Systems analysis of metabolism in the pathogenic trypanosomatid Leishmania major

Systems analyses have facilitated the characterization of metabolic networks of several organisms. We have reconstructed the metabolic network of Leishmania major, a poorly characterized organism that causes cutaneous leishmaniasis in mammalian hosts. This network reconstruction accounts for 560 genes, 1112 reactions, 1101 metabolites and 8 unique subcellular localizations. Using a systems-based approach, we hypothesized a comprehensive set of lethal single and double gene deletions, some of which were validated using published data with approximately 70% accuracy. Additionally, we generated hypothetical annotations to dozens of previously uncharacterized genes in the L. major genome and proposed a minimal medium for growth. We further demonstrated the utility of a network reconstruction with two proof-of-concept examples that yielded insight into robustness of the network in the presence of enzymatic inhibitors and delineation of promastigote/amastigote stage-specific metabolism. This reconstruction and the associated network analyses of L. major is the first of its kind for a protozoan. It can serve as a tool for clarifying discrepancies between data sources, generating hypotheses that can be experimentally validated and identifying ideal therapeutic targets

A Participatory Science Approach to Expanding Instream Infrastructure Inventories

Over the past decade, remote sensing data have improved in resolution and become more widely available, bringing new opportunities for its use in environmental science and conservation. One potential application is to identify and map instream infrastructure across the world, with important implications for fisheries, hydrology, flooding, and more. To date, databases of instream infrastructure focus on larger dams with reservoirs that are comparatively easy to detect with remotely sensed imagery. Despite their impact on freshwater ecosystems, smaller infrastructure is often overlooked. To overcome these challenges, we require more systematic approaches, such as the Global River Obstruction Database (GROD) presented here, to map instream infrastructure. We present a participatory approach to identify, map, and validate infrastructure and provide an initial data set for the contiguous United States (n = 4,197). We highlight the value of participatory methods that include the public and suggest ways they could be fused with machine learning for future applications

Cell cycle genes and ovarian cancer susceptibility: a tagSNP analysis

BACKGROUND: Dysregulation of the cell cycle is a hallmark of many cancers including ovarian cancer, a leading cause of gynaecologic cancer mortality worldwide.METHODS: We examined single nucleotide polymorphisms (SNPs) (n = 288) from 39 cell cycle regulation genes, including cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors, in a two-stage study. White, non-Hispanic cases (n = 829) and ovarian cancer-free controls (n = 941) were genotyped using an Illumina assay.RESULTS: Eleven variants in nine genes (ABL1, CCNB2, CDKN1A, CCND3, E2F2, CDK2, E2F3, CDC2, and CDK7) were associated with risk of ovarian cancer in at least one genetic model. Seven SNPs were then assessed in four additional studies with 1689 cases and 3398 controls. Association between risk of ovarian cancer and ABL1 rs2855192 found in the original population [odds ratio, ORBB vs AA 2.81 (1.29-6.09), P = 0.01] was also observed in a replication population, and the association remained suggestive in the combined analysis [ORBB vs AA 1.59 (1.08-2.34), P = 0.02]. No other SNP associations remained suggestive in the replication populations.CONCLUSION: ABL1 has been implicated in multiple processes including cell division, cell adhesion and cellular stress response. These results suggest that characterization of the function of genetic variation in this gene in other ovarian cancer populations is warranted. British Journal of Cancer (2009) 101, 1461-1468. doi: 10.1038/sj.bjc.6605284 www.bjcancer.com Published online 8 September 2009 (C) 2009 Cancer Research U

Absence of truncating BRIP1 mutations in chromosome 17q-linked hereditary prostate cancer families

Background:In a genome-wide scan (GWS) of 175 multiplex prostate cancer (PCa) families from the University of Michigan Prostate Cancer Genetics Project (PCGP), linkage was observed to markers on chromosome 17q21–24, a region that includes two breast cancer susceptibility genes, BRCA1 and BRIP1. BRIP1 is a Fanconi anaemia gene (FANCJ) that interacts with the BRCT domain of BRCA1 and has a role in DNA damage repair. Protein truncating mutations in BRIP1 have been identified in hereditary breast and ovarian cancer families, and a recent report suggested that a recurrent truncating mutation (R798X) may have a role in PCa susceptibility.Methods:We examined the role of BRIP1 mutations in hereditary PCa through sequence analysis of 94 individuals from PCGP families showing linkage to 17q.Results:A total of 24 single-nucleotide polymorphisms, including 7 missense variants but no protein truncating mutations, were observed.Conclusion:The data presented here suggest that BRIP1 truncating mutations are uncommon in PCa cases and do not account for the linkage to chromosome 17q observed in our GWS. Additional investigation is needed to determine the significance, if any, of the observed BRIP1 missense variants in hereditary PCa

Effect of Myostatin Depletion on Weight Gain, Hyperglycemia, and Hepatic Steatosis during Five Months of High-Fat Feeding in Mice

The marked hypermuscularity in mice with constitutive myostatin deficiency reduces fat accumulation and hyperglycemia induced by high-fat feeding, but it is unclear whether the smaller increase in muscle mass caused by postdevelopmental loss of myostatin activity has beneficial metabolic effects during high-fat feeding. We therefore examined how postdevelopmental myostatin knockout influenced effects of high-fat feeding. Male mice with ubiquitous expression of tamoxifen-inducible Cre recombinase were fed tamoxifen for 2 weeks at 4 months of age. This depleted myostatin in mice with floxed myostatin genes, but not in control mice with normal myostatin genes. Some mice were fed a high-fat diet (60% of energy) for 22 weeks, starting 2 weeks after cessation of tamoxifen feeding. Myostatin depletion increased skeletal muscle mass ∼30%. Hypermuscular mice had ∼50% less weight gain than control mice over the first 8 weeks of high-fat feeding. During the subsequent 3 months of high-fat feeding, additional weight gain was similar in control and myostatin-deficient mice. After 5 months of high-fat feeding, the mass of epididymal and retroperitoneal fat pads was similar in control and myostatin-deficient mice even though myostatin depletion reduced the weight gain attributable to the high-fat diet (mean weight with high-fat diet minus mean weight with low-fat diet: 19.9 g in control mice, 14.1 g in myostatin-deficient mice). Myostatin depletion did not alter fasting blood glucose levels after 3 or 5 months of high-fat feeding, but reduced glucose levels measured 90 min after intraperitoneal glucose injection. Myostatin depletion also attenuated hepatic steatosis and accumulation of fat in muscle tissue. We conclude that blocking myostatin signaling after maturity can attenuate some of the adverse effects of a high-fat diet

Ovarian cancer histology-specific incidence trends in Canada 1969–1993: age-period-cohort analyses

This study examined histology-specific incidence trends of ovarian cancer in Canada, 1969–1993. The impact of age, period and cohort effects on these trends were studied by means of age-period-cohort analysis. Age-standardized incidence rates of serous, endometrioid, clear cell and germ cell tumours increased significantly and the rates of sex cord-stromal and other classified epithelial ovarian tumours decreased considerably. The rates of mucinous and NOS/unclassified tumours remained unchanged. Cohort effect has a major impact on incidence trends of serous, endometrioid, germ cell, sex cord-stromal and other classified epithelial ovarian tumours but no meaningful impact on trends of mucinous, clear cell, or NOS/unclassified ovarian tumours. Various cohort patterns by histology subtypes were observed: the risk of developing serious tumours increased markedly among birth cohorts of 1895–1930, stabilized thereafter and decreased among young cohorts of 1950–1960; the risk of germ cell tumours increased significantly among young cohorts of 1965–1980; and the risk of sex cord-stromal tumours dropped constantly among cohorts 1910–1950. Various period patterns by histology subtypes observed in this study suggested changes in histology classification criteria over the period. Further studies need to consider the various etiologies and the classification criteria changes according to histology subtypes. © 1999 Cancer Research Campaig

Ovarian cysts in women receiving tamoxifen for breast cancer

Tamoxifen is a nonsteroidal anti-oestrogen with gynaecological side-effects. Only recently, ovarian cyst formation during tamoxifen treatment has been reported. The present study aimed to evaluate patient-related parameters that determine ovarian cyst formation in women using tamoxifen for breast cancer. A cross-sectional study was performed in 142 breast cancer patients using tamoxifen. Forty-five patients were also examined prior to tamoxifen treatment. Gynaecological assessment, transvaginal ultrasonography (TVU) and serum oestradiol (E2) and follicle stimulating hormone (FSH) analysis were performed. Follow-up assessments were performed twice a year. Uni- or bilateral ovarian cysts were detected by TVU in 24 tamoxifen-using patients and in one patient before tamoxifen treatment. Multiple regression analysis showed that cyst development is related (multiple R = 0.73) to high E2 (P < 0.001), younger age (P < 0.001) and absence of high-dose chemotherapy (P = 0.007). Patients with ovarian cysts had higher serum E2 levels compared to patients without cysts (1.95 vs 0.05 nmol l−1; P < 0.001). All patients after high-dose chemotherapy or older than 50 years had E2 < 0.10 nmol l−1 and/or amenorrhoea > 1 year and did not develop ovarian cysts. Patients still having a menstrual cycle during tamoxifen had a high chance (81%) of developing ovarian cysts. Breast cancer patients receiving tamoxifen only develop ovarian cysts if their ovaries are able to respond to FSH stimulation as shown by E2 production. © 1999 Cancer Research Campaig