Analysis of Radioactive Releases During Proposed Demolition Activities for the 224-U and 224-UA Buildings - Addendum

A post-demolition modeling analysis is conducted that compares during-demolition atmospheric concentration monitoring results with modeling results based on the actual meteorological conditions during the demolition activities. The 224-U and 224-UA Buildings that were located in the U-Plant UO3 complex in the 200 West Area of the Hanford Site were demolished during the summer of 2010. These facilities converted uranyl nitrate hexahydrate (UNH), a product of Hanford’s Plutonium-Uranium Extraction (PUREX) Plant, into uranium trioxide (UO3). This report is an addendum to a pre-demolition emission analysis and air dispersion modeling effort that was conducted for proposed demolition activities for these structures

Stability analysis of the Martian obliquity during the Noachian era

We performed numerical simulations of the obliquity evolution of Mars during the Noachian era, at which time the giant planets were on drastically different orbits than today. For the preferred primordial configuration of the planets we find that there are two large zones where the Martian obliquity is stable and oscillates with an amplitude lower than 20$^\circ$. These zones occur at obliquities below 30$^\circ$ and above 60$^\circ$; intermediate values show either resonant or chaotic behaviour depending on the primordial orbits of the terrestrial planets

Insights From Liver-Humanized Mice on Cholesterol Lipoprotein Metabolism and LXR-Agonist Pharmacodynamics in Humans

Background and Aims Genetically modified mice have been used extensively to study human disease. However, the data gained are not always translatable to humans because of major species differences. Liver-humanized mice (LHM) are considered a promising model to study human hepatic and systemic metabolism. Therefore, we aimed to further explore their lipoprotein metabolism and to characterize key hepatic species-related, physiological differences. Approach and Results Fah(-/-), Rag2(-/-), and Il2rg(-/-) knockout mice on the nonobese diabetic (FRGN) background were repopulated with primary human hepatocytes from different donors. Cholesterol lipoprotein profiles of LHM showed a human-like pattern, characterized by a high ratio of low-density lipoprotein to high-density lipoprotein, and dependency on the human donor. This pattern was determined by a higher level of apolipoprotein B100 in circulation, as a result of lower hepatic mRNA editing and low-density lipoprotein receptor expression, and higher levels of circulating proprotein convertase subtilisin/kexin type 9. As a consequence, LHM lipoproteins bind to human aortic proteoglycans in a pattern similar to human lipoproteins. Unexpectedly, cholesteryl ester transfer protein was not required to determine the human-like cholesterol lipoprotein profile. Moreover, LHM treated with GW3965 mimicked the negative lipid outcomes of the first human trial of liver X receptor stimulation (i.e., a dramatic increase of cholesterol and triglycerides in circulation). Innovatively, LHM allowed the characterization of these effects at a molecular level. Conclusions LHM represent an interesting translatable model of human hepatic and lipoprotein metabolism. Because several metabolic parameters displayed donor dependency, LHM may also be used in studies for personalized medicine.Peer reviewe

Channels as Objects in Concurrent Object-Oriented Programming

There is often a sort of a protocol associated to each class, stating when and how certain methods should be called. Given that this protocol is, if at all, described in the documentation accompanying the class, current mainstream object-oriented languages cannot provide for the verification of client code adherence against the sought class behaviour. We have defined a class-based concurrent object-oriented language that formalises such protocols in the form of usage types. Usage types are attached to class definitions, allowing for the specification of (1) the available methods, (2) the tests clients must perform on the result of methods, and (3) the object status - linear or shared - all of which depend on the object's state. Our work extends the recent approach on modular session types by eliminating channel operations, and defining the method call as the single communication primitive in both sequential and concurrent settings. In contrast to previous works, we define a single category for objects, instead of distinct categories for linear and for shared objects, and let linear objects evolve into shared ones. We introduce a standard sync qualifier to prevent thread interference in certain operations on shared objects. We formalise the language syntax, the operational semantics, and a type system that enforces by static typing that methods are called only when available, and by a single client if so specified in the usage type. We illustrate the language via a complete example.Comment: In Proceedings PLACES 2010, arXiv:1110.385

Characterizing Genetic Risk at Known Prostate Cancer Susceptibility Loci in African Americans

GWAS of prostate cancer have been remarkably successful in revealing common genetic variants and novel biological pathways that are linked with its etiology. A more complete understanding of inherited susceptibility to prostate cancer in the general population will come from continuing such discovery efforts and from testing known risk alleles in diverse racial and ethnic groups. In this large study of prostate cancer in African American men (3,425 prostate cancer cases and 3,290 controls), we tested 49 risk variants located in 28 genomic regions identified through GWAS in men of European and Asian descent, and we replicated associations (at p≤0.05) with roughly half of these markers. Through fine-mapping, we identified nearby markers in many regions that better define associations in African Americans. At 8q24, we found 9 variants (p≤6×10−4) that best capture risk of prostate cancer in African Americans, many of which are more common in men of African than European descent. The markers found to be associated with risk at each locus improved risk modeling in African Americans (per allele OR = 1.17) over the alleles reported in the original GWAS (OR = 1.08). In summary, in this detailed analysis of the prostate cancer risk loci reported from GWAS, we have validated and improved upon markers of risk in some regions that better define the association with prostate cancer in African Americans. Our findings with variants at 8q24 also reinforce the importance of this region as a major risk locus for prostate cancer in men of African ancestry

Runx1 Loss Minimally Impacts Long-Term Hematopoietic Stem Cells

RUNX1 encodes a DNA binding subunit of the core-binding transcription factors and is frequently mutated in acute leukemia, therapy-related leukemia, myelodysplastic syndrome, and chronic myelomonocytic leukemia. Mutations in RUNX1 are thought to confer upon hematopoietic stem cells (HSCs) a pre-leukemic state, but the fundamental properties of Runx1 deficient pre-leukemic HSCs are not well defined. Here we show that Runx1 deficiency decreases both apoptosis and proliferation, but only minimally impacts the frequency of long term repopulating HSCs (LT-HSCs). It has been variously reported that Runx1 loss increases LT-HSC numbers, decreases LT-HSC numbers, or causes age-related HSC exhaustion. We attempt to resolve these discrepancies by showing that Runx1 deficiency alters the expression of several key HSC markers, and that the number of functional LT-HSCs varies depending on the criteria used to score them. Finally, we identify genes and pathways, including the cell cycle and p53 pathways that are dysregulated in Runx1 deficient HSCs

The Effect of Urban Street Gang Densities on Small Area Homicide Incidence in a Large Metropolitan County, 1994–2002

The presence of street gangs has been hypothesized as influencing overall levels of violence in urban communities through a process of gun–drug diffusion and cross-type homicide. This effect is said to act independently of other known correlates of violence, i.e., neighborhood poverty. To test this hypothesis, we independently assessed the impact of population exposure to local street gang densities on 8-year homicide rates in small areas of Los Angeles County, California. Homicide data from the Los Angeles County Coroners Office were analyzed with original field survey data on street gang locations, while controlling for the established covariates of community homicide rates. Bivariate and multivariate regression analyses explicated strong relationships between homicide rates, gang density, race/ethnicity, and socioeconomic structure. Street gang densities alone had cumulative effects on small area homicide rates. Local gang densities, along with high school dropout rates, high unemployment rates, racial and ethnic concentration, and higher population densities, together explained 90% of the variation in local 8-year homicide rates. Several other commonly considered covariates were insignificant in the model. Urban environments with higher densities of street gangs exhibited higher overall homicide rates, independent of other community covariates of homicide. The unique nature of street gang killings and their greater potential to influence future local rates of violence suggests that more direct public health interventions are needed alongside traditional criminal justice mechanisms to combat urban violence and homicides

NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology