174 research outputs found
A comparative analysis of the circadian clock in diptera
No full textThe circadian central oscillator of Drosophila melanogaster consists of at least two interlocked negative transcriptional feedback loops. This has been taken to be a general model for higher eukaryotes with the core components conserved but their regulation altered. The work presented here indicates that in Musca domestica, a dipteran closely related to Drosophila, one of these regulatory loops, involving PERIOD (PER) and TIMELESS (TIM), functions in a completely different manner. This study shows that in contrast to Drosophila, Musca PER remains constant in western studies in any lighting condition, whereas like Drosophila TIM cycles in both LD and DD and is constantly degraded in LL. In addition within the central brain immunostaining revealed that even in the small set of cells thought to contain the central pacemaker PER staining was restricted exclusively to the cytoplasm. However following the Drosophila model PER was observed to cycle in the cytoplasm of these cells. Although TIM co-localises with PER in these cells, unlike PER, TIM does become nuclear. This indicates that the negative feedback model illustrated by analysis of the Drosophila is inadequate to explain clock function in Musca. A putative Musca PER nuclear export sequence which functions in other species was tested in GFP constructs but not shown to be involved in altered localisation. In contrast in peripheral tissue such as photoreceptor cells both PER and TIM cycle and both proteins become nuclear late at night as in Drosophila. Stability of Musca PER in LL and an altered relationship between transgenic Musca PER and Drosophila DOUBLETIME indicates an altered relationship between PER and the DBT kinase that may be responsible for PER stability. Thus although it can be seen that a different model is required for other insect species how these proteins act remains to be elucidated
Light-dependent interaction between Drosophila CRY and the clock protein PER mediated by the carboxy terminus of CRY
No full textBACKGROUND:
The biological clock synchronizes the organism with the environment, responding to changes in light and temperature. Drosophila CRYPTOCHROME (CRY), a putative circadian photoreceptor, has previously been reported to interact with the clock protein TIMELESS (TIM) in a light-dependent manner. Although TIM dimerizes with PERIOD (PER), no association between CRY and PER has previously been revealed, and aspects of the light dependence of the TIM/CRY interaction are still unclear.
RESULTS:
Behavioral analysis of double mutants of per and cry suggested a genetic interaction between the two loci. To investigate whether this was reflected in a physical interaction, we employed a yeast-two-hybrid system that revealed a dimerization between PER and CRY. This was further supported by a coimmunoprecipitation assay in tissue culture cells. We also show that the light-dependent nuclear interactions of PER and TIM with CRY require the C terminus of CRY and may involve a trans-acting repressor.
CONCLUSIONS:
This study shows that, as in mammals, Drosophila CRY interacts with PER, and, as in plants, the C terminus of CRY is involved in mediating light responses. A model for the light dependence of CRY is discussed
Posttraumatic stress disorder and not depression is associated with shorter leukocyte telomere length: findings from 3,000 participants in the population-based KORA F4 study.
No full textBackgroundA link between severe mental stress and shorter telomere length (TL) has been suggested. We analysed the impact of Posttraumatic Stress Disorder (PTSD) on TL in the general population and postulated a dose-dependent TL association in subjects suffering from partial PTSD compared to full PTSD.MethodsData are derived from the population-based KORA F4 study (2006-2008), located in southern Germany including 3,000 individuals (1,449 men and 1,551 women) with valid and complete TL data. Leukocyte TL was measured using a quantitative PCR-based technique. PTSD was assessed in a structured interview and by applying the Posttraumatic Diagnostic Scale (PDS) and the Impact of Event Scale (IES). A total of 262 (8.7%) subjects qualified for having partial PTSD and 51 (1.7%) for full PTSD. To assess the association of PTSD with the average TL, linear regression analyses with adjustments for potential confounding factors were performed.ResultsThe multiple model revealed a significant association between partial PTSD and TL (beta = -0.051, p = 0.009) as well as between full PTSD and shorter TL (beta = -0.103, p = 0.014) indicating shorter TL on average for partial and full PTSD. An additional adjustment for depression and depressed mood/exhaustion gave comparable beta estimations.ConclusionsParticipants with partial and full PTSD had significantly shorter leukocyte TL than participants without PTSD. The dose-dependent variation in TL of subjects with partial and full PTSD exceeded the chronological age effect, and was equivalent to an estimated 5 years in partial and 10 years in full PTSD of premature aging
Association of shorter leucocyte telomere length with risk of frailty.
No full textBACKGROUND: Frailty is a multidimensional syndrome of decline that affects multiple systems and predisposes to adverse health outcomes. Although chronological age is the major risk factor, inter-individual variation in risk is not fully understood. Leucocyte telomere length (LTL), a proposed marker of biological age, has been associated with risk of many diseases. We sought to determine whether LTL is associated with risk of frailty. METHODS: We utilized cross-sectional data from 441 781 UK Biobank participants (aged 40-69 years), with complete data on frailty indicators and LTL. Frailty was defined as the presence of at least three of five indicators: weaker grip strength, slower walking pace, weight loss in the past year, lower physical activity, and exhaustion in the past 2 weeks. LTL was measured using a validated qPCR method and reported as a ratio of the telomere repeat number (T) to a single-copy gene (S) (T/S ratio). Association of LTL with frailty was evaluated using adjusted (chronological age, sex, deprivation, smoking, alcohol intake, body mass index, and multimorbidity) multinomial and ordinal regression models, and results are presented as relative risk (RRR) or odds ratios (OR), respectively, alongside the 95% confidence interval (CI). Mendelian randomization (MR), using 131 genetic variants associated with LTL, was used to assess if the association of LTL with frailty was causal. RESULTS: Frail participants (4.6%) were older (median age difference (95% CI): 3 (2.5; 3.5) years, P = 2.73 × 10-33 ), more likely to be female (61%, P = 1.97 × 10-129 ), and had shorter LTL (-0.13SD vs. 0.03SD, P = 5.43 × 10-111 ) than non-frail. In adjusted analyses, both age and LTL were associated with frailty (RRR = 1.03 (95% CI: 1.02; 1.04) per year of older chronological age, P = 3.99 × 10-12 ; 1.10 (1.08; 1.11) per SD shorter LTL, P = 1.46 × 10-30 ). Within each age group (40-49, 50-59, 60-69 years), the prevalence of frailty was about 33% higher in participants with shorter (-2SD) versus longer telomeres (+2SD). MR analysis showed an association of LTL with frailty that was directionally consistent with the observational association, but not statistically significant (MR-Median: OR (95% CI): 1.08 (0.98; 1.19) per SD shorter LTL, P = 0.13). CONCLUSIONS: Inter-individual variation in LTL is associated with the risk of frailty independently of chronological age and other risk factors. Our findings provide evidence for an additional biological determinant of frailty
Variants near TERT and TERC influencing telomere length are associated with high-grade glioma risk
No full textLonger genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk
No full textTelomere maintenance has emerged as an important molecular feature with impacts on adult glioma susceptibility and prognosis. Whether longer or shorter leukocyte telomere length (LTL) is associated with glioma risk remains elusive and is often confounded by the effects of age and patient treatment. We sought to determine if genotypically-estimated LTL is associated with glioma risk and if inherited single nucleotide polymorphisms (SNPs) that are associated with LTL are glioma risk factors. Using a Mendelian randomization approach, we assessed differences in genotypically-estimated relative LTL in two independent glioma case-control datasets from the UCSF Adult Glioma Study (652 patients and 3735 controls) and The Cancer Genome Atlas (478 non-overlapping patients and 2559 controls). LTL estimates were based on a weighted linear combination of subject genotype at eight SNPs, previously associated with LTL in the ENGAGE Consortium Telomere Project. Mean estimated LTL was 31bp (5.7%) longer in glioma patients than controls in discovery analyses (P = 7.82x10-8) and 27bp (5.0%) longer in glioma patients than controls in replication analyses (1.48x10-3). Glioma risk increased monotonically with each increasing septile of LTL (O.R.=1.12; P = 3.83x10-12). Four LTL-associated SNPs were significantly associated with glioma risk in pooled analyses, including those in the telomerase component genes TERC (O.R.=1.14; 95% C.I.=1.03-1.28) and TERT (O.R.=1.39; 95% C.I.=1.27-1.52), and those in the CST complex genes OBFC1 (O.R.=1.18; 95% C.I.=1.05-1.33) and CTC1 (O.R.=1.14; 95% C.I.=1.02-1.28). Future work is needed to characterize the role of the CST complex in gliomagenesis and further elucidate the complex balance between ageing, telomere length, and molecular carcinogenesis
Telomere length and risk of incident fracture and arthroplasty: findings from UK Biobank.
No full textWe investigated independent associations between telomere length and risk of fracture and arthroplasty in UK Biobank participants. Leucocyte telomere length (LTL) was measured in baseline samples using a validated PCR method. We used, in men and women separately, Cox proportional hazards models to calculate the hazard ratio for incident fracture (any, osteoporotic) or arthroplasty (hip or knee) over 1,186,410 person-years of follow-up. Covariates included age, white cell count, ethnicity, smoking, alcohol, physical activity and menopause (women). In further analyses we adjusted for either estimated bone mineral density from heel quantitative ultrasound, handgrip strength, gait speed, total fat mass (bioimpedance) or blood biomarkers, all measured at baseline (2006-2010). We studied 59,500 women and 51,895 men, mean(SD) age 56.4(8.0) and 57.0(8.3) years respectively. During follow-up there were 5,619 fractures; 5,285 hip and 4,261 knee arthroplasties. In confounder-adjusted models, longer LTL was associated with reduced risk of incident knee arthroplasty in both men [hazard ratio/SD (95%CI): 0.93 (0.88,0.97)] and women [0.92 (0.88,0.96)] and hip arthroplasty in men [0.91 (0.87,0.95)] but not women [0.98 (0.94,1.01)]. Longer LTL was weakly associated with reduced risk of any incident fracture in women [hazard ratio/SD (95% CI): 0.96 (0.93,1.00)] with less evidence in men [0.98 (0.93,1.02)]. Associations with incident outcomes were not materially altered by adjustment for heel estimated bone mineral density, grip strength, gait speed, fat mass or blood biomarker measures. In this, the largest study to date, longer LTL was associated with lower risk of incident knee or hip arthroplasty, but only weakly associated with lower risk of fracture. The relative risks were low at a population level, but our findings suggest that common factors acting on the myeloid and musculoskeleletal systems might influence later life musculoskeletal outcomes. This article is protected by copyright. All rights reserved
Correction: Micronutrient intake and telomere length: findings from the UK Biobank (European Journal of Nutrition, (2024), 63, 8, (2871-2883), 10.1007/s00394-024-03460-5)
No full texthttps://doi.org/10.1007/s00394-024-03460-5. In the original version of this article, e-mail address of the corresponding author Vasiliki Bountziouka was incorrectly given as [email protected] but should have been [email protected]. © Springer-Verlag GmbH Germany, part of Springer Nature 2024
Lack of association between air pollutants and telomere length: findings from the UK Biobank study
No full textBackground: Air pollution has been extensively associated with diseases more common in the elderly, and with disease risk factors associated with ageing such as atherosclerosis and reduced lung function. Shorter telomere length (TL) is often considered a biological marker of advanced biological ageing, also and is associated with the risk of many age-related degenerative diseases. Common mechanisms of oxidative stress and inflammation have been identified for TL shortening and air pollution damage. There are few studies of air pollution and TL in adults, but associations were seen between in utero and early life air pollution exposures and shorter TL at age 8 years in the HELIX study (Clemente, 2019). //
Methods: We investigated cross-sectional associations between European Study of Cohorts and Air Pollution Effects (ESCAPE) modelled air pollutants (NO2, NO, PM10, PM2.5, PM2.5absorbance, PMcoarse) and leucocyte TL (LTL) in 299,786 UK Biobank participants. We used multivariable linear regression models adjusted for age, sex, ethnicity, white cell blood count, deprivation, family income, education, and smoking.
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Results: The association between any air pollutant and LTL was negligible, after accounting for major determinants of LTL, socio-economic status and smoking. Findings were unchanged in multiple imputation models to investigate impact of missing confounders, and when stratifying by deprivation quintile. //
Conclusions: Studies using UK Biobank have found associations between air pollution and organ damage also associated with ageing such as reduced lung function (Doiron, 2019), but we did not find associations with TL shortening in cross-sectional analyses, suggesting air pollution mediated TL damage is unlikely to be a key mechanism. However, findings need confirmation in longitudinal analyses, ideally complemented by experimental studies and further epidemiological studies investigating other air pollutants
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