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TRAF1/C5 was among the first loci shown to confer risk for inflammatory arthritis in the absence of an associated coding variant, but its genetic mechanism remains undefined. Using ImmunoChip data from 3,939 juvenile idiopathic arthritis (JIA) patients and 14,412 controls, we identified 132 plausible common non-coding variants, reduced serially by SNP-seq, electrophoretic mobility shift, and luciferase studies to the single variant rs7034653 in the third intron ofTRAF1. Genetically manipulated experimental cells and primary monocytes from genotyped donors establish that the risk G allele reduces binding of Fos-Related Antigen 2 (FRA2), resulting in reduced TRAF1 expression and enhanced TNF production. Conditioning on this variant eliminates attributable risk for rheumatoid arthritis, implicating a mechanism shared across the arthritis spectrum. These findings reveal that rs7034653, FRA2, and TRAF1 mediate a pathway through which a non-coding causal variant drives risk of inflammatory arthritis in children and adults.

Common collectors for rare earth mineral (REM) flotation, which include carboxylates and hydroxamates, face problems such as being non-selective and sensitive to impurity ions. A type of ionic liquid (IL), tetraethylammonium mono-(2-ethylhexyl)2-ethylhexyl phosphonate ([N2222][EHEHP]), has been investigated previously for rare earth elements (REE) solvent extraction, and was proven to be selective and effective. In this work, [N2222][EHEHP] was evaluated as a collector in bastnasite (a primary REM source for REE production) flotation for the first time. The results were compared with quartz and hematite, two common gangue minerals in REM deposits. Zeta potential measurements and Fourier-transform infrared spectroscopy (FT-IR) were completed to investigate the surface chemical properties involved in the flotation of these minerals using this collector. The findings were compared with microflotation results. FT-IR and zeta potential measurements suggest adsorption of the collector's phosphonate group onto bastnasite and hematite, likely through chemisorption; whereas for quartz, the minimum microflotation recovery is likely due to no adsorption of IL on its surface. Microflotation results show higher collectability of [N2222][EHEHP] for hematite than bastnasite, the latter only shows appreciable recovery at pH 5 with elevated dosage of IL (500 g/t). To achieve better separation, a two-stage flotation scheme was designed and evaluated by bench scale flotation on a synthetic mineral mixture. The concentrates and tails were analyzed by magnetic separation, and it is found that bastnasite recovery over 90% with maximum upgrade ratio 1.7 can be achieved with elevated collector dosage.

Anti-SSA/Ro antibodies, while strongly linked to fetal cardiac injury and neonatal rash, can associate with a spectrum of disease in the mother, ranging from completely asymptomatic to overt Systemic Lupus Erythematosus (SLE) or Sjögren's Syndrome (SS). This study was initiated to test the hypothesis that the microbiome, influenced in part by genetics, contributes to disease state. The stool microbiome of healthy controls (HC) was compared to that of anti-SSA/Ro positive women whose children had neonatal lupus. At the time of sampling, these women were either asymptomatic (Asym), had minor rheumatic symptoms or signs considered as an undifferentiated autoimmune syndrome (UAS), or were diagnosed with SLE or SS. Differences in microbial relative abundances among these three groups were tested assuming an ordering in clinical severity (HCAsym/UASSS/SLE) and then again without the ordinal assumption. Those taxa that showed differential relative abundances were then tested for whether the effect size differed depending on the women's HLA SLE-risk allele genotype (DRB1*03:01, DRB1*15:01, DQB1*02:01 and DQB1*06:02) or anti-SSA/Ro autoantibody levels. Multiple genera within the families

Intensive blood pressure control decreases the rate of cardiovascular events by >25% compared with standard blood pressure control. We sought to determine whether the decrease in cardiovascular events seen with intensive blood pressure control is associated with an increased rate of other causes of hospitalization. This is a post hoc analysis of SPRINT (Systolic Blood Pressure Intervention Trial) in 9361 adult participants with hypertension and elevated cardiovascular risk. Participants were randomly assigned to an intensive or standard systolic blood pressure goal (P =0.37). Equivalence testing shows that these hospitalization rates were statistically equivalent at the P =0.05 level. Of those with hospitalizations, >1 hospitalization was seen in 38.8% of intensive arm participants and 41.9% of standard arm participants ( P =0.08). The mean cumulative count of nonprimary event hospitalizations was comparable between the two arms. The most common causes of hospitalization were cardiovascular (23.6%) followed by injuries, including bone and joint therapeutic procedures (15.7%), infections (12.0%), and nervous systems disorders (10.7%). No categories of hospitalization were statistically more common in the intensive arm compared with the standard arm. Thus, the decrease in cardiovascular events seen with intensive blood pressure control is not associated with an increased rate of other causes of hospitalization. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01206062.

Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disorder with a prominent genetic component. Individuals of African ancestry (AA) experience the disease more severely and with an increased co-morbidity burden compared to European ancestry (EA) populations. We hypothesize that the disparities in disease prevalence, activity, and response to standard medications between AA and EA populations is partially conferred by genomic influences on biological pathways. To address this, we applied a comprehensive approach to identify all genes predicted from SNP-associated risk loci detected with the Immunochip. By combining genes predicted via eQTL analysis, as well as those predicted from base-pair changes in intergenic enhancer sites, coding-region variants, and SNP-gene proximity, we were able to identify 1,731 potential ancestry-specific and trans-ancestry genetic drivers of SLE. Gene associations were linked to upstream and downstream regulators using connectivity mapping, and predicted biological pathways were mined for candidate drug targets. Examination of trans-ancestral pathways reflect the well-defined role for interferons in SLE and revealed pathways associated with tissue repair and remodeling. EA-dominant genetic drivers were more often associated with innate immune and myeloid cell function pathways, whereas AA-dominant pathways mirror clinical findings in AA subjects, suggesting disease progression is driven by aberrant B cell activity accompanied by ER stress and metabolic dysfunction. Finally, potential ancestry-specific and non-specific drug candidates were identified. The integration of all SLE SNP-predicted genes into functional pathways revealed critical molecular pathways representative of each population, underscoring the influence of ancestry on disease mechanism and also providing key insight for therapeutic selection.

Multiple emitters systems have been previously used so as to increase charge density in the drift region, many times without producing sensible increment neither in total current nor ionic wind. This contribution focuses on analyzing the detailed physics behind this failure, that is named ‘multiple emitters un-scalability’. It is established that multiple emitters un-scalability is related to the inability of multiple corona discharge inceptions when increasing the emitter number and/or density. This confirms recent findings that corona discharge inception is shielded by electro-static interactions between emitters. This contribution demonstrates that this shielding can be balanced by emitter/collector electrostatic interactions depending on the considered configuration. For sufficiently close collector-emitter distances, ignition starts at the array center, whereas, on the contrary, when the collector is distant, the ignition not only starts at the array’s periphery but might also be limited there. It is also demonstrated that emitter/emitter electrostatic interactions can be balanced by emitter/collector ones, depending of their chosen configuration. This lead to a variety of multi-inception patterns, the condition of which are analyzed. Intermediate configurations for which the collector is neither sufficiently close nor distant from the emitter array center provide a variety of multi-inception patterns that are hereby analyzed. Combining finite element computations of multi-inception drift-diffusion modeling with experimental measurements, provides a coherent picture explaining why multiple emitters sources systems do not lead to full ignition, and also exhibit conditions for which it does, leading to multiple emitters scalable systems.

Alongside Edward, Lemieux was among the earliest researchers studying negative hyperconjugation (i.e. the anomeric effect) or the preference for gauche conformations about the C1-O5 bond in carbohydrates. Lemieux also studied an esoteric, if not controversial, theory known as the reverse anomeric effect (RAE). This theory is used to rationalize scenarios where predicted anomeric stabilization does not occur. One such example is the Kochetkov amination, where reducing end amines exist solely as the β-anomer. Herein, we provide a brief account of Lemieux’s contributions to the area of stereoelectronic effects and apply this knowledge toward the synthesis of β-amino human milk oligosaccharides (βA-HMOs). These molecules were evaluated for their ability to inhibit growth and biofilm production in Group B Streptococcus (GBS) and Staphylococcus aureus. While the parent HMOs lacked antimicrobial and antibiofilm activity, their β-amino derivatives significantly inhibit biofilm formation in both species. Field Emission Gun-Scanning Single Electron Microscopy (FEG-SEM) revealed that treatment of the β-amino HMOs significantly inhibits bacterial adherence and eliminates the ability of both microbes to form biofilms.

ObjectiveTo ascertain the role of platelet glycoprotein Ib α‐chain (GPIbα) plasma protein levels in cardiovascular, autoimmune, and autoinflammatory diseases and whether its effects are mediated by platelet count.MethodsWe performed a two‐sample Mendelian randomization (MR) study, using both a cis‐acting protein quantitative trait locus (cis‐pQTL) and trans‐pQTL near the GP1BA and BRAP genes as instruments. To assess if platelet count mediated the effect, we then performed a two‐step MR study. Putative associations (GPIbα/platelet count/disease) detected by MR analyses were subsequently assessed using multiple‐trait colocalization analyses.ResultsAfter correction for multiple testing (Bonferroni‐corrected threshold P ≤ 2 × 10−3), GPIbα, instrumented by either cis‐pQTL or trans‐pQTL, was causally implicated with an increased risk of oligoarticular and rheumatoid factor (RF)–negative polyarticular juvenile idiopathic arthritis (JIA). These effects of GPIbα appeared to be mediated by platelet count and were supported by strong evidence of colocalization (probability of all 3 traits sharing a common causal variant ≥0.80). GPIbα instrumented by cis‐pQTL did not appear to affect cardiovascular risk, although the GPIbα trans‐pQTL was associated with an increased risk of cardiovascular diseases and autoimmune diseases but a decreased risk of autoinflammatory diseases, suggesting that this trans‐acting instrument operates through other pathways.ConclusionThe role of platelets in thrombosis is well‐established; however, our findings provide some novel genetic evidence that platelets may be causally implicated in the development of oligoarticular and RF‐negative polyarticular JIA, and indicate that GPIbα may serve as a putative therapeutic target for these JIA subtypes.

International audience; Because of its size and geographical position, the Cherbourg roadstead appears as a favourable site for Marine Renewable Energy (MRE) industry. As a result, Cherbourg harbour has undergone profound changes (2015 and 2016) due to the installation of industrial infrastructures to service the needs of expanding MRE further offshore. However, little is known about the morpho-sedimentary distribution and associated dynamics of seabed sediments before and after harbour transformations. This study focuses on sedimentary dynamics using detailed morphological and sedimentological analyses based on data acquired before changes (2012). The main map includes a unique bathymetric map (1:35,000) and sedimentary maps showing the percentage of the characteristic grain size fractions of 184 seabed samples. Despite the high tidal conditions, the roadstead construction had a significant impact on the sedimentary facies and distribution. This study provides a basis for future investigations on geomorphological evolution linked to the impact of anthropogenic development.

Fine grinding, required to liberate valuable minerals in finely disseminated deposits, creates significant challenges for beneficiation. For these deposits, traditional gravity separation techniques are often ineffective, and centrifugal separators, such as the Knelson Concentrator, are required. The Knelson Concentrator is well established for treating gold ores, and due to its relatively low cost and small environmental impact when compared to other separation techniques, it has become an active area of research for the processing of lower specific gravity (SG) minerals. This work investigates the optimum operating conditions when processing fine (−53 μm) low SG material using a laboratory Knelson Concentrator. A synthetic feed comprised of magnetite (SG 5.2) and quartz (SG 2.65), with grades of 5%, 10% and 15% magnetite, was used to mimic a low-density ore. Central composite design was used to design the experiments and response surface method was used for optimization, with the experimental variables being bowl speed (G), fluidizing water rate (L/min) and solids feed rate (g/min). The results indicate, for 5% and 10% magnetite feeds, that bowl speed impacts concentrate grade negatively and heavy mineral recovery positively, while the fluidizing water rate has an opposite effect on separation. A trade off between grade and recovery must therefore be made when processing this material. When processing the 15% feed, maximum concentrate grade and magnetite recovery were achieved at high bowl speeds and low fluidizing water rates.

Objective Variants in the SLCO1B1 gene, encoding a hepatic methotrexate (MTX) transporter, affect clearance of high-dose MTX. We tested whether in the *14 and *15 alleles of SLCO1B1 influenced the response to low-dose MTX in juvenile idiopathic arthritis (JIA) patients. Methods The study included 310 JIA patients genotyped for three single nucleotide polymorphisms (SNPs) in SLCO1B1 (rs4149056, rs2306283, and rs11045819). A patient's SLCO1B1 diplotype was determined by combining the SNPs into the *1a, *1b, *4, *5, *14, and *15 alleles. Number of active joints at follow-up (visit closest to 6 months of treatment and prior to starting a tumor necrosis factor inhibitor) was used as the dependent variable in a negative binomial regression model that included active joint count at baseline as a covariate. Results The SLCO1B1*14 allele was associated with less response to MTX (P = 0.024) and the *15 allele was not associated with response to MTX (P = 0.392). Conclusion SLCO1B1 alleles may be associated with poor response to MTX in JIA patients. The *14 allele has been associated with fast clearance (low exposure) after high-dose MTX in patients with leukemia. Thus, the SLCO1B1 gene may be informative for precision dosing of MTX in JIA patients. Patients carrying the *14 allele may require a higher dose than noncarriers to achieve a similar response to MTX.

Resume La structure anatomique unissant la patella au tibia porte a present la denomination internationale de « ligament patellaire ». Si le terme parait consacre, son choix peut etre source de confusion aupres des confreres non experts. En effet, le role de cette structure n’est pas en priorite la stabilite articulaire du genou comme les ligaments croises ou collateraux mais une prolongation de l’action mecanique du quadriceps vers le squelette jambier au-dela du « sesamoide patellaire ». Les atteintes de ce que nous nommerons le tendon patellaire sont tres frequentes en pathologie sportive. Une majorite de ces atteintes touche le tiers proximal sous la pointe de la patella. Cette tres frequente tendinopathie continue d’etre decrite comme tendinopathie d’insertion. A partir de la relecture de 100 IRM consecutives du genou et de dissection cadaverique, nous confirmons que l’insertion du tendon patellaire a lieu sur la face anterieure de la patella et non la pointe. Nous decrivons egalement deux variantes anatomiques du tendon patellaire sain (type 1 et 2) qu’il convient de ne pas confondre avec un foyer de tendinopathie. Les limites anatomiques entre le tissu tendineux et le corps adipeux infra-patellaire (lig. adipeux de Hoffa), notamment sur le tiers superieur, manquent encore de clarte et meritent d’autres travaux.

Common carbohydrate protecting group reactions under continuous flow processes are reported in the context of producing partially-protected glucose building blocks from levoglucosan. Benzyl ether protection was demonstrated without the use of NaH using barium oxide, which, however, pointed to the need for forms of this catalyst not as susceptible to close packing under flow. Acylation conditions were developed under continuous flow in acetonitrile and avoiding pyridine. Ring-opening the derivatized levoglucosan with propanethiol was also demonstrated producing S-alkyl 2,4-di-O-benzyl-glucopyranoside building block in 2 rather than 12 steps in increased overall yield.

ObjectivesJuvenile idiopathic arthritis (JIA) is the most prevalent form of juvenile rheumatic disease. Our understanding of the genetic risk factors for this disease is limited due to low disease prevalence and extensive clinical heterogeneity. The objective of this research is to identify novel JIA susceptibility variants and link these variants to target genes, which is essential to facilitate the translation of genetic discoveries to clinical benefit.MethodsWe performed a genome-wide association study (GWAS) in 3305 patients and 9196 healthy controls, and used a Bayesian model selection approach to systematically investigate specificity and sharing of associated loci across JIA clinical subtypes. Suggestive signals were followed-up for meta-analysis with a previous GWAS (2751 cases/15 886 controls). We tested for enrichment of association signals in a broad range of functional annotations, and integrated statistical fine-mapping and experimental data to identify target genes.ResultsOur analysis provides evidence to support joint analysis of all JIA subtypes with the identification of five novel significant loci. Fine-mapping nominated causal single nucleotide polymorphisms with posterior inclusion probabilities ≥50% in five JIA loci. Enrichment analysis identified RELA and EBF1 as key transcription factors contributing to disease risk. Our integrative approach provided compelling evidence to prioritise target genes at six loci, highlighting mechanistic insights for the disease biology andIL6STas a potential drug target.ConclusionsIn a large JIA GWAS, we identify five novel risk loci and describe potential function of JIA association signals that will be informative for future experimental works and therapeutic strategies.

Tertiary lymphoid structures (TLS) are ectopic lymphoid formations that form within nonlymphoid tissue. They share structural and functional characteristics with secondary lymphoid structures such as lymph nodes and can contain B-cell follicles and germinal centers surrounded by a T-cell region. TLS have been described in several types of cancers and are usually associated with positive patient outcomes. However, TLS differ vastly in cellular composition and location within tissue types. In this review, we discuss factors confounding the interpretation of the evidence for a prognostic role for TLS in cancer and frame these factors in the context of translation to regular clinical use.

Background Juvenile idiopathic arthritis (JIA) is a clinically heterogeneous group of childhood onset inflammatory joint diseases with strong evidence to support a genetic contribution to susceptibility. JIA is divided into seven clinical subgroups based on observed patterns of clinical symptoms using the International League of Associations for Rheumatology (ILAR) classification system. The genetic overlap between these groups is not completely understood and this lack of knowledge typically leads to the different ILAR groups being analysed as discrete entities potentially reducing the power of genetic association studies. The aim of this study was to conduct a large case-control association study on susceptibility to JIA to identify novel susceptibility loci and to investigate differences in these associations between the different ILAR groups for the purposes of maximising power. Methods JIA participants were genotyped on the Illumina Infinium CoreExome or OmniExpress arrays. UK population control genotype data was obtained from the Understanding Society Longitudinal Study. Quality control of data was performed conforming to conventional standards and imputation was performed using the Haplotype Reference Consortium panel on the Michigan Imputation Server. Association testing of all SNPs was performed with an additive model incorporating imputation uncertainty using SNPTEST. Testing for specificity and sharing across ILAR groups was performed using Bayesian multinomial regression in the Trinculo software package. Loci passing the suggestive significance threshold (5x10-6) were selected for meta-analysis with previously published JIA GWAS data assuming fixed effects and weighted by inverse-variance using the software package GWAMA. Results Following quality control the dataset consisted of > 7.4 million SNPs for 3305 JIA cases and 9196 controls. We found no strong evidence to support association of any SNP to a specific ILAR group with most of the SNPs showing evidence for sharing across multiple groups. Association testing in a combined dataset of all ILAR groups identified seven SNPs associated at genome-wide significance (5x10-8); six of these have previously been reported for JIA while one is a novel association. The novel association (rs497523, p-value = 7.12x10-9) maps to chromosome 16p11 and is located within intron one of the CCDC101 gene. Meta-analysis identified association to rs7647909 which is an intronic variant in the FOXP1 gene (p-value 2.0x10-9) and rs2614258 within the AHI1 gene (p-value 9.5x10-12). Conclusion We identified novel associations to SNPs in the CCDC101 and FOXP1 genes. In addition, we report a genome-wide significant association to AHI1, previously reported at suggestive significance levels. Fine mapping with the integration of genomic data will be required to identify the true causal gene at each of these loci. The results provide little evidence to support ILAR subgroup specificity for any of the associated variants and combined analysis of data across subgroups maximised power to identify novel associations. Disclosures J. Bowes None. M.C. Marion None. S. Smith None. A. Yarwood None. M. Sudman None. D. Tarasek None. C.D. Langefeld None. S.D. Thompson None. W. Thomson None.

Objective Variants in the SLCO1B1 gene, encoding a hepatic methotrexate (MTX) transporter, affect clearance of high‐dose MTX. We tested whether in the *14 and *15 alleles of SLCO1B1 influenced the response to low‐dose MTX in juvenile idiopathic arthritis (JIA) patients. Methods The study included 310 JIA patients genotyped for three single nucleotide polymorphisms (SNPs) in SLCO1B1 (rs4149056, rs2306283, and rs11045819). A patient's SLCO1B1 diplotype was determined by combining the SNPs into the *1a, *1b, *4, *5, *14, and *15 alleles. Number of active joints at follow‐up (visit closest to 6 months of treatment and prior to starting a tumor necrosis factor inhibitor) was used as the dependent variable in a negative binomial regression model that included active joint count at baseline as a covariate. Results The SLCO1B1*14 allele was associated with less response to MTX (P = 0.024) and the *15 allele was not associated with response to MTX (P = 0.392). Conclusion SLCO1B1 alleles may be associated with poor response to MTX in JIA patients. The *14 allele has been associated with fast clearance (low exposure) after high‐dose MTX in patients with leukemia. Thus, the SLCO1B1 gene may be informative for precision dosing of MTX in JIA patients. Patients carrying the *14 allele may require a higher dose than noncarriers to achieve a similar response to MTX.

Energy-transport effects can alter the structure that develops as a supernova evolves into a supernova remnant. The Rayleigh–Taylor instability is thought to produce structure at the interface between the stellar ejecta and the circumstellar matter, based on simple models and hydrodynamic simulations. Here we report experimental results from the National Ignition Facility to explore how large energy fluxes, which are present in supernovae, affect this structure. We observed a reduction in Rayleigh–Taylor growth. In analyzing the comparison with supernova SN1993J, a Type II supernova, we found that the energy fluxes produced by heat conduction appear to be larger than the radiative energy fluxes, and large enough to have dramatic consequences. No reported astrophysical simulations have included radiation and heat conduction self-consistently in modeling supernova remnants and these dynamics should be noted in the understanding of young supernova remnants., Radiation and conduction are generally considered as the main energy transport mechanisms for the evolution of early supernova remnants. Here the authors experimentally show the role of electron heat transfer on the growth of Rayleigh–Taylor instability in young supernova remnants.

Systemic lupus erythematosus (SLE) is a chronic, multisystem, autoimmune inflammatory disease with genomic and non-genomic contributions to risk. We hypothesize that epigenetic factors are a significant contributor to SLE risk and may be informative for identifying pathogenic mechanisms and therapeutic targets. To test this hypothesis while controlling for genetic background, we performed an epigenome-wide analysis of DNA methylation in genomic DNA from whole blood in three pairs of female monozygotic (MZ) twins of European ancestry, discordant for SLE. Results were replicated on the same array in four cell types from a set of four Danish female MZ twin pairs discordant for SLE. Genes implicated by the epigenetic analyses were then evaluated in 10 independent SLE gene expression datasets from the Gene Expression Omnibus (GEO). There were 59 differentially methylated loci between unaffected and affected MZ twins in whole blood, including 11 novel loci. All but two of these loci were hypomethylated in the SLE twins relative to the unaffected twins. The genes harboring these hypomethylated loci exhibited increased expression in multiple independent datasets of SLE patients. This pattern was largely consistent regardless of disease activity, cell type, or renal tissue type. The genes proximal to CpGs exhibiting differential methylation (DM) in the SLE-discordant MZ twins and exhibiting differential expression (DE) in independent SLE GEO cohorts (DM-DE genes) clustered into two pathways: the nucleic acid-sensing pathway and the type I interferon pathway. The DM-DE genes were also informatically queried for potential gene–drug interactions, yielding a list of 41 drugs including a known SLE therapy. The DM-DE genes delineate two important biologic pathways that are not only reflective of the heterogeneity of SLE but may also correlate with distinct IFN responses that depend on the source, type, and location of nucleic acid molecules and the activated receptors in individual patients. Cell- and tissue-specific analyses will be critical to the understanding of genetic factors dysregulating the nucleic acid-sensing and IFN pathways and whether these factors could be appropriate targets for therapeutic intervention.

Objective Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease and has a strong genomic component. To date, JIA genetic association studies have had limited sample sizes, used heterogeneous patient populations, or included only candidate regions. The aim of this study was to identify new associations between JIA patients with oligoarticular disease and those with IgM rheumatoid factor (RF)−negative polyarticular disease, which are clinically similar and the most prevalent JIA disease subtypes. Methods Three cohorts comprising 2,751 patients with oligoarticular or RF-negative polyarticular JIA were genotyped using the Affymetrix Genome-Wide SNP Array 6.0 or the Illumina HumanCoreExome-12+ Array. Overall, 15,886 local and out-of-study controls, typed on these platforms or the Illumina HumanOmni2.5, were used for association analyses. High-quality single-nucleotide polymorphisms (SNPs) were used for imputation to 1000 Genomes prior to SNP association analysis. Results Meta-analysis showed evidence of association (P < 1 × 10−6) at 9 regions: PRR9_LOR (P = 5.12 × 10−8), ILDR1_CD86 (P = 6.73 × 10−8), WDFY4 (P = 1.79 × 10−7), PTH1R (P = 1.87 × 10−7), RNF215 (P = 3.09 × 10−7), AHI1_LINC00271 (P = 3.48 × 10−7), JAK1 (P = 4.18 × 10−7), LINC00951 (P = 5.80 × 10−7), and HBP1 (P = 7.29 × 10−7). Of these, PRR9_LOR, ILDR1_CD86, RNF215, LINC00951, and HBP1 were shown, for the first time, to be autoimmune disease susceptibility loci. Furthermore, associated SNPs included cis expression quantitative trait loci for WDFY4, CCDC12, MTP18, SF3A1, AHI1, COG5, HBP1, and GPR22. Conclusion This study provides evidence of both unique JIA risk loci and risk loci overlapping between JIA and other autoimmune diseases. These newly associated SNPs are shown to influence gene expression, and their bounding regions tie into molecular pathways of immunologic relevance. Thus, they likely represent regions that contribute to the pathology of oligoarticular JIA and RF-negative polyarticular JIA.

The beneficiation of rare earth element (REE) minerals may include many different beneficiation unit operations, but the final process choice typically depends on the inherent mineral characteristics. The Nechalacho REE deposit contains multiple low specific gravity, diamagnetic silicate gangue minerals (predominantly feldspars and quartz) and high specific gravity, iron oxide minerals (magnetite and hematite). The valuable REE minerals (REM) in the deposit consist of a variety of relatively high specific gravity, paramagnetic minerals. A process has been proposed to concentrate the value REM through a combination of gravity (rejecting silicate gangue) and magnetic (rejecting iron oxide gangue) separation steps prior to froth flotation. This work employed a laboratory-scale process including two different gravity separation steps (Knelson and Falcon centrifugal concentrators) followed by a series of varying intensity wet drum magnetic separation steps as well as dry induced roll magnetic separation and wet high intensity magnetic separation steps. The resultant fractions have been characterized by XRD, ICP-MS, and QEMSCAN to identify the optimum fraction for downstream flotation separation. The combination of a Knelson Concentrator with low intensity wet drum magnetic separation was found to efficiently concentrate REM while also rejecting high specific gravity iron oxide minerals. A novel finding from this study is the concentration of heavy REE-bearing zircon into coarse size fractions after grinding.

The application of mineral beneficiation techniques to valuable rare earth element (REE) bearing minerals requires a significant amount of research. A previous paper (Jordens et al., 2016) described a series of physical separation processes employed to pre-concentrate rare earth minerals (REM) and reject iron oxide minerals from the Nechalacho Deposit. In addition to grade and recovery information it is important to understand the performance of these separations from a mineralogical perspective. Information on liberation, mineral associations, magnetic properties and size-by-size recoveries can be used to further improve process designs for this deposit. This work employs automated mineralogy (QEMSCAN), scanning electron microscopy and a vibrating sample magnetometer to characterise the products from laboratory gravity separation (Knelson and Falcon centrifugal concentrators) and magnetic separation (varying intensity wet drum magnetic separators). The information gathered is then used to identify the optimum fraction for downstream flotation separation. The selected flowsheet included a Knelson centrifugal concentrator and low intensity drum magnetic separation resulting in a total rare earth oxide (TREO) recovery of 11.75% and a TREO grade of 7.50%.

Muscovite mica is an industrial mineral used in many different applications including coatings, construction materials and polymers. This mineral is commonly beneficiated using froth flotation, especially when treating finer particle sizes. A common flotation scheme employs a cationic amine collector for mica, at alkaline pH, with a depressant added to depress some of the common gangue minerals in muscovite deposits such as quartz and feldspars. This work examines the effects of Custamine 8113 (collector) and Norlig-H (depressant) on the flotation of a muscovite ore from a mineralogical perspective using QEMSCAN. In addition to traditional grade-recovery curves for the various mineral components of the ore, the QEMSCAN data are used to look at: size-by-size flotation recoveries, particle size differences between flotation concentrates and tailings, and mineral liberation and association. The lab-scale flotation results are then compared to idealized size-by-size grade-recovery curves calculated from the measured QEMSCAN data.

Resume La douleur meniscale est un symptome frequent, notamment chez le sportif d’âge mur. Les lesions responsables sont tres polymorphes, isolees ou associees a des atteintes ligamentaires ou cartilagineuses. La preservation du capital meniscal est a present unanimement reconnue et la prise en charge non chirurgicale d’emblee favorisee. Nous allons detailler la technique d’infiltration du mur meniscal guidee par l’echographie. Cette therapeutique, dont l’evaluation est en cours, pourrait constituer un traitement de premiere intention, sur, de realisation simple, peu onereux, lorsque les symptomes le justifient.

Dense medium separation (DMS) is a technique used to separate particles based on specific gravity. Conventional DMS is, however, limited to coarse particle sizes and is not practical when processing fines. To improve the separation efficiency when processing fine particles, centrifugal separators have been employed. This work investigates DMS in a lab centrifuge and a modified Falcon Concentrator, in order to process the slimes of a rare earth ore. It has been shown that centrifugal concentration using a dense medium is possible when recovering values from a slimes fraction. Both the lab centrifuge and modified Falcon Concentrator result in a similar performance.

Background/Purpose High serum interferon alpha (IFN-α) is an important heritable phenotype in systemic lupus erythematosus (SLE) which is involved in primary disease pathogenesis. High vs. low levels of IFN-α are associated with disease severity and account for some of the biological heterogeneity between SLE patients. The aim of the study was to replicate and fine-map previously detected genetic associations with serum IFN-α in SLE. Methods We previously undertook a case-case genome-wide association study of SLE patients stratified by ancestry and extremes of phenotype in serum IFN-α. Single nucleotide polymorphisms (SNPs) in seven loci identified in this screen were selected for follow up in a large independent cohort of 1370 SLE patients (703 European-ancestry, 432 African ancestry, and 235 Amerindian ancestry). Each ancestral background was analyzed separately, and ancestry-informative markers were used to control for ancestry and admixture. Results We find a rare haplotype spanning the promoter region of EFNA5 that is strongly associated with serum IFN-α in both African-American and European-American SLE patients (OR = 3.0, p = 3.7 × 10−6). We also find SNPs in the PPM1H, PTPRM, and NRGN regions associated with IFN-α levels in European-American, Amerindian, and African-American SLE patients respectively. Many of these associations are within regulatory regions of the gene, suggesting an impact on transcription. Conclusion This study demonstrates the power of molecular sub-phenotypes to reveal genetic factors involved in complex autoimmune disease. The distinct associations observed in different ancestral backgrounds emphasize the heterogeneity of molecular pathogenesis in SLE.

This paper presents a size-by-size kinetic characterization for copper-lead separation from a complex ore. Batch tests are run under extended flotation times to obtain approximately steady recoveries (unscreened samples) at the end of the tests. The size-by-size time-recovery curves are fitted to the Gamma model to obtain estimates for the maximum recovery R∞ and the flotation rate distribution f(k). From reverse J-shaped distributions to normal probability density functions are representable from a Gamma f(k). Four size classes are studied: −20 μm, +20/−38 μm, +38/−75 μm and +75/−150 μm. The concave relationship between recovery and particle size is obtained up to a limiting flotation time; thereafter, a decreasing trend is observed for Pb and Cu. The finest (−20 μm) and coarsest (+75/−150 μm) classes present slower average rate constants. However, the different f(k) shapes (reverse J-shaped versus mound-shaped distributions) indicate that the use of average rate constants leads to limited conclusions in terms of mineral losses. Therefore, better kinetic interpretations can be obtained from the overall analysis of: the R∞ estimates, a location parameter of f(k) and the metal losses in a low f(k) percentile (e.g., 5%). From the proposed methodology, the poor performance of any erratic component can then be characterized as slow-rate-limited, R∞-limited or both together.

Mothers giving birth to children with manifestations of neonatal lupus (NL) represent a unique population at risk for the development of clinically evident pathologic autoimmunity since many are asymptomatic and only become aware of anti-SSA/Ro positivity (anti-Ro+) based on heart block in their fetus. Accordingly, we hypothesized that the microbiome in saliva is associated with the development of autoreactivity and in some cases the progression in health status from benign to overt clinical disease including Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE). The study comprised a clinical spectrum of anti-Ro+ mothers, all of whom gave birth to a child with NL: 9 were asymptomatic or had an undifferentiated autoimmune disease (Asym/UAS) and 16 fulfilled criteria for SS and/or SLE. Microbial diversity was reduced across all levels from kingdom to species for the anti-Ro+ mothers vs healthy controls; however, there were no significant differences between Asym/UAS and SS/SLE mothers. Relative abundance of Proteobacteria and more specifically class Betaproteobacteria decreased with clinical severity (healthy controls Asym/UAS SS/SLE). These ordered differences were maintained through the taxonomic hierarchy to three genera (Lautropia, Comamonas, and Neisseria) and species within these genera (L. mirabilis, N. flavescens and N. oralis). Biometric analysis comparing von Willebrand Factor domains present in human Ro60 with L. mirabilis proteins support the hypothesis of molecular mimicry. These data position the microbiome in the development of anti-Ro reactivity and subsequent clinical spectrum of disease.

This paper presents the use and evaluation of enrichment ratios (ER) from different batch flotation protocols. Two protocols under flotation time extensions (>20 min) are analysed, which favour steady recoveries to be obtained at the end of the process. Agar’s criterion is used to evaluate the consistency between the maximum recovery obtained by regression and the total measured recoveries. A good agreement is observed under critical flotation times (tcrit) lower than 40% of the total flotation time, where tcrit corresponds to the time at which the incremental concentrate grade equals the feed grade (grinding product). A discretized ER is used as an approximation of instantaneous ER to characterize the evolution of the enrichment along the process. This discrete ER is defined as the ratio between the incremental concentrate grade and the grade of the solid in the flotation cell prior to the respective flotation interval. Discrete ERs greater than 1 along with significant discrete recoveries are feasible, suggesting that further analyses are required to evaluate the process exhaustion. Four size-by-size tests are also studied to assess the distribution of the discrete ERs at long flotation times. Almost all the evaluated classes present discrete ERs greater than 1 in the last flotation intervals. Therefore, the non-selective mechanisms (i.e., entrainment, true flotation of gangue and gangue association) cannot be considered as the predominant contributions to the overall discrete recoveries. Exceptions may be laboratory tests under very fast kinetic responses, high mass recoveries, long flotation times and high content of non-floatable valuable minerals.

BANK1 is a susceptibility gene for several systemic autoimmune diseases in several populations. Using the genome-wide association study (GWAS) data from Europeans (EUR) and African Americans (AA), we performed an extensive fine mapping of ankyrin repeats 1 (BANK1). To increase the SNP density, we used imputation followed by univariate and conditional analysis, combinedwith a haplotypic and expression quantitative trait locus (eQTL) analysis. The data from Europeans showed that the associated region was restricted to a minimal and dependent set of SNPs covering introns two and three, and exon two. In AA, the signal found in the Europeans was split into two independent effects. All of the major risk associated SNPs were eQTLs, and the risks were associated with an increased BANK1 gene expression. Functional annotation analysis revealed the enrichment of repressive B cell epigenomicmarks (EZH2 and H3K27me3) and a strong enrichment of splice junctions. Furthermore, one eQTL located in intron two, rs13106926, was found within the binding site for RUNX3, a transcriptional activator. These results connect the local genome topography, chromatin structure, and the regulatory landscape of BANK1 with co-transcriptional splicing of exon two. Our data defines a minimal set of risk associated eQTLs predicted to be involved in the expression of BANK1 modulated through epigenetic regulation and splicing. These findings allow us to suggest that the increased expression of BANK1 will have an impact on B-cell mediated disease pathways., The work presented in this paper has been supported by the Ministerio de Economía y Competitividad, Spain (SAF2016-78631-P), partly co-financed by FEDER funds of the European Union, the Gustaf den V:e-80-års Fond and the Swedish Association against Rheumatism to M.E.A-R. In addition, this work was financed by the NIH P01 grant P01-AI-083194 to C.D.L., J.B.H., R.K., and M.E.A-R. JBH: NIH grants: R01 AI024717, U01 HG00866, P30 AR070549 and U01 AI130830 and the US Department of Veterans Affairs: I01 BX001834.C.D.L.: Center for Public Health Genomics. R.K.: NIH grant R01-AR33062. J.A.J.: NIH grants U54GM104938, P30AR053483.

Background Systemic lupus erythematosus (SLE) exhibits marked ethnic disparities. The SLE Immunochip Consortium’s transancestral association study of SLE (27 574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry) raised the number of common risk variants to >100 (Langefeld 2017). There, we proposed the cumulative hit hypothesis, where the cumulative effect of individual loci is greater than if each locus acted independently. Here, we explore the joint contribution of SLE-susceptibility loci, how it varies by ethnicity, and whether there are distinct genetic risk profiles. Methods The SLE Immunochip study design, identification of risk loci, and genetic load (risk allele count (RAC) in EA samples) were previously described (Langefeld 2017). Genetic load was tested for association with SLE in an independent set of 2000/2000 EA case/controls, and in the AA and HA cohorts. Individuals in lowest 10% of the RAC distribution were the reference sample. A logistic regression model, adjusting for admixture, computed the odds ratio (OR) comparing the reference group to samples within a moving window of 20 unweighted RAC (moving window of 4 for the weighted (SNP’s log(OR)) analysis). Lasso regression identified EA risk SNPs that maximally predict SLE status in EA, then applied prediction to AA and HA. Factor analysis identified individual genetic risk profiles. Results The OR comparing lowest versus highest 10% of RAC was ∼30,∼6, and ∼3 for EA, HA and AA, respectively (figure 1), showing EA risk loci were not highly predictive of SLE risk in HA and AA. In EA, the moving window genetic load OR showed an increase beyond that predicted by independence but did not in HA and AA due to lower predictive ability. Lasso regression identified 51 risk alleles that maximally predicted SLE in EA, and a factor analysis identified seven uncorrelated risk profiles (one driven by HLA alleles and six by non-HLA loci). The lasso identified 31 (3 HLA) and 8 (no HLA) EA risk alleles as predictive in the HA and AA, respectively. Using predicted probabilities from the lasso in EA, the area under the ROC curve was 0.75 for EA, 0.72 for HA, and 0.60 for AA. Conclusions The EA SLE risk loci are highly predictive in EA (with a greater than additive effect), modestly predictive in HA, and weakly predictive in AA. We posit that the SLE genetics of AA are meaningfully different from EA and HA, merit increased study, and will require ethnicity-informed treatment strategies. Acknowledgements We would like to thank the SLE Immunochip Consortium, the Lupus Research Alliance, NIH (NIAMS and NIAID) and RILITE Foundation.

Background Systemic lupus erythematosus (SLE) in African-Americans (AA) is more prevalent, more severe and associated with an increased burden of co-morbidities compared to European-American (EA) populations. Genome-wide association studies (GWAS) have linked many single nucleotide polymorphisms (SNPs) to SLE. Recently, Langefeld (2017) conducted a large-scale transancestral association study of SLE to identify ancestry-dependent and independent contributions to SLE risk. We extend these findings to include a transancestral analysis linking SLE-associated SNPs to candidate-causal E-Genes specific to AA and EA populations and differential gene expression in these populations with the goal of matching genetic and genomic disease characteristics with available treatments unique to each ancestral group. Methods SNPs proxy to SLE-associated SNPs were compared with known expression quantitative trait loci (eQTLs) contained in the GTEx (version 6) database. E-QTLs and their associated E-Genes were divided by ancestry and compared to differentially expressed (DE) genes from multiple SLE gene expression datasets. For both ancestral groups, E-Gene lists were examined for the significant enrichment of BIG-C categories and IPA (Qiagen) Canonical Pathways to predict novel upstream regulators (UPRs). For visualization and clustering analysis, STRING-generated networks of DE E-Genes were imported into Cytoscape (version 3.6.1) and partitioned with the community clustering (GLay) algorithm via the clusterMaker2 (version 1.2.1) plugin. Finally, drug candidates targeting E-Genes, DE genes and UPRs were identified using CLUE, REST, API, IPA and STITCH (version 5.0; http://stitch.embl.de). The process of unpacking an SLE-associated SNP is shown in figure 1. Results E-QTL and DE gene queries of GTEx were combined and newly predicted E-Genes were pooled by ancestry. Here, we identify 52 SNPs with eQTLs unique to AA ancestry, 260 SNPs unique to EA ancestry and 1 SNP shared between ancestries. Together, these SNPs identified a total of 891 distinct E-Genes associated with both ancestral groups. In studies comparing E-Genes to SLE DE data sets, 516 EA E-Genes were differential expressed compared to 48 AA E-Genes. Comparison with various drug candidate databases resulted in the identification of 12 drugs targeting genes specific for AA, 77 drugs specific for EA genes and 13 shared between EA and AA. Predicted EA-specific drugs include hydroxychloroquine and drugs-in-development targeting CD40LG, CXCR1 and CXCR2 whereas AA-specific drugs include HDAC inhibitors, retinoids, and drugs targeting IRAK4 and CTLA4. Drugs targeting E-Genes/pathways shared by EA and AA include ibrutinib, ruxolitinib and ustekinumab. Conclusions The ancestral SNP-associated E-Genes and gene expression profiles outlined here illustrate fundamental differences in lupus molecular pathways between AA and EA. Our results indicate that unique sets of drugs may be particularly effective at treating lupus within each ancestral group. Acknowledgments Financial support for this research was provided by RILITE Research Institute.

Systemic lupus erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341. In B cell lines from patients with lupus and healthy controls, the lupus risk allele of rs11889341 was associated with increased STAT1 expression. We demonstrated that the transcription factor HMGA1, a member of the HMG transcription factor family with an AT-hook DNA-binding domain, has enriched binding to the risk allele compared with the non-risk allele of rs11889341.We identified a genotype-dependent repressive element in the DNA within the intron of STAT4 surrounding rs11889341. Consistent with expression quantitative trait locus (eQTL) analysis, the lupus risk allele of rs11889341 decreased the activity of this putative repressor. Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1. © The Author(s) 2018. Published by Oxford University Press. All rights reserved.