Technical Risk Rating of Doe Environmental Projects - 9153

The U.S. Department of Energy's Office of Environmental Management (DOE-EM) was established to achieve the safe and compliant disposition of legacy wastes and facilities from defense nuclear applications. The scope of work is diverse, with projects ranging from single acquisitions to collections of projects and operations that span several decades and costs from hundreds of millions to billions US$. The need to be able to manage and understand the technical risks from the project to senior management level has been recognized as an enabler to successfully completing the mission. In 2008, DOE-EM developed the Technical Risk Rating as a new method to assist in managing technical risk based on specific criteria. The Technical Risk Rating, and the criteria used to determine the rating, provides a mechanism to foster open, meaningful communication between the Federal Project Directors and DOE-EM management concerning project technical risks. Four indicators (technical maturity, risk urgency, handling difficulty and resolution path) are used to focus attention on the issues and key aspects related to the risks. Pressing risk issues are brought to the forefront, keeping DOE-EM management informed and engaged such that they fully understand risk impact. Use of the Technical Risk Rating and criteria during reviews provides the Federal Project Directors the opportunity to openly discuss the most significant risks and assists in the management of technical risks across the portfolio of DOE-EM projects. Technical Risk Ratings can be applied to all projects in government and private industry. This paper will present the methodology and criteria for Technical Risk Ratings, and provide specific examples from DOE-EM projects

Sub-types of insomnia in adolescents: insights from a quantitative/ molecular twin study

Background: Insomnia with short sleep duration has been postulated as more severe than that accompanied by normal/long sleep length. While the short duration subtype is considered to have greater genetic influence than the other subtype, no studies have addressed this question. This study aimed to compare these subtypes in terms of: 1) the heritability of insomnia symptoms; 2) polygenic scores (PGS) for insomnia symptoms and sleep duration; 3) the associations between insomnia symptoms and a wide variety of traits/disorders. Methods: The sample comprised 4,000 pairs of twins aged 16 from the Twins Early Development Study. Twin models were fitted to estimate the heritability of insomnia in both groups. PGS were calculated for self-reported insomnia and sleep duration and compared among participants with short and normal/long sleep duration. Results: Heritability was not significantly different in the short sleep duration group (A=0.13 [95%CI=0.01, 0.32]) and the normal/long sleep duration group (A=0.35 [95%CI=0.29, 0.40]). Shared environmental factors accounted for a substantial proportion of the variance in the short sleep duration group (C=0.19 [95%CI= 0.05, 0.32]) but not in the normal/long sleep duration group (C=0.00 [95%CI=0.00, 0.04]). PGS did not differ significantly between groups although results were in the direction expected by the theory. Our results also showed that insomnia with short (as compared to normal/long) sleep duration had a stronger association with anxiety and depression (p<.05) - although not once adjusting for multiple testing. Conclusions: We found mixed results in relation to the expected differences between the insomnia subtypes in adolescents. Future research needs to further establish cut-offs for ‘short’ sleep at different developmental stages and employ objective measures of sleep

HPA axis related genes and response to psychological therapies: genetics and epigenetics

Background Hypothalamic–pituitary–adrenal (HPA) axis functioning has been implicated in the development of stress-related psychiatric diagnoses and response to adverse life experiences. This study aimed to investigate the association between genetic and epigenetics in HPA axis and response to cognitive behavior therapy (CBT). Methods Children with anxiety disorders were recruited into the Genes for Treatment project (GxT, N = 1,152). Polymorphisms of FKBP5 and GR were analyzed for association with response to CBT. Percentage DNA methylation at the FKBP5 and GR promoter regions was measured before and after CBT in a subset (n = 98). Linear mixed effect models were used to investigate the relationship between genotype, DNA methylation, and change in primary anxiety disorder severity (treatment response). Results Treatment response was not associated with FKBP5 and GR polymorphisms, or pretreatment percentage DNA methylation. However, change in FKBP5 DNA methylation was nominally significantly associated with treatment response. Participants who demonstrated the greatest reduction in severity decreased in percentage DNA methylation during treatment, whereas those with little/no reduction in severity increased in percentage DNA methylation. This effect was driven by those with one or more FKBP5 risk alleles, with no association seen in those with no FKBP5 risk alleles. No significant association was found between GR methylation and response. Conclusions Allele-specific change in FKBP5 methylation was associated with treatment response. This is the largest study to date investigating the role of HPA axis related genes in response to a psychological therapy. Furthermore, this is the first study to demonstrate that DNA methylation changes may be associated with response to psychological therapies in a genotype-dependent manner

Labial soft tissue volume evaluation of different techniques for ridge preservation after tooth extraction: a randomized controlled clinical trial

OBJECTIVE: To volumetrically evaluate soft tissue changes of different ridge preservation techniques compared to spontaneous healing 6 months after tooth extraction. MATERIALS AND METHODS: In each of 40 patients, one single-rooted tooth was extracted and four treatment modalities were randomly assigned to the following groups (n = 10 each): A) ß-tricalcium-phosphate-particles with a polylactid coating (ß-TCP), B) demineralized bovine bone mineral with 10% collagen covered with a collagen matrix (DBBM-C/CM), C) DBBM with 10% collagen covered with an autogenous soft tissue punch graft (DBBM-C/PG), D) spontaneous healing (control). Impressions were obtained before extraction and 6 months later, casts were digitized and volumetric changes at the buccal soft tissues were determined. One-way anova was performed and pair-wise Wilcoxon rank sum test with Bonferroni-Holm method was applied for comparison of differences between two groups. RESULTS: After 6 months, horizontal contour changes accounted for -1.7 ± 0.7 mm (A), -1.2 ± 0.5 mm (B), -1.2 ± 0.7 mm (C) and -1.8 ± 0.8 mm (D). None of the group comparisons reached statistical significance. CONCLUSIONS: Six months after tooth extraction all groups revealed a horizontal volume change in the buccal soft tissue contour. Application of DBBM-C/CM or DBBM-C/PG reduced the amount of volume resorption compared to ß-TCP or spontaneous healing without reaching statistically significant difference

Predicting distributions of known and unknown reptile species in Madagascar

Despite the importance of tropical biodiversity(1), informative species distributional data are seldom available for biogeographical study or setting conservation priorities(2,3). Modelling ecological niche distributions of species offers a potential soluion(4-7); however, the utility of old locality data from museums, and of more recent remotely sensed satellite data, remains poorly explored, especially for rapidly changing tropical landscapes. Using 29 modern data sets of environmental land coverage and 621 chameleon occurrence localities from Madagascar ( historical and recent), here we demonstrate a significant ability of our niche models in predicting species distribution. At 11 recently inventoried sites, highest predictive success (85.1%) was obtained for models based only on modern occurrence data (74.7% and 82.8% predictive success, respectively, for pre-1978 and all data combined). Notably, these models also identified three intersecting areas of over-prediction that recently yielded seven chameleon species new to science. We conclude that ecological niche modelling using recent locality records and readily available environmental coverage data provides informative biogeographical data for poorly known tropical landscapes, and offers innovative potential for the discovery of unknown distributional areas and unknown species.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62843/1/nature02205.pd

MEK inhibition is a promising therapeutic strategy for MLL-rearranged infant acute lymphoblastic leukemia patients carrying RAS mutations

Acute lymphoblastic leukemia (ALL) in infants is an aggressive malignancy with a poor clinical outcome, and is characterized by translocations of the Mixed Lineage Leukemia (MLL) gene. Previously, we identified RAS mutations in 14-24% of infant ALL patients, and showed that the presence of a RAS mutation decreased the survival chances even further. We hypothesized that targeting the RAS signaling pathway could be a therapeutic strategy for RAS-mutant infant ALL patients. Here we show that the MEK inhibitors Trametinib, Selumetinib and MEK162 severely impair primary RAS-mutant MLL-rearranged infant ALL cells in vitro. While all RAS-mutant samples were sensitive to MEK inhibitors, we found both sensitive and resistant samples among RAS-wildtype cases. We confirmed enhanced RAS pathway signaling in RASmutant samples, but found no apparent downstream over-activation in the wildtype samples. However, we did confirm that MEK inhibitors reduced p-ERK levels, and induced apoptosis in the RAS-mutant MLL-rearranged ALL cells. Finally, we show that MEK inhibition synergistically enhances prednisolone sensitivity,

HST Time-Series Photometry of the Transiting Planet of HD 209458

We have observed 4 transits of the planet of HD 209458 using the STIS spectrograph on HST. Summing the recorded counts over wavelength between 582 nm and 638 nm yields a photometric time series with 80 s time sampling and relative precision of about 1.1E-4 per sample. The folded light curve can be fit within observational errors using a model consisting of an opaque circular planet transiting a limb-darkened stellar disk. In this way we estimate the planetary radius R_p = 1.347 +/- 0.060 R_Jup, the orbital inclination i = 86.68 +/- 0.14 degrees, the stellar radius R_* = 1.146 +/- 0.050 R_solar, and one parameter describing the stellar limb darkening. Our estimated radius is smaller than those from earlier studies, but is consistent within measurement errors, and is also consistent with theoretical estimates of the radii of irradiated Jupiter-like planets. Satellites or rings orbiting the planet would, if large enough, be apparent from distortions of the light curve or from irregularities in the transit timings. We find no evidence for either satellites or rings, with upper limits on satellite radius and mass of 1.2 Earth radii and 3 Earth masses, respectively. Opaque rings, if present, must be smaller than 1.8 planetary radii in radial extent. The high level of photometric precision attained in this experiment confirms the feasibility of photometric detection of Earth-sized planets circling Sun-like stars.Comment: 28 pages, 9 figures. To be published in the Astrophysical Journa

PAF-Mediated MAPK Signaling Hyperactivation via LAMTOR3 Induces Pancreatic Tumorigenesis

SummaryDeregulation of mitogen-activated protein kinase (MAPK) signaling leads to development of pancreatic cancer. Although Ras-mutation-driven pancreatic tumorigenesis is well understood, the underlying mechanism of Ras-independent MAPK hyperactivation remains elusive. Here, we have identified a distinct function of PCNA-associated factor (PAF) in modulating MAPK signaling. PAF is overexpressed in pancreatic cancer and required for pancreatic cancer cell proliferation. In mouse models, PAF expression induced pancreatic intraepithelial neoplasia with expression of pancreatic cancer stem cell markers. PAF-induced ductal epithelial cell hyperproliferation was accompanied by extracellular signal-regulated kinase (ERK) phosphorylation independently of Ras or Raf mutations. Intriguingly, PAF transcriptionally activated the expression of late endosomal/lysosomal adaptor, MAPK and mTOR activator 3 (LAMTOR3), which hyperphosphorylates MEK and ERK and is necessary for pancreatic cancer cell proliferation. Our results reveal an unsuspected mechanism of mitogenic signaling activation via LAMTOR3 and suggest that PAF-induced MAPK hyperactivation contributes to pancreatic tumorigenesis

Target Zones in History and Theory: Lessons from an Austro-Hungarian Experiment (1896-1914)

The first known experiment with an exchange rate band took place in Austria- Hungary between 1896 and 1914. The rationale for introducing this policy rested on precisely those intuitions that the modern literature has emphasized: the band was designed to secure both exchange rate stability and monetary policy autonomy. However, unlike more recent experiences, such as the ERM, this policy was not undermined by credibility problems. The episode provides an ideal testing ground for some important ideas in modern macroeconomics: specifically, can formal rules, when faithfully adhered to, provide policy makers with some advantages such as short term autonomy? First, we find that a credible band has a "microeconomic" influence on exchange rate stability. By reducing uncertainty, a credible fluctuation band improves the quality of expectations, a channel that has been neglected in the modern literature. Second, we show that the standard test of the basic target zone model is flawed and develop an alternative methodology. We believe that these findings shed a new light on the economics of exchange rate bands