733 research outputs found
Distribution and consequences of VKORC1 polymorphisms in Germany
Runge, M., Von Keyserlingk, M., Braune, S., Freise, J., Eiler, T., Plenge-Bönig, A., Becker, D., Pelz, H.-J., Esther, A., Rost, S., MĂŒller, C.R
Integration of Sequence Data from a Consanguineous Family with Genetic Data from an Outbred Population Identifies PLB1 as a Candidate Rheumatoid Arthritis Risk Gene
Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G. C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P = 0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF = 0.042] and rs116541814 [MAF = 0.021], combined P = 3.26 x 10(-6)). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P = 0.049 for C-alpha test and P = 0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted
Theory of traveling filaments in bistable semiconductor structures
We present a generic nonlinear model for current filamentation in
semiconductor structures with S-shaped current-voltage characteristics. The
model accounts for Joule self-heating of a current density filament. It is
shown that the self-heating leads to a bifurcation from static to traveling
filament. Filaments start to travel when increase of the lattice temperature
has negative impact on the cathode-anode transport. Since the impact ionization
rate decreases with temperature, this occurs for a wide class of semiconductor
systems whose bistability is due to the avalanche impact ionization. We develop
an analytical theory of traveling filaments which reveals the mechanism of
filament motion, find the condition for bifurcation to traveling filament, and
determine the filament velocity.Comment: 13 pages, 5 figure
Polyubiquitin binding to ABIN1 is required to prevent autoimmunity
The protein ABIN1 possesses a polyubiquitin-binding domain homologous to that present in nuclear factor kappa B (NF-kappa B) essential modulator (NEMO), a component of the inhibitor of NF-kappa B (I kappa B) kinase (IKK) complex. To address the physiological significance of polyubiquitin binding, we generated knockin mice expressing the ABIN1[D485N] mutant instead of the wild-type (WT) protein. These mice developed all the hallmarks of autoimmunity, including spontaneous formation of germinal centers, isotype switching, and production of autoreactive antibodies. Autoimmunity was suppressed by crossing to MyD88(-/-) mice, demonstrating that toll-like receptor (TLR)-MyD88 signaling pathways are needed for the phenotype to develop. The B cells and myeloid cells of the ABIN1[D485N] mice showed enhanced activation of the protein kinases TAK, IKK-alpha/beta, c-Jun N-terminal kinases, and p38 alpha mitogen-activated protein kinase and produced more IL-6 and IL-12 than WT. The mutant B cells also proliferated more rapidly in response to TLR ligands. Our results indicate that the interaction of ABIN1 with polyubiquitin is required to limit the activation of TLR-MyD88 pathways and prevent autoimmunity
Single-shot velocity-map imaging of attosecond light-field control at kilohertz rate
High-speed, single-shot velocity-map imaging (VMI) is combined with carrier-
envelope phase (CEP) tagging by a single-shot stereographic above-threshold
ionization (ATI) phase-meter. The experimental setup provides a versatile tool
for angle-resolved studies of the attosecond control of electrons in atoms,
molecules, and nanostructures. Single-shot VMI at kHz repetition rate is
realized with a highly sensitive megapixel complementary metal-oxide
semiconductor camera omitting the need for additional image intensifiers. The
developed camerasoftware allows for efficient background suppression and the
storage of up to 1024 events for each image in real time. The approach is
demonstrated by measuring the CEP-dependence of the electron emission from ATI
of Xe in strong (â1013âW/cm2) near single-cycle (4 fs) laser fields. Efficient
background signal suppression with the system is illustrated for the electron
emission from SiO2nanospheres
- âŠ