Insights into the Genetic Architecture of Early Stage Age-Related Macular Degeneration: A Genome-Wide Association Study Meta-Analysis

10.1371/journal.pone.0053830PLoS ONE81

Pathogens and host immunity in the ancient human oral cavity.

Calcified dental plaque (dental calculus) preserves for millennia and entraps biomolecules from all domains of life and viruses. We report the first, to our knowledge, high-resolution taxonomic and protein functional characterization of the ancient oral microbiome and demonstrate that the oral cavity has long served as a reservoir for bacteria implicated in both local and systemic disease. We characterize (i) the ancient oral microbiome in a diseased state, (ii) 40 opportunistic pathogens, (iii) ancient human-associated putative antibiotic resistance genes, (iv) a genome reconstruction of the periodontal pathogen Tannerella forsythia, (v) 239 bacterial and 43 human proteins, allowing confirmation of a long-term association between host immune factors, 'red complex' pathogens and periodontal disease, and (vi) DNA sequences matching dietary sources. Directly datable and nearly ubiquitous, dental calculus permits the simultaneous investigation of pathogen activity, host immunity and diet, thereby extending direct investigation of common diseases into the human evolutionary past

A longitudinal study of the self-concepts and experiential components of self-worth and affect across adolescence

Classic theories depict adolescence as a period of emotional "storm and stress". Empirical evidence, mostly from cross-sectional studies, suggests that emotional development presents a mixture of continuity, swings, and resilience. We examined longitudinally the average grade trends in components of self-concept and experiential components of self-worth and affect across adolescence. We followed 1,165 6th through 12th graders for 4 years using a 3-wave, accelerated longitudinal design. Participants completed self-concept scales (global self-esteem and locus of control), and the Experience Sampling Method, which provided daily self- reports on self-worth (living up to one’s own expectations, to the expectations of others, feeling successful, and feeling in control of the situation) and affect (feeling good about oneself and feeling happy). Multilevel modeling indicated that both self-esteem and locus of control grow linearly over time. Self-worth components of experience showed a concave-up trend bottoming around Grade 10, suggesting a pubertal swing and partial readjustment by the end of adolescence. Affect declined quadratically across adolescence. Compared to White students, less positive grade trends were found for Hispanics, Asian Americans, and adolescents from nontraditional families. A mixed pattern emerged for African Americans. Behind the stable growth of components of self-concept, adolescents experience a certain degree of discontinuity as to how they evaluate their capability to meet everyday life demands and their affect declines. The modifications in grade trends due to ethnicity and family structure call for studies on the possible influence exercised by family processes and school environments

As cold as a fish? Relationships between the Dark Triad personality traits and affective experience during the day: A day reconstruction study

The Dark Triad of personality is a cluster of three socially aversive personality traits: Machiavellianism, narcissism and psychopathy. These traits are associated with a selfish, aggressive and exploitative interpersonal strategy. The objective of the current study was to establish relationships between the Dark Triad traits (and their dimensions) and momentary affect. Machiavellianism, grandiose narcissism, vulnerable narcissism and the dimensions of the Triarchic model of psychopathy (namely, boldness, meanness and disinhibition) were examined. We used the Day Reconstruction Method, which is based on reconstructing affective states experienced during the previous day. The final sample consisted of 270 university students providing affective ratings of 3047 diary episodes. Analyses using multilevel modelling showed that only boldness had a positive association with positive affective states and affect balance, and a negative association with negative affective states. Grandiose narcissism and its sub-dimensions had no relationship with momentary affect. The other dark traits were related to negative momentary affect and/or inversely related to positive momentary affect and affect balance. As a whole, our results empirically demonstrated distinctiveness of the Dark Triad traits in their relationship to everyday affective states. These findings are not congruent with the notion that people with the Dark Triad traits, who have a dispositional tendency to manipulate and exploit others, are generally cold and invulnerable to negative feelings. The associations between the Dark Triad and momentary affect were discussed in the contexts of evolutionary and positive psychology, in relation to the role and adaptive value of positive and negative emotions experienced by individuals higher in Machiavellianism, narcissism and psychopathy

Molecular control of HIV-1 postintegration latency: implications for the development of new therapeutic strategies

The persistence of HIV-1 latent reservoirs represents a major barrier to virus eradication in infected patients under HAART since interruption of the treatment inevitably leads to a rebound of plasma viremia. Latency establishes early after infection notably (but not only) in resting memory CD4+ T cells and involves numerous host and viral trans-acting proteins, as well as processes such as transcriptional interference, RNA silencing, epigenetic modifications and chromatin organization. In order to eliminate latent reservoirs, new strategies are envisaged and consist of reactivating HIV-1 transcription in latently-infected cells, while maintaining HAART in order to prevent de novo infection. The difficulty lies in the fact that a single residual latently-infected cell can in theory rekindle the infection. Here, we review our current understanding of the molecular mechanisms involved in the establishment and maintenance of HIV-1 latency and in the transcriptional reactivation from latency. We highlight the potential of new therapeutic strategies based on this understanding of latency. Combinations of various compounds used simultaneously allow for the targeting of transcriptional repression at multiple levels and can facilitate the escape from latency and the clearance of viral reservoirs. We describe the current advantages and limitations of immune T-cell activators, inducers of the NF-κB signaling pathway, and inhibitors of deacetylases and histone- and DNA- methyltransferases, used alone or in combinations. While a solution will not be achieved by tomorrow, the battle against HIV-1 latent reservoirs is well- underway

Krüppel-like factor 3 (KLF3/BKLF) is required for widespread repression of the inflammatory modulator galectin-3 (Lgals3)

The Lgals3 gene encodes a multifunctional β-galactoside-binding protein, galectin-3. Galectin-3 has been implicated in a broad range of biological processes from chemotaxis and inflammation to fibrosis and apoptosis. The role of galectin-3 as a modulator of inflammation has been studied intensively, and recent evidence suggests that it may serve as a protective factor in obesity and other metabolic disorders. Despite considerable interest in galectin-3, little is known about its physiological regulation at the transcriptional level. Here, using knockout mice, chromatin immunoprecipitations, and cellular and molecular analyses, we show that the zinc finger transcription factor Krüppel-like factor 3 (KLF3) directly represses galectin-3 transcription. We find that galectin-3 is broadly up-regulated in KLF3-deficient mouse tissues, that KLF3 occupies regulatory regions of the Lgals3 gene, and that KLF3 directly binds its cognate elements (CACCC boxes) in the galectin-3 promoter and represses its activation in cellular assays. We also provide mechanistic insights into the regulation of Lgals3, demonstrating that C-terminal binding protein (CtBP) is required to drive optimal KLF3-mediated silencing. These findings help to enhance our understanding of how expression of the inflammatory modulator galectin-3 is controlled, opening up avenues for potential therapeutic interventions in the future

Eosinophil function in adipose tissue is regulated by Kruppel-like factor 3 (KLF3)

The conversion of white adipocytes to thermogenic beige adipocytes represents a potential mechanism to treat obesity and related metabolic disorders. However, the mechanisms involved in converting white to beige adipose tissue remain incompletely understood. Here we show profound beiging in a genetic mouse model lacking the transcriptional repressor Krüppel-like factor 3 (KLF3). Bone marrow transplants from these animals confer the beige phenotype on wild type recipients. Analysis of the cellular and molecular changes reveal an accumulation of eosinophils in adipose tissue. We examine the transcriptomic profile of adipose-resident eosinophils and posit that KLF3 regulates adipose tissue function via transcriptional control of secreted molecules linked to beiging. Furthermore, we provide evidence that eosinophils may directly act on adipocytes to drive beiging and highlight the critical role of these little-understood immune cells in thermogenesis

Pathways-driven sparse regression identifies pathways and genes associated with high-density lipoprotein cholesterol in two Asian cohorts.

Standard approaches to data analysis in genome-wide association studies (GWAS) ignore any potential functional relationships between gene variants. In contrast gene pathways analysis uses prior information on functional structure within the genome to identify pathways associated with a trait of interest. In a second step, important single nucleotide polymorphisms (SNPs) or genes may be identified within associated pathways. The pathways approach is motivated by the fact that genes do not act alone, but instead have effects that are likely to be mediated through their interaction in gene pathways. Where this is the case, pathways approaches may reveal aspects of a trait's genetic architecture that would otherwise be missed when considering SNPs in isolation. Most pathways methods begin by testing SNPs one at a time, and so fail to capitalise on the potential advantages inherent in a multi-SNP, joint modelling approach. Here, we describe a dual-level, sparse regression model for the simultaneous identification of pathways and genes associated with a quantitative trait. Our method takes account of various factors specific to the joint modelling of pathways with genome-wide data, including widespread correlation between genetic predictors, and the fact that variants may overlap multiple pathways. We use a resampling strategy that exploits finite sample variability to provide robust rankings for pathways and genes. We test our method through simulation, and use it to perform pathways-driven gene selection in a search for pathways and genes associated with variation in serum high-density lipoprotein cholesterol levels in two separate GWAS cohorts of Asian adults. By comparing results from both cohorts we identify a number of candidate pathways including those associated with cardiomyopathy, and T cell receptor and PPAR signalling. Highlighted genes include those associated with the L-type calcium channel, adenylate cyclase, integrin, laminin, MAPK signalling and immune function