DSNF AND OTHER WASTE FORM DEGRADATION ABSTRACTION

The purpose of this analysis/model report (AMR) is to select and/or abstract conservative degradation models for DOE-(US. Department of Energy) owned spent nuclear fuel (DSNF) and the immobilized ceramic plutonium (Pu) disposition waste forms for application in the proposed monitored geologic repository (MGR) postclosure Total System Performance Assessment (TSPA). Application of the degradation models abstracted herein for purposes other than TSPA should take into consideration the fact that they are, in general, very conservative. Using these models, the forward reaction rate for the mobilization of radionuclides, as solutes or colloids, away from the waste fondwater interface by contact with repository groundwater can then be calculated. This forward reaction rate generally consists of the dissolution reaction at the surface of spent nuclear fuel (SNF) in contact with water, but the degradation models, in some cases, may also include and account for the physical disintegration of the SNF matrix. The models do not, however, account for retardation, precipitation, or inhibition of the migration of the mobilized radionuclides in the engineered barrier system (EBS). These models are based on the assumption that all components of the DSNF waste form are released congruently with the degradation of the matrix

Genome-Wide Admixture Mapping of Estimated Glomerular Filtration Rate and Chronic Kidney Disease Identifies European and African Ancestry-of-Origin Loci in Hispanic and Latino Individuals in the United States

Background Admixture mapping is a powerful approach for gene mapping of complex traits that leverages the diverse genetic ancestry in populations with recent admixture, such as Hispanic or Latino individuals in the United States. These individuals have an increased risk of CKD. Methods We performed genome-wide admixture mapping for both CKD and eGFR in a sample of 12,601 participants from the Hispanic Community Health Study/Study of Latinos, with validation in a sample of 8191 Black participants from the Women’s Health Initiative (WHI). We also compared the findings with those from a conventional genome-wide association study. Results Three novel ancestry-of-origin loci were identified on chromosomes 2, 14, and 15 for CKD and eGFR. The chromosome 2 locus comprises two European ancestry regions encompassing the FSHR and NRXN1 genes, with European ancestry at this locus associated with increased CKD risk. The chromosome 14 locus, found within the DLK1-DIO3 imprinted domain, was associated with lower eGFR and driven by European ancestry. The eGFR-associated locus on chromosome 15 included intronic variants of RYR3 and was within an African-specific genomic region associated with higher eGFR. The genome-wide association study failed to identify significant associations in these regions. We validated the chromosome 14 and 15 loci associated with eGFR in the WHI Black participants. Conclusions This study provides evidence of shared ancestry-specific genomic regions influencing eGFR in Hispanic or Latino individuals and Black individuals and illustrates the potential for leveraging genetic ancestry in recently admixed populations for the discovery of novel candidate loci for kidney phenotypes

Multiparameter MR Imaging in the 6-OPRI

BACKGROUND AND PURPOSE: Inherited prion diseases represent over 15% of human prion cases and are a frequent cause of early onset dementia. The purpose of this study was to define the distribution of changes in cerebral volumetric and microstructural parenchymal tissues in a specific inherited human prion disease mutation combining VBM with VBA of cerebral MTR and MD. MATERIALS AND METHODS: VBM and VBA of cerebral MTR and MD were performed in 16 healthy control participants and 9 patients with the 6-OPRI mutation. An analysis of covariance consisting of diagnostic grouping with age and total intracranial volume as covariates was performed. RESULTS: On VBM, there was a significant reduction in gray matter volume in patients compared with control participants in the basal ganglia, perisylvian cortex, lingual gyrus, and precuneus. Significant MTR reduction and MD increases were more anatomically extensive than volume differences on VBM in the same cortical areas, but MTR and MD changes were not seen in the basal ganglia. CONCLUSIONS: Gray matter and WM changes were seen in brain areas associated with motor and cognitive functions known to be impaired in patients with the 6-OPRI mutation. There were some differences in the anatomic distribution of MTR-VBA and MD-VBA changes compared with VBM, likely to reflect regional variations in the type and degree of the respective pathophysiologic substrates. Combined analysis of complementary multiparameter MR imaging data furthers our understanding of prion disease pathophysiology

The C-terminal dimerization domain of the respiratory mucin MUC5B functions in mucin stability and intracellular packaging before secretion

Mucin 5B (MUC5B) has an essential role in mucociliary clearance that protects the pulmonary airways. Accordingly, knowledge of MUC5B structure and its interactions with itself and other proteins is critical to better understand airway mucus biology and improve the management of lung diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD). The role of an N-terminal multimerization domain in the supramolecular organization of MUC5B has been previously described, but less is known about its C-terminal dimerization domain. Here, using cryogenic electron microscopy (cryo-EM) and small-angle X-ray scattering (SAXS) analyses of recombinant disulfide-linked dimeric MUC5B dimerization domain we identified an asymmetric, elongated twisted structure, with a double globular base. We found that the dimerization domain is more resistant to disruption than the multimerization domain suggesting the twisted structure of the dimerization domain confers additional stability to MUC5B polymers. Size-exclusion chromatography-multiangle light scattering (SEC-MALS), SPR-based biophysical analyses and microscale thermophoresis of the dimerization domain disclosed no further assembly, but did reveal reversible, calciumdependent interactions between the dimerization and multimerization domains that were most active at acidic pH, suggesting that these domains have a role in MUC5B intragranular organization. In summary, our results suggest a role for the C-terminal dimerization domain of MUC5B in compaction of mucin chains during granular packaging via interactions with the N-terminal multimerization domain. Our findings further suggest that the less stable multimerization domain provides a potential target for mucin depolymerization to remove mucus plugs in COPD and other lung pathologies

A powerful statistical framework for generalization testing in GWAS, with application to the HCHS/SOL

In genome-wide association studies (GWAS), “generalization” is the replication of genotype-phenotype association in a population with different ancestry than the population in which it was first identified. Current practices for declaring generalizations rely on testing associations while controlling the family-wise error rate (FWER) in the discovery study, then separately controlling error measures in the follow-up study. This approach does not guarantee control over the FWER or false discovery rate (FDR) of the generalization null hypotheses. It also fails to leverage the two-stage design to increase power for detecting generalized associations. We provide a formal statistical framework for quantifying the evidence of generalization that accounts for the (in)consistency between the directions of associations in the discovery and follow-up studies. We develop the directional generalization FWER (FWERg) and FDR (FDRg) controlling r-values, which are used to declare associations as generalized. This framework extends to generalization testing when applied to a published list of Single Nucleotide Polymorphism-(SNP)-trait associations. Our methods control FWERg or FDRg under various SNP selection rules based on P-values in the discovery study. We find that it is often beneficial to use a more lenient P-value threshold than the genome-wide significance threshold. In a GWAS of total cholesterol in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), when testing all SNPs with P-values < 5 × 10-8 (15 genomic regions) for generalization in a large GWAS of whites, we generalized SNPs from 15 regions. But when testing all SNPs with P-values < 6.6 × 10-5 (89 regions), we generalized SNPs from 27 regions

Simulations of edge localised mode instabilities in MAST-U Super-X tokamak plasmas

The high heat fluxes to the divertor during edge localised mode (ELM) instabilities have to be reduced for a sustainable future tokamak reactor. A solution to reduce the heat fluxes could be the Super-X divertor, which will be tested on MAST-U. ELM simulations for MAST-U Super-X tokamak plasmas have been obtained, using JOREK. A factor 10 decrease in the peak heat flux to the outer target and almost a factor 8 decrease in the ELM energy fluence when comparing the Super-X to a conventional divertor configuration has been found. A detached MAST-U case, after the roll-over in the target parallel electron density flux, is used as a starting point for ELM burn-through simulations. The plasma burns through the neutrals front during the ELM causing the divertor plasma to re-attach. After the crash a transition back to detachment is indicated, where the recovery to pre-ELM divertor conditions occurs in a few milliseconds, when the neutral pressure is high in the divertor. Recovery times are shorter than the inter-ELM phase in previous MAST experiments. The peak ELM energy fluence obtained after the ELM burn-through is 0.82 kJ/m2, which is significantly lower than that predicted from the empirical scaling of the ELM energy fluence - indicating promising results for future MAST-U operations

Soluble Urokinase Plasminogen Activator Receptor: Genetic Variation and Cardiovascular Disease Risk in Black Adults

BACKGROUND: suPAR (Soluble urokinase plasminogen activator receptor) has emerged as an important biomarker of coagulation, inflammation, and cardiovascular disease (CVD) risk. The contribution of suPAR to CVD risk and its genetic influence in Black populations have not been evaluated. METHODS: We measured suPAR in 3492 Black adults from the prospective, community-based JHS (Jackson Heart Study). Cross-sectional associations of suPAR with lifestyle and CVD risk factors were assessed, whole-genome sequence data were used to evaluate genetic associations of suPAR, and relationships of suPAR with incident CVD outcomes and overall mortality were estimated over follow-up. RESULTS: In Cox models adjusted for traditional CVD risk factors, estimated glomerular filtration rate, and CRP (C-reactive protein), each 1-SD higher suPAR was associated with a 21% to 31% increased risk of incident coronary heart disease, heart failure, stroke, and mortality. In the genome-wide association study, 2 missense (rs399145 encoding p.Thr86Ala, rs4760 encoding p.Phe272Leu) and 2 noncoding regulatory variants (rs73935023 within an enhancer element and rs4251805 within the promoter) of PLAUR on chromosome 19 were each independently associated with suPAR and together explained 14% of suPAR phenotypic variation. The allele frequencies of each of the four suPAR-associated genetic variants differ considerably across African and European populations. We further show that PLAUR rs73935023 can alter transcriptional activity in vitro. We did not find any association between genetically determined suPAR and CVD in JHS or a larger electronic medical record-based analyses of Blacks or Whites. CONCLUSIONS: Our results demonstrate the importance of ancestry-differentiated genetic variation on suPAR levels and indicate suPAR is a CVD biomarker in Black adults

Mitral regurgitation quantification by cardiac magnetic resonance imaging (MRI) remains reproducible between software solutions [version 3; peer review: 2 approved]

Background: The reproducibility of mitral regurgitation (MR) quantification by cardiovascular magnetic resonance (CMR) imaging using different software solutions remains unclear. This research aimed to investigate the reproducibility of MR quantification between two software solutions: MASS (version 2019 EXP, LUMC, Netherlands) and CAAS (version 5.2, Pie Medical Imaging). Methods: CMR data of 35 patients with MR (12 primary MR, 13 mitral valve repair/replacement, and ten secondary MR) was used. Four methods of MR volume quantification were studied, including two 4D-flow CMR methods (MRMVAV and MRJet) and two non-4D-flow techniques (MRStandard and MRLVRV). We conducted within-software and inter-software correlation and agreement analyses. Results: All methods demonstrated significant correlation between the two software solutions: MRStandard (r=0.92, p<0.001), MRLVRV (r=0.95, p<0.001), MRJet (r=0.86, p<0.001), and MRMVAV (r=0.91, p<0.001). Between CAAS and MASS, MRJet and MRMVAV, compared to each of the four methods, were the only methods not to be associated with significant bias. Conclusions: We conclude that 4D-flow CMR methods demonstrate equivalent reproducibility to non-4D-flow methods but greater levels of agreement between software solutions

Mitral regurgitation quantification by cardiac magnetic resonance imaging (MRI) remains reproducible between software solutions [version 1; peer review: 1 approved with reservations]

Background: The reproducibility of mitral regurgitation (MR) quantification by cardiovascular magnetic resonance (CMR) imaging using different software solutions remains unclear. This research aimed to investigate the reproducibility of MR quantification between two software solutions: MASS (version 2019 EXP, LUMC, Netherlands) and CAAS (version 5.2, Pie Medical Imaging). Methods: CMR data of 35 patients with MR (12 primary MR, 13 mitral valve repair/replacement, and ten secondary MR) was used. Four methods of MR volume quantification were studied, including two 4D-flow CMR methods (MRMVAV and MRJet) and two non-4D-flow techniques (MRStandard and MRLVRV). We conducted within-software and inter-software correlation and agreement analyses. Results: All methods demonstrated significant correlation between the two software solutions: MRStandard (r=0.92, p<0.001), MRLVRV (r=0.95, p<0.001), MRJet (r=0.86, p<0.001), and MRMVAV (r=0.91, p<0.001). Between CAAS and MASS, MRJet and MRMVAV, compared to each of the four methods, were the only methods not to be associated with significant bias. Conclusions: We conclude that 4D-flow CMR methods demonstrate equivalent reproducibility to non-4D-flow methods but greater levels of agreement between software solutions