Emerging patterns of genetic overlap across autoimmune disorders.

Most of the recently identified autoimmunity loci are shared among multiple autoimmune diseases. The pattern of genetic association with autoimmune phenotypes varies, suggesting that certain subgroups of autoimmune diseases are likely to share etiological similarities and underlying mechanisms of disease. In this review, we summarize the major findings from recent studies that have sought to refine genotype-phenotype associations in autoimmune disease by identifying both shared and distinct autoimmunity loci. More specifically, we focus on information from recent genome-wide association studies of rheumatoid arthritis, ankylosing spondylitis, celiac disease, multiple sclerosis, systemic lupus erythematosus, type 1 diabetes and inflammatory bowel disease. Additional work in this area is warranted given both the opportunity it provides to elucidate pathogenic mechanisms in autoimmunity and its potential to inform the development of improved diagnostic and therapeutic tools for this group on complex human disorders

Understanding Plant Cell Death With “bak to life” Screens

As sessile organisms, plants often need to activate a sophisticated immune system to evade pathogen infections. However, uncontrolled activation of defense pathways can have extremely damaging effects to the host. Many elements that control these events are still unknown. Defense receptors like Brassinosteroid Insensitive 1-Associated Receptor Kinase 1(BAK1) and Somatic Embryogenesis Receptor Kinase 4 (SERK4) are a vital part of plant defense, growth and development. However, when they become suppressed, it can lead to defense over-activation and cell death. My research focuses on finding suppressors of cell death caused by silencing BAK1 and SERK4 with virus-induced gene silencing (VIGS) on Arabidopsis knockout collections. My research will provide insight into the understanding of BAK/SERK4-mediated cell death and how plants activate defense without causing massive cell death. Likewise, this research may impact the future of crop production by genetically modifying the plants for maximizing defense without detrimental defect. I showed that “bak to life” (btl) mutants have reduced cell death phenotype compared to wild type plants, when BAK1/SERK4 are silenced

Early detection of disease program: Evaluation of the cellular immune response

Surfaces of normal, cultured, and mitogen-stimulated mouse lymphoid cells were examined by scanning electron microscopy (SEM). Lymphocytes with smooth, highly villous and intermediate surfaces were observed in cell suspensions from both spleens and thymuses of normal mice and from spleens of congenitally athymic (nude) mice. Several strain-specific surface features were noted, including the spine-like appearance of microvilli on C57B1/6 lymphocytes. Although thymus cell suspensions contained somewhat more smooth cells than did spleen cell preparations, lymphocyte derivation could not be inferred from SEM examination. Studies of cells stimulated with mitogenic agents for thymus-derived lymphocytes (concanavalin A) or for bone marrow-derived lymphocytes (lipopolysaccharide) suggested that, in the mouse, development of a complex villous surface is a general concomitant of lymphocyte activation and transformation

Conditional analysis of the major histocompatibility complex in rheumatoid arthritis

We performed a whole-genome association study of rheumatoid arthritis susceptibility using Illumina 550k single-nucleotide polymorphism (SNP) genotypes of 868 cases and 1194 controls from the North American Rheumatoid Arthritis Consortium (NARAC). Structured association analysis with adjustment for potential population stratification yielded 200 SNPs with p < 1 × 10-8 for association with RA, all of which were on chromosome 6 in a 2.7-Mb region of the major histocompatibility complex (MHC). Given the extensive linkage equilibrium in the region and known risk of HLA-DRB1 alleles, we then applied conditional analyses to ascertain independent signals for RA susceptibility among these 200 candidate SNPs. Conditional analyses incorporating risk categories of the HLA-DRB1 "shared epitope" revealed three SNPs having independent associations with RA (conditional p < 0.001). This supports the presence of significant effects on RA susceptibility in the MHC in addition to the shared epitope

Health-related quality of life and depression among participants in the Sjögren's International Collaborative Clinical Alliance registry.

ObjectiveTo examine health-related quality of life (HRQoL) and depression among participants in an international Sjögren's syndrome (SS) registry, comparing those with and without SS.MethodsCross-sectional study of participants in the Sjögren's International Collaborative Clinical Alliance (SICCA) registry. The 2016 American College of Rheumatology/European League Against Rheumatism SS classification criteria were used to determine disease status. HRQoL was assessed using the Short Form 12, version 2 Health Survey to derive scores for physical component summary (PCS) and mental component summary (MCS). Depression was assessed using the 9-Item Patient Health Questionnaire. Multivariate linear and logistic regression analyses were performed to identify predictors of HRQoL and depression while controlling for potential confounders.ResultsAmong 2401 SICCA participants who had symptoms of dry eyes and dry mouth, 1051 had SS (44%) and 1350 did not (56%). After controlling for confounders, when compared with non-SS participants, those with SS had better PCS (p&lt;0.001, β=2.43, 95% CI 1.57 to 3.29), MCS (p=0.002, β=1.37, 95% CI 0.50 to 2.23) and lower adjusted odds of depression (p&lt;0.001, OR 0.67, 95% CI 0.55 to 0.81). Other significant predictors of HRQoL and depression included employment, country of residence and use of medication with anticholinergic effect or for management of SS-related signs and symptoms.ConclusionOur results suggest that among symptomatic patients, having a diagnosis of SS may be associated with better emotional and psychological well-being compared with patients without a diagnosis. Having a definitive diagnosis of SS may encourage patients to obtain a better understanding of their disease and have coping mechanisms in place to better manage their symptoms

Design study of a device to simulate the dynamic environment encountered under condi- tions of reduced or zero gravity final report

Design study of reduced or zero gravity environment simulation devic

PBW Bases and Marginally Large Tableaux in Types B and C

We explicitly describe the isomorphism between two combinatorial realizations of Kashiwara’s infinity crystal in types B and C. The first realization is in terms of marginally large tableaux and the other is in terms of Kostant partitions coming from PBW bases. We also discuss a stack notation for Kostant partitions which simplifies that realization

Exploring the Form and the Function: a Review of Science Discourse Frameworks in the Service of Research and Practice

The importance of how classroom discourse can be used to support science learning has gained national attention with respect to both science teaching and research across K12 and higher education. In this review article, we examine a commonly referenced set of nine frameworks for use inscienceclassrooms. Specifically, we examine the ways in which various frameworks emphasize the structure (i.e.,form) or practical use (i.e.,function) of language across classroom settings, and the impact of such an emphasis on the facilitation and analysis of science classroom discourse. The findings from this review should help researchers investigate and educators facilitate classroom discourse in ways that ensure that all students can participate in and demonstrate their scientific understanding

Cell-type-specific resolution epigenetics without the need for cell sorting or single-cell biology.

High costs and technical limitations of cell sorting and single-cell techniques currently restrict the collection of large-scale, cell-type-specific DNA methylation data. This, in turn, impedes our ability to tackle key biological questions that pertain to variation within a population, such as identification of disease-associated genes at a cell-type-specific resolution. Here, we show mathematically and empirically that cell-type-specific methylation levels of an individual can be learned from its tissue-level bulk data, conceptually emulating the case where the individual has been profiled with a single-cell resolution and then signals were aggregated in each cell population separately. Provided with this unprecedented way to perform powerful large-scale epigenetic studies with cell-type-specific resolution, we revisit previous studies with tissue-level bulk methylation and reveal novel associations with leukocyte composition in blood and with rheumatoid arthritis. For the latter, we further show consistency with validation data collected from sorted leukocyte sub-types

Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus

Abstract Introduction Plasmacytoid dendritic cells (pDCs) constitutively express two members of the Toll-like receptor (TLR) family, TLR-9 and TLR-7, through which they can be stimulated to produce high levels of interferon (IFN)-α, a key mediator of the pathogenesis of systemic lupus erythematosus (SLE). Given the known efficacy of hydroxychloroquine (HCQ) in the treatment of SLE, we examined its ability to inhibit such pDC function in vivo. Methods Peripheral blood mononuclear cells (PBMCs) from SLE subjects treated or not with HCQ and from healthy controls were stimulated with the TLR-9 agonist, CpG oligodeoxynucleotides (CpG-A ODN)-2216, and the TLR-7 agonist, imiquimod. The proportion of monocytes, B cells, myeloid dendritic cells, pDCs, and natural killer (NK) cells producing IFN-α and tumor necrosis factor alpha (TNF-α) was then analyzed by multiparameter flow cytometry. Results After TLR-9/7 stimulation in both SLE and healthy subjects, significant production of IFN-α and TNF-α was only observed in pDCs. TLR-7 and TLR-9 induced IFN-α and TNF-α production by pDCs from subjects with SLE was decreased relative to that found in controls (TLR-9/IFN-α, P &lt; 0.0001; TLR-9/TNF-α P &lt; 0.0001; TLR-7/TNF-α P = 0.01). TLR-9 and TLR-7 induced IFN-α and TNF-α production by pDCs was severely impaired in 36% (TLR-9) and 33% (TLR-7) of SLE subjects. In almost all cases, these subjects were being treated with HCQ (HCQ vs. no HCQ: impaired TLR-9/IFN-α, P = 0.0003; impaired TLR-7/IFN-α, P = 0.07; impaired TLR-9/TNF-α, P &lt; 0.009; impaired TLR-7/TNF-α, P &lt; 0.01). Conclusions Treatment with HCQ is associated with impaired ability of pDCs from subjects with SLE to produce IFN-α and TNF-α upon stimulation with TLR-9 and TLR-7 agonists