32 research outputs found
The POT1-TPP1 telomere complex is a telomerase processivity factor
Telomeres were originally defined as chromosome caps that prevent the natural ends of linear chromosomes from undergoing deleterious degradation and fusion events. POT1 ( protection of telomeres) protein binds the single-stranded G-rich DNA overhangs at human chromosome ends and suppresses unwanted DNA repair activities. TPP1 is a previously identified binding partner of POT1 that has been proposed to form part of a six-protein shelterin complex at telomeres. Here, the crystal structure of a domain of human TPP1 reveals an oligonucleotide/oligosaccharide-binding fold that is structurally similar to the beta-subunit of the telomere end-binding protein of a ciliated protozoan, suggesting that TPP1 is the missing beta-subunit of human POT1 protein. Telomeric DNA end-binding proteins have generally been found to inhibit rather than stimulate the action of the chromosome end-replicating enzyme, telomerase. In contrast, we find that TPP1 and POT1 form a complex with telomeric DNA that increases the activity and processivity of the human telomerase core enzyme. We propose that POT1 - TPP1 switches from inhibiting telomerase access to the telomere, as a component of shelterin, to serving as a processivity factor for telomerase during telomere extension.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62923/1/nature05454.pd
PrevalĂȘncia e fatores de risco para transtornos mentais comuns entre estudantes de medicina
Mental health problems among medical students in Brazil: a systematic review and meta-analysis
Sensitivity of South American tropical forests to an extreme climate anomaly
This is the final version. Available on open access from Nature Research via the DOI in this recordData availability:
Publicly available climate data used in this paper are available from ERA5 (ref. 64), CRU ts.4.03 (ref. 65), WorldClim v2 (ref. 66), TRMM product 3B43 V7 (ref. 67) and GPCC, Version 7 (ref. 68). The input data are available on ForestPlots42.Code availability
R code for graphics and analyses is available on ForestPlots42.The tropical forest carbon sink is known to be drought sensitive, but it is unclear which forests are the most vulnerable to extreme events. Forests with hotter and drier baseline conditions may be protected by prior adaptation, or more vulnerable because they operate closer to physiological limits. Here we report that forests in drier South American climates experienced the greatest impacts of the 2015â2016 El Niño, indicating greater vulnerability to extreme temperatures and drought. The long-term, ground-measured tree-by-tree responses of 123 forest plots across tropical South America show that the biomass carbon sink ceased during the event with carbon balance becoming indistinguishable from zero (â0.02â±â0.37âMgâCâhaâ1 per year). However, intact tropical South American forests overall were no more sensitive to the extreme 2015â2016 El Niño than to previous less intense events, remaining a key defence against climate change as long as they are protected
Endemic pemphigus in the peruvian Amazon: epidemiology and risk factors for the development of complications during treatment PĂȘnfigo endĂȘmico na AmazĂŽnia peruana: epidemiologia e fatores de risco para o desenvolvimento de complicaçÔes durante o tratamento
BACKGROUND: Pemphigus is an autoimmune blistering disease. According to a report, in areas of endemic pemphigus foliaceus (EPF) in Peru there are cases of pemphigus vulgaris with epidemiologic, clinical and histopathologic characteristics similar to those of "endemic pemphigus vulgaris" (EPV) in Brazil. OBJECTIVES: To determine the clinical and epidemiologic characteristics of endemic pemphigus and the risk factors of patients for developing complications during treatment. METHODS: A study was carried out from July 2003 to March 2008. The study population was 60 patients with EPF and 7 patients with EPV evaluated in hospitals and clinics in the Peruvian Amazon and Lima. A multivariate analysis was carried out using binary logistic regression. RESULTS: The average age of EPF patients was 31.4 years; 55% were men; 60% presented the generalized clinical variant. Non-compliance with the treatment was seen in 57.1% of the patients. Thirty-five percent presented complications (e.g. pyodermitis and pyelonephritis) during treatment. The risk factors for developing complications during treatment were non-compliance with the treatment and having the generalized clinical form. In the EPV group, the average age was 21.7 years; 71.4% were men. All patients presented with the mucocutaneous clinical variant and the initial presentation consisted of oral mucosa lesions; 71.4% presented complications during treatment, pyodermitis being the most frequent. CONCLUSIONS: Non-compliance with the treatment and the generalized clinical form are risk factors for the development of complications during treatment of patients with EPF. Peru indeed has EPV cases with epidemiologic characteristics similar to EPF. Living in a rural area may represent a risk factor for the development of complications during treatment of patients with EPV.<br>FUNDAMENTOS: O pĂȘnfigo Ă© uma doença auto-imune bolhosa. Segundo um relatĂłrio, em ĂĄreas de pĂȘnfigo foliĂĄceo endĂȘmico no Peru hĂĄ casos de pĂȘnfigo vulgar com caracterĂsticas epidemiolĂłgicas, clĂnicas e histopatolĂłgicas semelhantes Ă s do "pĂȘnfigo vulgar endĂȘmico" no Brasil. OBJETIVOS: Determinar as caracterĂsticas clĂnicas e epidemiolĂłgicas do pĂȘnfigo endĂȘmico e os fatores de risco para o desenvolvimento de complicaçÔes durante o tratamento. MĂTODOS: Um estudo foi realizado de julho de 2003 a março de 2008. 60 doentes de pĂȘnfigo foliĂĄceo endĂȘmico e 7 de pĂȘnfigo vulgar endĂȘmico foram avaliados em hospitais e clĂnicas na AmazĂŽnia peruana e em Lima. Uma anĂĄlise multivariante foi feita usando regressĂŁo logĂstica binĂĄria. RESULTADOS: A idade mĂ©dia dos doentes de pĂȘnfigo foliĂĄceo endĂȘmico foi 31,4 anos; 55% eram homens, 60% apresentavam a forma clĂnica generalizada. 57,1% nao cumpriram o tratamento. 35% apresentaram complicaçÔes (por exemplo, piodermites e pielonefrite). Os fatores de risco foram nĂŁo cumprir o tratamento e ter a forma clĂnica generalizada. No grupo pĂȘnfigo vulgar endĂȘmico, a idade mĂ©dia foi 21,7 anos; 71,4% eram homens. Todos os pacientes apresentavam a variante clĂnica mucocutĂąnea e a apresentação inicial consistia de lesĂ”es da mucosa bucal; 71,4% apresentaram complicaçÔes durante o tratamento, piodermites sendo a mais freqĂŒente. CONCLUSĂES: NĂŁo cumprir o tratamento e ter a forma clĂnica generalizada sĂŁo fatores de risco para o desenvolvimento de complicaçÔes durante o tratamento de pĂȘnfigo foliĂĄceo endĂȘmico. Peru realmente tem casos de pĂȘnfigo vulgar endĂȘmico com caracterĂsticas epidemiolĂłgicas semelhantes Ă s do pĂȘnfigo foliĂĄceo endĂȘmico. Viver numa ĂĄrea rural pode ser um fator de risco para o desenvolvimento de complicaçÔes
Structural and functional analysis of the human POT1-TPP1 telomeric complex
POT1 and TPP1 are part of the shelterin complex and are essential for telomere length
regulation and maintenance. Naturally occurring mutations of the telomeric POT1âTPP1
complex are implicated in familial glioma, melanoma and chronic lymphocytic leukaemia.
Here we report the atomic structure of the interacting portion of the human telomeric POT1â
TPP1 complex and suggest how several of these mutations contribute to malignant cancer.
The POT1 C-terminus (POT1C) forms a bilobal structure consisting of an OB-fold and a
holiday junction resolvase domain. TPP1 consists of several loops and helices involved in
extensive interactions with POT1C. Biochemical data shows that several of the cancerassociated
mutations, partially disrupt the POT1âTPP1 complex, which affects its ability to
bind telomeric DNA efficiently. A defective POT1âTPP1 complex leads to longer and fragile
telomeres, which in turn promotes genomic instability and cancer
The effect of sunlight exposure on interleukin-6 levels in depressive and non-depressive subjects
Background: The objective of this epidemiological study was to evaluate the effect of length of sunlight exposure on interleukin 6 (IL-6) levels in depressive and non-depressive subjects. Methods: This was a cross-sectional study with 154 subjects (54 males, mean age: 43.5 ± 12.8 years) who were living in a rural area in south Brazil. Chronobiological and light parameters were assessed using the Munich Chronotype Questionnaire. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index. Depressive symptoms were assessed with the Beck Depression Inventory. Plasma levels of inflammatory cytokines (IL-2, IL-4, IL-6, IL-10, tumor necrosis factor-α, and interferon) were collected during the daytime and measured. Results: IL-6 levels showed a positive correlation with light exposure (r = 0.257; p < 0.001) and a negative correlation with the mid-sleep phase on work-free days (r = â0.177; p = 0.028). Multiple linear regression analysis showed that only the length of light exposure was an independent factor for predicting IL-6 levels (Ă = 0.26; p = 0.002). In non-depressed subjects, exposure to a different intensity of light did not affect IL-6 levels (t = â1.6; p = 0.1). However, when the two depressive groups with low and high light exposure were compared, the low light exposure group had lower levels of IL-6 compared with the high light exposure group (t = â2.19 and p = 0.0037). Conclusions: The amount of time that participants are exposed to sunlight is directly related to their IL-6 levels. Additionally, depressed subjects differ in their IL-6 levels if they are exposed to light for differing amounts of time
POT1b protects telomeres from end-to-end chromosomal fusions and aberrant homologous recombination
POT1 (protection of telomere 1) is a highly conserved single-stranded telomeric binding protein that is essential for telomere end protection. Here, we report the cloning and characterization of a second member of the mouse POT family. POT1b binds telomeric DNA via conserved DNA binding oligonucleotide/oligosaccharide (OB) folds. Compared to POT1a, POT1b OB-folds possess less sequence specificity for telomeres. In contrast to POT1a, truncated POT1b possessing only the OB-folds can efficiently localize to telomeres in vivo. Overexpression of a mutant Pot1b allele that cannot bind telomeric DNA initiated a DNA damage response at telomeres that led to p53-dependent senescence. Furthermore, a reduction of the 3âČ G-rich overhang, increased chromosomal fusions and elevated homologous recombination (HR) were observed at telomeres. shRNA mediated depletion of endogenous Pot1b in Pot1a deficient cells resulted in increased chromosomal aberrations. Our results indicate that POT1b plays important protective functions at telomeres and that proper maintenance of chromosomal stability requires both POT proteins