Single-cell transcriptomics reveals variations in monocytes and Tregs between gout flare and remission.

Gout commonly manifests as a painful, self-limiting inflammatory arthritis. Nevertheless, the understanding of the inflammatory and immune responses underlying gout flares and remission remains ambiguous. Here, based on single-cell RNA-Seq and an independent validation cohort, we identified the potential mechanism of gout flare, which likely involves the upregulation of HLA-DQA1+ nonclassical monocytes and is related to antigen processing and presentation. Furthermore, Tregs also play an essential role in the suppressive capacity during gout remission. Cell communication analysis suggested the existence of altered crosstalk between monocytes and other T cell types, such as Tregs. Moreover, we observed the systemic upregulation of inflammatory and cytokine genes, primarily in classical monocytes, during gout flares. All monocyte subtypes showed increased arachidonic acid metabolic activity along with upregulation of prostaglandin-endoperoxide synthase 2 (PTGS2). We also detected a decrease in blood arachidonic acid and an increase in leukotriene B4 levels during gout flares. In summary, our study illustrates the distinctive immune cell responses and systemic inflammation patterns that characterize the transition from gout flares to remission, and it suggests that blood monocyte subtypes and Tregs are potential intervention targets for preventing recurrent gout attacks and progression.

MSU crystal deposition contributes to inflammation and immune responses in gout remission.

As a prominent feature of gout, monosodium urate (MSU) crystal deposition induces gout flares, but its impact on immune inflammation in gout remission remains unclear. Using single-cell RNA sequencing (scRNA-seq), we characterize the transcription profiling of peripheral blood mononuclear cells (PBMCs) among intercritical remission gout, advanced remission gout, and normal controls. We find systemic inflammation in gout remission with MSU crystal deposition at the intercritical and advanced stages, evidenced by activated inflammatory pathways, strengthened inflammatory cell-cell interactions, and elevated arachidonic acid metabolic activity. We also find increased HLA-DQA1high classic monocytes and PTGS2high monocytes in advanced gout and overactivated CD8+ T cell subtypes in intercritical and advanced gout. Additionally, the osteoclast differentiation pathway is significantly enriched in monocytes, T cells, and B cells from advanced gout. Overall, we demonstrate systemic inflammation and distinctive immune responses in gout remission with MSU crystal deposition, allowing further exploration of the underlying mechanism and clinical significance in conversion from intercritical to advanced stage.

Metabolomics analysis of human plasma reveals decreased production of trimethylamine N-oxide retards the progression of chronic kidney disease.

BACKGROUND AND PURPOSE: Chronic kidney disease (CKD) is a global public health problem and one of the leading causes of all-cause mortality. However, the pathogenic mechanisms and intervention methods for CKD progression are not fully understood. EXPERIMENTAL APPROACH: Plasma from patients with uraemia and from healthy controls (n = 30 per group) was analysed with LC-MS/MS-based non-targeted metabolomics to identify potential markers of uraemia. These potential markers were validated in the same cohort and a second cohort (n = 195) by quantitative analysis of the markers, using LC-MS/MS. The most promising marker was identified by correlation analysis and further validated using HK-2 cells and mouse models. KEY RESULTS: Trimethylamine N-oxide (TMAO) was identified as a promising marker among the 18 potential markers found in the first cohort, and it was optimally correlated with renal function of CKD patients in the second cohort. Treatment of HK-2 cells with TMAO decreased cell viability and up-regulated expression of α-smooth muscle actin. In mice, a TMAO-containing diet decreased kidney mass and increased protein expression of α-smooth muscle actin. Also, control of TMAO production by inhibiting its biosynthetic pathway with 3,3-dimethyl-1-butanol or disrupting gut microbiota function with an antibiotic cocktail, attenuated renal injury in a murine model of CKD. CONCLUSION AND IMPLICATIONS: Our data show that decreased TMAO production could be a new strategy to attenuate the progression of renal injury in CKD.

Quantitative proteomics by iTRAQ-PRM based reveals the new characterization for gout.

BACKGROUND: Gout is a common and complex form of immunoreactive arthritis based on hyperuricemia, while the symptoms would turn to remission or even got worse. So, it is hard to early identify whether an asymptomatic hyperuricemia (AHU) patient will be susceptible to get acute gout attack and it is also hard to predict the process of gout remission to flare. Here, we report that the plasma proteins profile can distinguish among acute gout (AG), remission of gout (RG), AHU patients, and healthy controls. METHODS: We established an isobaric tags for relative and absolute quantification (iTRAQ) and parallel reaction monitoring (PRM) based method to measure the plasma proteins for AG group (n = 8), RG group (n = 7), AHU group (n = 7) and healthy controls (n = 8). RESULTS: Eleven differentially expressed proteins such as Histone H2A, Histone H2B, Thrombospondin-1 (THBS1), Myeloperoxidase (MPO), Complement C2, Complement component C8 beta chain (C8B), Alpha-1-acid glycoprotein 1 (ORM1), Inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4), Carbonic anhydrase 1 (CA1), Serum albumin (ALB) and Multimerin-1 (MMRN1) were identified. Histone H2A, Histone H2B and THBS1 might be the strongest influential regulator to maintain the balance and stability of the gout process. The complement and coagulation cascades is one of the main functional pathways in the mechanism of gout process. CONCLUSIONS: Histone H2A, Histone H2B and THBS1 are potential candidate genes for novel biomarkers in discriminating gout attack from AHU or RG, providing new theoretical insights for the prognosis, treatment, and management of gout process. TRIAL REGISTRATION: This study is not a clinical trial.

Hydrodynamic and topography based cellular automaton model for simulating debris flow run-out extent and entrainment behavior.

As for late, studies have indicated that cellular automaton (CA) models are among the most effective solutions for simulating the extent of debris-flow run-out. However, it is currently difficult to effectively simulate both the inundated area and the erosion pattern of the debris flow process. This difficulty is caused by the lack of detailing regarding debris flow hydrodynamics as the primary concern of most CA-based models is the topographic gradient of the gully. In this study, we propose a two-dimensional Monte Carlo simulation-based CA model with hydrodynamic methods describing debris-flow behavior to address these problems. Herein, a topography function concerning slope gradient and bed roughness, and a persistence function regarding flow inertia, are combined to improve the flow routing algorithm for better determining the run-out extent of debris flow. Hydraulic links and discharge exchange between neighboring cells using sink-filling approach, as well as the bed sediment entrainment function, are incorporated into the CA model to describe the mass migration process along the flow path. To verify the performance of our proposed model, we further select the 2010 Yohutagawa debris flow event in Japan as a case study. The results indicate that the proposed model better simulates the complex dynamic process of debris flow.

A retrospective analysis reveals a predictor of survival for the patient with paraquat intoxication.

Feasible and accurate predictors are urgently needed to evaluate the survival for patients with paraquat poisoning since the high mortality of paraquat poisoning always resulted in the loss of both life and money. Multiple predictors have been developed to predict prognosis of the patients with PQ poisoning, which however heavily depend on the time of admission to hospitals. Here we reported a feasible and accurate prognosis predictor for patients with paraquat poisoning that is independent of the time of admission to hospitals. Patients with paraquat poisoning were enrolled in this study according to the inclusion and exclusion criteria, which were grouped into survivors and non-survivors based on the 90-days follow-up investigation. The concentration of paraquat in serum and urine, and the baseline clinical parameters associated with the injuries of the liver, kidney, and lung were evaluated to predict the survival of these patients by using receiver operating characteristic curve (ROC) analysis, univariate and multivariate cox regression analyses. A total of 114 patients was included in this study with a survival rate of 54.4%. The median survival days of non-survivors were 6.0 (95%Cl: 4.0-7.8). A new predictor, namely paraquat concentration-associated multiorgan injury index (PCAMII), was established by integrating serum and urine paraquat concentration, serum creatinine, alanine aminotransferase, aspartate transaminase, total and direct bilirubin, at different weighting coefficients, with the accuracy of about 90%. The model to predict the survival probability by PCAMII was established with good fitness (R2 = 0.9325), providing the simulated survival rates comparable to the clinical data. PCAMII, which is independent of hospital admission time, is a feasible and accurate marker to predict the survival rate of patients with PQ poisoning.

Comprehensive analysis of landslide stability and related countermeasures: a case study of the Lanmuxi landslide in China.

We report on a comprehensive method for analyzing landslide stability and the mitigation effect of countermeasures in this paper. The proposed method is a combination of theoretical method and numerical method. To address the uncertainties of the soil strength parameters, the rational values of these parameters are comprehensively determined by the back-analysis result of the reliability method and the result by the quantitative method, as well as the in-situ geological test. To evaluate the slope stability, the limit analysis using the 2D upper bound method and the FEM simulation using strength reduction method are performed, respectively. In order to illustrate the presented method, the so-called Lanmuxi landslide in China is selected as a case study. Results demonstrated that the stress and strain majorly concentrated at the toe and crown of the slope. According to the analysis results, countermeasures consisting of anchor lattice beams, landslide piles, and cracks filling, are suggested to reduce the failure risk of the landslide. Effect assessment based on the FEM analysis verifies the feasibility and effectiveness of the recommended countermeasures.

Soft-template construction of three-dimensionally ordered inverse opal structure from Li2FeSiO4/C composite nanofibers for high-rate lithium-ion batteries.

Exploring a new method to fabricate small-sized nanofibers is essential to achieve superior performances for energy conversion and storage devices. Here, a novel soft-template strategy is developed to synthesize a three-dimensionally ordered macroporous (3DOM) architecture constructed from small-sized nanofibers. The effectiveness of a nanofiber-assembled three-dimensional inverse opal material as an electrode for high-rate lithium-ion batteries is demonstrated. The small-sized Li2FeSiO4/C composite nanofibers with a diameter of 20-30 nm are grown by employing a tri-block copolymer P123 as a structure directing agent. Accordingly, the macro-mesoporous hierarchical 3DOM architecture constructed from Li2FeSiO4/C nanofibers is further templated from P123 for the nanofibers and a polystyrene colloidal crystal array for the 3DOM architecture. We find that the thermal stability of the nanofiber morphology depends on the self-limited growth of Li2FeSiO4 nanocrystals in a crystalline-amorphous hybrid. As a cathode for a lithium-ion battery, the 3D hierarchical macro-mesoporous cathodes exhibit outstanding high-rate and ultralong-life performances with a capacity retention of 84% after 1500 cycles at 5 C in the voltage window of 1.5-4.5 V, which is greatly improved compared with a simple 3DOM Li2FeSiO4/C nanocomposite.

BRAFV600E mutation in papillary thyroid microcarcinoma: a meta-analysis.

The prognostic value of the BRAFV600E mutation, resulting in poor clinical outcomes of papillary thyroid carcinoma, has been generally confirmed. However, the association of BRAFV600E with aggressive clinical behaviors of papillary thyroid microcarcinoma (PTMC) has not been firmly established in individual studies. We performed this meta-analysis to examine the relationship between BRAFV600E mutation and the clinicopathological features of PTMC. We conducted a systematic search in PubMed, EMBASE, and the Cochrane library for relevant studies. We selected all the studies that reported clinicopathological features of PTMC patients with information available on BRAFV600E mutation status. Nineteen studies involving a total of 3437 patients met these selection criteria and were included in the analyses. The average prevalence of the BRAFV600E mutation was 47.48%, with no significant difference with respect to patient sex (male versus female) and age (younger than 45 years versus 45 years or older). Compared with the WT BRAF gene, the BRAFV600E mutation was associated with tumor multifocality (odds ratio (OR) 1.38; 95% CI, 1.04-1.82), extrathyroidal extension (OR 3.09; 95% CI, 2.24-4.26), lymph node metastases (OR 2.43; 95% CI, 1.28-4.60), and advanced stage (OR 2.39; 95% CI, 1.38-4.15) of PTMC. Thus, our findings from this large meta-analysis definitively demonstrate that BRAFV600E-mutation-positive PTMC are more likely to manifest with aggressive clinicopathological characteristics. In appropriate clinical settings, testing for the BRAFV600E mutation is likely to be useful in assisting the risk stratification and management of PTMC.