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Background: Pain often occurs in parallel with many neuropsychiatric disorders. However, the underlying mechanisms and potential causality have not been well studied. Methods: We collected the genome-wide association study (GWAS) summary statistics of 26 common pain and neuropsychiatric disorders with sample size ranging from 17,310 to 482,730 in European population. The genetic correlation between pair of pain and neuropsychiatric disorders, as well as the relevant cell types were investigated by linkage disequilibrium (LD) score regression analyses. Then transcriptome-wide association study (TWAS) was applied to identify the potential shared genes by integrating the gene expression information and GWAS. In addition, Mendelian randomization (MR) analyses were conducted to infer the potential causality between pain and neuropsychiatric disorders. Results: Among the 169 pairwise pain and neuropsychiatric disorders, 55 pairs showed significant ( P < 1.54×10 −4 ) positive correlations (median r g = 0.43) and 9 pairs showed negative correlations (median r g = −0.31). MR analyses identified 26 significant ( P Conclusion: Our findings provided the evidence of shared genetic structure, causality and potential shared pathogenic mechanisms between pain and neuropsychiatric disorders, and enhanced our understanding of the comorbidities of pain and neuropsychiatric disorders.

Using A-share listed companies in Shanghai and Shenzhen from 2008 to 2020 as the original sample, this paper focuses on the impact of M&A goodwill and on the total factor productivity of firms, so as to gain an in-depth understanding of the profound effect of M&A goodwill on firms. The main findings of this paper are: (1) M&A goodwill is negatively related to total factor productivity, i.e., it significantly reduces the total factor productivity of firms. (2) The mechanisms by which M&A goodwill affects firms' total factor productivity are: first, M&A goodwill changes asset allocation decisions, and second, it increases firms' executive compensation and Over-indebtedness. The research in this paper is based on a new perspective of M&A goodwill, which enriches and extends the micro foundations of total factor productivity theory. It also provides a detailed empirical analysis of the association between M&A goodwill and corporate total factor productivity from the perspective of listed companies as a whole, which is innovative. The further analysis of the relevant reasons remedies the lack of understanding of this aspect in the previous literature. In addition, the findings of this paper provide reflections and policy implications from three perspectives: firms themselves, regulators and investors.

Lightweight 3D porous self-floating platforms with enriched light-water-air-material interactive interfaces are promising candidates to promote solar energy utilization, regarding the requirements of solar-inspired reactions such as photothermal spill oil recovery and photocatalytic hydrogen production. Herein, we report a facile and controllable method to prepare lightweight porous carbon sponges by using low-cost melamine-formaldehyde (MF) foams as an environmental-friendly template and raw material, which are a widely-used mass disposal building solid waste with high porosity. Scanning electron microscopy shows the natural 100 μm level porous network structure of the MF foams is retained after carbonization. Nitrogen adsorption-desorption isotherms and corresponding pore size distributions clearly indicate the carbon sponges have unique hierarchical mesoporous features, which are beneficial for remediation of spilt oil or composite photocatalysis. X-ray diffraction data and Raman spectra verify the partial graphitization of the mesoporous carbon sponges, and Fourier-transform infrared spectroscopy and X-ray photoelectron spectroscopy confirm the presence of N- and O-containing functional groups. Joule-heating performance testing in a simulated oil spill case under sunlight shows that the carbon sponges are superior over the supported graphene containing a positive control in terms of heating and rheological regulation effects, and thus are useful in oil spill recovery. Further photocatalytic hydrogen evolution experiments using the graphitic carbon nitride (g-C3N4) semiconductor-coated carbon sponge suggest the successful assembly of an efficient carbon/g-C3N4 H2 production platform. Hence, this low-cost waste MF foam-derived carbon sponge platform with high mechanical applicability and durability is promising for use in various energy and environmental applications.

Objectives The anti-melanoma differentiation-associated gene 5 (MDA5) antibody is the main predictor of interstitial lung disease (ILD) in DM and clinically amyopathic DM (CADM). Nevertheless, a subset of MDA5+ patients have a favourable prognosis. We aimed to determine the possibility of using anti-MDA5 antibody isotypes and IgG subclasses for evaluating ILD risk. Methods The isotypes (IgG, IgA and IgM) of anti-MDA5 were detected in serum samples of 36 anti-MDA5+ patients with DM/CADM using ELISA. IgG subclasses of anti-MDA5 antibodies were further investigated. Laboratory findings and cumulative survival were analysed based on the isotypes of anti-MDA5 and subclasses of anti-MDA5 IgG. Results Among the MDA5+ patients with DM/CADM, the positive rates of anti-MDA5 IgG, IgA and IgM were 100, 97 and 6%, respectively. The positive rates of anti-MDA5 IgG1, IgG2, IgG3 and IgG4 were 72, 25, 0 and 28%, respectively. The incidence of acute interstitial pneumonia, mortality rate and serum ferritin were significantly higher in anti-MDA5 IgG1+ patients than in anti-MDA5 IgG1− patients with DM/CADM (P = 0.0027, 0.015, 0.0011, respectively). The sensitivity and specificity of anti-MDA5 IgG1 for predicting mortality were 100 and 41.7%, respectively. A combination of anti-MDA5 IgG1 and IgG4 for predicting mortality yielded better specificity (87.5%). Conclusion IgA and IgG are the primary anti-MDA5 antibody isotypes. Anti-MDA5 IgG1 is the primary component of MDA5 IgG subclasses and anti-MDA5 IgG1 and IgG4 might serve as useful biomarkers for predicting mortality in DM-ILD.

Objectives Extrahepatic tryptophan (Trp)-kynurenine (Kyn) metabolism via indoleamine 2,3-dioxygenase 1 (IDO1) induction was found to be associated with intrinsic immune regulation. However, the Trp-Kyn metabolism–associated immune regulation in dermatomyositis (DM) remains unknown. Therefore, we aimed to investigate the clinical relevance of the Trp-Kyn metabolism via IDO1 induction in DM. Methods Liquid chromatography-mass spectrometry (HPLC–MS) was used to examine the serum Kyn and Trp concentrations in DM. In addition, we used X-tile software to determine the optimal cutoff value of the Kyn/Trp ratio, a surrogate marker for Trp-Kyn metabolism. Spearman analysis was performed to evaluate the association of Trp-Kyn metabolism with muscle enzymes and inflammatory markers. Results DM patients had significantly higher serum Kyn/Trp ratio (× 10−3) when compared with the healthy controls. The serum Kyn/Trp ratio was positively correlated with the levels of muscle enzymes and inflammatory markers. In addition, the serum Kyn/Trp ratio significantly decreased (36.89 (26.00–54.00) vs. 25.00 (18.00–37.00), P = 0.0006) after treatment. DM patients with high serum Kyn/Trp ratio had a significantly higher percentage of muscle weakness symptoms (62.5% vs. 20.0%, P = 0.019) and higher levels of LDH (316.0 (236.0–467.0) vs. 198.0 (144.0–256.0), P = 0.004) and AST (56.5 (35.0–92.2) vs. 23.0 (20.0–36.0), P = 0.002)) than those with low serum Kyn/Trp ratio. Multiple Cox regression analyses identified ln(Kyn/Trp) (HR 4.874, 95% CI 1.105–21.499, P = 0.036) as an independent prognostic predictor of mortality in DM. Conclusions DM patients with enhanced Trp-Kyn metabolism at disease onset are characterized by more severe disease status and poor prognosis. Intrinsic immune regulation function via enhanced Trp-Kyn metabolism by IDO1 induction may be a potential therapeutic target in DM. Key Points• HPLC–MS identified increased serum Kyn/Trp ratio in DM patients, which positively correlated with levels of muscle enzymes and inflammatory markers and was downregulated upon treatment.• Cox regression analyses identified ln(Kyn/Trp) as an independent prognostic predictor of mortality in DM.• Monitoring intrinsic immune regulation function should be considered a potential therapeutic target in DM patients.

Fluorescence labeled ligands have been gaining importance as molecular tools, enabling receptor-ligand-binding studies by various fluorescence-based techniques. Aiming at red-emitting fluorescent ligands for the hH(2)R, a series of squaramides labeled with pyridinium or cyanine fluorophores (19-27) was synthesized and characterized. The highest hH(2)R affinities in radioligand competition binding assays were obtained in the case of pyridinium labeled antagonists 19-21 (pK(i): 7.71-7.76) and cyanine labeled antagonists 23 and 25 (pK(i): 7.67, 7.11). These fluorescent ligands proved to be useful tools for binding studies (saturation and competition binding as well as kinetic experiments), using confocal microscopy, flow cytometry, and high content imaging. Saturation binding experiments revealed pK(d) values comparable to the pK(i) values. The fluorescent probes 21, 23, and 25 could be used to localize H-2 receptors in HEK cells and to determine the binding affinities of unlabeled compounds.

High reactive oxygen species (ROS) generation efficiency and induction of targeted cell apoptosis are recognized as key objectives to achieve a highly efficient strategy for cancer therapy with minimum side effects of inflammatory reactions. However, it is still a challenge to realize higher therapeutic efficiency with a cell apoptosis model. Herein, we present strong upconversion luminescent biosafe cores derived from Linde Type A (LTA) zeolites and modification with targeted/therapeutic drugs for multimodal therapy, in which sonodynamic therapy (SDT) combined with photodynamic therapy (PDT) increases therapeutic efficiency especially in deep sites of tumor via producing cytoplasmic ROS and mitochondrial superoxide and photothermal therapy (PTT) enhances PDT effects via higher fluorescence resonance energy transfer (FRET) efficacy attributed to an increased temperature. Furthermore, the transcriptomic analysis reveals that cellular internalization of the nanosystem can lead to tumor ablation via cell apoptosis. We expect that the multimodal therapy based on LTA zeolite drug nanocarriers could be applied in the cancer therapeutics in the near future.

The co-modulation of the oxygen-containing and amino groups in the polymeric semiconductor graphitic carbon nitride (g-CN) has increasingly become a common concern toward advanced catalysis, energy and biomedicine applications. The intensive understanding of the existence state of oxygen-containing and amino groups in the polymeric structure of g-CN and the controllable methods of modulating these groups is highly desirable. Herein, a rational industrially applicable plasma strategy was designed and applied for controllable modulation of oxygen-containing and amino groups in g-CN within 10 min. X-ray diffractometry, Fourier transform infrared spectrometry, and X-ray photoelectron spectroscopy results indicated that the oxygen-containing and amino groups were controllably introduced after plasma treatment. Transmission electron microscopy, atomic force microscopy and N2 adsorption-desorption measurements verified the ultra-thin and two-dimensional in-plane mesoporous morphology of the optimized g-CN-O-NH2. As a result, the rational g–CN–O-NH2 performed well in Cr(VI) photoreduction, photocatalytic bacterial disinfection and inactivation of tumor cells. The remarkable extensively applicable photocatalytic activity can be ascribed to the fast charge carrier transfer benefiting from the enriched preferable internal edge sites and ideal joint effect of internal –NH2 and OH- groups, as confirmed by the significantly weakened PL fluorescence intensity and prolonged fluorescence lifetime of the excited states under visible light irradiation. This work provides an impressive industrially applicable strategy for the structure optimization and functional groups modulation of polymeric materials towards enhanced electronic and catalytic performances.

Fluorescently labeled dibenzodiazepinone-type muscarinic acetylcholine receptor (MR) antagonists, including dimeric ligands, were prepared using red-emitting cyanine dyes. Probes containing a fluorophore with negative charge showed high M2R affinities (pKi (radioligand competition binding): 9.10-9.59). Binding studies at M1 and M3-M5 receptors indicated a M2R preference. Flow cytometric and high-content imaging saturation and competition binding (M1R, M2R, and M4R) confirmed occupation of the orthosteric site. Confocal microscopy revealed that fluorescence was located mainly at the cell membrane (CHO-hM2R cells). Results from dissociation and saturation binding experiments (M2R) in the presence of allosteric M2R modulators (dissociation: W84, LY2119620, and alcuronium; saturation binding: W84) were consistent with a competitive mode of action between the fluorescent probes and the allosteric ligands. Taken together, these lines of evidence indicate that these ligands are useful fluorescent molecular tools to label the M2R in imaging and binding studies and suggest that they have a dualsteric mode of action.

Long non-coding RNA (lncRNA) H19 is associated with inflammatory diseases, but the molecular mechanism of H19 in the inflammatory process of ankylosing spondylitis (AS) is unclear. Here, we investigated the role of H19 and its downstream molecules in the inflammation of AS by microarray analysis, qRT-PCR, western blot, and dual-luciferase reporter assay. H19 small interfering RNA (siRNA) (Si-H19) and adenovirus (AD-H19) were used to decrease and increase H19 expression, respectively. 42 annotated lncRNAs were identified, and H19 was overexpressed. H19, vitamin D receptor (VDR), and transforming growth factor β (TGF-β) can bind to microRNA22-5p (miR22-5p) and miR675-5p. Si-H19 significantly downregulated miR22-5p and upregulated miR675-5p expression; Si-H19 decreased the protein and mRNA expression of VDR and decreased the cytokine and mRNA levels of interleukin-17A (IL-17A) and IL-23. These results were verified by AD-H19. In addition, miR22-5p and miR675-5p inhibitors increased the protein and mRNA expression of VDR and increased the cytokine and mRNA levels of IL-17A and IL-23. These results were also confirmed by miRNA mimics. Furthermore, H19 directly interfered with miR22-5p and miR675-5p expression, whereas the two miRNAs directly inhibited VDR expression. Overall, the H19-miR22-5p/miR675-5p-VDR-IL-17A/IL-23 signaling pathways have important roles in the pathogenesis of AS.

Structural defects and surface functional groups defects engineering in the graphitic carbon nitride (g-C3N4) polymer semiconductor usually has great benefit in optimizing its electron structure and photocatalytic performance. In this study, one type of carboxyl group defects-grafting g-C3N4 was prepared through glucose oxidase treatment on the initial O sites in the g-C3N4, which played multi-functional roles in the generation of carboxyl groups and melon structure defect. FT-IR, XPS and 13C NMR analysis verified the presence of highly favorable carboxyl groups, which was beneficial to the fast separation and migration of photogenerated carriers. The singularity of enzyme mediated defects control of carbon nitride materials was greatly boosted on O-enriched g-C3N4 (OCN) further supporting the overall O sites ring-opening hypothesis. The glucose oxidase (GOD) treated reconstructed g-C3N4 photocatalysts showed narrowed band gaps and fast charge separation ability as verified by UV–vis DRS and electrochemical tests. As a result, the optimized photocatalyst (GOD-OCN-3d) showed a high Cr(VI) photocatalytic detoxification rate of 99 %, which was 6.6 times higher than that of raw g-C3N4 (15 %) in 120 min. These findings open the understanding on precise molecular defects modulation of g-C3N4 via an environmental-friendly enzyme treatment approach, as well as providing a new avenue for understanding the function of structural defects of photocatalysts on prompting charge separation.

Previous studies found that the interleukin (IL)-17 level was elevated in inflammatory arthritis, but results were inconsistent. This meta-analysis aimed to investigate the association of IL-17 cytokine with osteoarthritis (OA), rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA).Relevant studies were searched using databases. Standardized mean difference (SMD) was calculated. Correlation coefficient was utilized to evaluate the relationship between IL-17 and disease activity of AS and RA. Subgroup analysis, sensitivity analysis and meta-regression were applied to explore the sources of heterogeneity.83 records were enrolled. The IL-17 level was elevated in AS (SMD = 2.348, P .001), RA (SMD = 1.502, P .001), PsA (SMD = 1.710, P .001) and OA (SMD = 1.192, P = .016), and similar results occurred in subgroup analysis. Furthermore, the IL-17 level was positively associated with disease activity of AS and RA.Circulating IL-17 level is significantly elevated in inflammatory arthritis and is related to the disease activity of AS and RA, suggesting that it plays an important role in the pathogenesis and progression of inflammatory arthritis (especially in AS and RA).

This study was conducted to clarify the associations of tumor necrosis factor-α induced protein 3 (TNFAIP3) and TNFAIP3-interacting protein 1 (TNIP1) genetic polymorphisms with ankylosing spondylitis (AS) susceptibility. Five single nucleotide polymorphisms (SNPs) in TNFAIP3 gene and four in TNIP1 gene were genotyped in 667 AS patients and 667 matched healthy controls. Genotypes and haplotype analysis were conducted by using SPSS 23.0 and Haploview 4.2 software. The T allele and CT genotype in TNFAIP3 rs10499194 were significantly associated with a reduced AS risk (T allele vs. C allele, OR = 0.619, 95% CI = 0.430–0.889, P = 0.009; CT vs. CC, OR = 0.603, 95% CI = 0.416–0.875, P = 0.007). However, no association remained significant after Bonferroni correction. The rs13207033A- rs10499194T haplotype of TNFAIP3 conferred a protective effect on AS susceptibility. Stratification analyses suggested that rs10499194 polymorphism decreased the risk of AS in the male subgroup, subgroup aged ≥ 29, HLA-B27 positive subgroup as well as the subgroups of BASFI P

To investigate the role of methylation levels of the IFN regulatory factor 8 (IRF8) gene promoter in the development of ankylosing spondylitis (AS). In this study, we compared the methylation levels of the IRF8 gene promoter between 99 AS patients and 99 healthy controls using MethylTarget approach. Quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) was performed to compare the mRNA levels of the IRF8 gene in the other 19 AS patients and 19 healthy controls. Differential methylation was found in 91 CpG sites of the IRF8 gene promoter, and 4 CpG regions were highly methylated in AS patients compared to healthy controls (p

Aim: Inflammatory arthritis (IA) diseases are relevant with subclinical atherosclerosis, but the data in ankylosing spondylitis (AS) were inconsistent. Therefore, we performed this meta-analysis to explore the relationship between the marker of subclinical atherosclerosis (carotid intima-media thickness (IMT)) and AS. Methods: We performed a systematic literature review using PubMed, Web of Science, Chinese National Knowledge Infrastructure (CNKI) and Chinese Biomedical Database (CBM) databases up to March 2018. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated to assess the association between carotid IMT and AS. Subgroup analysis, sensitivity analysis, and meta-regression were applied to explore the sources of heterogeneity, and publication bias was calculated to access the quality of pooled studies. Results: A total of 24 articles were collected. The carotid IMT was significantly increased in AS compared with healthy controls (SMD = 0.725, 95% CI = 0.443–1.008, p < 0.001). Subgroup analyses showed the Bath Ankylosing Spondylitis Activity Index (BASDAI) was the source of heterogeneity. Notably, IMT was not significantly increased in those studies that included > 50% patients treated with anti-TNF. Meta-regression revealed severe inflammation status (BASDAI and C-reactive protein (CRP)) could significantly impact carotid IMT in AS. Conclusions: Carotid IMT was significantly increased in patients with AS compared with healthy controls, which suggested subclinical atherosclerosis is related to AS.

As a promising visible-light-responsive catalyst, graphitic carbon nitride (g-C 3 N 4 ) has been widely used in environmental and energy applications owing to its unique semiconducting optoelectronic properties. However, the photocatalytic performance of bulk g-C 3 N 4 synthesized using N-containing precursors via a conventional thermal polycondensation process is generally limited by low crystallinity caused by incomplete polymerization. In addition to forced polymerization under high-pressure conditions, removing the unpolymerized and inactive part of bulk g-C 3 N 4 through controllable etching is another practical way to optimize its crystallinity. Therefore, we developed an economical and general method to fabricate g-C 3 N 4 with high crystallinity and excellent photocatalytic properties, in which cheap sodium nitrite aqueous solution is utilized as a moderate etching agent. The compositions and physiochemical properties of the products were comprehensively investigated by X-ray diffraction, Fourier-transform infrared spectroscopy, ultraviolet visible diffuse reflectance spectroscopy, X-ray photoelectron spectroscopy, N 2 adsorption-desorption, and electrochemical impedance spectroscopy measurements. In addition, ToF-SIMS (time-of-flight secondary ion mass spectrometry), a new surface analysis technology, was also used to determine the surface and structural characteristics of all samples. The obtained g-C 3 N 4 shows ideal high-crystallinity features and excellent charge transfer ability, leading to significantly improved Cr(vi) reduction activity under visible light. Moreover, there is only a low content of nitrite residue (63.3 mg g -1 ) in the final g-C 3 N 4 product, indicating that the method employing NaNO 2 , which is widely used in the food industry, is safe and waste-free. Therefore, the new controllable NaNO 2 etching method is cleaner and more efficient than commonly-used corrosion approaches based on strong acids or strong oxidants, and thus affords a new strategy in the regulation and structural design of various catalysts.

Recent advances in neuroscience make the extraction of full neuronal morphology at whole brain dataset available. To produce quality morphometry at large scale, it is highly desirable but extremely challenging to efficiently handle petabyte-scale high-resolution whole brain imaging database. Here, we developed a multi-level method to produce high quality somatic, dendritic, axonal, and potential synaptic morphometry, which was made possible by utilizing necessary petabyte hardware and software platform to optimize both the data and workflow management. Our method also boosts data sharing and remote collaborative validation. We highlight a petabyte application dataset involving 62 whole mouse brains, from which we identified 50,233 somata of individual neurons, profiled the dendrites of 11,322 neurons, reconstructed the full 3-D morphology of more than one thousand neurons including their dendrites and full axons, and detected million scale putative synaptic sites derived from axonal boutons. Analysis and simulation of these data indicate the promise of this approach for modern large-scale morphology applications.

Recent advances in brain imaging allow producing large amounts of 3-D volumetric data from which morphometry data is reconstructed and measured. Fine detailed structural morphometry of individual neurons, including somata, dendrites, axons, and synaptic connectivity based on digitally reconstructed neurons, is essential for cataloging neuron types and their connectivity. To produce quality morphometry at large scale, it is highly desirable but extremely challenging to efficiently handle petabyte-scale high-resolution whole brain imaging database. Here, we developed MorphoHub to address this challenge by optimizing both the data and workflow management. In particular, this work presents a multi-level method to produce high quality somatic, dendritic, axonal, and potential synaptic morphometry. Our method also boosts data sharing and remote collaborative validation. We applied MorphoHub to a petabyte application dataset involving 62 whole mouse brains, and identified 50,233 somata of individual neurons, profiled the dendrites of 11,322 neurons, reconstructed the full 3-D morphology of 1,050 neurons including their dendrites and full axons, and detected 1.9 million putative synaptic sites derived from axonal boutons. Analysis and simulation of these data indicate the promise of this approach for modern large-scale morphology applications.