899 research outputs found
Two subsets of human alphoid repetitive DNA show distinct preferential localization in the pericentromeric heterochromatin of chromosomes 13, 21 and 18
No full textIdentifying the genomic determinants of aging and longevity in human population studies: Progress and challenges.
No full textHuman lifespan variation is mainly determined by environmental factors, whereas the genetic contribution is 25-30% and expected to be polygenic. Two complementary fields go hand in hand in order to unravel the mechanisms of biological aging: genomic and biomarker research. Explorative and candidate gene studies of the human genome by genetic, transcriptomic, and epigenomic approaches have resulted in the identification of a limited number of interesting positive linkage regions, genes, and pathways that contribute to lifespan variation. The possibilities to further exploit these findings are rapidly increasing through the use of novel technologies, such as next-generation sequencing. Genomic
research is progressively being integrated with biomarker studies on aging, including the application of (noninvasive) deep phenotyping and omics data - generated using novel technologies - in a wealth of studies in human populations.
Hence, these studies may assist in obtaining a more holistic perspective on the role of the genome in aging and lifespan regulatio
Secondary phenotype analysis in ascertained family designs: application to the Leiden longevity study
No full textThe case-control design is often used to test associations between the case-control status and genetic variants. In addition to this primary phenotype, a number of additional traits, known as secondary phenotypes, are routinely recorded, and typically, associations between genetic factors and these secondary traits are studied too. Analysing secondary phenotypes in case-control studies may lead to biased genetic effect estimates, especially when the marker tested is associated with the primary phenotype and when the primary and secondary phenotypes tested are correlated. Several methods have been proposed in the literature to overcome the problem, but they are limited to case-control studies and not directly applicable to more complex designs, such as the multiple-cases family studies. A proper secondary phenotype analysis, in this case, is complicated by the within families correlations on top of the biased sampling design. We propose a novel approach to accommodate the ascertainment process while explicitly modelling the familial relationships. Our approach pairs existing methods for mixed-effects models with the retrospective likelihood framework and uses a multivariate probit model to capture the association between the mixed type primary and secondary phenotypes. To examine the efficiency and bias of the estimates, we performed simulations under several scenarios for the association between the primary phenotype, secondary phenotype and genetic markers. We will illustrate the method by analysing the association between triglyceride levels and glucose (secondary phenotypes) and genetic markers from the Leiden Longevity Study, a multiple-cases family study that investigates longevity. © 2017 The Authors. Statistics in Medicine Published by JohnWiley & Sons Ltd
Survival analysis with delayed entry in selected families with application to human longevity
No full textIn the field of aging research, family-based sampling study designs are commonly used to study the lifespans of long-lived family members. However, the specific sampling procedure should be carefully taken into account in order to avoid biases. This work is motivated by the Leiden Longevity Study, a family-based cohort of long-lived siblings. Families were invited to participate in the study if at least two siblings were ‘long-lived’, where ‘long-lived’ meant being older than 89 years for men or older than 91 years for women. As a result, more than 400 families were included in the study and followed for around 10 years. For estimation of marker-specific survival probabilities and correlations among life times of family members, delayed entry due to outcome-dependent sampling mechanisms has to be taken into account. We consider shared frailty models to model left-truncated correlated survival data. The treatment of left truncation in shared frailty models is still an open issue and the literature on this topic is scarce. We show that the current approaches provide, in general, biased estimates and we propose a new method to tackle this selection problem by applying a correction on the likelihood estimation by means of inverse probability weighting at the family level
FIGURE 22. Proekes species habitus views. A–I, P in Leafhoppers of the Fynbos Biome of South Africa: Colistra, Proekes, Proekoides and a new genus (Insecta, Hemiptera, Cicadellidae, Deltocephalinae, Bonaspeiini)
No full textFIGURE 22. Proekes species habitus views. A–I, P. cephaleus (Naudé, 1926), male, female and nymph. A, male, dorsally, Hawekwa specimen. B, male, dorsally, Fisantekraal specimen. C, female, dorsally, Slagboom specimen. D, female, dorsally, Caledon specimen. E, F, nymphs, pale and dark Fisantekraal specimens, respectively. G, female terminalia, ventrally, Caledon specimen. H, head and pronotum dorsally, Slagboom specimen. I, female, face, Caledon specimen. P. hemiplatyphalis sp. n., female, male and nymph. J, K, female, dorsally, laterally respectively. L, male, dorsally. M, nymph. A–G, J–M, scale=1 mm.Published as part of Stiller, Michael & Webb, Michael D., 2022, Leafhoppers of the Fynbos Biome of South Africa: Colistra, Proekes, Proekoides and a new genus (Insecta, Hemiptera, Cicadellidae, Deltocephalinae, Bonaspeiini), pp. 1-79 in Zootaxa 5199 (1) on page 56, DOI: 10.11646/zootaxa.5199.1.1, http://zenodo.org/record/725176
N-glycomic biomarkers of biological aging and longevity: A link with inflammaging
No full textGlycosylation is a frequent co/post-translational modification of proteins which modulates a variety of biological functions. The analysis of N-glycome, i.e. the sugar chains N-linked to asparagine, identified new candidate biomarkers of aging such as N-glycans devoid of galactose residues on their branches, in a variety of human and experimental model systems, such as healthy old people, centenarians and their offspring and caloric restricted mice. These agalactosylated biantennary structures mainly decorate Asn297 of Fc portion of IgG (IgG-G0), and are present also in patients affected by progeroid syndromes and a variety of autoimmune/inflammatory diseases. IgG-G0 exert a pro-inflammatory effect through different mechanisms, including the lectin pathway of complement, binding to Fcgamma receptors and formation of autoantibody aggregates. The age-related accumulation of IgG-G0 can contribute to inflammaging, the low-grade pro-inflammatory status that characterizes elderly, by creating a vicious loop in which inflammation is responsible for the production of aberrantly glycosylated IgG which, in turn, would activate the immune system, exacerbating inflammation. Moreover, recent data suggest that the N-glycomic shift observed in aging could be related not only to inflammation but also to alteration of important metabolic pathways. Thus, altered N-glycans are both powerful markers of aging and possible contributors to its pathogenesi
A mixture model with random-effects components for classifying sibling pairs
No full textIn healthy aging research, typically multiple health outcomes are measured, representing health status. The aim of this paper was to develop a model-based clustering approach to identify homogeneous sibling pairs according to their health status. Model-based clustering approaches will be considered on the basis of linear mixed effect model for the mixture components. Class memberships of siblings within pairs are allowed to be correlated, and within a class the correlation between siblings is modeled using random sibling pair effects. We propose an expectation-maximization algorithm for maximum likelihood estimation. Model performance is evaluated via simulations in terms of estimating the correct parameters, degree of agreement, and the ability to detect the correct number of clusters. The performance of ourmodel is compared with the performance of standard model-based clustering approaches. The methods are used to classify sibling pairs from the Leiden Longevity Study according to their health status. Our results suggest that homogeneous healthy sibling pairs are associated with a longer life span. Software is available for fitting the new models. Copyright (C) 2011 John Wiley & Sons, Ltd
Ticagrelor Alone Versus Dual Antiplatelet Therapy From 1 Month After Drug-Eluting Coronary Stenting
No full textBackground: The GLOBAL LEADERS (GLOBAL LEADERS: A Clinical Study Comparing Two Forms of Anti-platelet Therapy After Stent Implantation) study randomly assigned 15,991 patients undergoing percutaneous coronary intervention to 1-month dual antiplatelet therapy (DAPT) followed by 23-month ticagrelor monotherapy or conventional 12-month DAPT followed by 12-month aspirin. Apart from Q-wave myocardial infarction (MI), all study endpoints were analyzed as investigator reported. Objectives: This was a pre-specified ancillary study assessing whether experimental therapy is noninferior, and if met, superior, to conventional treatment for the coprimary efficacy endpoint of all-cause death, nonfatal MI, nonfatal stroke, or urgent target vessel revascularization and superior in preventing BARC 3 (Bleeding Academic Research Consortium) or 5 bleeding (coprimary safety endpoint) at 2 years with a 0.025 significance level to preserve nominal 5% alpha error. Methods: An independent clinical event committee adjudicated investigator-reported and eventually unreported events of 7,585 patients from the 20 top-enrolling participating sites. Results: The 2-year coprimary efficacy endpoint occurred in 271 (7.14%) and in 319 (8.41%) patients in the experimental and conventional groups, respectively (rate ratio [RR]: 0.85; 95% confidence interval [CI]: 0.72 to 0.99), fulfilling noninferiority (p noninferiority <0.001), but not superiority (p superiority = 0.0465). The rates of BARC 3 or 5 bleeding did not differ (RR: 1.00; 95% CI: 0.75 to 1.33; p = 0.986). A time-dependent treatment effect was observed with the experimental strategy being associated with a lower risk of MI (RR: 0.54; 95% CI: 0.33 to 0.88; p interaction = 0.062) and definite stent thrombosis (RR: 0.14; 95% CI: 0.03 to 0.63; p interaction = 0.007) after 1-year post-percutaneous coronary intervention. Conclusions: Ticagrelor monotherapy after 1-month DAPT was noninferior, but not superior, to conventional treatment in the prevention of ischemic events, and it did not decrease major bleeding risk as compared with conventional treatment. (GLOBAL LEADERS Adjudication Sub-Study [GLASSY]; NCT03231059)
Genetic variation in pentraxin (PTX) 3 gene associates with PTX3 production and fertility in women
No full textPentraxin 3 (PTX3) plays an important role in innate immune responses and in female fertility, as discovered with studies in mice. However, the role of PTX3 in human fertility is unknown. Here, we report on a population-based study from a rural area of Upper East Ghana (n = 4346). We studied the association between the number of children given birth by women during their lifetime and ex vivo, lipopolysaccharide (LPS)-induced PTX3 production (n = 362). In addition, we studied the association of genetic variation in the PTX3 gene with PTX3 production (n = 617) and with female fertility (n = 1999). We found that ex vivo LPS-induced PTX3 production was associated with fertility (P = 0.040). Furthermore, we identified genetic variants in the PTX3 gene that influence PTX3 production, and also fertility. The strongest associations were observed for the rs6788044 single-nucleotide polymorphism (SNP). We found that carriers of this SNP had higher PTX3 production capacity (P = 0.003) and higher fertility (P = 0.043). The results reported here provide the first evidence, based on protein production and analysis of polymorphisms, that the long pentraxin PTX3 plays a role in female fertility in humans
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