Epigenetic mechanisms can integrate gene-environment interactions that mediate disease transition from preclinical to clinically overt rheumatoid arthritis (RA). To better understand their role, we ...evaluated microRNA (miRNA, miR) expression profile in indigenous North American patients with RA who were positive for anticitrullinated protein antibodies; their autoantibody-positive, asymptomatic first-degree relatives (FDRs); and disease-free healthy control subjects (HCs).
Total RNA was isolated from whole blood samples obtained from HC (n = 12), patients with RA (n = 18), and FDRs (n = 12). Expression of 35 selected relevant miRNAs, as well as associated downstream messenger RNA (mRNA) targets of miR-103a-3p, was determined by qRT-PCR.
Whole blood expression profiling identified significantly differential miRNA expression in patients with RA (13 miRNAs) and FDRs (10 miRNAs) compared with HCs. Among these, expression of miR-103a-3p, miR-155, miR-146a-5p, and miR-26b-3p was significantly upregulated, whereas miR-346 was significantly downregulated, in both study groups. Expression of miR-103a-3p was consistently elevated in FDRs at two time points 1 year apart. We also confirmed increased miR-103a-3p expression in peripheral blood mononuclear cells from patients with RA compared with HCs. Predicted target analyses of differentially expressed miRNAs in patients with RA and FDRs showed overlapping biological networks. Consistent with these curated networks, mRNA expression of DICER1, AGO1, CREB1, DAPK1, and TP53 was downregulated significantly with miR-103a-3p expression in FDRs.
We highlight systematically altered circulating miRNA expression in at-risk FDRs prior to RA onset, a profile they shared with patients with RA. Prominently consistent miR-103a-3p expression indicates its utility as a prognostic biomarker for preclinical RA while highlighting biological pathways important for transition to clinically detectable disease.
Objective
Anti–citrullinated protein antibodies (ACPAs) are disease‐specific biomarkers in rheumatoid arthritis (RA). More than 90% of IgG ACPAs harbor N‐linked glycans in the antibody variable (V) ...domain. The corresponding N‐glycosylation sites in ACPA V‐region sequences result from somatic hypermutation, a T cell–dependent process. As ample evidence indicates that T cells drive the maturation of the ACPA response prior to arthritis onset, we undertook this study to investigate whether the presence of glycans in IgG ACPA V domains predicts the transition from predisease autoimmunity to overt RA.
Methods
We analyzed 2 independent sets of serum samples obtained from 126 ACPA‐positive first‐degree relatives (FDRs) of RA patients. Both sets originated from an Indigenous North American population and comprised cross‐sectional and longitudinal samples of individuals who did or did not develop inflammatory arthritis. Serum IgG ACPAs were affinity‐purified and subjected to ultra high‐performance liquid chromatography–based glycan analysis.
Results
In both data sets, FDR‐derived IgG ACPA displayed markedly lower levels of V domain glycans (<50%) compared to IgG ACPA from RA patients. Notably, FDRs who later developed RA showed extensive V‐domain glycosylation before the onset of arthritis. Moreover, IgG ACPA V‐domain glycosylation was strongly associated with future development of RA (hazard ratio 6.07 95% confidence interval 1.46–25.2; P = 0.013).
Conclusion
Extensive glycosylation of the IgG ACPA V domain is present in a subset of predisposed FDRs of Indigenous North American RA patients. The presence of this feature substantially increases the risk of RA development. Based on these findings, we propose that glycosylation of the IgG ACPA V domain represents a predictive marker for RA development in ACPA‐positive individuals and may serve to better target prevention measures.
A pollution flashover along an insulation surface—a catastrophic accident in electrical power system—threatens the safe and reliable operation of a power grid. Silicone rubber coatings are applied to ...the surfaces of other insulation materials in order to improve the pollution flashover voltage of the insulation structure. It is generally believed that the hydrophobicity of the silicone rubber coating is key to blocking the physical process of pollution flashover, which prevents the formation of continuously wet pollution areas. However, it is unclear whether silicone rubber coating can suppress the generation of pre-discharges such as corona discharge and streamer discharge. In this research, the influence of silicone rubber coating on the characteristics of surface streamer discharge was researched in-depth. The streamer ‘stability’ propagation fields of the polymer are lower than that of the polymer with silicone rubber coating. The velocities of the streamer propagation along the polymer are higher than those along the polymer with silicone rubber coating. This indicates that the surface properties of the polymer with the silicone rubber coating are less favorable for streamer propagation than those of the polymer.
The flashover along the insulator endangers the reliable operation of the electrical power system. The reasonable curved profiles of the shed could improve the flashover voltage, which would reduce ...power system outages. The research on the influence of the curved profiles of the shed on the streamer propagation along the insulator made of polymer was presented in the paper. The streamer propagation "stability" field, path, and velocity affected by the curved profiles of the shed, were measured by ultraviolet camera, ICCD camera, and photomultipliers. The "surface" component of the streamer is stopped at the shed with the different curved profiles, while the "air" component could go round the shed and reach the cathode. The streamer propagation "stability" fields are inversely proportional to the curved profiles of the shed. The streamer propagation velocities are proportional to the curved profiles of the shed. The relationship between the streamer propagation and the flashover propagation was discussed in depth. The subsequent flashover propagation is greatly affected by the streamer propagation path and "stability" field. Furthermore, the influence of the material properties on the streamer propagation path was also discussed in depth.
This study investigated the influencing mechanisms of shed shape on direct-current pollution flashover voltage and pressure decrease exponent through artificial pollution tests on a glass ...experimental model in Beijing (50 m altitude) and Tibet (4300 m altitude). Arc development before the flashover was quantitatively recorded using a high-speed camera. Three arc development modes along the pollution surface or in the inter-shed space were then extracted through arc development analysis. The occurrence probabilities of the three arc modes under various shed overhangs, altitudes, and shed spacings were analyzed. Mode probability was used to interpret the decreasing flashover voltage gradient with increasing shed overhang and decreasing shed spacing. Research indicates that pressure decrease exponent rises with shed overhang increase, as explained from the perspective of arc development probability. The quantitative relation between leakage distance efficiency and pressure decrease exponent was theoretically derived, and its validity was proven by comparing the calculated with the measured.
Epidemiological studies suggest vitamin D deficiency as a potential risk factor for rheumatoid arthritis (RA) development, a chronic autoimmune disorder highly prevalent in indigenous North American ...(INA) population. We therefore profiled the circulating levels of 25-hydroxyvitaminD 25(OH)D, an active metabolite of vitamin D, in a cohort of at-risk first-degree relatives (FDR) of INA RA patients, a subset of whom subsequently developed RA (progressors).
2007 onward, serum samples from INA RA patients and FDR were collected at the time of a structured baseline visit and stored at -20°C. Anti-citrullinated protein antibodies (ACPA), 25(OH)D, hs-CRP, vitamin-D binding protein (VDBP) and parathyroid hormone (PTH) levels were determined using ELISA and rheumatoid factor (RF) seropositivity was determined by nephelometry.
We demonstrate that 25 (OH) D concentrations were lower in winter than summer (P = 0.0538), and that serum 25(OH)D levels were higher in samples collected and stored after 2013 (P<0.0001). Analysis of samples obtained after 2013 demonstrated that 37.6% of study participants were 25(OH)D insufficient (<75nmol/L). Also, seropositive RA patients and FDR had lower 25(OH)D levels compared to ACPA-/FDR (P<0.05, P<0.01 respectively). Linear regression analysis showed 25(OH)D insufficiency was inversely associated with presence of RA autoantibodies. Longitudinal samples from 14 progressors demonstrated a consistent increase in 25(OH)D levels at the time they exhibited clinically detectable joint inflammation, without any significant change in VDBP or PTH levels. Spearman rank correlation analysis showed significant association between 25(OH)D and PTH levels, both in RA patients and progressors at RA onset time.
We demonstrate that 25(OH)D levels in serum increased at RA onset in progressors. The potential role that vitamin D metabolites and their downstream effects play in RA transition requires further investigation.
Rheumatoid arthritis (RA) is typically preceded by an extended preclinical period where circulating autoantibodies, particularly anti-citrullinated protein antibodies (ACPA), are detectable in the ...absence of clinical arthritis. Increased dietary intake of anti-inflammatory omega-3 (ω3) polyunsaturated fatty acids (PUFA) has been shown to be associated with a lower the risk of developing incident RA in large epidemiological studies. It is currently not known how changes in fatty acid (FA) metabolism may impact on the progression towards RA in at-risk individuals. To begin to address this question, we profiled serum FAs and oxylipins in an established cohort of at-risk ACPA-positive first-degree relatives (FDR) of RA patients (N = 31), some of whom developed RA (N = 4), and compared their profile to ACPA-negative FDR from the same population (N = 10).
Gas chromatography (GC) was used for FA quantitation. Oxylipins were extracted and quantified using high-performance liquid chromatography-tandem mass spectrometry (HPLC/MS/MS).
Although we did not detect any meaningful differences in overall FA content between ACPA + and ACPA - FDR, the levels of oxylipins derived from FA metabolism demonstrated significant differences between the two groups, with the ACPA + group demonstrating enrichment in circulating arachidonic acid- and eicosapentaenoic acid-derived molecules. Compared with the ACPA - FDR group, the ACPA + FDR, including those who progressed into inflammatory arthritis, displayed higher levels of LOX-derived oxylipins.
ACPA seropositivity in otherwise unaffected individuals at-risk for developing future RA based on family history (FDR) is associated with alterations in the serum oxylipin profile that suggests dysregulated LOX activity.
Aluminum alloys are widely used due to their exceptional properties, but the systematic relationship between their grain size and their tensile strength has not been thoroughly explored in the ...literature. This study aims to fill this gap by compiling a comprehensive dataset and utilizing machine learning models that consider both the alloy composition and the grain size. A pivotal enhancement to this study was the integration of hardness as a feature variable, providing a more robust predictor of the tensile strength. The refined models demonstrated a marked improvement in predictive performance, with XGBoost exhibiting an R2 value of 0.914. Polynomial regression was also applied to derive a mathematical relationship between the tensile strength, alloy composition, and grain size, contributing to a more profound comprehension of these interdependencies. The improved methodology and analytical techniques, validated by the models’ enhanced accuracy, are not only relevant to aluminum alloys, but also hold promise for application to other material systems, potentially revolutionizing the prediction of material properties.
Microseismic monitoring is crucial to improving stimulation efficiency of hydraulic fracturing treatment, as well as to mitigating potential induced seismic hazard. We applied an improved matching ...and locating technique to the downhole microseismic data set during one treatment stage along a horizontal well within the Weiyuan shale gas play inside Sichuan Basin in SW China, resulting in 3,052 well‐located microseismic events. We employed this expanded catalog to investigate the spatiotemporal evolution of the microseismicity in order to constrain migration of the injected fluids and the associated dynamic processes. The microseismicity is generally characterized by two distinctly different clusters, both of which are highly correlated with the injection activity spatially and temporarily. The distant and well‐confined cluster (cluster A) is featured by relatively large‐magnitude events, with ~40 events of M −1 or greater, whereas the cluster in the immediate vicinity of the wellbore (cluster B) includes two apparent lineations of seismicity with a NE‐SW trending, consistent with the predominant orientation of natural fractures. We calculated the b‐value and D‐value, an index of fracture complexity, and found significant differences between the two seismicity clusters. Particularly, the distant cluster showed an extremely low b‐value (~0.47) and D‐value (~1.35). We speculate that the distant cluster is triggered by reactivation of a preexisting critically stressed fault, whereas the two lineations are induced by shear failures of optimally oriented natural fractures associated with fluid diffusion. In both cases, the spatially clustered microseismicity related to hydraulic stimulation is strongly controlled by the preexisting faults and fractures.
Key Points
The expanded microseismic catalog from the iMLT provides more easily interpretable spatiotemporal evolution of the microseismicity
We identify two distinct clusters that are closely related to the injection activity both spatially and temporarily
One cluster is triggered by the reactivation of a preexisting fault, and the other one is controlled by shear failures of natural fractures
Background
Despite immune cell dysregulation being an important event preceding the onset of rheumatoid arthritis (RA), the phenotype of T and B cells in preclinical RA is less understood. The aim of ...this study was to characterize T and B cell populations in RA patients and their autoantibody (aAb) negative and positive first-degree relatives (FDR).
Methods
Cryopreserved peripheral blood mononuclear cells (PBMCs) collected at scheduled visits from aAb-(n=25), and aAb+ FDR (n=10) and RA patients (n=13) were thawed and stained using optimized antibody cocktails as per a specific 13-color T or B cell panel. Immunophenotyping was performed using a Cytoflex LX (Beckman-Coulter) flow cytometer and FlowJo software was used for analyzing the frequency of immune cell populations.
Results
Multicolor flow cytometry experiments identified an increased TIGIT expression in circulating lymphocytes of aAb+ FDR and RA patients, relative to aAb- FDR (P<0.01). These TIGIT
+
T cells exhibited a memory phenotype and expressed high levels of PD-1, ICOS, HLA-DR, CXCR3 and CXCR5. Moreover, increased TIGIT
+
CD4 T cell frequency correlated with the frequency of PD-1
+
CD4 T cells (r = 0.4705:
P
= 0.0043) and circulating levels of ACPA and RF. We also identified a decreased frequency of CD27+IgD- switched memory B cells in RA patients (
P
< 0.01), while increased frequency of TIGIT+ CD4 T cells in FDR correlated with the frequency of PD1
+
PTEN
+
B cells (r = 0.6838,
P
= 0.0004) and autoantibody positivity (
P
= 0.01).
Conclusion
We demonstrate TIGIT as a distinct CD4 T cell marker for differentiating aAb- FDR from aAb+FDR and might play a critical role in regulating T and B cell crosstalk in preclinical RA.
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