Genetics of rheumatoid arthritis contributes to biology and drug discovery

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological datasets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here, we performed a genome-wide association study (GWAS) meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single nucleotide polymorphisms (SNPs). We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 1012–4. We devised an in-silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci (cis-eQTL)6, and pathway analyses7–9 – as well as novel methods based on genetic overlap with human primary immunodeficiency (PID), hematological cancer somatic mutations and knock-out mouse phenotypes – to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery

In-situ surface study on the mechanism of high-strain-rate superplasticity in an Al–Cu–Li alloy

An elongation of 880 % was obtained at a high initial strain rate of 1 × 10−2 s−1 at 470 °C in an Al–Cu–Li alloy produced by traditional thermomechanical-processing. The high-strain-rate superplastic deformation mechanisms during the whole deformation process were studied by SEM, EBSD, and FIB techniques. High-resolution surface studies employing focused ion beams reveal that grain boundary sliding accounts for up to 70 % of the overall strain. Furthermore, this phenomenon consistently maintains a high level, with a minimum value of 56 %, throughout the entire deformation process. Meanwhile, diffusion creep plays an accommodating role and stimulates the formation of striated bands

Superplastic Deformation Mechanisms in Fine-Grained 2050 Al-Cu-Li Alloys

The deformation behavior and microstructural evolution of fine-grained 2050 alloys at elevated temperatures and slow strain rates were investigated. The results showed that significant dynamic anisotropic grain growth occurred at the primary stage of deformation. Insignificant dislocation activity, particle-free zones, and the complete progress of grain neighbor switching based on diffusion creep were observed during superplastic deformation. Quantitative calculation showed that diffusion creep was the dominant mechanism in the superplastic deformation process, and that grain boundary sliding was involved as a coordination mechanism. Surface studies indicated that the diffusional transport of materials was accomplished mostly through the grain boundary, and that the effect of the bulk diffusion was not significant

Hydrogen-induced failure in a partially-recrystallized Al-Zn-Mg-Cu alloy with different aging conditions: Influence of deformation behavior dominated by microstructures

Hydrogen-induced failure in a partially-recrystallized Al-Zn-Mg-Cu alloy with different aging conditions was studied by in-situ electrochemical hydrogen charging method, and the hydrogen-induced cracking mechanism was elucidated by investigating the microstructure-dominated deformation behavior. It was found that in naturally-aged and peak-aged samples, cracks initiate at sample surfaces, and deformation dominated by shearing facilitates hydrogen diffusion, resulting in a high hydrogen embrittlement susceptibility. However, in the over-aged sample, deformation dominated by bypassing cannot transport hydrogen efficiently, which exerts no effect on crack initiation at the sample center. In addition, the same cracking pattern exists on all samples in silicone oil and in-situ hydrogen charging environments. The grain boundary of recrystallized grains is prone to strain localization, leading to intergranular cracking. In unrecrystallized grains, transgranular cracks propagate along intersections of slip lines and subgrain boundaries. This study improves the understanding of hydrogen embrittlement in new generation Al-Zn-Mg-Cu alloy by linking the existing hydrogen embrittlement mechanism to the deformation behavior dominated by microstructures

Sutureless Intrascleral Haptic-Hook Lens Implantation Using 25-Gauge Trocars

Purpose. To report a new technique for sutureless intrascleral fixation of three-piece foldable intraocular lenses (IOLs) using 25-gauge trocars. Methods. We performed this technique on patients with insufficient posterior capsule support. Seventeen eyes from 15 patients with aphakia, dislocated IOL, or subluxated crystalline lens undergoing posterior chamber sutureless implantation of an IOL were studied. The haptics of the IOL were externalized using two 25-gauge forceps. The haptics were bended back (hook-like) into the vitreous cavity through a scleral incision made by using a 25-gauge trocar. And, IOL tilt was determined by using a slit lamp and UBM, and complications were recorded. Results. The IOLs were fixed with exact centration and axial stability. No wound leakage was reported even without the use of sutures. The mean best-corrected visual acuity (BCVA) was 0.82 logarithm of the minimum angle of resolution (logMAR) units preoperatively, and the mean BCVA was 0.44 logMAR units at the 6-month follow-up visit. No postoperative retinal detachment, endophthalmitis, IOL tilt or dislocation, or vitreous hemorrhage was noted. Conclusion. Sutureless intrascleral haptic-hook posterior chamber IOL implantation using 25-gauge trocars provides good IOL fixation with reliable wound closure without the use of sutures. This trial is registered with ChiCTR1800017436

Effect of Aging Time on Crushing Performance of Al-0.5Mg-0.4Si Alloy for Safety Components of Automobile

The effect of aging time on the crushing performance of Al-0.5Mg-0.4Si alloy used for safety components of automobile was investigated by tensile test and crush test. Moreover, the microstructure of the alloy was investigated by transmission electron microscopy (TEM). The results show that the localized deformation ductility index, ΔAabs, which is defined as the difference between total elongation and uniform elongation, of Al-0.5Mg-0.4Si alloy is 6.5%, 7.0% and 8.5%, respectively, after being aged at 210 °C for 1, 3 and 6 h, and this tendency is the same as that of the crushing performance. The spacing of grain boundary precipitates (GBPs) from TEM results are found to be 94.9, 193.6 and 408.2 nm after being aged at 210 °C for 1, 3 and 6 h, respectively, and this tendency is same to that of ΔAabs. A mechanism about the relation between the spacing of GBPs and the ductility index ΔAabs has been proposed based on localized deformation around GBPs. With the increase of GBPs spacing, the ΔAabs increases, and the crushing performance is improved

Spontaneous axial myopia and emmetropization in a strain of wild-type guinea pig (Cavia porcellus). Invest Ophthalmol Vis Sci 50

PURPOSE. To describe a wild-type guinea pig strain with an incidence of spontaneous axial myopia, minimal pupil responses, lack of accommodation, and apparently normal spatial vision. Such a strain is of interest because it may permit the exploration of defective emmetropization and mapping of the underlying quantitative trait loci. METHODS. Twenty-eight guinea pigs were selected from 220 animals based on binocular myopia (exceeding Ϫ1.50 diopter [D]) or anisometropia (difference between both eyes exceeding 10 D) at 4 weeks of age. Refractions and pupil responses were measured with eccentric infrared photoretinoscopy, corneal curvature by modified conventional keratometer, and axial lengths by A-scan ultrasonography once a week. Twentyone guinea pigs were raised under a normal 12-hour light/12-hour dark cycle. From a sample of 18 anisometropic guinea pigs, 11 were raised under normal light cycle and 7 were raised in the dark to determine the extent to which visual input guides emmetropization. Spatial vision was tested in an automated optomotor drum. RESULTS. In 10 guinea pigs with myopia in both eyes, refractive errors ranged from Ϫ15.67 D to Ϫ1.50 D at 3 weeks with a high interocular correlation (R ϭ 0.82); axial length and corneal curvature grew almost linearly over time. Strikingly, two patterns of recovery were observed in anisometropic guinea pigs: in 12 (67%) anisometropia persisted, and in 6 (33%) it declined over time. These ratios remained similar in darkreared guinea pigs. Unlike published strains, all guinea pigs of this strain showed weak pupil responses and no signs of accommodation but up to 3 cyc/deg of spatial resolution. CONCLUSIONS. This strain of guinea pigs has spontaneous axial refractive errors that may be genetically or epigenetically determined. Interestingly, it differs from other published strains that show no refractive errors, vivid accommodation, or pupil responses. (Invest Ophthalmol Vis Sci