Major depressive disorder (MDD), one of the most frequently encountered forms of mental illness and a leading cause of disability worldwide1, poses a major challenge to genetic analysis. To date no robustly replicated genetic loci have been identified 2, despite analysis of more than 9,000 cases3. Using low coverage genome sequence of 5,303 Chinese women with recurrent MDD selected to reduce phenotypic heterogeneity, and 5,337 controls screened to exclude MDD, we identified and replicated two genome-wide significant loci contributing to risk of MDD on chromosome 10: one near the SIRT1 gene (P-value = 2.53×10−10) the other in an intron of the LHPP gene (P = 6.45×10−12). Analysis of 4,509 cases with a severe subtype of MDD, melancholia, yielded an increased genetic signal at the SIRT1 locus. We attribute our success to the recruitment of relatively homogeneous cases with severe illness.

HPLC with electrochemical array detection (HPLC-ECD) was used to quantify 3,3Ј-dityrosine (diTyr) and 3-nitrotyrosine (3-NO 2 -Tyr) in four regions of the human brain that are differentially affected in Alzheimer's disease (AD). DiTyr and 3-NO 2 -Tyr levels were elevated consistently in the hippocampus and neocortical regions of the AD brain and in ventricular cerebrospinal fluid (VF), reaching quantities five-to eightfold greater than mean concentrations in brain and VF of cognitively normal subjects. Uric acid, a proposed peroxynitrite scavenger, was decreased globally in the AD brain and VF. The results suggest that AD pathogenesis may involve the activation of oxidant-producing inflammatory enzyme systems, including nitric oxide synthase.Key words: HPLC; nitrotyrosine; dityrosine; Alzheimer's disease; protein oxidation; inflammation The Alzheimer's disease (AD) brain exhibits region-specific patterns of amyloid plaque deposition, neurofibrillary tangle (NFT) accumulation, and neuron death. The limbic system and association areas of the neocortex show the most pronounced histopathological alterations in AD, whereas cortical somatosensory and cerebellar neurons are relatively spared (Pearson et al., 1985;Henderson and Finch, 1989;Braak and Braak, 1994). Recent models of AD attempt to link disease progression with an inflammatory component combined with increased oxidative stress (Rogers et al., 1996). C lassical hallmarks of inflammation such as edema and neutrophil infiltration are not acknowledged characteristics of the AD brain, although numerous correlates of inflammation are present. Acute-phase reactants such as C-reactive protein, major histocompatibility complex glycoproteins, complement, monocyte chemoattractants, interleukin-1, and interleukin-6 are elevated in AD brain in spatial association with neuritic plaques (Griffin et al., 1989McGeer et al., 1989;Bauer et al., 1991;Strauss et al., 1992;C arpenter et al., 1993; Wood et al., 1993;Iwamoto et al., 1994;Mrak et al., 1995;Pereira et al., 1996;Rogers et al., 1996;Sheng et al., 1996). Reactive microglia, f unctionally similar to monocytes, are increased in the AD brain and concentrate near senile plaques (McGeer et al., 1987;Haga et al., 1989;Itagaki et al., 1989; Carpenter et al., 1993;MacKenzie et al., 1995).Enhanced oxidative stress in the AD brain is manifested by increases in protein carbonyl content and lipid and DNA oxidation products and by inactivation of sensitive enzymes (Oliver et al., 1987;C. Smith et al., 1991C. Smith et al., , 1992Mecocci et al., 1993;Balazs and Leon, 1994;Chen et al., 1994;Hensley et al., 1995; Lovell et al., 1995;M. Smith et al., 1996;Butterfield et al., 1997;Lyras et al., 1997;Sayre et al., 1997). Correlation between oxidative and inflammatory biomarkers has not been achieved in the AD brain, although the activation of an inflammatory response might, in large part, explain AD brain oxidation. For instance, activated microglia release superoxide (O 2 ⅐ Ϫ ) and hydrogen peroxide (H 2 O 2 ) (Colton et al., 1994), whe...

SummaryAdversity, particularly in early life, can cause illness. Clues to the responsible mechanisms may lie with the discovery of molecular signatures of stress, some of which include alterations to an individual’s somatic genome. Here, using genome sequences from 11,670 women, we observed a highly significant association between a stress-related disease, major depression, and the amount of mtDNA (p = 9.00 × 10−42, odds ratio 1.33 [95% confidence interval [CI] = 1.29–1.37]) and telomere length (p = 2.84 × 10−14, odds ratio 0.85 [95% CI = 0.81–0.89]). While both telomere length and mtDNA amount were associated with adverse life events, conditional regression analyses showed the molecular changes were contingent on the depressed state. We tested this hypothesis with experiments in mice, demonstrating that stress causes both molecular changes, which are partly reversible and can be elicited by the administration of corticosterone. Together, these results demonstrate that changes in the amount of mtDNA and telomere length are consequences of stress and entering a depressed state. These findings identify increased amounts of mtDNA as a molecular marker of MD and have important implications for understanding how stress causes the disease.

Removal of choline from the diet results in accumulation of triglycerides in the liver, and chronic dietary deficiency produces a non-genotoxic model of hepatocellular carcinoma. An early event in choline deficiency is the appearance of oxidized lipid, DNA and protein, suggesting that increased oxidative stress may facilitate neoplasia in the choline deficient liver. In this study, we find that mitochondria isolated from rats fed a choline-deficient, L-amino acid defined diet (CDAA) demonstrate impaired respiratory function, particularly in regard to complex I-linked (NADH-dependent) respiration. This impairment in mitochondrial electron transport occurs coincidentally with alterations in phosphatidylcholine metabolism as indicated by an increased ratio of long-chain to short-chain mitochondrial phosphatidylcholine. Moreover, hydrogen peroxide (H(2)O(2)) generation is significantly increased in mitochondria isolated from CDAA rats compared with mitochondrial from normal rats, and the NADH-specific yield of H(2)O(2) is increased by at least 2.5-fold. These findings suggest an explanation for the rapid onset of oxidative stress and energy compromise in the choline deficiency model of hepatocellular carcinoma and indicate that dietary choline withdrawal may be a useful paradigm for the study of mitochondrial pathophysiology in carcinogenesis.

Lung cancer is a malignancy with high morbidity and mortality worldwide. More evidences indicated that gut microbiome plays an important role in the carcinogenesis and progression of cancers by metabolism, inflammation and immune response. However, the study about the characterizations of gut microbiome in lung cancer is limited. In this study, the fecal samples were collected from 16 healthy individuals and 30 lung cancer patients who were divided into 3 groups based on different tumor biomarkers (cytokeratin 19 fragment, neuron specific enolase and carcinoembryonic antigen, respectively) and were analyzed using 16S rRNA gene amplicon sequencing. Each lung cancer group has characterized gut microbial community and presents an elimination, low-density, and loss of bacterial diversity microbial ecosystem compared to that of the healthy control. The microbiome structures in family and genera levels are more complex and significantly varied from each group presenting more different and special pathogen microbiome such as Enterobacteriaceae, Streptococcus, Prevotella, etc and fewer probiotic genera including Blautia, Coprococcus, Bifidobacterium and Lachnospiraceae. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and COG annotation demonstrated decreased abundance of some dominant metabolism-related pathways in the lung cancer. This study explores for the first time the features of gut microbiome in lung cancer patients and may provide new insight into the pathogenesis of lung cancer system, with the implication that gut microbiota may serve as a microbial marker and contribute to the derived metabolites, development and differentiation in lung cancer system.