrium test (QTDT) significant association was detected between age at onset of daily smoking and variants located upstream of CHRNB4. Multivariate analysis using a Cox proportional hazards model further revealed that these variants significantly predict the age at onset of habitual smoking among daily smokers. These variants were not in high linkage disequilibrium (0.28相似文献   

Forecasting phenology: from species variability to community patterns

Shifts in species' phenology in response to climate change have wide-ranging consequences for ecological systems. However, significant variability in species' responses, together with limited data, frustrates efforts to forecast the consequences of ongoing phenological changes. Herein, we use a case study of three North American plant communities to explore the implications of variability across levels of organisation (within and among species, and among communities) for forecasting responses to climate change. We show how despite significant variation among species in sensitivities to climate, comparable patterns emerge at the community level once regional climate drivers are accounted for. However, communities differ with respect to projected patterns of divergence and overlap among their species' phenological distributions in response to climate change. These analyses and a review of hypotheses suggest how explicit consideration of spatial scale and levels of biological organisation may help to understand and forecast phenological responses to climate change.     

Perception of male-male competition influences Drosophila copulation behaviour even in species where females rarely remate

Males in many taxa are known to exhibit behavioural plasticity in response to the perceived intensity of sperm competition, reflected in Drosophila melanogaster by increased copulation duration following prior exposure to a rival. We tested the prediction that males do not adjust their copulation effort in response to the presence of a competitor in Drosophila species where there is little or no sperm competition. Contrary to expectations, male plasticity in copulation duration was found in both Drosophila subobscura and Drosophila acanthoptera, species in which females rarely remate. These results are discussed in relation to the adaptive basis of plasticity in these species.     

Crystal structure of the C1 domain of cardiac myosin binding protein-C: implications for hypertrophic cardiomyopathy

C-protein is a major component of skeletal and cardiac muscle thick filaments. Mutations in the gene encoding cardiac C-protein [cardiac myosin binding protein-C (cMyBP-C)] are one of the principal causes of hypertrophic cardiomyopathy. cMyBP-C is a string of globular domains including eight immunoglobulin-like and three fibronectin-like domains termed C0-C10. It binds to myosin and titin, and probably to actin, and may have both a structural and a regulatory role in muscle function. To help to understand the pathology of the known mutations, we have solved the structure of the immunoglobulin-like C1 domain of MyBP-C by X-ray crystallography to a resolution of 1.55 Å. Mutations associated with hypertrophic cardiomyopathy are clustered at one end towards the C-terminus, close to the important C1C2 linker, where they alter the structural integrity of this region and its interactions.     

Development and cross-species testing of western bluebird (Sialia mexicana) microsatellite primers

Western and eastern bluebirds (Sialia mexicana and S. sialis) are socially monogamous passerines that engage in extra‐pair copulations. We obtained microsatellites from S. mexicana and optimized and characterized 15 microsatellite DNA loci in 60 individuals of this species. Primer pairs yielded an average of 13 alleles per locus in western bluebirds (range 3–35 alleles) with an average observed heterozygosity of 0.68 (range 0.27–0.88). All 15 loci also successfully amplified in S. sialis (n = 24), with an average of 11.5 alleles per locus (range 4–26) and an average observed heterozygosity of 0.59 (range 0.22–0.90).     

Interleukin-7 deficiency in rheumatoid arthritis: consequences for therapy-induced lymphopenia

We previously demonstrated prolonged, profound CD4⁺ T-lymphopenia in rheumatoid arthritis (RA) patients following lymphocyte-depleting therapy. Poor reconstitution could result either from reduced de novo T-cell production through the thymus or from poor peripheral expansion of residual T-cells. Interleukin-7 (IL-7) is known to stimulate the thymus to produce new T-cells and to allow circulating mature T-cells to expand, thereby playing a critical role in T-cell homeostasis. In the present study we demonstrated reduced levels of circulating IL-7 in a cross-section of RA patients. IL-7 production by bone marrow stromal cell cultures was also compromised in RA. To investigate whether such an IL-7 deficiency could account for the prolonged lymphopenia observed in RA following therapeutic lymphodepletion, we compared RA patients and patients with solid cancers treated with high-dose chemotherapy and autologous progenitor cell rescue. Chemotherapy rendered all patients similarly lymphopenic, but this was sustained in RA patients at 12 months, as compared with the reconstitution that occurred in cancer patients by 3–4 months. Both cohorts produced naïve T-cells containing T-cell receptor excision circles. The main distinguishing feature between the groups was a failure to expand peripheral T-cells in RA, particularly memory cells during the first 3 months after treatment. Most importantly, there was no increase in serum IL-7 levels in RA, as compared with a fourfold rise in non-RA control individuals at the time of lymphopenia. Our data therefore suggest that RA patients are relatively IL-7 deficient and that this deficiency is likely to be an important contributing factor to poor early T-cell reconstitution in RA following therapeutic lymphodepletion. Furthermore, in RA patients with stable, well controlled disease, IL-7 levels were positively correlated with the T-cell receptor excision circle content of CD4⁺ T-cells, demonstrating a direct effect of IL-7 on thymic activity in this cohort.     

Akt activity protects rheumatoid synovial fibroblasts from Fas-induced apoptosis by inhibition of Bid cleavage

Introduction  

Synovial hyperplasia is a main feature of rheumatoid arthritis pathology that leads to cartilage and bone damage in the inflamed joints. Impaired apoptosis of resident synoviocytes is pivotal in this process. Apoptosis resistance seems to involve defects in the extrinsic and intrinsic apoptotic pathways. The aim of this study was to investigate the association of PI3Kinase/Akt and the mitochondrial apoptotic pathway in the resistance of rheumatoid arthritis (RA) fibroblast like synovial cells (FLS) to Fas-mediated apoptosis.     

Secreted alpha amidating enzymes are generated by specific posttranslational processing of precursors containing transmembrane domains

The biosynthesis and secretion of alpha amidating enzymes from CA-77 cells has been investigated to determine the relationship among the various forms of alpha amidating enzyme seen after purification of alpha amidating enzyme activity from conditioned cell culture media. Initially 2 proteins of 104 kD and 94 kD are synthesized. With time the 104 kD precursor is processed to 41 kD and 43 kD, and the 94 kD precursor is processed to 75 kD. The 41 kD, 43 kD, and 75 kD proteins are secreted into the medium as functional enzymes. In comparing these data with known cDNA sequence for alpha amidating enzyme we conclude that the 104 kD and 94 kD precursors are membrane bound proteins which are posttranslationally processed to generate secreted alpha amidating enzyme.     

Afterword: Thick Time,Heavy Time

ABSTRACT

The paper sums up and comments on the contributions of the Special Issue edited by Katrien Pype and Richard Vokes. The theme of the papers was the impact of new media and radio on life styles and life worlds in Africa with a focus on regions of postcolonial Africa: Congo DRC.