Telomere Length and the Cancer–Atherosclerosis Trade-Off

Modern humans, the longest-living terrestrial mammals, display short telomeres and repressed telomerase activity in somatic tissues compared with most short-living small mammals. The dual trait of short telomeres and repressed telomerase might render humans relatively resistant to cancer compared with short-living small mammals. However, the trade-off for cancer resistance is ostensibly increased age-related degenerative diseases, principally in the form of atherosclerosis. In this communication, we discuss (a) the genetics of human telomere length, a highly heritable complex trait that is influenced by genetic ancestry, sex, and paternal age at conception, (b) how cancer might have played a role in the evolution of telomere biology across mammals, (c) evidence that in modern humans telomere length is a determinant (rather than only a biomarker) of cancer and atherosclerosis, and (d) the potential influence of relatively recent evolutionary forces in fashioning the variation in telomere length across and within populations, and their likely lasting impact on major diseases in humans. Finally, we propose venues for future research on human telomere genetics in the context of its potential role in shaping the modern human lifespan

SLX4 Assembles a Telomere Maintenance Toolkit by Bridging Multiple Endonucleases with Telomeres

SummarySLX4 interacts with several endonucleases to resolve structural barriers in DNA metabolism. SLX4 also interacts with telomeric protein TRF2 in human cells. The molecular mechanism of these interactions at telomeres remains unknown. Here, we report the crystal structure of the TRF2-binding motif of SLX4 (SLX4TBM) in complex with the TRFH domain of TRF2 (TRF2TRFH) and map the interactions of SLX4 with endonucleases SLX1, XPF, and MUS81. TRF2 recognizes a unique HxLxP motif on SLX4 via the peptide-binding site in its TRFH domain. Telomeric localization of SLX4 and associated nucleases depend on the SLX4-endonuclease and SLX4-TRF2 interactions and the protein levels of SLX4 and TRF2. SLX4 assembles an endonuclease toolkit that negatively regulates telomere length via SLX1-catalyzed nucleolytic resolution of telomere DNA structures. We propose that the SLX4-TRF2 complex serves as a double-layer scaffold bridging multiple endonucleases with telomeres for recombination-based telomere maintenance

Rhythm in the speech of a person with right hemisphere damage: Applying the pairwise variability index

Although several aspects of prosody have been studied in speakers with right hemisphere damage (RHD), rhythm remains largely uninvestigated. This study compares the rhythm of an Australian English speaker with right hemisphere damage (due to a stroke, but with no concomitant dysarthria) to that of a neurologically unimpaired individual. The speakers' rhythm is compared using the pairwise variability index (PVI) which allows for an acoustic characterization of rhythm by comparing the duration of successive vocalic and intervocalic intervals. A sample of speech from a structured interview between a speech and language therapist and each participant was analysed. Previous research has shown that speakers with RHD may have difficulties with intonation production, and therefore it was hypothesized that there may also be rhythmic disturbance. Results show that the neurologically normal control uses a similar rhythm to that reported for British English (there are no previous studies available for Australian English), whilst the speaker with RHD produces speech with a less strongly stress-timed rhythm. This finding was statistically significant for the intervocalic intervals measured (t(8) = 4.7, p < .01), and suggests that some aspects of prosody may be right lateralized for this speaker. The findings are discussed in relation to previous findings of dysprosody in RHD populations, and in relation to syllable-timed speech of people with other neurological conditions

Gene expression differences in relation to age and social environment in queen and worker bumble bees

Eusocial insects provide special insights into the genetic pathways influencing aging because of their long-lived queens and flexible aging schedules. Using qRT-PCR in the primitively eusocial bumble bee Bombus terrestris (Linnaeus), we investigated expression levels of four candidate genes associated with taxonomically widespread age-related pathways (coenzyme Q biosynthesis protein 7, COQ7; DNA methyltransferase 3, Dnmt3; foraging, for; and vitellogenin, vg). In Experiment 1, we tested how expression changes with queen relative age and productivity. We found a significant age-related increase in COQ7 expression in queen ovary. In brain, all four genes showed higher expression with increasing female (queen plus worker) production, with this relationship strengthening as queen age increased, suggesting a link with the positive association of fecundity and longevity found in eusocial insect queens. In Experiment 2, we tested effects of relative age and social environment (worker removal) in foundress queens and effects of age and reproductive status in workers. In this experiment, workerless queens showed significantly higher for expression in brain, as predicted if downregulation of for is associated with the cessation of foraging by foundress queens following worker emergence. Workers showed a significant age-related increase in Dnmt3 expression in fat body, suggesting a novel association between aging and methylation in B. terrestris. Ovary activation was associated with significantly higher vg expression in fat body and, in younger workers, in brain, consistent with vitellogenin's ancestral role in regulating egg production. Overall, our findings reveal a mixture of novel and conserved features in age-related genetic pathways under primitive eusociality

Polymorphisms in signal transducer and activator of transcription 3 and lung function in asthma

BACKGROUND: Identifying genetic determinants for lung function is important in providing insight into the pathophysiology of asthma. Signal transducer and activator of transcription 3 is a transcription factor latent in the cytoplasm; the gene (STAT3) is activated by a wide range of cytokines, and may play a role in lung development and asthma pathogenesis. METHODS: We genotyped six single nucleotide polymorphisms (SNPs) in the STAT3 gene in a cohort of 401 Caucasian adult asthmatics. The associations between each SNP and forced expiratory volume in 1 second (FEV(1)), as a percent of predicted, at the baseline exam were tested using multiple linear regression models. Longitudinal analyses involving repeated measures of FEV(1 )were conducted with mixed linear models. Haplotype analyses were conducted using imputed haplotypes. We completed a second association study by genotyping the same six polymorphisms in a cohort of 652 Caucasian children with asthma. RESULTS: We found that three polymorphisms were significantly associated with baseline FEV(1): homozygotes for the minor alleles of each polymorphism had lower FEV(1 )than homozygotes for the major alleles. Moreover, these associations persisted when we performed an analysis on repeated measures of FEV(1 )over 8 weeks. A haplotypic analysis based on the six polymorphisms indicated that two haplotypes were associated with baseline FEV(1). Among the childhood asthmatics, one polymorphism was associated with both baseline FEV(1 )and the repeated measures of FEV(1 )over 4 years. CONCLUSION: Our results indicate that genetic variants in STAT3, independent of asthma treatment, are determinants of FEV(1 )in both adults and children with asthma, and suggest that STAT3 may participate in inflammatory pathways that have an impact on level of lung function

What makes community psychiatric nurses label non-psychotic chronic patients as ‘difficult’: patient, professional, treatment and social variables

Contains fulltext : 99981.pdf (publisher's version ) (Open Access)Purpose To determine which patient, professional, treatment and/or social variables make community psychiatric nurses (CPNs) label non-psychotic chronic patients as ‘difficult’. Methods A questionnaire was designed and administered to 1,946 CPNs in the Netherlands. Logistic regression was used to design models that most accurately described the variables that contributed to perceived difficulty. Results Six variables were retained in the final logistic model. Perception-related variables (feeling powerless, feeling that the patient is able but unwilling to change, and pessimism about the patient’s change potential) dominated treatment-related variables (number of contacts per week and admission to a locked ward in the last year) and social variables (number of psychosocial problems). Conclusion This research shows that perceived difficulty is related to complex treatment situations, not so much to individual patient characteristics. If the constructed model has good predictive qualities, which remains to be tested in longitudinal research, it may be possible to accurately predict perceived patient difficulty. When used as a screening tool, such a model could improve treatment outcomes.9 p

Host Specific Diversity in Lactobacillus johnsonii as Evidenced by a Major Chromosomal Inversion and Phage Resistance Mechanisms

Genetic diversity and genomic rearrangements are a driving force in bacterial evolution and niche adaptation. We sequenced and annotated the genome of Lactobacillus johnsonii DPC6026, a strain isolated from the porcine intestinal tract. Although the genome of DPC6026 is similar in size (1.97mbp) and GC content (34.8%) to the sequenced human isolate L. johnsonii NCC 533, a large symmetrical inversion of approximately 750 kb differentiated the two strains. Comparative analysis among 12 other strains of L. johnsonii including 8 porcine, 3 human and 1 poultry isolate indicated that the genome architecture found in DPC6026 is more common within the species than that of NCC 533. Furthermore a number of unique features were annotated in DPC6026, some of which are likely to have been acquired by horizontal gene transfer (HGT) and contribute to protection against phage infection. A putative type III restriction-modification system was identified, as were novel Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) elements. Interestingly, these particular elements are not widely distributed among L. johnsonii strains. Taken together these data suggest intra-species genomic rearrangements and significant genetic diversity within the L. johnsonii species and indicate towards a host-specific divergence of L. johnsonii strains with respect to genome inversion and phage exposure

A Genome-Wide Association Study of Pulmonary Function Measures in the Framingham Heart Study

The ratio of forced expiratory volume in one second to forced vital capacity (FEV1/FVC) is a measure used to diagnose airflow obstruction and is highly heritable. We performed a genome-wide association study in 7,691 Framingham Heart Study participants to identify single-nucleotide polymorphisms (SNPs) associated with the FEV1/FVC ratio, analyzed as a percent of the predicted value. Identified SNPs were examined in an independent set of 835 Family Heart Study participants enriched for airflow obstruction. Four SNPs in tight linkage disequilibrium on chromosome 4q31 were associated with the percent predicted FEV1/FVC ratio with p-values of genome-wide significance in the Framingham sample (best p-value = 3.6e-09). One of the four chromosome 4q31 SNPs (rs13147758; p-value 2.3e-08 in Framingham) was genotyped in the Family Heart Study and produced evidence of association with the same phenotype, percent predicted FEV1/FVC (p-value = 2.0e-04). The effect estimates for association in the Framingham and Family Heart studies were in the same direction, with the minor allele (G) associated with higher FEV1/FVC ratio levels. Results from the Family Heart Study demonstrated that the association extended to FEV1 and dichotomous airflow obstruction phenotypes, particularly among smokers. The SNP rs13147758 was associated with the percent predicted FEV1/FVC ratio in independent samples from the Framingham and Family Heart Studies producing a combined p-value of 8.3e-11, and this region of chromosome 4 around 145.68 megabases was associated with COPD in three additional populations reported in the accompanying manuscript. The associated SNPs do not lie within a gene transcript but are near the hedgehog-interacting protein (HHIP) gene and several expressed sequence tags cloned from fetal lung. Though it is unclear what gene or regulatory effect explains the association, the region warrants further investigation

DNA methylation levels in candidate genes associated with chronological age in mammals are not conserved in a long-lived seabird

© 2017 De Paoli-Iseppi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Most seabirds do not have any outward identifiers of their chronological age, so estimation of seabird population age structure generally requires expensive, long-term banding studies. We investigated the potential to use a molecular age biomarker to estimate age in short-tailed shearwaters (Ardenna tenuirostris). We quantified DNA methylation in several A. tenuirostris genes that have shown age-related methylation changes in mammals. In birds ranging from chicks to 21 years of age, bisulphite treated blood and feather DNA was sequenced and methylation levels analysed in 67 CpG sites in 13 target gene regions. From blood samples, five of the top relationships with age were identified in KCNC3 loci (CpG66: R2 = 0.325, p = 0.019). In feather samples ELOVL2 (CpG42: R2 = 0.285, p = 0.00048) and EDARADD (CpG46: R2 = 0.168, p = 0.0067) were also weakly correlated with age. However, the majority of markers had no clear association with age (of 131 comparisons only 12 had a p-value &lt; 0.05) and statistical analysis using a penalised lasso approach did not produce an accurate ageing model. Our data indicate that some age-related signatures identified in orthologous mammalian genes are not conserved in the long-lived short tailed shearwater. Alternative molecular approaches will be required to identify a reliable biomarker of chronological age in these seabirds

Age-related gene expression changes, and transcriptome wide association study of physical and cognitive aging traits, in the Lothian Birth Cohort 1936

Gene expression is influenced by both genetic variants and the environment. As individuals age, changes in gene expression may be associated with decline in physical and cognitive abilities. We measured transcriptome-wide expression levels in lymphoblastoid cell lines derived from members of the Lothian Birth Cohort 1936 at mean ages 70 and 76 years. Changes in gene expression levels were identified for 1,741 transcripts in 434 individuals. Gene Ontology enrichment analysis indicated an enrichment of biological processes involved in the immune system. Transcriptome-wide association analysis was performed for eleven cognitive, fitness, and biomedical aging-related traits at age 70 years (N=665 to 781) and with mortality. Transcripts for genes (F2RL3, EMILIN1 and CDC42BPA) previously identified as being differentially methylated or expressed in smoking or smoking-related cancers were overexpressed in smokers compared to non-smokers and the expression of transcripts for genes (HERPUD1, GAB2, FAM167A and GLS) previously associated with stress response, autoimmune disease and cancer were associated with telomere length. No associations between expression levels and other traits, or mortality were identified