A comparison of discrete versus continuous environment in a variance components-based linkage analysis of the COGA data

BACKGROUND: The information content of a continuous variable exceeds that of its categorical counterpart. The parameterization of a model may diminish the benefit of using a continuous variable. We explored the use of continuous versus discrete environment in variance components based analyses examining gene × environment interaction in the electrophysiological phenotypes from the Collaborative Study on the Genetics of Alcoholism. RESULTS: The parameterization using the continuous environment produced a greater number of significant gene × environment interactions and lower AICs (Akaike's information criterion). In these cases, the genetic variance increased with increasing cigarette pack-years, the continuous environment of interest. This did not, however, result in enhanced LOD scores when linkage analyses incorporated the gene × continuous environment interaction. CONCLUSION: Alternative parameterizations may better represent the functional relationship between the continuous environment and the genetic variance

Note on the pseudo-Nambu-Goldstone Boson of Meta-stable SUSY Violation

Many models of meta-stable supersymmetry (SUSY) breaking lead to a very light scalar pseudo-Nambu Goldstone boson (PNGB), P, associated with spontaneous breakdown of a baryon number like symmetry in the hidden sector. Current particle physics data provide no useful constraints on the existence of P. For example, the predicted decay rates for both K --> pi + P, b--> s + P and Upsilon --> photon + P are many orders of magnitude below the present experimental bounds. We also consider astrophysical implications of the PNGB and find a significant constraint from its effect on the evolution of red giants. This constraint either rules out models with a hidden sector gauge group larger than SU(4), or requires a new intermediate scale, of order at most 10^{10} GeV, at which the hidden sector baryon number is explicitly broken.Comment: 17 pages, 3 figures. Version 2: minor typographical errors fixed. Version 3: a more reliable estimate for the decay rate of K-->pi+PNGB is provided, and the predicted rate for b-->s+PNGB is now include

Environmental and Genetic Correlations Between the Metabolic Syndrome (MS) and System Variables Representing Adaptive Immunity, Innate Immunity and Hemostasis

The MS is prevalent in Mexican Americans (MAs) and is projected to increase. It is important therefore to better understand its genetic and environmental determinants. We hypothesized that the MS reflects dysfunction in important biological systems. To evaluate this concept, we analyzed gene expression data for the adaptive-immune, innate-immune, and hemostasis systems in relation to the MS from a study on MAs of San Antonio and the Rio Grande Valley

Role of miRNA-mRNA Interaction in Neural Stem Cell Differentiation of Induced Pluripotent Stem Cells

miRNA regulates the expression of protein coding genes and plays a regulatory role in human development and disease. The human iPSCs and their differentiated progenies provide a unique opportunity to identify these miRNA-mediated regulatory mechanisms. To identify miRNA–mRNA regulatory interactions in human nervous system development, well characterized NSCs were differentiated from six validated iPSC lines and analyzed for differentially expressed (DE) miRNome and transcriptome by RNA sequencing. Following the criteria, moderated t statistics, FDR-corrected p-value ≤ 0.05 and fold change—absolute (FC-abs) ≥2.0, 51 miRNAs and 4033 mRNAs were found to be significantly DE between iPSCs and NSCs. The miRNA target prediction analysis identified 513 interactions between 30 miRNA families (mapped to 51 DE miRNAs) and 456 DE mRNAs that were paradoxically oppositely expressed. These 513 interactions were highly enriched in nervous system development functions (154 mRNAs; FDR-adjusted p-value range: 8.06 × 10−15–1.44 × 10−4). Furthermore, we have shown that the upregulated miR-10a-5p, miR-30c-5p, miR23-3p, miR130a-3p and miR-17-5p miRNA families were predicted to down-regulate several genes associated with the differentiation of neurons, neurite outgrowth and synapse formation, suggesting their role in promoting the self-renewal of undifferentiated NSCs. This study also provides a comprehensive characterization of iPSC-generated NSCs as dorsal neuroepithelium, important for their potential use in in vitro modeling of human brain development and disease

Peptides identified on monocyte-derived dendritic cells: a marker for clinical immunogenicity to FVIII products

The immunogenicity of protein therapeutics is an important safety and efficacy concern during drug development and regulation. Strategies to identify individuals and subpopulations at risk for an undesirable immune response represent an important unmet need. The major histocompatibility complex (MHC)–associated peptide proteomics (MAPPs) assay directly identifies the presence of peptides derived from a specific protein therapeutic on a donor’s MHC class II (MHC-II) proteins. We applied this technique to address several questions related to the use of factor VIII (FVIII) replacement therapy in the treatment of hemophilia A (HA). Although .12 FVIII therapeutics are marketed, most fall into 3 categories: (i) human plasma-derived FVIII (pdFVIII), (ii) full-length (FL)–recombinant FVIII (rFVIII; FL-rFVIII), and (iii) B-domain–deleted rFVIII. Here, we investigated whether there are differences between the FVIII peptides found on the MHC-II proteins of the same individual when incubated with these 3 classes. Based on several observational studies and a prospective, randomized, clinical trial showing that the originally approved rFVIII products may be more immunogenic than the pdFVIII products containing von Willebrand factor (VWF) in molar excess, it has been hypothesized that the pdFVIII molecules yield/ present fewer peptides (ie, potential T-cell epitopes). We have experimentally tested this hypothesis and found that dendritic cells from HA patients and healthy donors present fewer FVIII peptides when administered pdFVIII vs FL-rFVIII, despite both containing the same molar VWF excess. Our results support the hypothesis that synthesis of pdFVIII under physiological conditions could result in reduced heterogeneity and/or subtle differences in structure/conformation which, in turn, may result in reduced FVIII proteolytic processing relative to FL-rFVIII

Study of safeguards system on dry reprocessing for fast breeder reactor

A 'Feasibility Study on the Commercialized Fast Breeder Reactor (FBR) Cycle System' is underway at Japan Nuclear Cycle Development Institute (JNC). Concepts to commercialize the FBR fuel cycle are being created together with their necessary research and development (R&D) tasks. 'Dry,' non-aqueous, processes are candidates for FBR fuel reprocessing. Dry reprocessing technology takes advantage of proliferation barriers, due to the lower decontamination factors achievable by the simple pyrochemical processes proposed. The concentration o f highly radioactive impurities and non-fissile materials in products from a dry reprocess is generally significantly larger than the normal aqueous (Purex) process. However, the safeguards of dry reprocesses have not been widely analyzed. In 2000, JNC and Los Alamos National Laboratoiy (LANL) initiated a joint research program to study the safeguards aspects of dry reprocessing. In this study, the safeguardability of the three options: metal electrorefining, oxide electrowinning, and fluoride volatility processes, are assessed. FBR spent fuels are decladded and powdered into mixed oxides (MOX) at the Head-End process either by oxidation-reduction reactions (metal electrorefining and fluoride volatility) or mechanically (oxide electrowinning). At the oxide electrowinning process, the spent MOX he1 powder is transferred to chloride in molten salt and nuclear materials are extracted onto cathode as oxides. For metal electrorefining process, on the other hand, the MOX fuel is converted to chloride in molten salt, and nuclear materials are extracted onto cathode as a metal fomi. At lhe fluoride volatility process, the MOX fuel powder is converted to U&/PuF6 (gaseous form) in a fluidized bed; plutonium and uranium fluorides are separated by volatilization properties and then are converted to oxides. Since the conceptual design of a dry reprocessing plant is incomplete, the operational mode, vessel capacities, residence times, and campaigns are not fully defined. Preliminary estimates of the longest acccptable campaign length while still meets loss detection goals were made using typical measurement errors and annual throughputs of plutonium within the facility. For all reprocessing facilities, both in-process inventory and the input/output materials measurements must be determined for closing the materials balance. Usually, operations are to be shut down periodically and plants are to be completely cleaned out to recover all materials in measurable forms during inventories. If there is no cleanout between campaigns, fluctuations of in-process inventory have to be monitored. We conclude that the three dry reprocessing methods will have adequate safeguardability, if limited to small-scale campaigns or to low annual throughputs. For a large scale, e.g,. 50 t(HM)/y FBR fuel reprocessing plant, there remain challenges to be addressed through process development in JNC and safeguards R&D study with LANL

Genomic variations in patients with myelodysplastic syndrome and karyotypes without numerical or structural changes

Myelodysplastic syndrome (MDS) is an onco-hematologic disease with distinct levels of peripheral blood cytopenias, dysplasias in cell differentiation and various forms of chromosomal and cytogenomic alterations. In this study, the Chromosomal Microarray Analysis (CMA) was performed in patients with primary MDS without numerical and/or structural chromosomal alterations in karyotypes. A total of 17 patients was evaluated by GTG banding and eight patients showed no numerical and/or structural alterations. Then, the CMA was carried out and identified gains and losses CNVs and long continuous stretches of homozygosity (LCSHs). They were mapped on chromosomes 1, 2, 3, 4, 5, 6, 7, 9, 10, 12, 14, 16, 17, 18, 19, 20, 21, X, and Y. Ninety-one genes that have already been implicated in molecular pathways important for cell viability were selected and in-silico expression analyses demonstrated 28 genes differentially expressed in mesenchymal stromal cells of patients. Alterations in these genes may be related to the inactivation of suppressor genes or the activation of oncogenes contributing to the evolution and malignization of MDS. CMA provided additional information in patients without visible changes in the karyotype and our findings could contribute with additional information to improve the prognostic and personalized stratification for patients

The Development of FVIII Inhibitor in Hispanic American Patients with Hemophilia A Critically Impacts Coagulation Potential

Background: Hemophilia A (HA) is caused by deficiencies in plasma-FVIII and heterogeneous factor-VIII-gene mutations that impair intrinsic coagulation amplification. In severe hemophilia A patients (HAPs), FVIII infusions are begun at toddlerhood to prevent hemarthrosis induced crippling. However, approximately 30% of these patients develop FVIII inhibitors. Gain-of-function mutations in the common pathway of coagulation increases coagulation potential and decreases bleeding and FVIII-utilization in HAPs which should decrease FVIII-inhibitor-risk. We identified loss-of-function mutations in this pathway which decrease coagulation-potential as they increase FVIII-inhibitor risk in HAPs. Methods: We screened Mexican-American-pedigrees of the South-Texas-Family-Study (STFS) for protein-altering-variants. Subjects were genotyped using Illumina-exome-24-chip. Protein-altering-variants were analyzed for associations with FII:C, PT, and aPTT. Linear-mixed-model-analyses was performed to estimate trait-heritability and examine single-nucleotide-variations (SNVs) for gene association. Significant associations’ p-values fell below Bonferroni-adjusted significance level. Results: Heritability-estimates for FII:C, aPTT, and PT were highly-significant with p-values of 0.49, 0.49, and 0.54 (for all, pT in the FII-gene (F2)—which encodes 543R\u3eL and has a large effect-size on each trait (for all, pT have lower FII:C levels but correspondingly prolonged aPTT and PT times. Conclusion: We hypothesize that FII-543R\u3eL (Prothrombin-RGV) likely contributes to the high-incidence of FVIII-inhibitor-development in HA-patients of Mexican-ancestry, resulting in higher risk of developing anti-tFVIII-antibodies than patients without the variant. Patients with the RGV variant are likely to bleed more which can require surgery, further increasing the development of FVIII inhibitor development