C5orf30 is a negative regulator of tissue damage in rheumatoid arthritis

The variant rs26232, in the first intron of the chromosome 5 open reading frame 30 (C5orf30) locus, has recently been associated with both risk of developing rheumatoid arthritis (RA) and severity of tissue damage. The biological activities of human C5orf30 are unknown, and neither the gene nor protein show significant homology to any other characterized human sequences. The C5orf30 gene is present only in vertebrate genomes with a high degree of conservation, implying a central function in these organisms. Here, we report that C5orf30 is highly expressed in the synovium of RA patients compared with control synovial tissue, and that it is predominately expressed by synovial fibroblast (RASF) and macrophages in the lining and sublining layer of the tissue. These cells play a central role in the initiation and perpetuation of RA and are implicated in cartilage destruction. RASFs lacking C5orf30 exhibit increased cell migration and invasion in vitro, and gene profiling following C5orf30 inhibition confirmed up-regulation of genes involved in cell migration, adhesion, angiogenesis, and immune and inflammatory pathways. Importantly, loss of C5orf30 contributes to the pathology of inflammatory arthritis in vivo, because inhibition of C5orf30 in the collagen-induced arthritis model markedly accentuated joint inflammation and tissue damage. Our study reveal C5orf30 to be a previously unidentified negative regulator of tissue damage in RA, and this protein may act by modulating the autoaggressive phenotype that is characteristic of RASFs.Rheumatoid arthritis is a chronic systemic autoimmune disease characterized by a symmetrical, inflammatory arthropathy that frequently results in damage to synovial-lined joints with consequent pain, stiffness, and reduced functional capacity. The prevalence of RA is 0.8–1% in Western Europe and North America, and it is believed to arise from an interplay between genetics and the environment. Smoking is known to be a major risk factor particularly for anticitrullinated protein antibody-positive RA (1), whereas consumption of alcohol reduces both the risk and the severity of RA (2). The severity of RA varies from a mild condition with little joint damage to an unremitting condition that leads to extensive bone and cartilage damage. The radiological severity of damage to the hands and feet is widely used to measure outcome of RA and has been shown to have a significant genetic component (3, 4). Loci genetically associated with radiological damage include DRB1 (5), CD40 (6) and TRAF1/C5 (7), IL-4 (8), and IL-15 (9).A genome-wide association study involving 12,277 RA cases and 28,975 controls, all of European descent, reported association of rs26232 in the first intron of chromosome 5 open reading frame 30 (C5orf30) with risk of RA (10). Importantly linkage disequilibrium did not extend to genes in the flanking regions, indicating that the association was arising from C5orf30. This association was subsequently replicated in a British study of 6,108 RA cases and 13,009 controls (11). In a study of three large European RA populations (n = 1,884), we reported an allele dose association of rs26232 with radiological damage (12).The biological activities of human C5orf30 are unknown, and the precise roles it plays in RA have not yet been reported. There is indirect evidence linking human C5orf30 with immune function via its association with intracellular UNC119 (13); the latter increasing both T-cell activation by up-regulating Lck/Fyn activity and Src kinases regulating macrophages activation (14, 15). There are, however, no studies of the biological functions of human C5orf30 and, in view of the genetic association with RA susceptibility and severity, we have undertaken in silico analysis and both in vitro and in vivo experiments to determine its functional activities in RA. Here, we report C5orf30 to be a yet unidentified negative regulator of tissue damage in RA, acting by modulating the autoaggressive phenotype that is characteristic of RA synovial fibroblasts (RASF). It is highly expressed in the synovium of RA patients compared with healthy and osteoarthritis (OA) predominately by RASF in the lining and sublining layer. These cells play an important role in the initiation and perpetuation of RA and are implicated in cartilage destruction (16). Targeting C5orf30 expression by using siRNA technology resulted in increased invasiveness, proliferation and migration of RASFs in vitro, and modulated expression of genes in RA-relevant pathways including migration and adhesion. Importantly, loss of C5orf30 contributes to the pathology of inflammatory arthritis in vivo, because inhibition of C5orf30 in the collagen-induced arthritis (CIA) model mice markedly accentuated joint inflammation and cartilage destruction. These data confirm C5orf30 as a previously unidentified regulator of tissue destruction in RA.     

On the materials basis of modern society

It is indisputable that modern life is enabled by the use of materials in its technologies. Those technologies do many things very well, largely because each material is used for purposes to which it is exquisitely fitted. The result over time has been a steady increase in product performance. We show that this materials complexity has markedly increased in the past half-century and that elemental life cycle analyses characterize rates of recycling and loss. A further concern is that of possible scarcity of some of the elements as their use increases. Should materials availability constraints occur, the use of substitute materials comes to mind. We studied substitution potential by generating a comprehensive summary of potential substitutes for 62 different metals in all their major uses and of the performance of the substitutes in those applications. As we show herein, for a dozen different metals, the potential substitutes for their major uses are either inadequate or appear not to exist at all. Further, for not 1 of the 62 metals are exemplary substitutes available for all major uses. This situation largely decouples materials substitution from price, thereby forcing material design changes to be primarily transformative rather than incremental. As wealth and population increase worldwide in the next few decades, scientists will be increasingly challenged to maintain and improve product utility by designing new and better materials, but doing so under potential constraints in resource availability.The degree to which the materials of modern technology enable and improve our state of life is not adequately appreciated. A century ago, or even half a century ago, less than 12 materials were in wide use: wood, brick, iron, copper, gold, silver, and a few plastics. Today, however, substantial materials diversity in products of every kind is the rule rather than the exception. [A modern computer chip, for example, employs more than 60 different elements (1).] This use of materials is not a whim of the designer, but a carefully calculated effort to achieve increasingly high performance in products simple to complex.     

Psychometric properties of the Pain Attitudes Questionnaire (revised) in adult patients with chronic pain

Previous evidence supports the utility of the newly developed pain attitudes questionnaire (PAQ) for assessing pain-related stoicism and cautiousness in community-dwelling pain-free adults (Yong et al., 2001). A revised questionnaire (PAQ-R) was examined in the present study to determine the generalizability of psychometric properties when used with chronic pain patients. Results from both exploratory and confirmatory factor analyses suggest that the factor-structure of the revised questionnaire was best represented by a five- rather than a four-factor solution, thus, suggesting that chronic pain patients do not conceptualize the questionnaire items, in particular, with respect to the stoicism attitudes, in the same manner as the community-dwelling adults. A satisfactory internal consistency reliability of the PAQ-R was replicated in chronic pain patients. There was also evidence to suggest that chronic pain patients from different age cohorts do apply a similar frame of reference and calibration scale when responding to the items on the questionnaire. However, the cohorts of patients across the age spectrum show some differences in pain attitudes and possible reasons were discussed.     

Cultural Influences on Sibling Relationships,Roles, and Self-Concept in the Context of Autism: Perspectives of Latino/a/x and non-Latino/a/x Siblings

Journal of Autism and Developmental Disorders - Siblings describe positive and negative aspects of autism and often assume lifelong support roles. Less is known about cultural influences on sibling...     

Subthalamic deep brain stimulation for refractory Gilles de la Tourette’s syndrome: clinical outcome and functional connectivity

Background

Deep brain stimulation (DBS) is a promising novel approach for managing refractory Gilles de la Tourette’s syndrome (GTS). The subthalamic nucleus (STN) is the most common DBS target for treating movement disorders, and smaller case studies have reported the efficacy of bilateral STN-DBS treatment for relieving tic symptoms. However, management of GTS and treatment mechanism of STN-DBS in GTS remain to be elucidated.

Methods

Ten patients undergoing STN-DBS were included. Tics severity was evaluated using the Yale Global Tic Severity Scale. The severities of comorbid psychiatric symptoms of obsessive–compulsive behavior (OCB), attention-deficit/hyperactivity disorder, anxiety, and depression; social and occupational functioning; and quality of life were assessed. Volumes of tissue activated were used as seed points for functional connectivity analysis performed using a control dataset.

Results

The overall tics severity significantly reduced, with 62.9% ± 26.2% and 58.8% ± 27.2% improvements at the 6- and 12-months follow-up, respectively. All three patients with comorbid OCB showed improvement in their OCB symptoms at both the follow-ups. STN-DBS treatment was reasonably well tolerated by the patients with GTS. The most commonly reported side effect was light dysarthria. The stimulation effect of STN-DBS might regulate these symptoms through functional connectivity with the thalamus, pallidum, substantia nigra pars reticulata, putamen, insula, and anterior cingulate cortices.

Conclusions

STN-DBS was associated with symptomatic improvement in severe and refractory GTS without significant adverse events. The STN is a promising DBS target by stimulating both sensorimotor and limbic subregions, and specific brain area doses affect treatment outcomes.

     

Ten years of enhancing neuro-imaging genetics through meta-analysis: An overview from the ENIGMA Genetics Working Group

Here we review the motivation for creating the enhancing neuroimaging genetics through meta-analysis (ENIGMA) Consortium and the genetic analyses undertaken by the consortium so far. We discuss the methodological challenges, findings, and future directions of the genetics working group. A major goal of the working group is tackling the reproducibility crisis affecting “candidate gene” and genome-wide association analyses in neuroimaging. To address this, we developed harmonized analytic methods, and support their use in coordinated analyses across sites worldwide, which also makes it possible to understand heterogeneity in results across sites. These efforts have resulted in the identification of hundreds of common genomic loci robustly associated with brain structure. We have found both pleiotropic and specific genetic effects associated with brain structures, as well as genetic correlations with psychiatric and neurological diseases.