Electrical Characterization of Intrinsic and Induced Deep Level Defects in Hexagonal SiC

Deep level defects in hexagonal SiC were studied using digital deep level transient spectroscopy (DLTS) methods over the temperature range of 100 to 800 deg K. New centers were found in bulk and epitaxial 6H-SiC with ionization energies between 0.38 to 1.3 eV, and levels from 0.2 to 0.856 eV were identified in 4H-SiC epitaxy. Direct correlation between inequivalent lattice sites was identified for energetic pairs associated with both vanadium and ion implanted Mg impurities. Nonradioative carrier capture mechanisms were studied and deep level trapping was found to proceed via lattice relaxation multi-phonon emission, indicating efficient electronic lattice coupling in the wide bandgap material. Junction transport characteristics of 4H-SiC p+/n bipolar devices were observed to be dominated by deep level defects in the epitaxial layers. Significant tunneling conduction in both forward and reverse bias conditions was directly correlated to deep level centers in these devices

Benchmarking High-Field Few-Electron Correlation and QED Contributions in Hg⁷⁵⁺ to Hg⁷⁸⁺ Ions. I. Experiment

The photorecombination of highly charged few-electron mercury ions Hg75+ to Hg78+ has been explored with the Heidelberg electron beam ion trap. By monitoring the emitted x rays (65-76 keV) and scanning the electron beam energy (45-54 keV) over the KLL dielectronic recombination (DR) region, the energies of state-selected DR resonances were determined to within ±4 eV (relative) and ±14 eV (absolute). At this level of experimental accuracy, it becomes possible to make a detailed comparison to various theoretical approaches and methods, all of which include quantum electrodynamic (QED) effects and finite nuclear size contributions (for a 1s electron, these effects can be as large as 160 and 50 eV, respectively). In He-like Hg78+, a good agreement between the experimental results and the calculations has been found. However, for the capture into Li-, Be-, and B-like ions, significant discrepancies have been observed for specific levels. The discrepancies suggest the need for further theoretical and experimental studies with other heavy ions along these isoelectronic sequences

Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren’s syndrome

Sjögren’s syndrome is a common autoimmune disease (~0.7% of European Americans) typically presenting as keratoconjunctivitis sicca and xerostomia. In addition to strong association within the HLA region at 6p21 (Pmeta=7.65×10−114), we establish associations with IRF5-TNPO3 (Pmeta=2.73×10−19), STAT4 (Pmeta=6.80×10−15), IL12A (Pmeta =1.17×10−10), FAM167A-BLK (Pmeta=4.97×10−10), DDX6-CXCR5 (Pmeta=1.10×10−8), and TNIP1 (Pmeta=3.30×10−8). Suggestive associations with Pmeta<5×10−5 were observed with 29 regions including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2, and PHIP amongst others. These results highlight the importance of genes involved in both innate and adaptive immunity in Sjögren’s syndrome

Trans-Ancestral Studies Fine Map the SLE-Susceptibility Locus TNFSF4

We previously established an 80 kb haplotype upstream of TNFSF4 as a susceptibility locus in the autoimmune disease SLE. SLE-associated alleles at this locus are associated with inflammatory disorders, including atherosclerosis and ischaemic stroke. In Europeans, the TNFSF4 causal variants have remained elusive due to strong linkage disequilibrium exhibited by alleles spanning the region. Using a trans-ancestral approach to fine-map the locus, utilising 17,900 SLE and control subjects including Amerindian/Hispanics (1348 cases, 717 controls), African-Americans (AA) (1529, 2048) and better powered cohorts of Europeans and East Asians, we find strong association of risk alleles in all ethnicities; the AA association replicates in African-American Gullah (152,122). The best evidence of association comes from two adjacent markers: rs2205960-T (P = 1.71×10-34, OR = 1.43[1.26-1.60]) and rs1234317-T (P = 1.16×10-28, OR = 1.38[1.24-1.54]). Inference of fine-scale recombination rates for all populations tested finds the 80 kb risk and non-risk haplotypes in all except African-Americans. In this population the decay of recombination equates to an 11 kb risk haplotype, anchored in the 5′ region proximal to TNFSF4 and tagged by rs2205960-T after 1000 Genomes phase 1 (v3) imputation. Conditional regression analyses delineate the 5′ risk signal to rs2205960-T and the independent non-risk signal to rs1234314-C. Our case-only and SLE-control cohorts demonstrate robust association of rs2205960-T with autoantibody production. The rs2205960-T is predicted to form part of a decameric motif which binds NF-κBp65 with increased affinity compared to rs2205960-G. ChIP-seq data also indicate NF-κB interaction with the DNA sequence at this position in LCL cells. Our research suggests association of rs2205960-T with SLE across multiple groups and an independent non-risk signal at rs1234314-C. rs2205960-T is associated with autoantibody production and lymphopenia. Our data confirm a global signal at TNFSF4 and a role for the expressed product at multiple stages of lymphocyte dysregulation during SLE pathogenesis. We confirm the validity of trans-ancestral mapping in a complex trait. © 2013 Manku et al

Preferential binding to elk-1 by sle-associated il10 risk allele upregulates il10 expression

Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (P = 2.7×10−8, OR = 1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele upregulates IL10 expression and confers increased risk for SLE in European Americans

Association of genetic variants in complement factor H and factor H-related genes with systemic lupus erythematosus susceptibility

Systemic lupus erythematosus (SLE), a complex polygenic autoimmune disease, is associated with increased complement activation. Variants of genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) within the chromosome 1q32 locus linked to SLE, have been associated with multiple human diseases and may contribute to dysregulated complement activation predisposing to SLE. We assessed 60 SNPs covering the CFH-CFHRs region for association with SLE in 15,864 case-control subjects derived from four ethnic groups. Significant allelic associations with SLE were detected in European Americans (EA) and African Americans (AA), which could be attributed to an intronic CFH SNP (rs6677604, in intron 11, Pmeta = 6.6×10-8, OR = 1.18) and an intergenic SNP between CFHR1 and CFHR4 (rs16840639, Pmeta = 2.9×10-7, OR = 1.17) rather than to previously identified disease-associated CFH exonic SNPs, including I62V, Y402H, A474A, and D936E. In addition, allelic association of rs6677604 with SLE was subsequently confirmed in Asians (AS). Haplotype analysis revealed that the underlying causal variant, tagged by rs6677604 and rs16840639, was localized to a ~146 kb block extending from intron 9 of CFH to downstream of CFHR1. Within this block, the deletion of CFHR3 and CFHR1 (CFHR3-1Δ), a likely causal variant measured using multiplex ligation-dependent probe amplification, was tagged by rs6677604 in EA and AS and rs16840639 in AA, respectively. Deduced from genotypic associations of tag SNPs in EA, AA, and AS, homozygous deletion of CFHR3-1Δ (Pmeta = 3.2×10-7, OR = 1.47) conferred a higher risk of SLE than heterozygous deletion (Pmeta = 3.5×10-4, OR = 1.14). These results suggested that the CFHR3-1Δ deletion within the SLE-associated block, but not the previously described exonic SNPs of CFH, might contribute to the development of SLE in EA, AA, and AS, providing new insights into the role of complement regulators in the pathogenesis of SLE

Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE

At the Crossroads of Sustainability: The Natural Recompositioning of Architecture

It is widely acknowledged that the mantra of sustainability has triggered a fundamental reversal in the core of design practice: If the original purpose of architecture was to protect humans from the destructive actions of nature,today it should protect nature from the damaging actions of humans. But sustainable design is far from being a coherent body of fully totalized ideas:it has a broad spectrum of disputing interpretations that oscillate between the deterministic models of energy control and technological efficiencies, and the moralistic and romantic approaches that attempt to see in nature and natural processes a fundamental way to de-escalate the global urban footprint and its associated patterns of consumption. However, mainstream green design has been evolving by progressively absorbing the narrative of deep ecology. Nature has been being integrated into architecture literally, by inserting vegetation onto buildings; digitally, by bringing environmental data into the design process (climate records, wind streams, sun rotation and air flows are computed, modelled and effectually shape architectures), and transcendentally, by claiming that sustainable architecture nurtures “the existing and evolving connections between spiritual and material consciousness.” The acknowledgement of the inexorable affiliation between architecture and the environment is, of course, not exactly new. What is distinctive today is the reification of the role of nature in architecture as an ideological stance, now totally intertwined with state-of-art data processing and the market-driven tools brought by Natural Capitalism. This paper will examine emblematic “green” buildings produced by leading architects such as Pelli Clarke Pelli, William McDonough, Stefano Boeri, Norman Foster and BIG in the light of Tim Morton’s, Slavoj Zizek and Bruno Latour’s critique of nature. It will illustrate how, despite being able to successfully forge new creative freedoms by exploring hybridizations between the domains of design and science, sustainability’s self-righteous “naturalistic” narrative is enabling a vision of the architect as an “expert manager” focused on producing projects of ecologic “beautification” while assumed to be “saving the world,” effectively depoliticizing the architectural practice. Nevertheless, these examples attest that there is a vast and fertile field of ideas to be explored and in this regard it is important to underline that we are still in the embryonic outset of the engagement of architecture with sustainability