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Image denoising is an important topic in the digital image processing field. This paper theoretically studies the validity of the classical non-local mean filter (NLM) for removing Gaussian noise from a novel statistic perspective. By regarding the restored image as an estimator of the clear image from the statistical view, we gradually analyse the unbiasedness and effectiveness of the restored value obtained by the NLM filter. Then, we propose an improved NLM algorithm called the clustering-based NLM filter (CNLM) that derived from the conditions obtained through the theoretical analysis. The proposed filter attempts to restore an ideal value using the approximately constant intensities obtained by the image clustering process. Here, we adopt a mixed probability model on a prefiltered image to generate an estimator of the ideal clustered components. The experimental results show that our algorithm obtains considerable improvement in peak signal-to-noise ratio (PSNR) values and visual results when removing Gaussian noise. On the other hand, the considerable practical performance of our filter shows that our method is theoretically acceptable as it can effectively estimates ideal images.

Abstract We present an effective spectral matching method based on a shape association graph for finding region correspondences between two cel animation keyframes. We formulate the correspondence problem as an adapted quadratic assignment problem, which comprehensively considers both the intrinsic geometric and topology of regions to find the globally optimal correspondence. To simultaneously represent the geometric and topological similarities between regions, we propose a shape association graph (SAG), whose node attributes indicate the geometric distance between regions, and whose edge attributes indicate the topological distance between combined region pairs. We convert topological distance to geometric distance between geometric objects with topological features of the pairs, and introduce Kendall shape space to calculate the intrinsic geometric distance. By utilizing the spectral properties of the affinity matrix induced by the SAG, our approach can efficiently extract globally optimal region correspondences, even if shapes have inconsistent topology and severe deformation. It is also robust to shapes undergoing similarity transformations, and compatible with parallel computing techniques.

Abstract Objectives The aim of this work is to verify the non-inferior efficacy and safety of CMAB008 compared with innovator infliximab in rheumatoid arthritis patients combined with methotrexate. Methods We conducted a randomized, double-blinded, parallel, positive control design, multicenter study, with a stable dose of methotrexate. Patients were enrolled randomly with a ratio of 1:1 to receive intravenously CMAB008 3 mg/kg or innovator infliximab 3 mg/kg at weeks 0, 2, 6, 14, 22 and 30. The primary efficacy endpoint was American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 30. The non-inferiority was established if the lower limit of the one-sided 97.5% confidence interval (CI) for the difference was more than − 15% and the equivalence was established if the two-sided 95% CI was within ± 15% in an exploratory equivalence analysis. The secondary endpoints included other efficacy assessment parameters, as well as immunogenicity, safety, and pharmacokinetics. Results In the full analysis population (FAS), 110 (57.6%) of 191 patients in the CMAB008 group and 120 (62.2%) of 193 patients in the innovator infliximab group reached the primary outcome of ACR20 at week 30. The differences of the rates were − 4.6% and the lower limit of one-sided 97.5% confidence interval was − 14.29%, not less than the lower limit of the non-inferiority margin (− 15%); so CMAB008 was non-inferior to innovator infliximab. Further, CMAB008 was equivalent to innovator infliximab both in FAS (difference − 4.6%, 95% CI − 14.29% to 5.12%) and PPS (difference – 3.3%, 95% CI – 13.18% to 6.62%). The efficacy, safety, immunogenicity, and pharmacokinetics are highly similar between CMAB008 and innovator infliximab. Conclusions Non-inferior efficacy of CMAB008 to innovator infliximab is illustrated with similar early and lasting therapeutic effects, and the equivalence is further demonstrated. CMAB008 is well tolerated and has semblable safety compared with the innovator infliximab. Trial registration number NCT03478111.

Abstract In the context of normal product, we use the method of the integration within an ordered product (IWOP) of operators to derive three representations of the two-mode Wigner operator: SU(2) symmetric description, SU(1,1) symmetric description and polar coordinate form. We find that two-mode Wigner operator has multiple potential degrees of freedom. As the physical meaning of the selected integral variable changes, Wigner operator shows different symmetries. In particular, in the case of polar coordinates, we reveal the natural connection between the two-mode Wigner operator and the entangled state representation.

Abstract Background: Interleukin‐21 (IL‐21) has a regulatory effect on various immune cells. Its effect on macrophage function remains unclear. Aims: This study aimed to investigate the effect of IL‐21 on the macrophages‐mediated inflammatory response and explore its mechanism. Materials & Methods: Phorbol myristate acetate was used to induce THP‐1‐derived macrophages. Then, cells were stimulated with IL‐21 and/or lipopolysaccharide (LPS). To determine the effect of IL‐21 on the production of inflammatory factors in THP‐1‐derived macrophages, the messenger RNA (mRNA) and protein levels of IL‐6, tumor necrosis factor‐α (TNF‐α), IL‐8, and IL‐10 were detected by real‐time polymerase chain reaction (RT‐PCR) and enzyme‐linked immunosorbent assay (ELISA), respectively. Meanwhile, to explore the effect of IL‐21 on macrophage polarization, macrophage phenotype, gene expression, and cytokine secretion mediated by THP‐1‐derived macrophage were detected by flow cytometry, RT‐PCR, and ELISA. Results: First, we found that the IL‐21 receptor was expressed in THP‐1‐derived macrophages. IL‐21 enhanced LPS‐mediated TNF‐α, IL‐6, and IL‐10 production in THP‐1‐derived macrophages. During the polarization of THP‐1‐derived macrophages to M1‐like macrophages, IL‐21 induced the expression of macrophage surface markers CD86 and CD80, and related genes, such as TNF‐α, IL‐6, IL‐1β, and DC‐SIGN mRNA, inhibited Dectin‐1 mRNA expression and promoted the secretion of TNF‐α. During the polarization of THP‐1‐derived macrophages to M2‐like macrophages, IL‐21 enhanced the expression of macrophage surface markers CD86 and CD163, and related genes, such as TNF‐α, IL‐1β, IL‐10, Dectin‐1, and DC‐SIGN mRNA, and promoted the secretion of IL‐10. Conclusion: IL‐21 promotes LPS‐mediated production of inflammatory cytokines by THP‐1‐derived macrophages; IL‐21 plays a two‐way regulatory role in THP‐1‐derived macrophage polarization.

Abstract Alveolar epithelial cells play an essential role in the initiation and progression of pulmonary fibrosis, and the occurrence of epithelial–mesenchymal transition (EMT) may be the early events of pulmonary fibrosis. Recent studies have shown chemokines are involved in the complex process of EMT, and CXC chemokine ligand 16 (CXCL16) is also associated with many fibrosis-related diseases. However, whether CXCL16 is dysregulated in alveolar epithelial cells and the role of CXCL16 in modulating EMT in pulmonary fibrosis has not been reported. In this study, we found that CXCL16 and its receptor C-X-C motif chemokine receptor 6 (CXCR6) were upregulated in bleomycin induced EMT in human alveolar type II-like epithelial A549 cells. Synergistic effect of CXCL16 and bleomycin in promoting EMT occurrence, extracellular matrix (ECM) excretion, as well as the pro-inflammatory and pro-fibrotic cytokines productions in A549 cells were observed, and those biological functions were impaired by CXCL16 siRNA. We further confirmed that CXCL16 regulated EMT in A549 cells via the TGF-β1/Smad3 pathways. These results indicated that CXCL16 could promote pulmonary fibrosis by promoting the process of EMT via the TGF-β1/Smad3 signaling pathway.

High-phosphorus diet (HPD) reduces lipid deposition and significantly influences lipid metabolism. However, the relevant mechanism is unknown. Herein, using widely-cultured teleost tilapia Oreochromis niloticus as the experimental animals, we found that HPD and Pi incubation reduced triglyceride (TG) content (P ≤ 0.05), suppressed lipogenesis, activated AMP-activated protein kinase (AMPK) pathway and autophagy (P ≤ 0.05), and increased fatty acid β-oxidation and lipolysis in tilapia liver and hepatocytes (P ≤ 0.05). Our further investigation indicated that Pi treatments activated the lipophagy and facilitated mitochondrial fatty acid β-oxidation, and according reduced TG deposition (P ≤ 0.05). Mechanistically, phosphorus increased the AMPKα1 phosphorylation level at S496 and Beclin1 phosphorylation at S90, and Beclin1 phosphorylation by AMPKα1 was required for phosphorus-induced lipophagy and lipolysis. Our study revealed a mechanism for Beclin1 regulation and autophagy induction in response to high-phosphorus diet, and provided novel evidences for the link between dietary phosphorus addition and lipolytic metabolism via the AMPK/Beclin1 pathway. Our results also suggested that AMPK should be the potential target for the prevention and control of lipid metabolic disorders. Overall, these results suggested that HPD reduced hepatic lipid deposition by activating AMPK pathway and Beclin1 phosphorylation levels to activate lipophagy, which provided potential targets for the prevention and control of fatty liver in fish.

ABSTRACT Escherichia coli K1 causes bacteremia and meningitis in human neonates. The K1 capsule, an α2,8-linked polysialic acid (PSA) homopolymer, is its essential virulence factor. PSA is usually partially modified by O-acetyl groups. It is known that O-acetylation alters the antigenicity of PSA, but its impact on the interactions between E. coli K1 and host cells is unclear. In this study, a phase variant was obtained by passage of E. coli K1 parent strain, which expressed a capsule with 44% O-acetylation whereas the capsule of the parent strain has only 3%. The variant strain showed significantly reduced adherence and invasion to macrophage-like cells in comparison to the parent strain. Furthermore, we found that O-acetylation of PSA enhanced the modulation of trafficking of E. coli-containing vacuoles (ECV), enabling them to avoid fusing with lysosomes in these cells. Intriguingly, by using quartz crystal microbalance, we demonstrated that the PSA purified from the parent strain interacted with human sialic acid-binding immunoglobulin-like lectins (Siglecs), including Siglec-5, Siglec-7, Siglec-11, and Siglec-14. However, O-acetylated PSA from the variant interacted much less and also suppressed the production of Siglec-mediated proinflammatory cytokines. The adherence of the parent strain to human macrophage-like cells was significantly blocked by monoclonal antibodies against Siglec-11 and Siglec-14. Furthermore, the variant strain caused increased bacteremia and higher lethality in neonatal mice compared to the parent strain. These data elucidate that O-acetylation of K1 capsule enables E. coli to escape from Siglec-mediated innate immunity and lysosomal degradation; therefore, it is a strategy used by E. coli K1 to regulate its virulence. IMPORTANCE Escherichia coli K1 is a leading cause of neonatal meningitis. The mortality and morbidity of this disease remain significantly high despite antibiotic therapy. One major limitation on advances in prevention and therapy for meningitis is an incomplete understanding of its pathogenesis. E. coli K1 is surrounded by PSA, which is observed to have high-frequency variation of O-acetyl modification. Here, we present an in-depth study of the function of O-acetylation in PSA at each stage of host-pathogen interaction. We found that a high level of O-acetylation significantly interfered with Siglec-mediated bacterial adherence to macrophage-like cells, and blunted the proinflammatory response. Furthermore, the O-acetylation of PSA modulated the trafficking of ECVs to prevent them from fusing with lysosomes, enabling them to escape degradation by lysozymes within these cells. Elucidating how subtle modification of the capsule enhances bacterial defenses against host innate immunity will enable the future development of effective drugs or vaccines against infection by E. coli K1.

Background: There is heterogeneity in the clinical manifestations and responses to drugs in RA patients due to variety of factors such as genes and environment. Despite advances in the treatment of rheumatoid arthritis (RA), approximately 40% of RA patients still do not achieve primary clinical outcomes in randomized trials, and its low remission rate and high economic consumption remain unresolved, especially in developing countries. Iguratimod (IGU) is a new disease-modifying anti-rheumatic drug (DMARD) with a low price that has demonstrated good efficacy and safety in clinical trials and was approved for active RA in China and Japan. As the most populous country in the Western Pacific region, it is warranted to conduct a study with a large scale of patients in a real-life setting. Our study confirms the new option for RA patients, which is potentially benificial for public health in developing countries. Methods: This was a nationwide, prospective real-world study of IGU. Eligible subjects were active adult RA patients who aged 18 to 85 with or without multiple comorbidities such as hypertension and diabetes with DMARDs at a stable dosage for at least 12 weeks, or without ongoing DMARDs. A two-stage design was used for this study. In the first stage (the first 12 weeks), IGU 25 mg bid was added as monotherapy or to the background therapy, and in the second stage (the latter 12 weeks), adjustment of RA medicines other than IGU was allowed according to the participants’ disease activity. The primary endpoints were American College of Rheumatology 20% response (ACR20) 24 weeks and adverse events during 24 weeks. The secondary endpoints were ACR50 and ACR70 over 24 weeks, the changes of DAS28 and Health Assessment Questionnaire (HAQ) at week 12 and week 24 from baseline. The trial was registered with ClinicalTrials.gov, number NCT01554917. Findings: Between March 2012 and January 2015, 1759 participants were enrolled, of whom 81•5% (1433/1759) completed the study. Notably, 1597 patients in the full analysis set were assessed for the effectiveness and 1751 patients were in the safety analysis set; 71•9% (1148/1597) of the patients achieved the primary endpoint of ACR20 response at week 24, and 51•7% (906/1751) patients had at least 1 adverse event (AE). The incidence of the clinical significant AE (grade≥3) of special interest was 3•4% (54 patients for grade 3 and 6 patients for grade 4), and 0•7% (13/1751) of patients developed SAEs associated with IGU. The most common clinical significant AEs were infection in 0•6% (10/1751) of the patients, abdominal discomfort in 0•5% (9/1751) of the patients including 0•2% (3/1751) gastric ulcer, fracture in 0•4% (7/1751), and increased alanine aminotransferase (ALT) in 0•2% (3/1751) of the patients. The secondary endpoint of ACR50 and ACR70 response rates at week 24 were 47•4% (757/1597) and 24•0% (384/1597). DAS28 was 4•11±1•27 and 3•75±1•32 at week 12 and 24, which was significantly decreased -1•40±1•10 and -1•75±1•26 compared with baseline (P

Objectives: A phase III, 24-weeks Chinese clinical trial demonstrated that efficacy and safety outcomes of treatments with 40 mg/0.8 ml HS016 (n = 416) or adalimumab (n = 232) for active ankylosing spondylitis (AS) patients was comparable. In the present study, a subanalysis of the clinical trial was conducted to determine whether also individual efficacy indicators were comparable between HS016 and adalimumab.Methods: The individual efficacy indicators total and nocturnal back pain, global assessment of disease activity, swollen joint count, Maastricht AS Enthesitis Score, Bath AS Disease Activity Index, Bath AS Functional Index, Bath AS Metrology Index and chest expansion, were assessed at baseline and every 2 weeks during the treatment period.Results: This subanalysis revealed no significant difference between the patient groups treated with HS016 or adalimumab for any individual efficacy indicator investigated at any time point (all p > 0.05) beside faster total back pain score improvements in the adalimumab group on week 10, 12 and 22, which became equal at week 24. Among these indicators, chest expansion showed a significant increase at each time point compared with baseline, whereas all other efficacy indicators showed significant decreases compared with baseline at each time point (all p < 0.05). All efficacy indicators had increased or decreased rapidly by week 2, and the values continued to increase/decrease up to week 12, with subsequent smaller changes thereafter up to week 24 of treatment.Conclusion: The response trajectory of most individual efficacy indicators was comparable between HS016 and adalimumab at each time point during the 24 weeks of the trial.Clinical Trial Registration:http://www.chictr.org.cn/showproj.aspx?proj=37910, identifier [ChiCTR1900022520]

We propose a superconducting nanowire single photon detector (SNSPD) that can work efficiently at two target wavelengths and has a significant improvement in the counting rate due to the low-filling-factor nanowires in the silicon slots and the silver reflector. Numerical simulations show that the absorption efficiency can be over 90% at a single wavelength, whether the incident light wavelength is 1550 nm or 1064 nm, and over 80% when the SNSPD is designed to work at both wavelengths. In addition, the reset time is about 24% of the conventional SNSPDs. Our work presents a design for fabricating faster, larger-area, and multispectral SNSPDs with a high efficiency, which can be applied in applications such as quantum optics communication and multiwavelength sensing.

The linewidth broadening of the circular-polarized continuous wave laser mitigates the recoil effects of the sodium laser guide star very well. By choice of the optimal laser linewidth, the relations between the laser intensity and average spontaneous emission rates are obtained. The numerically simulated results show that the 1–100 MHz linewidth broadening effectively weakens recoil and enhances the average spontaneous emission rates. For laser powers from 10 W to 60 W, considering the intensity distribution with random at the mesospheric sodium layer, when the laser linewidth is broadened to be 1–100 MHz from 0 MHz, increments of the return photons go up to 110% from 50% and do not have an effect on the spot sizes of the sodium laser guide star. Several cases have proven that the linewidth broadening method is correct. Further calculations show that the linewidth broadening method similarly applies to the case of the multi-mode laser. Furthermore, the linewidth broadening of re-pumping should be taken into account.

The instrument line shape (ILS), as a very important parameter, has a significant influence on the inversion of trace gas concentration. Different levels of ILS degradation for H2O, CO2, CH4, and CO gases were investigated, and the influence of ILS on the inversion of column-averaged dry air mole fractions (DMFs) was assessed. Our results indicate that the averages of XH2O, XCH4, and XCO with modulation efficiency (ME) amplitude values have a positive correlation, the correlation coefficients are 0.9925, 0.9968, and 0.9981 respectively, whereas the relationship between the average of XCO2 and ME is a negative correlation with 0.986 correlation coefficient. For a typical ILS degradation, a decrease of 5% in the modulation efficiency amplitude value results in the average of XCO2 changing by 0.744%, XCH4 and XH2O are less sensitive species, with average values of −0.206% and −0.464%, whereas XCO shows the strongest intraday variability with an average value of −0.238%. However, with a decrease of 2‰ in the phase error (PE) value, the average of XCO changed by −0.150%, XCO2 and XH2O almost coincided with the same average value of −0.141%, whereas XCH4 was the least sensitive species with an average value of −0.133%. At the same time, we measured the ILS for EM27/SUN spectrometers—the mean values of modulation efficiency amplitudes and phase errors were 0.9611 and 0.00593. Compared with standard values, the modulation efficiency amplitudes and the phase error deviations were 2.450% and 0.433%. During the observation period, the daily average of XCO2 ranged from 415.09 to 421.78 ppm. XCH4 ranged from 1.96 to 2.02 ppm with a mean of 1.982 ppm, and the daily average of XCO ranged from 0.118 to 0.157 ppm with a mean of 0.137 ppm. For the relationship between XCO2 and XCH4, the linear regression line shows a good correlation with the correlation coefficient R2 ≥ 0.5. Especially, for the correlation coefficient R2 = 0.82 on 8 October, our studies found a weak correlation in the variation of CO2 and CO during the observations. The correlation coefficient R2 ≥ 0.5 was only found on 30 September and 3 October. The trajectories dram at a height of 10 km give a hint of trace gas transport from the bay of western India, Bengal, and the Arabian Sea, whereas for the trajectories dram boundary layer height, trace gases were transported from southwest and east of China. These results provide a theoretical basis to understand the time and space distribution and the changes of greenhouse gas in the atmosphere as well as providing a theoretical basis for calculations of atmospheric radiation transmission.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare systemic vasculitis commonly with cardiac complications. We describe a case of anti-PR3 ANCA-positive EGPA complicated by congestive heart failure and intraventricular thrombosis. Interestingly, the thrombus was resolved rapidly with steroid and cyclophosphamide in the setting of interrupted anticoagulation. To the best of our knowledge, we report the first case of anti-PR3 positive EGPA with extensive cardiac involvement. Our patient had overlapping features with previously studied ANCA-positive and ANCA-negative EGPA cases. We also hypothesize that the thrombogenic potential of eosinophils may play a central role in thrombogenesis in EGPA and aggressive immunosuppressive therapy remains the cornerstone of treatment, and the addition of anticoagulation therapy in the setting of thrombus formation and also very high risk of bleeding needs to be considered cautiously.

The X-linked hyperimmunoglobulin M syndrome (HIGM), caused by mutations in the CD40LG gene, is a kind of primary immunodeficiency disease (PID). Patients with X-linked HIGM are susceptible to infection as well as autoimmune diseases. Lipoma arborescens (LA) is a rare benign tumor, of which the pathogenesis mechanism has not been clearly understood. We report a case of HIGM combined with LA in a 22-year-old male patient. A new deletion mutation of CD40LG gene was detected in this case. The possible relationship between HIGM and LA was also discussed.

Dichlorodiphenoxytrichloroethane (DDT) is a known persistent organic pollutant and liver damage toxicant. However, there has been little emphasis on the mechanism underlying liver damage toxicity of DDT and the relevant effective inhibitors. Hence, the present study was conducted to explore the protective effects of vitamin C (VC) and vitamin E (VE) on the cytotoxicity of DDT in HL-7702 cells and elaborate the specific molecular mechanisms. The results demonstrated that p,p'-DDT exposure at over 10 µM depleted cell viability of HL-7702 cells and led to cell apoptotic. p,p'-DDT treatment elevated the level of reactive oxygen species (ROS) generation, induced mitochondrial membrane potential, and released cytochrome c into the cytosol, with subsequent elevations of Bax and p53, along with suppression of Bcl-2. In addition, the activations of caspase-3 and -8 were triggered. Furthermore, p,p'-DDT promoted the expressions of NF-κB and FasL. When the cells were exposed to the NF-κB inhibitor (PDTC), the up-regulated expression of FasL was attenuated. Strikingly, these alterations caused by DDT treatment were prevented or reversed by the addition of VC or VE, and the protective effects of co-treatment with VC and VE were higher than the single supplement with p,p'-DDT. Taken together, these findings provide novel experimental evidences supporting that VC or/and VE could reduce p,p'-DDT-induced cytotoxicity of HL-7702 cells via the ROS-mediated mitochondrial pathway and NF-κB/FasL pathway.