Incubation of human articular chondrocytes with interleukin 1 beta results in the time-dependent expression of nitric oxide (NO) synthase. We report here the isolation of a cDNA clone which encodes a ...protein of 1153 amino acids with a molecular mass of 131,213 Da and a calculated isoelectric point of 7.9. CHO cells transfected with a plasmid harboring this cDNA clone expressed NO synthase activity that was inhibited by some L-arginine analogues. The deduced amino acid sequence of the human chondrocyte inducible NO synthase shows 51% identity and 68% similarity with the endothelial NO synthase and 54% identity and 70% similarity with the neuronal NO synthase. The similarity (88%) between the human chondrocyte NO synthase cDNA sequence and that reported for the murine macrophage suggests that the inducible class of enzyme is conserved between different cell types and across species.
Abstract Background Major depressive disorder (MDD) is a disabling mood disorder and, despite a known heritable component, a large meta-analysis of GWAS revealed no replicable genetic risk variants. ...Given prior evidence of heterogeneity by age-at-onset (AAO) in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by AAO. Method Discovery case-control GWASs were performed where cases were stratified using increasing/decreasing AAO-cutoffs; significant SNPs were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 controls for sub-setting. Polygenic score analysis was used to examine if differences in shared genetic risk exists between earlier and adult onset MDD with commonly co-morbid disorders of schizophrenia, bipolar disorder, Alzheimer’s disease, and coronary artery disease. Results We identify one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, OR=1.16, 95%CI=1.11-1.21, p=5.2x10-11 ). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset. Conclusions We demonstrate that using additional phenotype data previously collected by genetic studies to tackle phenotypic heterogeneity in MDD can successfully lead to the discovery of genetic risk factor despite reduced sample size. Furthermore, our results suggest that the genetic susceptibility to MDD differs between adult- and earlier-onset MDD, with earlier-onset cases having a greater genetic overlap with schizophrenia and bipolar disorder.
Rice was chosen as a model organism for genome sequencing because of its economic importance, small genome size, and syntenic relationship with other cereal species. We have constructed a bacterial ...artificial chromosome finger-print-based physical map of the rice genome to facilitate the whole-genome sequencing of rice. Most of the rice genome (∼90.6%) was anchored genetically by overgo hybridization, DNA gel blot hybridization, and in silico anchoring. Genome sequencing data also were integrated into the rice physical map. Comparison of the genetic and physical maps reveals that recombination is suppressed severely in centromeric regions as well as on the short arms of chromosomes 4 and 10. This integrated high-resolution physical map of the rice genome will greatly facilitate whole-genome sequencing by helping to identify a minimum tiling path of clones to sequence. Furthermore, the physical map will aid map-based cloning of agronomically important genes and will provide an important tool for the comparative analysis of grass genomes.
Abstract Background Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC‐specific survival (BCSS) compared to ...non‐carriers. Aim To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Methods Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow‐up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi‐state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. Results There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy HR (95% CI): 0.66 (0.55–0.78). No association was observed with radiotherapy. Results from the multi‐state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non‐carriers also after accounting for CBC occurrence HR (95% CI): 1.30 (1.09–1.56). Conclusion Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.
A survey of attitudes to mental illness was conducted in a quota sample of about 2000 subjects in Malvern and Bromsgrove. Factor analysis showed three main components - benevolence, authoritarianism, ...and fear of the mentally ill. Residents of Bromsgrove, which is served by a traditional mental hospital, were slightly more tolerant than those living in Malvern, which has a community-based service, and has seen the closure of two mental hospitals in its vicinity during the last 10 years. The main demographic determinants of tolerance are age, education, occupation, and acquaintance with the mentally ill.
The Electronic Medical Records and Genomics (eMERGE) network is a network of medical centers with electronic medical records linked to existing biorepository samples for genomic discovery and genomic ...medicine research. The network sought to unify the genetic results from 78 Illumina and Affymetrix genotype array batches from 12 contributing medical centers for joint association analysis of 83,717 human participants. In this report, we describe the imputation of eMERGE results and methods to create the unified imputed merged set of genome‐wide variant genotype data. We imputed the data using the Michigan Imputation Server, which provides a missing single‐nucleotide variant genotype imputation service using the minimac3 imputation algorithm with the Haplotype Reference Consortium genotype reference set. We describe the quality control and filtering steps used in the generation of this data set and suggest generalizable quality thresholds for imputation and phenotype association studies. To test the merged imputed genotype set, we replicated a previously reported chromosome 6 HLA‐B herpes zoster (shingles) association and discovered a novel zoster‐associated loci in an epigenetic binding site near the terminus of chromosome 3 (3p29).
The purpose of this study was to determine the effect of left atrial circumferential ablation on the size of the left atrium and pulmonary veins (PVs).
The long-term effects of left atrial ...circumferential ablation on left atrial and PV size and anatomy have not been analyzed in quantitative fashion.
PV and left atrial sizes were analyzed in 41 consecutive patients (mean age 54 +/- 12 years) with paroxysmal (n = 25) or chronic (n = 16) atrial fibrillation. Computed tomography of the chest with three-dimensional reconstruction was performed before and 4 +/- 2 months after left atrial circumferential ablation. Left atrial circumferential ablation was performed to encircle the PVs 1 to 2 cm from the ostia, using a power output of 70 W. Additional ablation lines were created in the posterior left atrium and mitral isthmus. Radiofrequency energy also was delivered within the circles and at the PV ostia in 51% of patients at a reduced power output of 35 W.
At 6 months, 36 patients (88%) were in sinus rhythm without antiarrhythmic drug therapy, including 3 patients (7%) who developed persistent left atrial flutter and underwent subsequent successful ablation of atrial flutter. There was a 15 +/- 16% decrease in left atrial volume (P < .01) and 10 +/- 35% decrease in PV ostial area (P < .01), without focal narrowing, in patients with a successful outcome. Focal PV stenosis did not occur in any of the 41 patients.
Maintenance of sinus rhythm after left atrial circumferential ablation is associated with reduced left atrial and PV ostial size. Left atrial circumferential ablation for atrial fibrillation does not cause PV stenosis.
Optical variability occurs in the near‐surface and upper ocean on very short time and space scales (e.g., milliseconds and millimeters and less) as well as greater scales. This variability is caused ...by solar, meteorological, and other physical forcing as well as biological and chemical processes that affect optical properties and their distributions, which in turn control the propagation of light across the air‐sea interface and within the upper ocean. Recent developments in several technologies and modeling capabilities have enabled the investigation of a variety of fundamental and applied problems related to upper ocean physics, chemistry, and light propagation and utilization in the dynamic near‐surface ocean. The purpose here is to provide background for and an introduction to a collection of papers devoted to new technologies and observational results as well as model simulations, which are facilitating new insights into optical variability and light propagation in the ocean as they are affected by changing atmospheric and oceanic conditions.
Key Points
Optical variability ocean on very short time and space scales
Factors affecting optical properties and propagation of light in the ocean
New research and increased understanding of light propagation at small scale
Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686).
To further investigate the rs865686-breast cancer association, we conducted a ...replication study within the Breast Cancer Association Consortium, which comprises 37 case-control studies (48,394 cases, 50,836 controls).
This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10(-29) among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls 0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (P(het)) = 1.3 × 10(-143), but no evidence of ethnic differences in per allele OR (P(het) = 0.43). rs865686 was associated with estrogen receptor-positive (ER(+)) disease (per G-allele OR, 0.89; 95% CI, 0.86-0.91; P = 3.13 × 10(-22)) but less strongly, if at all, with ER-negative (ER(-)) disease (OR, 0.98; 95% CI, 0.94-1.02; P = 0.26; P(het) = 1.16 × 10(-6)), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER(+) tumors.
This study is the first to show that rs865686 is a susceptibility marker for ER(+) breast cancer.
The findings further support the view that genetic susceptibility varies according to tumor subtype.
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