Exome sequencing of liver fluke-associated cholangiocarcinoma

Opisthorchis viverrini-related cholangiocarcinoma (CCA), a fatal bile duct cancer, is a major public health concern in areas endemic for this parasite. We report here whole-exome sequencing of eight O. viverrini-related tumors and matched normal tissue. We identified and validated 206 somatic mutations in 187 genes using Sanger sequencing and selected 15 genes for mutation prevalence screening in an additional 46 individuals with CCA (cases). In addition to the known cancer-related genes TP53 (mutated in 44.4% of cases), KRAS (16.7%) and SMAD4 (16.7%), we identified somatic mutations in 10 newly implicated genes in 14.8-3.7% of cases. These included inactivating mutations in MLL3 (in 14.8% of cases), ROBO2 (9.3%), RNF43 (9.3%) and PEG3 (5.6%), and activating mutations in the GNAS oncogene (9.3%). These genes have functions that can be broadly grouped into three biological classes: (i) deactivation of histone modifiers, (ii) activation of G protein signaling and (iii) loss of genome stability. This study provides insight into the mutational landscape contributing to O. viverrini-related CCA.     

Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome

IMAGe syndrome (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies) is an undergrowth developmental disorder with life-threatening consequences. An identity-by-descent analysis in a family with IMAGe syndrome identified a 17.2-Mb locus on chromosome 11p15 that segregated in the affected family members. Targeted exon array capture of the disease locus, followed by high-throughput genomic sequencing and validation by dideoxy sequencing, identified missense mutations in the imprinted gene CDKN1C (also known as P57KIP2) in two familial and four unrelated patients. A familial analysis showed an imprinted mode of inheritance in which only maternal transmission of the mutation resulted in IMAGe syndrome. CDKN1C inhibits cell-cycle progression, and we found that targeted expression of IMAGe-associated CDKN1C mutations in Drosophila caused severe eye growth defects compared to wild-type CDKN1C, suggesting a gain-of-function mechanism. All IMAGe-associated mutations clustered in the PCNA-binding domain of CDKN1C and resulted in loss of PCNA binding, distinguishing them from the mutations of CDKN1C that cause Beckwith-Wiedemann syndrome, an overgrowth syndrome.     

Temporal and spatial patterns of small mammal density and species composition on a radioactive waste disposal area: the role of edge habitat

Small mammal populations inhabiting radioactive waste disposal areas could be important vectors of contaminant redistribution, given sufficiently high numbers. Earlier studies conducted at the Subsurface Disposal Area (SDA) in southeastern Idaho found small mammal densities equaling or exceeding densities in native habitat. Our live-trapping study was conducted in 1988 and 1989 to assess the role of edge habitat (where SDA crested wheatgrass [ Agropyron cristatum ] plantings and native sagebrush habitat are separated by an earthen dike) in facilitating use of this highly modified site by small mammals. Small mammals had a significantly greater density in SDA edge habitat than in the interior. Total density of small mammals and immediately around the SDA appeared to be less variable over time than density in native sagebrush habitat for years when data were available. This phenomenon was largely attributable to steady or increasing SDA population densities of the most common species, Peromyscus maniculatus and Perognathus parvus , during 1988-89, when most small mammal species had below-average densities in surrounding areas. The variety of foraging options in edge habitat may have allowed these relatively opportunistic species to avoid widespread population declines associated with drought years in 1988-89. Movements by P. manicualtus across the boundary were common, suggesting that this species did indeed utilize both habitat types. Preferences for edge habitat could potentially be used to formulate strategies that reduce use of waste site by small mammals.     

Nesting and summer habitat use by translocated Sage Grouse ( Centrocercus Urophasianus ) in central Idaho

We translocated 196 Sage Grouse ( Centrocercus urophasianus into Sawtooth Valley, Idaho, during March-April 1986-87 to augment a small resident population. Forty-four grouse equipped with radio transmitters were monitored through spring and summer. Nest sites ( n = 6) had greater ( P = .032) horizontal cover than did independent random plots ( n = 7). During summer, grouse used sites ( n = 50) with taller live and dead shrub heights, greater shrub canopy cover, and more ground litter ( P n = 50) 50-300 m from use sites. Distance to edge and mountain sagebrush ( Artemisia tridentata vaseyana ) density best separated use sites from independent random plots in logistic regression analysis and correctly classified 64% of the use sites and 78% of the independent random plots. Sage Grouse used sties that had narrower frequency distributions for many variables than did independent plots ( P < .04), suggesting selection for uniform habitat.     

Diatom species composition and ecology of the Animas River Watershed, Colorado, USA

The diatom flora of selected sites in the Animas River Watershed, San Juan County, Colorado, was studied. Eighty diatom taxa were identified from 10 sites: 8 sites on the Animas River and 1 site each on the Cement and Cascade tributaries. The sample diatom abundance was dominated by Achnanthidium minutissimum , Encyonema silesiacum , Aulacoseira distans , Hannaea arcus , and Diatoma mesodon . The presence of teratologic specimens of Fragilaria and Achnanthidium in the samples indicated the possibility of metals contamination. Diatom diversity was low and Lange-Bertalot pollution index scores indicated little organic pollution evidenced from diatom composition. There was evidence that diatom composition at the sites was differentially affected by pH and possibly by the concentrations of Zn alone or in combination with Cd, Cu, and Fe.     

Life histories of stoneflies (Plecoptera) in the Rio Conejos of southern Colorado

Thirty-one stonefly species representing eight families were collected during the March 1987 to May 1990 study period. Genera represented by more than one species included Capnia, Utacapnia, Taenionema, Suwallia, Triznaka, Isogenoides, and Isoperla . Peak species richness was recorded on or near the summer solstice in 1988 and 1989. Climatic differences between years were reflected in nymphal development and emergence phenology of most species. New or important corroborative life history data are presented for 11 stonefly species of this assemblage. The hyporheic nymphal development of most cholroperlid species limited the number of early instars sampled and our capacity to interpret voltinism. Limited nymphal data suggested a univoltine-slow cycle for Plumiperla diversa (Frison). Adults of Suwallia pallidula (Banks) and S. wardi (Banks) were present for an extended summer period, but the bulk of their respective emergence times was temporally separated. Isogenoides zionensis Hanson, Pteronarcella badia (Hagen), and Pteronarcys californica Newport were all shown for the first time to have a 9-10 mo egg diapauses, and all three species have a semivoltine life cycle. Skwala Americana (Klápalek) and Isoperla fulva Claassen were further confirmed to have univoltine-slow cycles. Univoltine-fast and univoltine-slow life cycles are reported for the first time in I. phalerata and I. quinquepunctata , respectively. Regression analysis revealed that six of the eight abunduant species had extended emergence patterns (slopes of < 5%/d), while only two had synchronous patterns. Warmer spring and summer temperatures in 1989 increased the slopes for five of the eight species studied, but did not change their synchrony designation. Nine of 11 abundant species advanced their median emergence date in 1989 over 1988. This and the higher slope values are consistent with a hurried nymphal development and narrower emergence period due to the warmer thermal regime of 1989.     

Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1

We report a genome-wide association study for open-angle glaucoma (OAG) blindness using a discovery cohort of 590 individuals with severe visual field loss (cases) and 3,956 controls. We identified associated loci at TMCO1 (rs4656461[G] odds ratio (OR) = 1.68, P = 6.1 × 10(-10)) and CDKN2B-AS1 (rs4977756[A] OR = 1.50, P = 4.7 × 10(-9)). We replicated these associations in an independent cohort of cases with advanced OAG (rs4656461 P = 0.010; rs4977756 P = 0.042) and two additional cohorts of less severe OAG (rs4656461 combined discovery and replication P = 6.00 × 10(-14), OR = 1.51, 95% CI 1.35-1.68; rs4977756 combined P = 1.35 × 10(-14), OR = 1.39, 95% CI 1.28-1.51). We show retinal expression of genes at both loci in human ocular tissues. We also show that CDKN2A and CDKN2B are upregulated in the retina of a rat model of glaucoma.     

Cytoglobin: biochemical,functional and clinical perspective of the newest member of the globin family

Since the discovery of cytoglobin (Cygb) a decade ago, growing amounts of data have been gathered to characterise Cygb biochemistry, functioning and implication in human pathologies. Its molecular roles remain under investigation, but nitric oxide dioxygenase and lipid peroxidase activities have been demonstrated. Cygb expression increases in response to various stress conditions including hypoxia, oxidative stress and fibrotic stimulation. When exogenously overexpressed, Cygb revealed cytoprotection against these factors. Cygb was shown to be upregulated in fibrosis and neurodegenerative disorders and downregulated in multiple cancer types. CYGB was also found within the minimal region of a hereditary tylosis with oesophageal cancer syndrome, and its expression was reduced in tylotic samples. Recently, Cygb has been shown to inhibit cancer cell growth in vitro, thus confirming its suggested tumour suppressor role. This article aims to review the biochemical and functional aspects of Cygb, its involvement in various pathological conditions and potential clinical utility.     

An eicosanoid-centric view of atherothrombotic risk factors

Cardiovascular disease is the foremost cause of morbidity and mortality in the Western world. Atherosclerosis followed by thrombosis (atherothrombosis) is the pathological process underlying most myocardial, cerebral, and peripheral vascular events. Atherothrombosis is a complex and heterogeneous inflammatory process that involves interactions between many cell types (including vascular smooth muscle cells, endothelial cells, macrophages, and platelets) and processes (including migration, proliferation, and activation). Despite a wealth of knowledge from many recent studies using knockout mouse and human genetic studies (GWAS and candidate approach) identifying genes and proteins directly involved in these processes, traditional cardiovascular risk factors (hyperlipidemia, hypertension, smoking, diabetes mellitus, sex, and age) remain the most useful predictor of disease. Eicosanoids (20 carbon polyunsaturated fatty acid derivatives of arachidonic acid and other essential fatty acids) are emerging as important regulators of cardiovascular disease processes. Drugs indirectly modulating these signals, including COX-1/COX-2 inhibitors, have proven to play major roles in the atherothrombotic process. However, the complexity of their roles and regulation by opposing eicosanoid signaling, have contributed to the lack of therapies directed at the eicosanoid receptors themselves. This is likely to change, as our understanding of the structure, signaling, and function of the eicosanoid receptors improves. Indeed, a major advance is emerging from the characterization of dysfunctional naturally occurring mutations of the eicosanoid receptors. In light of the proven and continuing importance of risk factors, we have elected to focus on the relationship between eicosanoids and cardiovascular risk factors.