Uranium diboride (UB2) and uranium tetraboride (UB4) are candidate constituents for multi-phase accident tolerant fuel due to their anticipated high thermal conductivity. These fuels have high ...uranium density that contributes to fission, and by tailoring the ratio of 10B/11B, can also act as an integrated burnable poison. Understanding the thermophysical and mechanical properties of uranium borides, for which only limited data are available in the literature, is of importance to determine their accident tolerance. In this work UB2 and UB4 have been synthesized via arc melting and sintered to high densities via spark plasma sintering (SPS). High density samples, >90% theoretical density, were used to measure the thermal diffusivity and thermal expansion of UB2 and UB4 and, in conjunction with specific heat literature data, their thermal conductivities were calculated from 298 to 1773 K. Additionally, resonance ultrasound spectroscopy (RUS) and nanoindentation were performed to investigate the mechanical properties of the uranium borides. Our results are discussed in the context of available literature. Both UB2 and UB4 exhibit thermal conductivities higher than that of UO2, with UB2 having the highest. The thermal conductivity of UB2 increases with temperature above 874 K, while for UB4 there is a linear increase over the entire measured range. X-ray diffraction (XRD) results indicate that impurity phases were present in the fabricated materials, which could explain why literature density functional theory (DFT) results predict higher values. This suggests that if impurity phases or any microstructural defects can be eliminated then the thermal conductivity can be further increased.
•Uranium boride phases can be used as secondary phases in composite fuels to increase the overall thermal conductivity. This comes in addition to contributing as fissile and burnable poison phases, when tailoring the ratio of 10B/11B.•The materials were synthesized via arc melting and sintered to high densities via spark plasma sintering.•The measured thermal conductivities were significantly higher than that of UO2 indicating that composites of UO2-UBx would have increased thermal conductivities.•The bulk, shear and Young’s moduli were measured and the results indicate good mechanical integrity for both materials.
We performed a two-tiered, whole-genome association study of Parkinson disease (PD). For tier 1, we individually genotyped 198,345 uniformly spaced and informative single-nucleotide polymorphisms ...(SNPs) in 443 sibling pairs discordant for PD. For tier 2a, we individually genotyped 1,793 PD-associated SNPs (P<.01 in tier 1) and 300 genomic control SNPs in 332 matched case–unrelated control pairs. We identified 11 SNPs that were associated with PD (P<.01) in both tier 1 and tier 2 samples and had the same direction of effect. For these SNPs, we combined data from the case–unaffected sibling pair (tier 1) and case–unrelated control pair (tier 2) samples and employed a liberalization of the sibling transmission/disequilibrium test to calculate odds ratios, 95% confidence intervals, and P values. A SNP within the semaphorin 5A gene (SEMA5A) had the lowest combined P value (P=7.62×10−6). The protein encoded by this gene plays an important role in neurogenesis and in neuronal apoptosis, which is consistent with existing hypotheses regarding PD pathogenesis. A second SNP tagged the PARK11 late-onset PD susceptibility locus (P=1.70×10−5). In tier 2b, we also selected for genotyping additional SNPs that were borderline significant (P<.05) in tier 1 but that tested a priori biological and genetic hypotheses regarding susceptibility to PD (n=941 SNPs). In analysis of the combined tier 1 and tier 2b data, the two SNPs with the lowest P values (P=9.07×10−6; P=2.96×10−5) tagged the PARK10 late-onset PD susceptibility locus. Independent replication across populations will clarify the role of the genomic loci tagged by these SNPs in conferring PD susceptibility.
Uranium dioxide (UO2) composites with uranium diboride (UB2) and uranium tetraboride (UB4) have been proposed as advanced fuel candidates due to their high thermal conductivity, high melting point, ...high fissile density and their ability to incorporate a built-in burnable poison by tailoring the targeted 10B/11B ratio. As such, it is important to assess the fabrication, and thermal and micromechanical properties of such composites. In this work, UO2-UB2 and UO2-UB4 samples with boride phase fractions of 5, 15 and 30 wt% were fabricated to high densities (above 95% theoretical density) via spark plasma sintering (SPS). This enabled sintering at relatively low temperatures and short timescales. SPS also aided in maintaining the target phase fractions of the samples as reactions between the constituent phases were suppressed due to the short timescales and reducing environment during sintering. Thermal diffusivity measurements from 299 to 1273 K were conducted through laser flash analysis (LFA). The diffusivity increased as a function of boride weight fraction, and UB2 additions increased the thermal diffusivity of the composites more than UB4 additions. Assessment of the LFA results indicated that in-situ reactions between the UO2 and boride phases that suppress the thermal diffusivity occur above 800 K for all samples. Oxidation of the boride phase was proposed as the underlying reaction. This was supported by thermodynamic assessments from the literature, as well as microstructural, crystallographic, and nanoindentation characterization performed on these samples.
The Advanced Fuels Campaign performed a series of irradiation tests of minor actinide-bearing mixed oxide fuel (MA-MOX), the so-called AFC-2C&D experiments, to investigate the transmutation of ...long-lived transuranic actinide isotopes contained in spent nuclear fuel via fast reactor technology at burnups exceeding 10 % fission of initial metallic atoms. This manuscript reports the test results derived from one of the five MA-MOX rodlets taken to higher burnup in the AFC-2D irradiation. This includes both non-destructive investigations, such as gamma and neutron spectrometry, and destructive investigations, such as fission gas release, ceramography, and chemical burnup analysis. In addition, the microstructure of the fuel was investigated using advanced electron microscopy techniques including electron backscatter diffraction (EBSD) and transmission electron microscopy (TEM). It was observed with EBSD that the pellet had subdivision of the grains and the TEM observed migration of cladding material into the 5 metal precipitates in the fuel which could have been from the higher than desired oxygen/metal ratio. The TEM also showed an enrichment of Cr in fuel clad chemical interaction (FCCI) layer.
T-cell acute lymphoblastic leukemia (T-ALL) is a challenging clinical entity with high rates of induction failure and relapse. To discover the genetic changes occurring in T-ALL, and those ...contributing to relapse, we studied zebrafish (Danio rerio) T-ALL samples using array comparative genomic hybridization (aCGH). We performed aCGH on 17 T-ALLs from four zebrafish T-ALL models, and evaluated similarities between fish and humans by comparing all D. rerio genes with copy number aberrations (CNAs) with a cohort of 75 published human T-ALLs analyzed by aCGH. Within all D. rerio CNAs, we identified 893 genes with human homologues and found significant overlap (67%) with the human CNA dataset. In addition, when we restricted our analysis to primary T-ALLs (14 zebrafish and 61 human samples), 10 genes were recurrently altered in > 3 zebrafish cancers and ≥ 4 human cases, suggesting a conserved role for these loci in T-ALL transformation across species. We also conducted iterative allo-transplantation with three zebrafish malignancies. This technique selects for aggressive disease, resulting in shorter survival times in successive transplant rounds and modeling refractory and relapsed human T-ALL. Fifty-five percent of original CNAs were preserved after serial transplantation, demonstrating clonality between each primary and passaged leukemia. Cancers acquired an average of 34 new CNAs during passaging. Genes in these loci may underlie the enhanced malignant behavior of these neoplasias. We also compared genes from CNAs of passaged zebrafish malignancies with aCGH results from 50 human T-ALL patients who failed induction, relapsed or would eventually relapse. Again, many genes (88/164) were shared by both datasets. Further, nine recurrently altered genes in passaged D. rerio T-ALL were also found in multiple human T-ALL cases. These results suggest that zebrafish and human T-ALLs are similar at the genomic level, and are governed by factors that have persisted throughout evolution.
T-cell neoplasias are common in pediatric oncology, and include acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LBL). These cancers have worse prognoses than their B-cell ...counterparts, and their treatments carry significant morbidity. Although many pediatric malignancies have characteristic translocations, most T-lymphocyte-derived diseases lack cytogenetic hallmarks. Lacking these informative lesions, insight into their molecular pathogenesis is less complete. Although dysregulation of the NOTCH1 pathway occurs in a substantial fraction of cases, many other genetic lesions of T-cell malignancy have not yet been determined. To address this deficiency, we pioneered a phenotype-driven forward-genetic screen in zebrafish (Danio rerio). Using transgenic fish with T-lymphocyte-specific expression of enhanced green fluorescent protein (EGFP), we performed chemical mutagenesis, screened animals for GFP(+) tumors, and identified multiple lines with a heritable predisposition to T-cell malignancy. In each line, the patterns of infiltration and morphological appearance resembled human T-ALL and T-LBL. T-cell receptor analyses confirmed their clonality. Malignancies were transplantable and contained leukemia-initiating cells, like their human correlates. In summary, we have identified multiple zebrafish mutants that recapitulate human T-cell neoplasia and show heritable transmission. These vertebrate models provide new genetic platforms for the study of these important human cancers.
Many sequence variants have been linked to complex human traits and diseases
, but deciphering their biological functions remains challenging, as most of them reside in noncoding DNA. Here we have ...systematically assessed the binding of 270 human transcription factors to 95,886 noncoding variants in the human genome using an ultra-high-throughput multiplex protein-DNA binding assay, termed single-nucleotide polymorphism evaluation by systematic evolution of ligands by exponential enrichment (SNP-SELEX). The resulting 828 million measurements of transcription factor-DNA interactions enable estimation of the relative affinity of these transcription factors to each variant in vitro and evaluation of the current methods to predict the effects of noncoding variants on transcription factor binding. We show that the position weight matrices of most transcription factors lack sufficient predictive power, whereas the support vector machine combined with the gapped k-mer representation show much improved performance, when assessed on results from independent SNP-SELEX experiments involving a new set of 61,020 sequence variants. We report highly predictive models for 94 human transcription factors and demonstrate their utility in genome-wide association studies and understanding of the molecular pathways involved in diverse human traits and diseases.
Genetic variants affecting pancreatic islet enhancers are central to T2D risk, but the gene targets of islet enhancer activity are largely unknown. We generate a high-resolution map of islet ...chromatin loops using Hi-C assays in three islet samples and use loops to annotate target genes of islet enhancers defined using ATAC-seq and published ChIP-seq data. We identify candidate target genes for thousands of islet enhancers, and find that enhancer looping is correlated with islet-specific gene expression. We fine-map T2D risk variants affecting islet enhancers, and find that candidate target genes of these variants defined using chromatin looping and eQTL mapping are enriched in protein transport and secretion pathways. At IGF2BP2, a fine-mapped T2D variant reduces islet enhancer activity and IGF2BP2 expression, and conditional inactivation of IGF2BP2 in mouse islets impairs glucose-stimulated insulin secretion. Our findings provide a resource for studying islet enhancer function and identifying genes involved in T2D risk.
•FMR1 KO Fragile X syndrome model mice show impaired prepulse inhibition (PPI).•CGG repeat knockin FXTAS model mice show impaired prepulse inhibition.•These prepulse inhibition abnormalities in CGG ...knockin mice are age-dependent.•Fmr1 KO and CGG knockin animals share an impaired PPI phenotype.
Fragile X syndrome (FXS) is a common inherited cause of intellectual disability that results from a CGG repeat expansion in the FMR1 gene. Large repeat expansions trigger both transcriptional and translational suppression of Fragile X protein (FMRP) production. Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is an allelic neurodegenerative disease caused by smaller “pre-mutation” CGG repeat expansions that enhance FMR1 transcription but lead to translational inefficiency and reduced FMRP expression in animal models. Sensorimotor gating as measured by pre-pulse inhibition (PPI) is altered in both FXS patients and Fmr1 knock out (KO) mice. Similarly, FXTAS patients have demonstrated PPI deficits. Recent work suggests there may be overlapping synaptic defects between Fmr1 KO and CGG knock-in premutation mouse models (CGG KI). We therefore sought to interrogate PPI in CGG KI mice. Using a quiet PPI protocol more akin to human testing conditions, we find that Fmr1 KO animals have significantly impaired PPI. Using this same protocol, we find CGG KI mice demonstrate an age-dependent impairment in PPI compared to wild type (WT) controls. This study describes a novel phenotype in CGG KI mice that can be used in future therapeutic development targeting premutation associated symptoms.
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