Molecular basis for increased susceptibility of Indigenous North Americans to seropositive rheumatoid arthritis

Objective The pathogenetic mechanisms by which HLA-DRB1 alleles are associated with anticitrullinated peptide antibody (ACPA)-positive rheumatoid arthritis (RA) are incompletely understood. RA high-risk HLA-DRB1 alleles are known to share a common motif, the ‘shared susceptibility epitope (SE)’. Here, the electropositive P4 pocket of HLA-DRB1 accommodates self-peptide residues containing citrulline but not arginine. HLA-DRB1 His/Phe13β stratifies with ACPA-positive RA, while His13βSer polymorphisms stratify with ACPA-negative RA and RA protection. Indigenous North American (INA) populations have high risk of early-onset ACPA-positive RA, whereby HLA-DRB1*04:04 and HLA-DRB1*14:02 are implicated as risk factors for RA in INA. However, HLA-DRB1*14:02 has a His13βSer polymorphism. Therefore, we aimed to verify this association and determine its molecular mechanism. Methods HLA genotype was compared in 344 INA patients with RA and 352 controls. Structures of HLA-DRB1*1402-class II loaded with vimentin-64Arg59-71, vimentin-64Cit59-71 and fibrinogen β−74Cit69-81 were solved using X-ray crystallography. Vimentin-64Cit59-71-specific and vimentin59-71-specific CD4+ T cells were characterised by flow cytometry using peptide-histocompatibility leukocyte antigen (pHLA) tetramers. After sorting of antigen-specific T cells, TCRα and β-chains were analysed using multiplex, nested PCR and sequencing. Results ACPA+ RA in INA was independently associated with HLA-DRB1*14:02. Consequent to the His13βSer polymorphism and altered P4 pocket of HLA-DRB1*14:02, both citrulline and arginine were accommodated in opposite orientations. Oligoclonal autoreactive CD4+ effector T cells reactive with both citrulline and arginine forms of vimentin59-71 were observed in patients with HLA-DRB1*14:02+ RA and at-risk ACPA- first-degree relatives. HLA-DRB1*14:02-vimentin59-71-specific and HLA-DRB1*14:02-vimentin-64Cit59-71-specific CD4+ memory T cells were phenotypically distinct populations. Conclusion HLA-DRB1*14:02 broadens the capacity for citrullinated and native self-peptide presentation and T cell expansion, increasing risk of ACPA+ RA

A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis

Rheumatoid arthritis (RA) is strongly associated with the human leukocyte antigen (HLA)- DRB1 locus that possesses the shared susceptibility epitope (SE) and the citrullination of self-antigens. We show how citrullinated aggrecan and vimentin epitopes bind to HLADRB1* 04:01/04. Citrulline was accommodated within the electropositive P4 pocket of HLA-DRB1*04:01/04, whereas the electronegative P4 pocket of the RA-resistant HLADRB1* 04:02 allomorph interacted with arginine or citrulline-containing epitopes. Peptide elution studies revealed P4 arginine-containing peptides from HLA-DRB1*04:02, but not from HLA-DRB1*04:01/04. Citrullination altered protease susceptibility of vimentin, thereby generating self-epitopes that are presented to T cells in HLA-DRB1*04:01+ individuals. Using HLA-II tetramers, we observed citrullinated vimentin- and aggrecan-specific CD4+ T cells in the peripheral blood of HLA-DRB1*04:01+ RA-affected and healthy individuals. In RA patients, autoreactive T cell numbers correlated with disease activity and were deficient in regulatory T cells relative to healthy individuals. These findings reshape our understanding of the association between citrullination, the HLA-DRB1 locus, and T cell autoreactivity in RA

Patterns of Ancestry, Signatures of Natural Selection, and Genetic Association with Stature in Western African Pygmies

African Pygmy groups show a distinctive pattern of phenotypic variation, including short stature, which is thought to reflect past adaptation to a tropical environment. Here, we analyze Illumina 1M SNP array data in three Western Pygmy populations from Cameroon and three neighboring Bantu-speaking agricultural populations with whom they have admixed. We infer genome-wide ancestry, scan for signals of positive selection, and perform targeted genetic association with measured height variation. We identify multiple regions throughout the genome that may have played a role in adaptive evolution, many of which contain loci with roles in growth hormone, insulin, and insulin-like growth factor signaling pathways, as well as immunity and neuroendocrine signaling involved in reproduction and metabolism. The most striking results are found on chromosome 3, which harbors a cluster of selection and association signals between approximately 45 and 60 Mb. This region also includes the positional candidate genes DOCK3, which is known to be associated with height variation in Europeans, and CISH, a negative regulator of cytokine signaling known to inhibit growth hormone-stimulated STAT5 signaling. Finally, pathway analysis for genes near the strongest signals of association with height indicates enrichment for loci involved in insulin and insulin-like growth factor signaling

A Novel Statistical Timing and Leakage Power Characterization of Partially-Depleted

This paper presents a novel statistical characterization for accurate timing and a new probabilistic based analysis for leakage power estimation of Partially-Depleted Silicon-On-Insulator (PD-SOI) circuits in BSIMSOI3.2 100nm technology. The proposed timing and leakage power estimation algorithms are implemented in Matlab, Hspice, and C. The proposed methodology is applied to ISCAS85 benchmarks, and the results show that the error is within 5 % compared with Monte Carlo simulation results

Revised Split C-V Technique for Mobility Investigation in Advanced Devices

In this paper we revise the split C-V technique widely used for mobility extraction. To extend its applicability we propose to use an integral of transconductance measured at high frequencies (HF) instead of the DC drain current. For the first time it is shown that such procedure allows not only to suppress parasitic gate-induced floating body effect (GIFBE), but also to improve the accuracy of mobility extraction in weak inversion (WI) regime. In this paper we apply our technique to partially-depleted (PD) SOI MOSFETs from a FinFET process and demonstrate its advantages in comparison to the standard method

Structure of the brunnian nucleus 10^{10}C

International audienceThe 2 ALPHA+ 2p breakup and structure of the only known Brunnian nucleus, 10C, has been studied at 33.3 MeV/nucleon. Detection of the 2ALPHA + 2p breakup fragments using a highly segmented Si-Si-Si-CsI detector array has allowed the 10C -> 9B -> p, 9B -> 8Be + p, 8Be -> ALPHA + ALPHA and 10C -> 6Be + ALPHA, 6Be -> 5Li + p, 5Li -> ALPHA + p decay channels to be reconstructed. Proton emission was seen to be favoured. Resonant breakup was observed from excited states at Ex = 4.20, 5.31 and 6.74 MeV. The previously unobserved state at 4.20 MeV may correspond to a 0+ ALPHA + 2p + ALPHA cluster structure

Mobility improvement in nanowire junctionless transistors by uniaxial strain

Improvement of current drive in n- and p-type silicon junctionless metal-oxide-semiconductor-field-effect-transistors (MOSFETs) using strain is demonstrated. Junctionless transistors have heavily doped channels with doping concentrations in excess of 1019 cm−3 and feature bulk conduction, as opposed to surface channel conduction. The extracted piezoresistance coefficients are in good agreement with the piezoresistive theory and the published coefficients for bulk silicon even for 10 nm thick silicon nanowires as narrow as 20 nm. These experimental results demonstrate the possibility of enhancing mobility in heavily doped silicon junctionless MOSFETs using strain technology