Identification of proteomic signatures associated with depression and psychotic depression in post-mortem brains from major depression patients

Major depressive disorder (MDD) is a leading cause of disability worldwide and results tragically in the loss of almost one million lives in Western societies every year. This is due to poor understanding of the disease pathophysiology and lack of empirical medical tests for accurate diagnosis or for guiding antidepressant treatment strategies. Here, we have used shotgun proteomics in the analysis of post-mortem dorsolateral prefrontal cortex brain tissue from 24 MDD patients and 12 matched controls. Brain proteomes were pre-fractionated by gel electrophoresis and further analyzed by shotgun data-independent label-free liquid chromatography-mass spectrometry. This led to identification of distinct proteome fingerprints between MDD and control subjects. Some of these differences were validated by Western blot or selected reaction monitoring mass spectrometry. This included proteins associated with energy metabolism and synaptic function and we also found changes in the histidine triad nucleotide-binding protein 1 (HINT1), which has been implicated recently in regulation of mood and behavior. We also found differential proteome profiles in MDD with (n=11) and without (n=12) psychosis. Interestingly, the psychosis fingerprint showed a marked overlap to changes seen in the brain proteome of schizophrenia patients. These findings suggest that it may be possible to contribute to the disease understanding by distinguishing different subtypes of MDD based on distinct brain proteomic profiles

Skeletal muscle transcriptional coactivator PGC-1alpha mediates mitochondrial, but not metabolic, changes during calorie restriction

Calorie restriction (CR) is a dietary intervention that extends lifespan and healthspan in a variety of organisms. CR improves mitochondrial energy production, fuel oxidation, and reactive oxygen species (ROS) scavenging in skeletal muscle and other tissues, and these processes are thought to be critical to the benefits of CR. PGC-1alpha is a transcriptional coactivator that regulates mitochondrial function and is induced by CR. Consequently, many of the mitochondrial and metabolic benefits of CR are attributed to increased PGC-1alpha activity. To test this model, we examined the metabolic and mitochondrial response to CR in mice lacking skeletal muscle PGC-1alpha (MKO). Surprisingly, MKO mice demonstrated a normal improvement in glucose homeostasis in response to CR, indicating that skeletal muscle PGC-1alpha is dispensable for the whole-body benefits of CR. In contrast, gene expression profiling and electron microscopy (EM) demonstrated that PGC-1alpha is required for the full CR-induced increases in mitochondrial gene expression and mitochondrial density in skeletal muscle. These results demonstrate that PGC-1alpha is a major regulator of the mitochondrial response to CR in skeletal muscle, but surprisingly show that neither PGC-1alpha nor mitochondrial biogenesis in skeletal muscle are required for the whole-body metabolic benefits of CR

Stability of the monoclinic phase in the ferroelectric perovskite PbZr(1-x)TixO3

Recent structural studies of ferroelectric PbZr(1-x)TixO3 (PZT) with x= 0.48, have revealed a new monoclinic phase in the vicinity of the morphotropic phase boundary (MPB), previously regarded as the the boundary separating the rhombohedral and tetragonal regions of the PZT phase diagram. In the present paper, the stability region of all three phases has been established from high resolution synchrotron x-ray powder diffraction measurements on a series of highly homogeneous samples with 0.42 <=x<= 0.52. At 20K the monoclinic phase is stable in the range 0.46 <=x<= 0.51, and this range narrows as the temperature is increased. A first-order phase transition from tetragonal to rhombohedral symmetry is observed only for x= 0.45. The MPB, therefore, corresponds not to the tetragonal-rhombohedral phase boundary, but instead to the boundary between the tetragonal and monoclinic phases for 0.46 <=x<= 0.51. This result provides important insight into the close relationship between the monoclinic phase and the striking piezoelectric properties of PZT; in particular, investigations of poled samples have shown that the monoclinic distortion is the origin of the unusually high piezoelectric response of PZT.Comment: REVTeX file, 7 figures embedde

Avaliação da instabilidade genômica e prevenção de câncer

OBJECTIVES: This study aimed at verifying the damage index acquired from the environment and from an inherited condition in the leukocytes of workers occupationally exposed to Xradiation and antineoplastic drugs, patients with Down syndrome, Fanconi anemia, and controls. MATERIAL AND METHODS: Cytokinesis-block micronucleus assay (CB-MN) and single-cell-gel electrophoresis (SCGE) were employed in 22 workers potentially exposed to X-radiation and 22 controls matched for age, sex, and smoking habits from a hospital in southern Brazil. The same evaluation was employed in 12 individuals who had been occupationally exposed to antineoplastic drugs and in 14 patients with Fanconi anemia (FA), 30 with Down syndrome (DS), and 30 controls,in order to examine the sensitivity of the techniques to detect specific genome instability. RESULTS: Both CB-MN and SCGE showed increased genetic damage in the cells of exposed individuals. In individuals handling antineoplastic drugs, no statistically difference was found when using CB-MN; however, the mean value of SCGE was significantly higher in exposed individuals when compared to controls. Down syndrome presented an increase just in the SCGE technique; the frequency of micronuclei and dicentric bridges was similar to that found in controls. Both CB-MN and SCGE showed increased genetic damage in the cells of individuals with Fanconi anemia. The high frequency of micronuclei seems to be due to clastogenic events, since the frequency of dicentric bridges was also elevated. DISCUSSION: Both methods are efficient for monitoring mutagenic events in exposed populations or individuals presenting genetic instability. CB-MN represents a longer time of exposure, while SCGE detects momentary DNA damage and/or repair activity. The combination of both techniques is recommended to monitor chronically exposed populations. Changes in lifestyle may constitute an important way of preventing carcinogenesis, either in individuals presenting increased risk and in the general population.OBJETIVOS: Este estudo teve como objetivo avaliar o nível de mutagênese em indivíduos normais não expostos, em trabalhadores expostos à radiação ionizante e drogas antineoplásicas e em indivíduos portadores de doenças genéticas, comparando os níveis de mutagênese herdada com aqueles adquiridos por exposição a mutágenos. MÉTODOS: A técnica de micronúcleo em linfócitos do sangue periférico e a técnica do cometa ou eletroforese em célula única foram empregados em 22 trabalhadores potencialmente expostos à radiação X, 12 potencialmente expostos a drogas antineoplásicas, 34 controles adultos, 14 pacientes com anemia de Fanconi (AF), 30 com síndrome de Down (SD) e 30 controles infantis, do Hospital de Clínicas de Porto Alegre. RESULTADOS: As duas técnicas mostraram um aumento no dano genético em células de indivíduos expostos a radiação-X. Nos indivíduos que manuseiam drogas antineoplásicas, não foi encontrada diferença significativa com a técnica de micronúcleo; no entanto, o índice de dano avaliado pela técnica do cometa foi significativamente maior em indivíduos expostos em relação a controles. Pacientes com síndrome de Down apresentaram um aumento no índice medido pela técnica do cometa; a freqüência de micronúcleos e pontes dicêntricas foi semelhante ao valor encontrado em controles. Tanto a técnica de micronúcleo como a técnica do cometa mostraram aumento de dano genético nas células de indivíduos com anemia Fanconi. A alta freqüência de micronúcleos parece ser devida a eventos clastogênicos, uma vez que a freqüência de pontes dicêntricas também se encontrava elevada. DISCUSSÃO: As duas técnicas são eficientes na monitoração de eventos mutagênicos em populações expostas ou em indivíduos que apresentam instabilidade genética. A técnica de micronúcleo representa um tempo maior de exposição, enquanto que a técnica do cometa detecta dano momentâneo ao DNA e/ou atividade de reparo. A combinação das duas técnicas é recomendada para monitorar populações cronicamente expostas. Mudanças no estilo de vida podem constituir uma forma importante de prevenir carcinogênese, tanto em indivíduos que apresentam risco aumentado como na população em geral