Left Ventricular Concentric Geometric Patterns Are Associated With Worse Prognosis Among Patients With Type-A Aortic Dissection.

Background This study compared left ventricular (LV) characteristics between patients with type-A and type-B aortic dissection (AD) and evaluated the ability of LV remodeling phenotypes (hypertrophy, concentricity, or geometric patterns) to predict mortality in both AD types. Methods and Results We evaluated 236 patients with type A and 120 patients with type B who had echocardiograms within 60 days before or after AD diagnosis (median [25th, 75th percentiles] time difference between echocardiogram and AD diagnosis=1 [0, 6] days) from 3 centers. Patients were stratified according to LV phenotypes, and early (90-day) and late (1-year) mortality after AD diagnosis were assessed. In adjusted logistic regression analysis, patients with type A had higher and lower odds of concentric and eccentric hypertrophy (odds ratio [OR], 2.56; 95% CI, 1.50-4.36; P<0.001; and OR, 0.55; 95% CI, 0.31-0.97; P=0.039, respectively) than those with type B. Results of multivariable Cox-regression analysis showed that LV remodeling phenotypes were not related to mortality in patients with type B. By contrast, LV concentricity was associated with greater early and late mortality (hazard ratio [HR], 2.22; 95% CI, 1.24-3.96; P=0.007 and HR, 2.06; 95% CI, 1.20-3.54; P=0.009, respectively) in type A. In further analysis considering normal LV geometry as reference, LV concentric remodeling and concentric hypertrophy were associated with early mortality (HR, 7.78; 95% CI, 2.35-25.78; P<0.001 and HR, 4.38; 95% CI, 1.47-13.11; P=0.008, respectively), whereas concentric remodeling was associated with late mortality (HR, 5.40; 95% CI, 1.91-15.26; P<0.001) among patients with type A. Assessment of LV geometric patterns and concentricity provided incremental prognostic value in predicting early and late mortality beyond clinical variables in patients with type A based on net reclassification improvement and integrated discrimination improvement. Conclusions LV geometric patterns derived from LV concentricity were associated with greater mortality among patients with type A and may be markers of adverse prognosis in this population.

Impact of Hypertension History and Blood Pressure at Presentation on Cardiac Remodeling and Mortality in Aortic Dissection.

OBJECTIVE: This study compared clinical, echocardiographic, and prognostic characteristics among patients with aortic dissection (AD) with (HypHist) and without (No-HypHist) hypertension history and evaluated the association of blood pressure (BP) at presentation with 1-year mortality, left ventricular (LV) remodeling and renal dysfunction. METHODS: We investigated clinical and echocardiographic characteristics and 1-year mortality among 367 patients with AD (81% HypHist, 66% Type-A) from three Brazilian centers. RESULTS: Patients with No-HypHist were more likely to have Marfan syndrome, bicuspid aortic valve, to undergo surgical therapy, were less likely to have LV hypertrophy and concentricity, and had similar mortality compared with HypHist patients. Adjusted restricted cubic spline analysis showed that systolic BP (SBP) and diastolic BP (DBP) at presentation had a J-curve association with mortality among patients with No-HypHist, but did not associate with death among patients with HypHist (p for interaction = 0.001 for SBP and = 0.022 for DBP). Conversely, the association between SBP at presentation and mortality was influenced by previous use of antihypertensive medications in the HypHist group (p for interaction = 0.002). Results of multivariable logistic regression analysis comprising the whole sample showed direct associations of SBP and DBP at presentation with LV hypertrophy (p = 0.009) and LV concentricity (p = 0.015), respectively, and an inverse association between pulse pressure at presentation and estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 (p = 0.008). CONCLUSION: Combined information on BP at presentation, previous diagnosis of hypertension, and use of antihypertensive medications might be useful to predict mortality risk and to estimate extra-aortic end-organ damage among patients with AD.

Increase in dNTP pool size during the DNA damage response plays a key role in spontaneous and induced-mutagenesis in Escherichia coli.

Exposure of Escherichia coli to UV light increases expression of NrdAB, the major ribonucleotide reductase leading to a moderate increase in dNTP levels. The role of elevated dNTP levels during translesion synthesis (TLS) across specific replication-blocking lesions was investigated. Here we show that although the specialized DNA polymerase PolV is necessary for replication across UV-lesions, such as cyclobutane pyrimidine dimers or pyrimidine(6-4)pyrimidone photoproduct, Pol V per se is not sufficient. Indeed, efficient TLS additionally requires elevated dNTP levels. Similarly, for the bypass of an N-2-acetylaminofluorene-guanine adduct that requires Pol II instead of PolV, efficient TLS is only observed under conditions of high dNTP levels. We suggest that increased dNTP levels transiently modify the activity balance of Pol III (i.e., increasing the polymerase and reducing the proofreading functions). Indeed, we show that the stimulation of TLS by elevated dNTP levels can be mimicked by genetic inactivation of the proofreading function (mutD5 allele). We also show that spontaneous mutagenesis increases proportionally to dNTP pool levels, thus defining a unique spontaneous mutator phenotype. The so-called "dNTP mutator" phenotype does not depend upon any of the specialized DNA polymerases, and is thus likely to reflect an increase in Pol III's own replication errors because of the modified activity balance of Pol III. As up-regulation of the dNTP pool size represents a common physiological response to DNA damage, the present model is likely to represent a general and unique paradigm for TLS pathways in many organisms.

Estratégias de enfrentamento e avaliação de stress em adolescentes atletas

O presente estudo teve por objetivos: a) descrever estratégias de enfrentamento (coping) utilizados por adolescentes atletas participantes de competições; b) descrever e relacionar os tipos de enfrentamento desses adolescentes segundo a prática esportiva individual e coletiva c) identificar o nível de stress desses atletas; d) relacionar as estratégias de enfrentamento com grau de stress. Selecionou-se por critério aleatório e conveniência, uma amostra de 141 atletas-adolescentes, estudantes, com idades entre 15 e 18 anos, sendo 66 meninas e 75 meninos. Estes eram estudantes do ensino médio de escolas privadas da região da Grande São Paulo, atletas que treinavam e participavam de competições esportivas de âmbito escolar e alto rendimento em categorias de base. Utilizou-se uma escala auto-aplicável de enfrentamento (coping) para adolescentes, composta por 80 itens, e um inventário de stress composto por 44 itens. Os resultados indicaram qure na amostra geral houve maior emprego da estratégia de aproximação; porém, numa separação em sub-grupos foram verificadas diferenças quanto ao gênero, pois as houve predomínio da estratégia de evitação entre as meninas. Quanto ao tipo de esporte coletivo e individual não se encontraram diferenças significativas, mestre entre meninos e meninas. O grau de stress esteve em média normal na amostra geral, porém quando se separa meninos e meninas, observou-se maior presença de sintomas entre os meninos e entre atletas praticantes da modalidade individual - xadrez. Também não foram encontradas diferenças significativas na correlação entre enfrentamento e stress. Entendeu-se que esse tipo de investigação pode auxiliar na compreensão desses jovens praticantes de esporte, bem como se levanta a hipótese de que a prática esportiva escolar, ainda que em nível de competição, pode ter uma influência positiva, tanto no enfrentamento quanto na administração do stress entre esses jovens

Fungal Rtt109 histone acetyltransferase is an unexpected structural homolog of metazoan p300/CBP.

Rtt109, also known as KAT11, is a recently characterized fungal-specific histone acetyltransferase (HAT) that modifies histone H3 lysine 56 (H3K56) to promote genome stability. Rtt109 does not show sequence conservation with other known HATs and depends on association with either of two histone chaperones, Asf1 or Vps75, for HAT activity. Here we report the X-ray crystal structure of an Rtt109-acetyl coenzyme A complex and carry out structure-based mutagenesis, combined with in vitro biochemical studies of the Rtt109-Vps75 complex and studies of Rtt109 function in vivo. The Rtt109 structure reveals noteworthy homology to the metazoan p300/CBP HAT domain but exhibits functional divergence, including atypical catalytic properties and mode of cofactor regulation. The structure reveals a buried autoacetylated lysine residue that we show is also acetylated in the Rtt109 protein purified from yeast cells. Implications for understanding histone substrate and chaperone binding by Rtt109 are discussed.

Clothing up DNA for all seasons: Histone chaperones and nucleosome assembly pathways.

In eukaryotes, the packaging of DNA into chromatin is essential for cell viability. Several important DNA metabolic events require the transient disruption of chromatin structure, but cells have evolved a number of elaborate pathways that operate throughout the cell cycle to prevent the deleterious effects of chromatin erosion. In this review, we describe a number of distinct nucleosome assembly pathways that function during DNA replication, transcription, cellular senescence and early embryogenesis. In addition, we illustrate some of the physiological consequences associated with defects in nucleosome assembly pathways.

Rational design of an estrogen receptor mutant with altered DNA-binding specificity.

Although artificial C2-H2 zinc fingers can be designed to recognize specific DNA sequences, it remains unclear to which extent nuclear receptor C4 zinc fingers can be tailored to bind novel DNA elements. Steroid receptors bind as dimers to palindromic response elements differing in the two central base pairs of repeated motifs. Predictions based on one amino acid-one base-pair relationships may not apply to estrogen receptors (ERs), which recognize the two central base pairs of estrogen response elements (EREs) via two charged amino acids, each contacting two bases on opposite DNA strands. Mutagenesis of these residues, E203 and K210 in ERalpha, indicated that both contribute to ERE binding. Removal of the electric charge and steric constraints associated with K210 was required for full loss of parental DNA-binding specificity and recognition of novel sequences by E203 mutants. Although some of the new binding profiles did not match predictions, the double mutation E203R-K210A generated as predicted a mutant ER that was transcriptionally active on palindromes of PuGCTCA motifs, but not on consensus EREs. This study demonstrates the feasibility of designing C4 zinc finger mutants with novel DNA-binding specificity, but also uncovers limitations of this approach.

Chromatin challenges during DNA replication and repair.

Inheritance and maintenance of the DNA sequence and its organization into chromatin are central for eukaryotic life. To orchestrate DNA-replication and -repair processes in the context of chromatin is a challenge, both in terms of accessibility and maintenance of chromatin organization. To meet the challenge of maintenance, cells have evolved efficient nucleosome-assembly pathways and chromatin-maturation mechanisms that reproduce chromatin organization in the wake of DNA replication and repair. The aim of this Review is to describe how these pathways operate and to highlight how the epigenetic landscape may be stably maintained even in the face of dramatic changes in chromatin structure.

Tamoxifen and raloxifene differ in their functional interactions with aspartate 351 of estrogen receptor alpha.

The bulky side chains of antiestrogens hinder folding of the ligand binding domain (LBD) of estrogen receptors (ERs) into a transcriptionally active conformation. The presence of a tertiary amine in the side chain of raloxifene, which interacts with a negatively charged residue in helix H3 of the ER LBD [Asp351 in human (h)ERalpha], is important for antiestrogenicity in animal and cellular models. To better understand the molecular basis of the differential activity of tamoxifen and raloxifene, we have examined the influence of tertiary amine substituents and of mutations at position 351 in hERalpha on the activity profiles of tamoxifen derivatives. Results obtained in several cellular model systems suggest that the degree of antagonist activity of tamoxifen derivatives does not strictly correlate with the basicity of the side chain but depends on an optimal spatial relationship between the tertiary amine of these antiestrogens and the negative charge at position 351. Although altering the position of the negative charge at residue 351 (mutation D351E) had little effect on transcriptional activity in the presence of tamoxifen, it drastically increased the partial agonist activity of a tamoxifen derivative with improved antagonist activity as well as that of raloxifene. Our results suggest that contrary to raloxifene, tamoxifen and most of its derivatives do not interact with Asp351 in an optimal manner, although this can be improved by modifying tertiary amine substituents.

Opposite effects of histone deacetylase inhibitors on glucocorticoid and estrogen signaling in human endometrial Ishikawa cells.

Histone deacetylase inhibitors (HDACi), which have emerged as a new class of anticancer agents, act by modulating expression of genes controlling apoptosis or cell proliferation. Here, we compared the effect of HDACi on transcriptional activation by estrogen or glucocorticoid receptors (ER and GR, respectively), two members of the steroid receptor family with cell growth regulatory properties. Like other transcription factors, steroid receptors modulate histone acetylation on target promoters. Using episomal reporter vectors containing minimal promoters to avoid promoter-specific effects, we observed that long-term (24-h) incubation with HDACi strongly stimulated GR-dependent but markedly repressed ER-dependent signaling in ER+/GR+ human endometrial carcinoma Ishikawa cells. These effects were reproduced on endogenous target genes and required incubation periods with HDACi substantially longer than necessary to increase global histone acetylation. Repression of estrogen signaling was due to direct inhibition of transcription from multiple ERalpha promoters and correlated with decreased histone acetylation of these promoters. In contrast, the strong HDACi stimulation of GR-dependent gene regulation was not accounted for by increased GR expression, but it was mimicked by overexpression of the histone acetyltransferase complex component transcriptional intermediary factor 2. Together, our results demonstrate striking and opposite effects of HDACi on ER and GR signaling that involve regulatory events independent of histone hyperacetylation on receptor target promoters.

Diversity in the mechanisms of gene regulation by estrogen receptors.

The sequencing of the human genome has opened the way for using bioinformatics to identify sets of genes controlled by specific regulatory signals. Here, we review the unexpected diversity of DNA response elements mediating transcriptional regulation by estrogen receptors (ERs), which control the broad physiological effects of estrogens. Consensus palindromic estrogen response elements are found in only a few known estrogen target genes, whereas most responsive genes contain only low-affinity half palindromes, which may also control regulation by other nuclear receptors. ERs can also regulate gene expression in the absence of direct interaction with DNA, via protein-protein interactions with other transcription factors or by modulating the activity of upstream signaling components, thereby significantly expanding the repertoire of estrogen-responsive genes. These diverse mechanisms of action must be taken into account in screening for potential estrogen-responsive sequences in the genome or in regulatory regions of target genes identified by expression profiling.

As células caliciformes linguais de alguns peixes brasileiros (Leporinus Octofasciatus, Pimelodus Maculatus e Hoplias Malabaricu): estudo morfológico e histoquímico / The globet cells of tongue of some brazilian fishes (Leporinus Octofascinatus, Pimelodus Maculatus and Hoplias Malabaricu)

Os autores estudaram morfológica e histoquimicamente as células caliciformes linguais de alguns peixes brasileiros. Baseados nos resultados, os autores concluíram: 1) A Piaba (Leporinus Ocotofasciatus) apresenta três tipos de células caliciformes, I, II e III e, no produto de secreçäo desses três tipos foram observadas somente nas células do tipo I. Radicais proteicos do tipo alfa-amino e cistina foram observados nas células do tipo I, enquanto nas células do tipo III foi observado somente radical alfa-amino; 2) No produto de secreçäo das células caliciformes do Mandi Amarelo (Pimelodus Maculatus) detectaram-se mucosubstâncias ácidas e neutras; 3) Na língua da traíra (Hoplias Malabaricus) foram observados dois tipos de células caliciformes, a saber: I e III. No produto de secreçäo dessas células foram detectadas mucosubstâncias neutras e ácidas

A glândula de Harder de Cuniculus Paca (Caviidae, Rodentia), estudo histológico e histoquímico / The Harderian gland of Cuniculus Paca (Caviidae, Rodentia). A histological and histochemical study

Os autores estudaram com métodos histoquímicos, a natureza do material elaborado pela glândula de arder de uniculus paca. Com base nos resultados obtidos, foi possível concluir que o produto de secreçäo desta glândula é constituído de muco-substâncias neutras e ácidas, e radicais proteicos alfa-amino, arginina e cistina

Estudo morfológico e histoquímico das glândulas salivares paratinas do Coendu Villosus (Rodentia, Mammalia) / Morphological and histochemical study of the salivary palatine glands of Coendu Villosus (Rodentia, Mammalia)

Os autores estudaram morfológica e histoquimicamente, a natureza do material elaborado pelas glândulas salivares palatinas do Coendu Villosus. Com base nos resultados obtidos foi possível concluir que: o produto de secreção das glândulas salivares palatinas contém uma sulfosialomucina, fato que permite classificar estas glândulas como sendo do tipo mucoso

Estudo histoquímico das glândulas salivares linguais posteriores do Coendu Villosus (Mammalia, Rodentia) / Histochemical study of the posterior lingual salivary glands of Coendu Villosus (Mammalia, Rodentia)

Os autores estudaram com métodos histoquímicos, a natureza do material elaborado pelas glândulas linguais posteriores de Coendu Villosus. Com base nos resultados obtidos, foi possível concluir que: 1) o produto de secreção das glândulas de Weber contém uma sulfosialomucina, fato que permite classificar essas glândulas como sendo do tipo mucoso; 2) o produto de secreção das glândulas de Von Ebner contém uma glico-proteína, tipo sero-mucoso

Efeito de um modulador da resposta imune (levamisole) na evolução da inflamação gengival: avaliação clínica / Efect of a modulator of the imune response (levamisole) on the evolution of the gingival inflammation: clinical evaluation

Os autores estudaram a possibilidade de se alterar a evolução da doença gengival inflamatória num grupo de pacientes jovens, do sexo masculino, de idade variável entre 11 e 15 anos, através de um agente modulador da resposta imune, Levamisole, durante 6 semanas consecutivas. Foi possível concluir que: 1) Levamisole provocou uma diferença significativa no índice de placa dos pacientes tratados; 2) Indice gengival dos pacientes tratados aumentou, consideravelmente do 21º ao 42º dia do experimento