Oncogenic Gain of Function in Glioblastoma Is Linked to Mutant p53 Amyloid Oligomers.

Tumor-associated p53 mutations endow cells with malignant phenotypes, including chemoresistance. Amyloid-like oligomers of mutant p53 transform this tumor suppressor into an oncogene. However, the composition and distribution of mutant p53 oligomers are unknown and the mechanism involved in the conversion is sparse. Here, we report accumulation of a p53 mutant within amyloid-like p53 oligomers in glioblastoma-derived cells presenting a chemoresistant gain-of-function phenotype. Statistical analysis from fluorescence fluctuation spectroscopy, pressure-induced measurements, and thioflavin T kinetics demonstrates the distribution of oligomers larger than the active tetrameric form of p53 in the nuclei of living cells and the destabilization of native-drifted p53 species that become amyloid. Collectively, these results provide insights into the role of amyloid-like mutant p53 oligomers in the chemoresistance phenotype of malignant and invasive brain tumors and shed light on therapeutic options to avert cancer

Mechanisms of ring chromosome formation, ring instability and clinical consequences

<p>Abstract</p> <p>Background</p> <p>The breakpoints and mechanisms of ring chromosome formation were studied and mapped in 14 patients.</p> <p>Methods</p> <p>Several techniques were performed such as genome-wide array, MLPA (Multiplex Ligation-Dependent Probe Amplification) and FISH (Fluorescent <it>in situ </it>Hybridization).</p> <p>Results</p> <p>The ring chromosomes of patients I to XIV were determined to be, respectively: r(3)(p26.1q29), r(4)(p16.3q35.2), r(10)(p15.3q26.2), r(10)(p15.3q26.13), r(13)(p13q31.1), r(13)(p13q34), r(14)(p13q32.33), r(15)(p13q26.2), r(18)(p11.32q22.2), r(18)(p11.32q21.33), r(18)(p11.21q23), r(22)(p13q13.33), r(22)(p13q13.2), and r(22)(p13q13.2). These rings were found to have been formed by different mechanisms, such as: breaks in both chromosome arms followed by end-to-end reunion (patients IV, VIII, IX, XI, XIII and XIV); a break in one chromosome arm followed by fusion with the subtelomeric region of the other (patients I and II); a break in one chromosome arm followed by fusion with the opposite telomeric region (patients III and X); fusion of two subtelomeric regions (patient VII); and telomere-telomere fusion (patient XII). Thus, the r(14) and one r(22) can be considered complete rings, since there was no loss of relevant genetic material. Two patients (V and VI) with r(13) showed duplication along with terminal deletion of 13q, one of them proved to be inverted, a mechanism known as inv-dup-del. Ring instability was detected by ring loss and secondary aberrations in all but three patients, who presented stable ring chromosomes (II, XIII and XIV).</p> <p>Conclusions</p> <p>We concluded that the clinical phenotype of patients with ring chromosomes may be related with different factors, including gene haploinsufficiency, gene duplications and ring instability. Epigenetic factors due to the circular architecture of ring chromosomes must also be considered, since even complete ring chromosomes can result in phenotypic alterations, as observed in our patients with complete r(14) and r(22).</p

Learning auditory space: generalization and long-term effects

Background: Previous findings have shown that humans can learn to localize with altered auditory space cues. Here we analyze such learning processes and their effects up to one month on both localization accuracy and sound externalization. Subjects were trained and retested, focusing on the effects of stimulus type in learning, stimulus type in localization, stimulus position, previous experience, externalization levels, and time. Method: We trained listeners in azimuth and elevation discrimination in two experiments. Half participated in the azimuth experiment first and half in the elevation first. In each experiment, half were trained in speech sounds and half in white noise. Retests were performed at several time intervals: just after training and one hour, one day, one week and one month later. In a control condition, we tested the effect of systematic retesting over time with post-tests only after training and either one day, one week, or one month later. Results: With training all participants lowered their localization errors. This benefit was still present one month after training. Participants were more accurate in the second training phase, revealing an effect of previous experience on a different task. Training with white noise led to better results than training with speech sounds. Moreover, the training benefit generalized to untrained stimulus-position pairs. Throughout the post-tests externalization levels increased. In the control condition the long-term localization improvement was not lower without additional contact with the trained sounds, but externalization levels were lower. Conclusion: Our findings suggest that humans adapt easily to altered auditory space cues and that such adaptation spreads to untrained positions and sound types. We propose that such learning depends on all available cues, but each cue type might be learned and retrieved differently. The process of localization learning is global, not limited to stimulus-position pairs, and it differs from externalization processes.Foundation for Science and TechnologyFEDE

Quantitative effects of tobacco smoking exposure on the maternal-fetal circulation

<p>Abstract</p> <p>Background</p> <p>Despite the existence of various published studies regarding the effects of tobacco smoking on pregnancy, and especially in regards to placental blood flow and vascular resistance, some points still require clarification. In addition, the amount of damage due to tobacco smoking exposure that occurs has not been quantified by objective means. In this study, we looked for a possible association between flow resistance indices of several arteries and the levels of urinary cotinine and the concentration of carbon monoxide in the exhaled air (COex) of both smoking and non-smoking pregnant women. We also looked for a relationship between those findings and fetal growth and birth weight.</p> <p>Methods</p> <p>In a prospective design, thirty pregnant smokers and thirty-four pregnant non-smokers were studied. The volunteers signed consent forms, completed a self-applied questionnaire and were subjected to Doppler velocimetry. Tobacco smoking exposure was quantified by subject provided information and confirmed by the measurement of urinary cotinine levels and by the concentration of carbon monoxide in the exhaled air (COex). The weight of newborns was evaluated immediately after birth.</p> <p>Results</p> <p>Comparing smoking to non-smoking pregnant women, a significant increase in the resistance index was observed in the uterine arteries (P = 0.001) and umbilical artery (P = 0.001), and a decrease in the middle cerebral artery (P = 0.450). These findings were associated with progressively higher concentrations of COex and urinary cotinine. A decrease in the birth weight was also detected (P < 0.001) in association with a progressive increase in the tobacco exposure of the pregnant woman.</p> <p>Conclusions</p> <p>In pregnant women who smoke, higher arterial resistance indices and lower birth weights were observed, and these findings were associated with increasing levels of tobacco smoking exposure. The values were significantly different when compared to those found in non-smoking pregnant women. This study contributes to the findings that smoking damage during pregnancy is dose-dependent, as demonstrated by the objective methods for measuring tobacco smoking exposure.</p

Contextual and individual factors associated with dental services utilisation by Brazilian adults: A multilevel analysis

BACKGROUND: Inequalities in the utilisation of dental services in Brazil are remarkable. The aim of this study was to evaluate the association of contextual and individual factors with the utilisation of dental services by Brazilian adults using the Andersen's behavioural model. METHODS: Individual-level data from 27,017 adults residents in the State capitals who were interviewed in the 2013 Brazilian National Health Survey were pooled with contextual city-level data. The outcomes were non-utilisation of dental services and last dental visit over 12 months ago. Individual predisposing variables were age, sex, race/skin colour, schooling and social network. Individual enabling variables included income, health insurance and registration in primary health care. Individual need variables were self-perceived dental health and self-reported missing teeth. Multilevel logistic regression models were performed to estimate odds ratio (OR) and 95% confidence intervals (95% CIs) of the association of contextual and individual predisposing, enabling and need-related variables with dental services outcomes. RESULTS: Predisposing (OR = 0.89; 95% CI 0.81-0.97) and enabling (OR = 0.90; 95% CI 0.85-0.96) contextual factors were associated with non-utilisation of dental services. Individual predisposing (sex, race/skin colour, schooling), enabling (income, health insurance) and need (self-perceived oral health, missing teeth) were associated with non-utilisation of dental services and last dental visit over 12 months ago. The latter was also associated with other individual predisposing (age, social network) and need (eating difficulties due to oral problems) characteristics. CONCLUSIONS: Individual and contextual determinants influenced dental services utilisation in Brazilian adults. These factors should be on the policy agenda and considered in the organisation of health services aiming to reduce oral health inequalities related to access and utilisation of dental services

Evapotranspiração e coeficientes de cultivo da beterraba orgânica sob cobertura morta de leguminosa e gramínea.

As práticas agrícolas que maximizam a produtividade e o uso da água são de vital importância para a agricultura. Assim, foram testados três tipos de manejo do solo com objetivo de determinar a evapotranspiração (ETc) e os coeficientes de cultivo (kc) da beterraba. Os tipos de manejo foram a utilização de coberturas mortas vegetais, denominadas capim cameroon (Pennisetum purpureum), gliricídia (Gliricidia sepium) e solo sem cobertura morta em área experimental do SIPA (Sistema Integrado de Produção Orgânica) localizado em Seropédica, Brasil. A lâmina de irrigação foi estimada com base no balanço de água no solo, cujo monitoramento foi realizado com a técnica da TDR. As ETc acumuladas para a cultura da beterraba foram 59,41; 55,31 e 119,62 mm, respectivamente, para capim cameroon, gliricídia e solo sem cobertura morta. A evapotranspiração de referência (ETo) foi obtida por meio do modelo de Penamn-Monteith. Os valores médios de kc obtidos para as fases inicial, média e final de desenvolvimento foram de 0,39; 0,42 e 1,02; 0,79; 0,76 e 1,18; e 0,56; 0,61 e 0,84, respectivamente, para capim cameroon, gliricídia e solo sem cobertura morta. O uso da cobertura do solo com gramínea ou leguminosa minimizou de forma expressiva a demanda hídrica da cultura da beterraba (Beta vulgaris)

Oral Treatment with γ-Aminobutyric Acid Improves Glucose Tolerance and Insulin Sensitivity by Inhibiting Inflammation in High Fat Diet-Fed Mice

Adipocyte and β-cell dysfunction and macrophage-related chronic inflammation are critical for the development of obesity-related insulin resistance and type 2 diabetes mellitus (T2DM), which can be negatively regulated by Tregs. Our previous studies and those of others have shown that activation of γ-aminobutyric acid (GABA) receptors inhibits inflammation in mice. However, whether GABA could modulate high fat diet (HFD)-induced obesity, glucose intolerance and insulin resistance has not been explored. Here, we show that although oral treatment with GABA does not affect water and food consumption it inhibits the HFD-induced gain in body weights in C57BL/6 mice. Furthermore, oral treatment with GABA significantly reduced the concentrations of fasting blood glucose, and improved glucose tolerance and insulin sensitivity in the HFD-fed mice. More importantly, after the onset of obesity and T2DM, oral treatment with GABA inhibited the continual HFD-induced gain in body weights, reduced the concentrations of fasting blood glucose and improved glucose tolerance and insulin sensitivity in mice. In addition, oral treatment with GABA reduced the epididymal fat mass, adipocyte size, and the frequency of macrophage infiltrates in the adipose tissues of HFD-fed mice. Notably, oral treatment with GABA significantly increased the frequency of CD4+Foxp3+ Tregs in mice. Collectively, our data indicated that activation of peripheral GABA receptors inhibited the HFD-induced glucose intolerance, insulin resistance, and obesity by inhibiting obesity-related inflammation and up-regulating Treg responses in vivo. Given that GABA is safe for human consumption, activators of GABA receptors may be valuable for the prevention of obesity and intervention of T2DM in the clinic