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1.
Nat Methods ; 17(7): 734-740, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32541853

RESUMO

An outstanding challenge in single-molecule localization microscopy is the accurate and precise localization of individual point emitters in three dimensions in densely labeled samples. One established approach for three-dimensional single-molecule localization is point-spread-function (PSF) engineering, in which the PSF is engineered to vary distinctively with emitter depth using additional optical elements. However, images of dense emitters, which are desirable for improving temporal resolution, pose a challenge for algorithmic localization of engineered PSFs, due to lateral overlap of the emitter PSFs. Here we train a neural network to localize multiple emitters with densely overlapping Tetrapod PSFs over a large axial range. We then use the network to design the optimal PSF for the multi-emitter case. We demonstrate our approach experimentally with super-resolution reconstructions of mitochondria and volumetric imaging of fluorescently labeled telomeres in cells. Our approach, DeepSTORM3D, enables the study of biological processes in whole cells at timescales that are rarely explored in localization microscopy.


Assuntos
Aprendizado Profundo , Imageamento Tridimensional/métodos , Imagem Individual de Molécula/métodos , Fenômenos Biológicos , Redes Neurais de Computação , Telômero/ultraestrutura
2.
FASEB J ; 34(6): 7247-7252, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32427393

RESUMO

The medical, public health, and scientific communities are grappling with monumental imperatives to contain COVID-19, develop effective vaccines, identify efficacious treatments for the infection and its complications, and find biomarkers that detect patients at risk of severe disease. The focus of this communication is on a potential biomarker, short telomere length (TL), that might serve to identify patients more likely to die from the SARS-CoV-2 infection, regardless of age. The common thread linking these patients is lymphopenia, which largely reflects a decline in the numbers of CD4/CD8 T cells but not B cells. These findings are consistent with data that lymphocyte TL dynamics impose a limit on T-cell proliferation. They suggest that T-cell lymphopoiesis might stall in individuals with short TL who are infected with SARS-CoV-2.


Assuntos
Betacoronavirus , Infecções por Coronavirus/patologia , Linfopenia/etiologia , Modelos Biológicos , Pneumonia Viral/patologia , Subpopulações de Linfócitos T/ultraestrutura , Encurtamento do Telômero , Telômero/ultraestrutura , Biomarcadores , Medula Óssea/patologia , Divisão Celular , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Progressão da Doença , Células-Tronco Hematopoéticas/patologia , Humanos , Ativação Linfocitária , Contagem de Linfócitos , Linfopenia/patologia , Linfopoese , Pandemias , Pneumonia Viral/genética , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Prognóstico , Risco
3.
Nat Struct Mol Biol ; 27(4): 313-318, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32231287

RESUMO

Telomeres arose from the need to stabilize natural chromosome ends, resulting in terminal chromatin structures with specific protective functions. Their constituent proteins also execute general functions within heterochromatin, mediating late replication and facilitating fork progression. Emerging insights into the mechanisms governing heterochromatin replication suggest telomeres and heterochromatin act in concert during development and aging. They also suggest a common evolutionary origin for these two chromosome regions that arose during eukaryogenesis.


Assuntos
Cromatina/genética , Heterocromatina/genética , Proteínas/genética , Telômero/genética , Cromatina/ultraestrutura , Replicação do DNA/genética , Heterocromatina/ultraestrutura , Humanos , Proteínas/química , Proteínas/ultraestrutura , Telômero/ultraestrutura
4.
Chemosphere ; 248: 126092, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32041072

RESUMO

Exposure to polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) may change leukocyte telomere length (TL) at the end of the DNA sequence. The purpose of this study was to investigate the association between PCBs and OCPs exposure with TL in Tehran adult males. Whole-blood samples were randomly taken from three hundred adult males in population-based cross-section study from October 2016 to November 2017. We studied the serum levels of PCBs, OCPs as well as socio-demographic characteristics of individuals. The quantitative PCR was used to investigate the number of the telomere (T) repeats to the number of a single copy gene. We measured the effect of each PCBs and OCPs congeners on TL using linear regressions adjusted for age, BMI, smoking, and dietary patterns. The median level of the six non-dioxin-likes, five dioxin-likes PCBs three OCPs and TL in the study population were 344.5, 306.0, 45.0 ng/g lipid and 5377.7 ± 573.4 base pairs, respectively. In the adjusted model, the percent difference in the TLs with exposure to Σnon-dioxin-like PCBs, Σdioxin-like PCBs, and OCPs were 1.93 (-0.70 to 5.4), 3.4 (1.8-8.3) and -2.4 (-0.80 to -6.2), respectively. In the fourth quartile compared to the first quartile, the percent difference in the TLs due to Σnon-dioxin-like PCBs, Σdioxin-like PCBs, and OCP exposure were 0.01 (-0.01 to 0.05), 10.3 (2.9-18.1) and -0.20 (-0.10 to -4.5), respectively. Exposures to ndl-PCBs and dl-PCBs (except for PCB28) were related to longer TLs, but OCPs exposure can be related to telomere shortening.


Assuntos
Hidrocarbonetos Clorados/sangue , Leucócitos/efeitos dos fármacos , Praguicidas/sangue , Bifenilos Policlorados/sangue , Encurtamento do Telômero/efeitos dos fármacos , Telômero/efeitos dos fármacos , Adulto , Estudos Transversais , Feminino , Humanos , Irã (Geográfico) , Leucócitos/ultraestrutura , Masculino , Distribuição Aleatória , Telômero/ultraestrutura , Adulto Jovem
5.
Nat Chem Biol ; 16(7): 801-809, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32066968

RESUMO

Telomere maintenance by telomerase is essential for continuous proliferation of human cells and is vital for the survival of stem cells and 90% of cancer cells. To compensate for telomeric DNA lost during DNA replication, telomerase processively adds GGTTAG repeats to chromosome ends by copying the template region within its RNA subunit. Between repeat additions, the RNA template must be recycled. How telomerase remains associated with substrate DNA during this critical translocation step remains unknown. Using a single-molecule telomerase activity assay utilizing high-resolution optical tweezers, we demonstrate that stable substrate DNA binding at an anchor site within telomerase facilitates the processive synthesis of telomeric repeats. The product DNA synthesized by telomerase can be recaptured by the anchor site or fold into G-quadruplex structures. Our results provide detailed mechanistic insights into telomerase catalysis, a process of critical importance in aging and cancer.


Assuntos
DNA/metabolismo , Quadruplex G , RNA/metabolismo , Telomerase/metabolismo , Telômero/enzimologia , Biocatálise , DNA/genética , Replicação do DNA , Expressão Gênica , Células HEK293 , Humanos , Pinças Ópticas , RNA/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Telomerase/genética , Telômero/ultraestrutura
6.
Anim Genet ; 51(1): 3-13, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31637754

RESUMO

Telomeres are genetically conserved nucleoprotein complexes located at the ends of chromosomes that preserve genomic stability. In large mammals, somatic cell telomeres shorten with age, owing to the end replication problem and lack of telomere-lengthening events (e.g. telomerase and ALT activity). Therefore, telomere length reflects cellular replicative reserve and mitotic potential. Environmental insults can accelerate telomere attrition in response to cell division and DNA damage. As such, telomere shortening is considered one of the major hallmarks of ageing. Much effort has been dedicated to understanding the environmental perturbations that accelerate telomere attrition and therapeutic strategies to preserve or extend telomeres. As telomere dynamics seem to reflect cumulative cellular stress, telomere length could serve as a biomarker of animal welfare. The assessment of telomere dynamics (i.e. rate of shortening) in conjunction with telomere-regulating genes and telomerase activity in racehorses could monitor long-term animal health, yet it could also provide some unique opportunities to address particular limitations with the use of other animal models in telomere research. Considering the ongoing efforts to optimise the health and welfare of equine athletes, the purpose of this review is to discuss the potential utility of assessing telomere length in Thoroughbred racehorses. A brief review of telomere biology in large and small mammals will be provided, followed by discussion on the biological implications of telomere length and environmental (e.g. lifestyle) factors that accelerate or attenuate telomere attrition. Finally, the utility of quantifying telomere dynamics in horses will be offered with directions for future research.


Assuntos
Cavalos/genética , Encurtamento do Telômero , Telômero/ultraestrutura , Animais , Instabilidade Genômica , Humanos
7.
Int J Radiat Biol ; 96(2): 214-219, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31622124

RESUMO

Purpose: The premature chromosome condensation (PCC) technique is used to study exposure to external radiation through the determination of chromosome fragments observed in interphase cells. The presence of large telomeric signals in CHO cells interferes with the detection of PCC fragments and the identification of dicentric chromosomes. We present an improved method for the fusion of G0-lymphocytes with mitotic Akodon cells (few chromosomes and weakly-staining telomeric sequences) to induce PCC in combination with rapid quantification of dicentric chromosomes and centric rings as an alternative to the classical CHO cell fusion technique.Materials and methods: Whole blood from three healthy volunteers was γ-irradiated with 0, 2, or 4 Gy. Following a 24 h incubation post-exposure at 37 °C, chromosome spreads of isolated lymphocytes were prepared by standard PCC procedures using mitotic Akodon cells.Results: The percentage of scorable fusions, measured by telomere/centromere (T/C) staining, for Akodon-induced PCC was higher than that for CHO-induced PCC, irrespective of radiation exposure. Importantly, both techniques gave the same result for biodosimetry evaluation.Conclusion: The mitotic Akodon cell-induced PCC fusion assay, in combination with the scoring of dicentric chromosomes and rings by T/C staining of G0-lymphocytes is a suitable alternative for fast and reliable dose estimation after accidental radiation exposure.


Assuntos
Cromossomos/efeitos da radiação , Cromossomos/ultraestrutura , Linfócitos/citologia , Mitose , Adulto , Animais , Células CHO , Centrômero/efeitos da radiação , Centrômero/ultraestrutura , Cricetinae , Cricetulus , Raios gama , Voluntários Saudáveis , Humanos , Pessoa de Meia-Idade , Radiometria , Roedores , Telômero/efeitos da radiação , Telômero/ultraestrutura , Adulto Jovem
8.
Probl Radiac Med Radiobiol ; 24: 503-515, 2019 Dec.
Artigo em Inglês, Ucraniano | MEDLINE | ID: mdl-31841491

RESUMO

OBJECTIVE: The objective was to study the relationship between functional status of bronchopulmonary system and telomere length in clean-up workers of Chornobyl NPP accident in a remote post-accident period. MATERIALS AND METHODS: A study was performed in 113 clean-up workers of Chornobyl NPP accident. Individual do- cumented doses of irradiation in clean-up workers ranged from 1,0 to 880 mSv (330.4 ± 317.7 (M ± SD)). The aver- age age of the Chornobyl NPP participants was (62.21 ± 6.99) years. A complex of functional pulmonary tests (spirometry, body plethysmography, examination of lung diffusion capacity) was performed. Relative telomere length (RTL) was analysed by flow-FISH. RESULTS: There was a tendency to decrease the relative telomere length in clean-up workers with COPD I-II stage and COPD III-IV, compared with patients with the absence of bronchopulmonary diseases (RTL 15,2 ± 2,7). Significantly shorter telomeres were observed in patients with COPD who were exposed to radiation at a dose of more than 500 mSv (13.6 ± 2.5) compared with COPD patients who were exposed at a dose <10 mSv (RTL 15.3 ± 2.3). When analyzing the correlation relationships of the studied indicators, no significant associations were found with the relative telomere length. At this stage of the study no association of relative telomere length with age, body mass index, and functional criteria (FEV1 (l), intrathoracic pressure (ITGV), total lung capacity (TLC), diffusion lung capac- ity (DLCO)) was detected. CONCLUSIONS: The analyzed telomere length relationship from liquidators of the Chernobyl found no direct associa- tion with indicators of lung function tests, however, showed a trend towards reducing the relative telomere length in clean-up workers who suffer from COPD and exposed to doses from 100 to 500 mSv and above 500 mSv.


Assuntos
Acidente Nuclear de Chernobyl , Socorristas , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Exposição à Radiação/efeitos adversos , Lesões por Radiação/fisiopatologia , Telômero/ultraestrutura , Idoso , Relação Dose-Resposta à Radiação , Humanos , Pulmão/patologia , Pulmão/efeitos da radiação , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/genética , Doses de Radiação , Lesões por Radiação/etiologia , Lesões por Radiação/genética , Testes de Função Respiratória , Sobreviventes , Encurtamento do Telômero , Fatores de Tempo , Ucrânia
9.
Nutr. hosp ; 36(6): 1403-1417, nov.-dic. 2019. tab, ilus
Artigo em Inglês | IBECS | ID: ibc-191162

RESUMO

Telomere length (TL) is a predictive biomarker of premature aging. Telomere shortening has been linked to age-related diseases and noncommunicable diseases (NCD), and may reflect the effects of behavioral, psychosocial and environmental factors on health status. Telomere attrition can be affected by lifestyle factors such as diet and physical activity. The search of studies included in this review was conducted on PubMed Central database. A majority of studies are cross-sectional, as there is a clear lack of prospective studies to evaluate the individual effect of dietary components, dietary patterns, and physical activity on TL in the long term. The current literature suggests that high adherence to Mediterranean diet (MD), with consumption of antioxidants, fiber and vegetables, as well as seeds and walnuts, is associated with longer TL. The dietary components of a healthy diet, such as carotenoids, vitamins A, C, D, E, polyphenols, fiber, and omega-3 fatty acids could help maintain TL. In contrast, a high consumption of sugary beverages, processed meat, and proinflammatory diets is associated with telomere shortening. In a majority of studies TL is positively associated with moderate physical activity. The predominant mechanisms through which a healthy diet and moderate physical exercise could mitigate telomere attrition include decreasing oxidative stress and inflammation. We shall not discuss the associations of possible risk or protective factors in terms of causality since the majority of studies are cross-sectional and randomized controlled trials are limited; accordingly, some results are inconclusive. For future research, we suggest evaluating the individual effects of dietary components, dietary patterns and physical activity, considering repeated measurements and exercise intensity, on TL. It is also advisable to include biomarkers of oxidative stress and inflammation proteins, and to measure telomerase activity


La longitud de los telómeros (TL) es un biomarcador predictivo del envejecimiento prematuro. El acortamiento de los telómeros se ha relacionado con las enfermedades asociadas a la edad y las enfermedades no transmisibles (ENT), y puede reflejar los efectos de los factores conductuales, psicosociales y ambientales en el estado de salud. El desgaste de los telómeros puede verse afectado por factores del estilo de vida, como la dieta y la actividad física. La búsqueda de los estudios incluidos en esta revisión se realizó en la base de datos PubMed Central. La mayoría de los estudios son transversales, por lo que está clara la falta de estudios prospectivos que evalúen el efecto individual de los componentes dietéticos, los patrones dietéticos y la actividad física sobre el TL a largo plazo. La literatura actual sugiere que una alta adherencia a la dieta mediterránea (DM) y el consumo de antioxidantes, fibra y vegetales, así como semillas y nueces, se asocia a una mayor TL. Los componentes dietéticos de una dieta saludable, como los carotenoides, las vitaminas A, C, D, E, los polifenoles, la fibra y los ácidos grasos omega-3, podrían ayudar a mantener la TL. En contraste, el alto consumo de bebidas azucaradas, carne procesada y dietas proinflamatorias se asocia al acortamiento de los telómeros. En la mayoría de los estudios, el TL se asocia positivamente con la actividad física moderada. Los mecanismos predominantes que, a través de una dieta saludable y un ejercicio físico moderado, podrían mitigar el desgaste de los telómeros son la disminución del estrés oxidativo y la inflamación. No se discute la asociación de posibles factores de riesgo o de protección en términos de causalidad, ya que la mayoría de los estudios son transversales y los ensayos controlados aleatorios son limitados; por consiguiente, algunos resultados no son concluyentes. Para investigaciones futuras se sugiere evaluar los efectos individuales de los componentes dietéticos, los patrones de actividad física y dietética, considerando mediciones repetidas y la intensidad del ejercicio, sobre el TL. También es aconsejable incluir biomarcadores de estrés oxidativo y proteínas inflamatorias, y medir la actividad de la telomerasa


Assuntos
Humanos , Dieta , Exercício Físico , Telômero/ultraestrutura , Pesquisa Biomédica/tendências , Ácidos Graxos Essenciais , Previsões , Inflamação , Micronutrientes , Estresse Oxidativo
10.
Commun Biol ; 2: 376, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31633067

RESUMO

Telomere movements during meiotic prophase I facilitate synapsis and recombination of homologous chromosomes. Hereby, chromosome movements depend on the dynamic attachment of meiotic telomeres to the nuclear envelope and generation of forces that actively move the telomeres. In most eukaryotes, forces that move telomeres are generated in the cytoplasm by microtubule-associated motor proteins and transduced into the nucleus through the LINC complexes of the nuclear envelope. Meiotic LINC complexes, in mouse comprised of SUN1/2 and KASH5, selectively localize to the attachment sites of meiotic telomeres. For a better understanding of meiotic telomere dynamics, here we provide quantitative information of telomere attachment sites that we have generated with the aid of electron microscope tomography (EM tomography). Our data on the number, length, width, distribution and relation with microtubules of the reconstructed structures indicate that an average number of 76 LINC complexes would be required to move a telomere attachment site.


Assuntos
Microtúbulos/ultraestrutura , Telômero/ultraestrutura , Animais , Sítios de Ligação , Proteínas de Ciclo Celular/metabolismo , Pareamento Cromossômico , Proteínas do Citoesqueleto/metabolismo , Tomografia com Microscopia Eletrônica , Masculino , Meiose , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/metabolismo , Microtúbulos/metabolismo , Complexos Multiproteicos/metabolismo , Complexos Multiproteicos/ultraestrutura , Membrana Nuclear/metabolismo , Membrana Nuclear/ultraestrutura , Proteínas Nucleares/metabolismo , Telômero/metabolismo , Proteínas de Ligação a Telômeros/metabolismo , Testículo/metabolismo , Testículo/ultraestrutura
11.
Mutat Res ; 846: 503084, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31585633

RESUMO

Cancer stem-like cells (CSCs) were reported to be linked with tumorigenesis, metastasis and resistant to chemo and radiotherapy in head and neck squamous cell carcinoma (HNSCC). In this study we investigated the role of CSCs in chemoresistance and abrogation of CSC mediated chemoresistance by combinatorial treatment with cisplatin and small molecule tankyrase inhibitor XAV-939. Two cisplatin-resistant HNSCC cells were generated by stepwise dose incremental strategy. We evaluated the chemoresistance, sphere forming capacity, extent of DNA damage and repair capacity in parental and cisplatin-resistant HNSCC cells. Furthermore, the abrogation of CSC mediated chemoresistance was evaluated in HNSCC cells with XAV-939 alone and in combination with cisplatin. It was observed that cisplatin-resistant HNSCC cell lines exhibited increase in chemoresistance, CSC phenotype and increased DNA repair capacity. We observed that combination of cisplatin and XAV-939 acts synergistically to abrogate chemoresistance by increasing DNA damage. Molecular docking study also revealed similar binding region that could contribute towards synergy predictions between cisplatin and XAV939. In conclusion, this study elucidated that combination of cisplatin and XAV-939 exerted cytotoxic and genotoxic effect to abrogate CSC mediated chemoresistance in HNSCC in synergistic manner.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Cisplatino/farmacologia , Neoplasias de Cabeça e Pescoço/patologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Tanquirases/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaio Cometa , Citocinese , Reparo do DNA , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Testes para Micronúcleos , Fenótipo , RNA Neoplásico/biossíntese , Esferoides Celulares/efeitos dos fármacos , Telômero/ultraestrutura , beta Catenina/antagonistas & inibidores
12.
Proc Natl Acad Sci U S A ; 116(30): 15122-15127, 2019 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-31285335

RESUMO

Telomere shortening to a critical length can trigger aging and shorter life spans in mice and humans by a mechanism that involves induction of a persistent DNA damage response at chromosome ends and loss of cellular viability. However, whether telomere length is a universal determinant of species longevity is not known. To determine whether telomere shortening can be a single parameter to predict species longevities, here we measured in parallel the telomere length of a wide variety of species (birds and mammals) with very different life spans and body sizes, including mouse (Mus musculus), goat (Capra hircus), Audouin's gull (Larus audouinii), reindeer (Rangifer tarandus), griffon vulture (Gyps fulvus), bottlenose dolphin (Tursiops truncatus), American flamingo (Phoenicopterus ruber), and Sumatran elephant (Elephas maximus sumatranus). We found that the telomere shortening rate, but not the initial telomere length alone, is a powerful predictor of species life span. These results support the notion that critical telomere shortening and the consequent onset of telomeric DNA damage and cellular senescence are a general determinant of species life span.


Assuntos
Longevidade/genética , Encurtamento do Telômero , Telômero/ultraestrutura , Animais , Golfinho Nariz-de-Garrafa/genética , Senescência Celular , Charadriiformes/genética , Elefantes/genética , Falconiformes/genética , Cabras/genética , Humanos , Camundongos , Análise de Regressão , Rena/genética , Especificidade da Espécie
13.
Hematology ; 24(1): 559-566, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31315542

RESUMO

Aplastic anemia (AA) is a rare and life-threatening bone marrow failure (BMF) that results in peripheral blood cytopenia and reduced bone marrow hematopoietic cell proliferation. The symptoms are similar to myelofibrosis, myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) making diagnosis of AA complicated. The pathogenesis of AA is complex and its mechanism needs to be deciphered on an individualized basis. This review summarizes several contributions made in trying to understand AA pathogenesis in recent years which may be helpful for the development of personalized therapies for AA.


Assuntos
Anemia Aplástica/etiologia , Anemia Aplástica/congênito , Anemia Aplástica/epidemiologia , Anemia Aplástica/terapia , Autoimunidade , Medula Óssea/patologia , Microambiente Celular , Células Dendríticas/imunologia , Predisposição Genética para Doença , Hematopoese , Células-Tronco Hematopoéticas/patologia , Humanos , Células Matadoras Naturais/imunologia , Linfocinas/fisiologia , Mutação , Linfócitos T/imunologia , Telômero/ultraestrutura
14.
Ecotoxicol Environ Saf ; 182: 109453, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31349105

RESUMO

Telomeres are DNA-protein structures that protect chromosome ends from degradation and fusion, which are shortened by oxidative stress, for example air pollution including benzene, toluene, Coke Oven Emissions (COEs), and so on. As a biomarker of health and disease, telomere length is associated with cardiovascular, diabetes and cancers. The aim of this study was to estimate the effects of COEs exposure on telomere length and the benchmark dose (BMD) of COEs. A total of 542 coke oven workers and 235 healthy controls without exposure to toxicants were recruited. Quantitative PCR was used to determine the telomere length in human peripheral blood leukocytes DNA. Propensity scoring was used to match coke oven workers to healthy controls. Linear regression models and trend tests were used to the relationship between COEs exposure and telomere length. Telomere length in COEs exposed group 0.764 (0.536, 1.092) was significantly shorter than that in the control group 1.064(0.762, 1.438), (P < 0.001). There were significantly dose-response relationships between COEs exposure and telomere damage with telomere length as a biomarker. A BMDL value lower than the present occupational exposure limits (OELs) of COEs exposure was evaluated using the BMD approach in coke oven workers. Our results suggested that shorter telomere length is related to occupational exposure to COEs and the level of COEs exposure lower than the current national OELs in China and many other countries could induce telomere damage.


Assuntos
Poluentes Ocupacionais do Ar/análise , Coque/análise , Exposição Ocupacional/análise , Telômero/efeitos dos fármacos , Adolescente , Adulto , Poluentes Ocupacionais do Ar/toxicidade , Benchmarking , Biomarcadores/análise , Estudos de Casos e Controles , China , Coque/toxicidade , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Exposição Ocupacional/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Telômero/ultraestrutura , Adulto Jovem
15.
Mol Cell ; 75(1): 131-144.e3, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31204167

RESUMO

In Saccharomyces cerevisiae, dicentric chromosomes stemming from telomere fusions preferentially break at the fusion. This process restores a normal karyotype and protects chromosomes from the detrimental consequences of accidental fusions. Here, we address the molecular basis of this rescue pathway. We observe that tandem arrays tightly bound by the telomere factor Rap1 or a heterologous high-affinity DNA binding factor are sufficient to establish breakage hotspots, mimicking telomere fusions within dicentrics. We also show that condensins generate forces sufficient to rapidly refold dicentrics prior to breakage by cytokinesis and are essential to the preferential breakage at telomere fusions. Thus, the rescue of fused telomeres results from a condensin- and Rap1-driven chromosome folding that favors fusion entrapment where abscission takes place. Because a close spacing between the DNA-bound Rap1 molecules is essential to this process, Rap1 may act by stalling condensins.


Assuntos
Adenosina Trifosfatases/genética , Cromossomos Fúngicos/metabolismo , DNA Fúngico/genética , Proteínas de Ligação a DNA/genética , Complexos Multiproteicos/genética , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Proteínas de Ligação a Telômeros/genética , Telômero/metabolismo , Fatores de Transcrição/genética , Adenosina Trifosfatases/metabolismo , Pontos de Quebra do Cromossomo , Cromossomos Fúngicos/ultraestrutura , Citocinese/genética , DNA Fúngico/metabolismo , Proteínas de Ligação a DNA/metabolismo , Expressão Gênica , Cariótipo , Modelos Genéticos , Complexos Multiproteicos/metabolismo , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/ultraestrutura , Proteínas de Saccharomyces cerevisiae/metabolismo , Telômero/ultraestrutura , Proteínas de Ligação a Telômeros/metabolismo , Fatores de Transcrição/metabolismo
16.
Clin Rheumatol ; 38(10): 2909-2915, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31187337

RESUMO

Rheumatoid arthritis (RA) has been associated with early senescent features. However, the effects of disease progression on senescence markers are largely unknown. Here, we evaluated key senescence markers in RA, including telomere length and T cell differentiation stages as well as cytomegalovirus (CMV) serology, previously associated with premature aging. In a cross-sectional study, 44 patients with active (Ac-RA), 26 patients with controlled (Co-RA), and 30 healthy controls were recruited. Peripheral blood was collected and differentiation stages of T cells analyzed by multi-color flow cytometry. Enzyme-linked immunosorbent assays were used to evaluate the CMV serology. The telomere length was measured by multiplex quantitative PCR. Patients with Ac-RA presented lower percentage of intermediate-differentiated T cells (CD4+CD27-CD28+ and CD8+CD27-CD28+; p < 0.001). All patients had a reduced proportion of cytotoxic T cells, and higher CD4/CD8 ratio compared with controls (p < 0.001). A lower proportion of CMV IgG+ subjects was found in the Co-RA group, (P < 0.001), although no differences in the CMV IgG titers were observed between groups. The groups had similar leukocyte telomere length. In addition, age was negatively correlated with CD8+CD27+CD28+ T (early-differentiated) cells (P < 0.05). Positive correlations between CMV IgG titers and age (P < 0.05) and CD4+CD27-CD28- T (late-differentiated) cells (P < 0.01) were observed. Furthermore, disease duration was correlated with CD4+CD27+CD28+ T cells (r = - 0.318, p < 0.05) and CD4+CD27-CD28- T cells (r = 0.308, p < 0.05). Our findings indicate that CMV and age may have a similar impact on T cells in both RA patients and controls. KEY POINTS: • Patients and controls were homogenous regarding CMV IgG titers and TL. • A lower proportion of CMV IgG+ subjects was found in the Co-RA group. • Anti-CMV levels were positively correlated with age and percentage of CD4+CD27-CD28- (late-differentiated) T cells.


Assuntos
Artrite Reumatoide/sangue , Senescência Celular , Progressão da Doença , Idoso , Artrite Reumatoide/patologia , Antígenos CD28/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Estudos Transversais , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/complicações , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Reumatologia , Telômero/ultraestrutura , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
17.
Am J Epidemiol ; 188(9): 1616-1626, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31145433

RESUMO

Telomere length is a heritable marker of cellular age that is associated with morbidity and mortality. Poor sleep behaviors, which are also associated with adverse health events, may be related to leukocyte telomere length (LTL). We studied a subpopulation of 3,145 postmenopausal women (1,796 European-American (EA) and 1,349 African-American (AA)) enrolled in the Women's Health Initiative in 1993-1998 with data on Southern blot-measured LTL and self-reported usual sleep duration and sleep disturbance. LTL-sleep associations were analyzed separately for duration and disturbance using weighted and confounder-adjusted linear regression models in the entire sample (AAs + EAs; adjusted for race/ethnicity) and in racial/ethnic strata, since LTL differs by ancestry. After adjustment for covariates, each additional daily hour of sleep beyond 5 hours, approximately, was associated with a 27-base-pair (95% confidence interval (CI): 6, 48) longer LTL in the entire sample. Associations between sleep duration and LTL were strongest among AAs (adjusted ß = 37, 95% CI: 4, 70); a similar, nonsignificant association was observed for EAs (adjusted ß = 20, 95% CI: -7, 48). Sleep disturbance was not associated with LTL in our study. Our models did not show departure from linearity (quadratic sleep terms: P ≥ 0.55). Our results suggest that longer sleep duration is associated with longer LTL in postmenopausal women.


Assuntos
Sono , Telômero/ultraestrutura , Afro-Americanos , Idoso , Estudos Transversais , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Modelos Lineares , Pessoa de Meia-Idade , Pós-Menopausa , Estudos Prospectivos , Autorrelato , Sono/genética , Sono/fisiologia , Fatores Socioeconômicos , Saúde da Mulher
18.
Artigo em Inglês | MEDLINE | ID: mdl-30931641

RESUMO

Background: Amyotrophic lateral sclerosis is a neurodegenerative disease of motor neurons resulting in progressive paralysis and death, typically within 3-5 years. Although the heritability of ALS is about 60%, only about 11% is explained by common gene variants, suggesting that other forms of genetic variation are important. Telomeres maintain DNA integrity during cellular replication and shorten naturally with age. Gender and age are risk factors for ALS and also associated with telomere length. We therefore investigated telomere length in ALS. Methods: We estimated telomere length by applying a bioinformatics analysis to whole genome sequence data of leukocyte-derived DNA from people with ALS and age and gender-matched matched controls in a UK population. We tested the association of telomere length with ALS and ALS survival. Results: There were 1241 people with ALS and 335 controls. The median age for ALS was 62.5 years and for controls, 60.1 years, with a male-female ratio of 62:38. Accounting for age and sex, there was a 9% increase of telomere length in ALS compared to matched controls. Those with longer telomeres had a 16% increase in median survival. Of nine SNPs associated with telomere length, two were also associated with ALS: rs8105767 near the ZNF208 gene (p = 1.29 × 10-4) and rs6772228 (p = 0.001), which is in an intron for the PXK gene. Conclusions: Longer telomeres in leukocyte-derived DNA are associated with ALS, and with increased survival in those with ALS.


Assuntos
Esclerose Amiotrófica Lateral/patologia , Telômero/ultraestrutura , Idade de Início , Idoso , Esclerose Amiotrófica Lateral/genética , Estudos de Casos e Controles , Biologia Computacional , DNA/química , Feminino , Variação Genética , Humanos , Íntrons/genética , Leucócitos/química , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Análise de Sobrevida , Telômero/genética , Sequenciamento Completo do Genoma
19.
Proc Natl Acad Sci U S A ; 116(17): 8350-8359, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-30944218

RESUMO

G-quadruplexes (GQs) can adopt diverse structures and are functionally implicated in transcription, replication, translation, and maintenance of telomere. Their conformational diversity under physiological levels of mechanical stress, however, is poorly understood. We used single-molecule fluorescence-force spectroscopy that combines fluorescence resonance energy transfer with optical tweezers to measure human telomeric sequences under tension. Abrupt GQ unfolding with K+ in solution occurred at as many as four discrete levels of force. Added to an ultrastable state and a gradually unfolding state, there were six mechanically distinct structures. Extreme mechanical diversity was also observed with Na+, although GQs were mechanically weaker. Our ability to detect small conformational changes at low forces enabled the determination of refolding forces of about 2 pN. Refolding was rapid and stochastically redistributed molecules to mechanically distinct states. A single guanine-to-thymine substitution mutant required much higher ion concentrations to display GQ-like unfolding and refolded via intermediates, contrary to the wild type. Contradicting an earlier proposal, truncation to three hexanucleotide repeats resulted in a single-stranded DNA-like mechanical behavior under all conditions, indicating that at least four repeats are required to form mechanically stable structures.


Assuntos
DNA/ultraestrutura , Transferência Ressonante de Energia de Fluorescência/métodos , Quadruplex G , Telômero/ultraestrutura , DNA/química , Guanina/química , Humanos , Pinças Ópticas , Sequências Repetitivas de Ácido Nucleico , Telômero/química , Timina/química
20.
Nucleic Acids Res ; 47(10): 5395-5404, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-30957851

RESUMO

Human telomeric guanine-rich DNA, which could adopt different G-quadruplex structures, plays important roles in protecting the cell from recombination and degradation. Although many of these structures were determined, the chair-type G-quadruplex structure remains elusive. Here, we present a crystal structure of the G-quadruplex composed of the human telomeric sequence d[GGGTTAGG8GTTAGGGTTAGG20G] with two dG to 8Br-dG substitutions at positions 8 and 20 with syn conformation in the K+ solution. It forms a novel three-layer chair-type G-quadruplex with two linking trinucleotide loops. Particularly, T5 and T17 are coplanar with two water molecules stacking on the G-tetrad layer in a sandwich-like mode through a coordinating K+ ion and an A6•A18 base pair. While a twisted Hoogsteen A12•T10 base pair caps on the top of G-tetrad core. The three linking TTA loops are edgewise and each DNA strand has two antiparallel adjacent strands. Our findings contribute to a deeper understanding and highlight the unique roles of loop and water molecule in the folding of the G-quadruplex.


Assuntos
DNA/química , Quadruplex G , Telômero/ultraestrutura , Dicroísmo Circular , Cristalografia por Raios X , Guanina/análogos & derivados , Guanina/química , Humanos , Concentração de Íons de Hidrogênio , Ligantes , Espectroscopia de Ressonância Magnética , Conformação de Ácido Nucleico , Potássio/química , Termodinâmica
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