Genomic analysis of Xanthomonas oryzae isolates from rice grown in the United States reveals substantial divergence from known X. oryzae pathovars.

The species Xanthomonas oryzae is comprised of two designated pathovars, both of which cause economically significant diseases of rice in Asia and Africa. Although X. oryzae is not considered endemic in the United States, an X. oryzae-like bacterium was isolated from U.S. rice and southern cutgrass in the late 1980s. The U.S. strains were weakly pathogenic and genetically distinct from characterized X. oryzae pathovars. In the current study, a draft genome sequence from two U.S. Xanthomonas strains revealed that the U.S. strains form a novel clade within the X. oryzae species, distinct from all strains known to cause significant yield loss. Comparative genome analysis revealed several putative gene clusters specific to the U.S. strains and supported previous reports that the U.S. strains lack transcriptional activator-like (TAL) effectors. In addition to phylogenetic and comparative analyses, the genome sequence was used for designing robust U.S. strain-specific primers, demonstrating the usefulness of a draft genome sequence in the rapid development of diagnostic tools.

Investigating neural primacy in Major Depressive Disorder: multivariate Granger causality analysis of resting-state fMRI time-series data.

Major Depressive Disorder (MDD) has been conceptualized as a neural network-level disease. Few studies of the neural bases of depression, however, have used analytical techniques that are capable of testing network-level hypotheses of neural dysfunction in this disorder. Moreover, of those that have, fewer still have attempted to determine the directionality of influence within functionally abnormal networks of structures. We used multivariate GC analysis, a technique that estimates the extent to which preceding neural activity in one or more seed regions predicts subsequent activity in target brain regions, to analyze blood-oxygen-level-dependent (BOLD) data collected during eyes-closed rest from depressed and never-depressed persons. We found that activation in the hippocampus predicted subsequent increases in ventral anterior cingulate cortex (vACC) activity in depression, and that activity in the medial prefrontal cortex and vACC were mutually reinforcing in MDD. Hippocampal and vACC activation in depressed participants predicted subsequent decreases in dorsal cortical activity. This study shows that, on a moment-by-moment basis, there is increased excitatory activity among limbic and paralimbic structures, as well as increased inhibition in the activity of dorsal cortical structures, by limbic structures in depression; these aberrant patterns of effective connectivity implicate disturbances in the mesostriatal dopamine system in depression. These findings advance the neural theory of depression by detailing specific patterns of limbic excitation in MDD, by making explicit the primary role of limbic inhibition of dorsal cortex in the cortico-limbic relation posited to underlie depression, and by presenting an integrated neurofunctional account of altered dopamine function in this disorder.

MicroRNA-192 and -215 are upregulated in human gastric cancer in vivo and suppress ALCAM expression in vitro.

The dismal outcome of gastric cancer patients highlights the need for diagnostic biomarkers and effective therapeutic targets, such as microRNAs. We sought to discover microRNAs involved in gastric cancer, and to elucidate their downstream target mechanisms. Both cultured gastric epithelial cells (HFE145 and NCI-N87) and primary human gastric tissues (31 non-neoplastic stomach (NS) and 25 gastric carcinomas (GC)) were studied. MicroRNA microarrays and quantitative RT-PCR were applied to discover and verify differentially expressed microRNAs. in vitro cell migration and invasion, cell proliferation, cell cycle and apoptosis assays were executed to elucidate biological effects of microRNA-192 and -215. Western blotting and luciferase assays were performed to confirm direct messenger RNA targeting by microRNA-192 and -215. MicroRNA microarray analyses revealed that 25 and 20 microRNAs were upregulated and downregulated in GC vs NS, respectively. Expression levels of both microRNA-192 and -215 were significantly higher in GC than in NS (P<0.05). Luciferase assays suggested that microRNA-215 inhibits activated leukocyte cell adhesion molecule (ALCAM) expression at the posttranscriptional level. In addition, expression levels of ALCAM were significantly lower in GC than in NS. Mimics and inhibitors, respectively, of microRNA-192 or -215 exerted no effect on cell cycle or apoptosis in the immortalized normal gastric cell line HFE145 or the gastric cancer cell line NCI-N87. However, mimics of microRNA-192 or -215 significantly increased growth rates in HFE145 cells, whereas inhibitors of microRNA-192 or -215 caused significant decreases in growth rates in NCI-N87 cells. ALCAM knockdown by an ALCAM-specific siRNA significantly increased cell growth in HFE145 cells. Both transfection of mimics of microRNA-192 or -215 and ALCAM knockdown by an ALCAM-specific siRNA significantly increased the migration of HFE145 cells. In conclusion, in gastric cancer, both microRNA-192 and -215 are overexpressed in vivo and exert cell growth and migration-promoting effects in vitro, thus representing potential microRNAs with a role in cancer in the human stomach.

Amygdala volume in major depressive disorder: a meta-analysis of magnetic resonance imaging studies.

Major depressive disorder has been associated with volumetric abnormality in the amygdala. In this meta-analysis we examine results from magnetic resonance imaging volumetry studies of the amygdala in depression in order to assess both the nature of the relationship between depression and amygdala volume as well as the influence of extraexperimental factors that may account for significant variability in reported findings. We searched PubMed and ISI Web of Knowledge databases for articles published from 1985 to 2008 that used the wildcard terms 'Depress*' and 'Amygdal*' in the title, keywords or abstract. From the 13 studies that met inclusion criteria for our meta-analysis, we calculated aggregate effect size and heterogeneity estimates from amygdala volumetric data; we then used meta-regression to determine whether variability in specific extraexperimental factors accounted for variability in findings. The lack of a reliable difference in amygdala volume between depressed and never-depressed individuals was accounted for by a positive correlation between amygdala volume differences and the proportion of medicated depressed persons in study samples: whereas the aggregate effect size calculated from studies that included only medicated individuals indicated that amygdala volume was significantly increased in depressed relative to healthy persons, studies with only unmedicated depressed individuals showed a reliable decrease in amygdala volume in depression. These findings are consistent with a formulation in which an antidepressant-mediated increase in levels of brain-derived neurotrophic factor promotes neurogenesis and protects against glucocorticoid toxicity in the amygdala in medicated but not in unmedicated depression.

Hypermethylation of the nel-like 1 gene is a common and early event and is associated with poor prognosis in early-stage esophageal adenocarcinoma.

The nel-like1 (NELL1) gene maps to chromosome 11p15, which frequently undergoes loss of heterozygosity in esophageal adenocarcinoma (EAC). NELL1 promoter hypermethylation was examined by real-time methylation-specific polymerase chain reaction in 259 human esophageal tissues. Hypermethylation of this promoter showed highly discriminative receiver-operator characteristic curve profiles, clearly distinguishing esophageal squamous cell carcinoma (ESCC) and EAC from normal esophagus (NE) (P<0.001). NELL1 normalized methylation values were significantly higher in Barrett's metaplasia (BE), dysplastic Barrett's (D) and EAC than in NE (P<0.0000001). NELL1 hypermethylation frequency was zero in NE but increased early during neoplastic progression, to 41.7% in BE from patients with Barrett's alone, 52.5% in D and 47.8% in EAC. There was a significant correlation between NELL1 hypermethylation and BE segment length. Three (11.5%) of 26 ESCCs exhibited NELL1 hypermethylation. Survival correlated inversely with NELL1 hypermethylation in patients with stages I-II (P=0.0264) but not in stages III-IV (P=0.68) EAC. Treatment of KYSE220 ESCC and BIC EAC cells with 5-aza-2'-deoxycytidine reduced NELL1 methylation and increased NELL1 mRNA expression. NELL1 mRNA levels in EACs with an unmethylated NELL1 promoter were significantly higher than those in EACs with a methylated promoter (P=0.02). Promoter hypermethylation of NELL1 is a common, tissue-specific event in human EAC, occurs early during Barrett's-associated esophageal neoplastic progression, and is a potential biomarker of poor prognosis in early-stage EAC.

Transcriptional profiling suggests that Barrett's metaplasia is an early intermediate stage in esophageal adenocarcinogenesis.

To investigate the relationship between Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC), we determined gene expression profiles of discrete pathological stages of esophageal neoplasia using a sequence-verified human cDNA microarray. Fifty one RNAs, comprising 24 normal esophagi (NE), 18 BEs, and nine EACs were hybridized to cDNA microarrays. Five statistical analyses were used for the data analysis. Genes showing significantly different expression levels among the three sample groups were identified. Genes were grouped into functional categories based on the Gene Ontology Consortium. Surprisingly, the expression pattern of BE was significantly more similar to EAC than to NE, notwithstanding the known histopathologic differences between BE and EAC. The pattern of NE was clearly distinct from that of EAC. Thirty-six genes were the most differentially modulated, according to these microarray data, in BE-associated neoplastic progression. Twelve genes were significantly differentially expressed in cancer-associated BE's plus EAC (as a single combined tissue group) vs noncancer-associated BE's. These genes represent potential biomarkers to diagnose EAC at its early stages. Our results demonstrate that molecular events at the transcriptional level in BE are remarkably similar to BE's-associated adenocarcinoma of the esophagus. This finding alarmingly implies that BE is biologically closer to cancer than to normal esophagus, and that the cancer risk of BE is perhaps higher than we had imagined. These findings suggest that changes modulated at the molecular biologic level supervene earlier than histologic changes, and that BE is an early intermediate stage in the process of EAC.

Mean annual temperature and total annual precipitation trends at Canadian biosphere reserves.

This article examines instrumental climate records from a variety of stations associated with the following Biosphere Reserves across Canada: (i) Waterton Lakes, (ii) Riding Mountain, (iii) Niagara Escarpment, (iv) Long Point, and (v) Kejimkujik (Candidate Biosphere Reserve). Annual series are generated from daily temperature and precipitation values. In addition, homogeneous data are used from other stations and regional records to supplement the records from the local biosphere stations. Long term trends are identified over the period of the instrumental record. In general, data from the interval 1900 to 1998 show cooler temperatures in the 1920's, warming from the early 1940's into the early 1950's, cooling into the 1970's, and subsequent warming. At many stations, 1998 is the warmest in the instrumental record. Comparisons with the regional data sets show good agreements between the temperature series. The 20th century warming is approximately 1.0 degree C in the Riding Mountain area and 0.6 degrees C in the Long Point, Niagara Escarpment, and Waterton Lakes areas. There has been slight cooling in the Kejimkujik area over the past half century. Precipitation data show increasing trends in the Kejimkujik. Long Point, Niagara Escarpment, and Waterton Lakes areas with no long term trend in the Riding Mountain area. This work is part of the Canadian Biosphere Reserves Association (CBRA) Climate Change Initiative (CCI), designed to present climate change information to Biosphere Reserve communities to allow local organizations to understand climate change and adapt to potential impacts.

Observations on the nature, biosynthesis, secretion and significance of endogenous ouabain.

The human circulation contains four readily distinguishable biologically active inhibitors of the sodium pump that appear to be endogenous to mammals. Of these, one has been purified to homogeneity and by numerous chromatographic, mass spectral, biochemical, and physiological analyses has been shown to be a novel steroidal isomer of ouabain in which the location and orientation of two or more steroidal hydroxyl groups differ. The human endogenous "ouabain" (EO) is a high affinity reversible inhibitor of the pump with inotropic and vasopressor activity. Circulating levels of EO depend upon the adrenal cortex and metabolic events preceding and following pregnenolone formation are involved in EO biosynthesis. Within the adrenal gland, the stimulus-secretion mechanisms for EO secretion are distinct from those for aldosterone highlighting different regulation. Among Caucasians with essential hypertension, 30-45% have elevated circulating levels of EO. Sustained elevation of plasma ouabain in rats induces chronic hypertension with characteristics similar to those in patients and whose severity is determined by inherited factors and renal function. In conclusion, at least one of the mammalian counterparts to the cardiac glycosides is a novel steroidal isomer of ouabain. The isomer is secreted by the adrenal cortex, and augments cardiovascular function. The observation of this entity in the human circulation, the demonstration of its biosynthesis, and the existence of specific receptors suggest to us that EO is a novel adrenocortical hormone and may be part of a broader family of novel mammalian steroids that regulate the sodium pump and other processes.