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Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the synovial membrane, leading to cartilage destruction and bone erosion. Due to the complex pathogenesis of RA and the limitations of current therapies, increasing research attention has been directed towards novel strategies targeting fibroblast-like synoviocytes (FLS), which are key cellular components of the hyperplastic pannus. Recent studies have highlighted the pivotal role of FLS in the initiation and progression of RA, driven by their tumour-like transformation and the secretion of pro-inflammatory mediators, including cytokines, chemokines and matrix metalloproteinases. The aggressive phenotype of RA-FLS is marked by excessive proliferation, resistance to apoptosis, and enhanced migratory and invasive capacities. Consequently, FLS-targeted therapies represent a promising avenue for the development of next-generation RA treatments. The efficacy of such strategies – particularly those aimed at modulating FLS signalling pathways – has been demonstrated in both preclinical and clinical settings, underscoring their therapeutic potential. This review provides an updated overview of the pathogenic mechanisms and functional roles of FLS in RA, with a focus on critical signalling pathways under investigation, including Janus kinase/signal transducer and activator of transcription (JAK/STAT), mitogen-activated protein kinase (MAPK), nuclear factor kappa B (NF-κB), Notch and interleukin-1 receptor-associated kinase 4 (IRAK4). In addition, we discuss the emerging understanding of FLS-subset-specific contributions to immunometabolism and explore how computational biology is shaping novel targeted therapeutic strategies. A deeper understanding of the molecular and functional heterogeneity of FLS may pave the way for more effective and precise therapeutic interventions in RA.
Studying the effect of interleukin-17 (IL-17) on the mechanism of CD4+ T-cell immune regulation and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway may offer new ideas and methods for the therapy of dilated cardiomyopathy.
Methods:
Naive CD4+ T cells were isolated from mice using a magnetic bead sorting reagent and manipulated by overexpression or knockdown of IL-17. Protein levels of Janus kinase 2 (JAK2), phosphorylated JAK2 (p-JAK2), signal transducer and activator of transcription 3 (STAT3), phosphorylated STAT3 (p-STAT3), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9) were determined by Western blotting. Quantitative polymerase chain reaction was used to assess the levels of JAK2, STAT3, MMP-2, and MMP-9. Expression of tumour necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-4 (IL-4), and interferon-gamma (IFNγ) was determined by enzyme-linked immunosorbent assay test kits. TNF-α, IL-1β, IL-4, and IFNγ secretion was measured by flow cytometry.
Results:
In CD4+ T cells, IL-17 overexpression increased TNF-α, IL-1β, IL-4, IFNγ, p-JAK2, p-STAT3, MMP-2, MMP-9 levels, and apoptosis. Knockdown of IL-17 reduced the levels of TNF-α, IL-1β, IL-4, IFNγ, p-JAK2, p-STAT3, MMP-2, and MMP-9, as well as the level of apoptosis.
Conclusion:
Through regulation of IL-17 expression in CD4+ T cells, this study reveals its crucial role in regulating the secretion of inflammatory factors, activation of the JAK/STAT signaling pathway, expression of matrix metalloproteinases, and apoptosis of CD4+ T cells.
Aerospace represents the development of national science and technology. It is an important foundation for exploring space and an important guarantee for the construction of aerospace power. There are many large workpieces in the aerospace field. The box insulation layer of large workpieces is an important processing problem. A new thick processing equipment is proposed to process the box insulation layer of large workpieces. The thick processing equipment consists of the XYZ shaft long guide rail and five degrees of freedom (5-DOF) RAPA. The mechanical structure of the 5-DOF RAPA is a redundantly actuated parallel mechanism (RAPM). Meanwhile, this paper proposes a new method to design 5-DOF redundantly actuated parallel mechanisms (RAPMs) with large output rotational angles. Based on configuration evolution and Li group, two articulated moving platforms (AMPs) and four kinds of limbs are designed, and a series of 3T2R (T represents translation, R represents rotation) RAPMs and 2T3R RAPMs are synthesized. To verify the designed RAPMs with large angle, an example of RAPMs, 4UPS-{2UPR}-R is analyzed. To ensure that the RAPM has no mechanism vibration impact in movement, this paper represents the RAPM adopts a newly proposed trajectory planning method. The results show that the 4SPU-(2UPR)R mechanism possesses large angles and verifies the efficiency of the new proposed trajectory planning method in simplified trajectories. This work lays the foundation for processing the box insulation layer of large workpieces with straight lines and arcs paths.
The target backsheath field acceleration mechanism is one of the main mechanisms of laser-driven proton acceleration (LDPA) and strongly depends on the comprehensive performance of the ultrashort ultra-intense lasers used as the driving sources. The successful use of the SG-II Peta-watt (SG-II PW) laser facility for LDPA and its applications in radiographic diagnoses have been manifested by the good performance of the SG-II PW facility. Recently, the SG-II PW laser facility has undergone extensive maintenance and a comprehensive technical upgrade in terms of the seed source, laser contrast and terminal focus. LDPA experiments were performed using the maintained SG-II PW laser beam, and the highest cutoff energy of the proton beam was obviously increased. Accordingly, a double-film target structure was used, and the maximum cutoff energy of the proton beam was up to 70 MeV. These results demonstrate that the comprehensive performance of the SG-II PW laser facility was improved significantly.
A study of small-amplitude shape oscillations of a viscous compound droplet suspended in a viscous host fluid is performed. A generalized eigenvalue problem is formulated and is solved by using the spectral method. The effects of the relevant non-dimensional parameters are examined for three cases, i.e. a liquid shell in a vacuum and a compound droplet in a vacuum or in a host fluid. The fundamental mode $l=2$ is found to be dominant. There exist two oscillatory modes: the in phase and the out of phase. In most situations, the interfaces oscillate in phase rather than out of phase. For the in-phase mode, in the absence of the host, as the viscosity of the core or the shell increases, the damping rate increases whereas the oscillation frequency decreases; when the viscosity exceeds a critical value, the mode becomes aperiodic with the damping rate bifurcating into two branches. In addition, when the tension of the inner interface becomes smaller than some value, the in-phase mode turns aperiodic. In the presence of the unbounded host fluid, there exists a continuous spectrum. The viscosity of the host may decrease or increase the damping rate of the in-phase mode. The mechanism behind it is discussed. The density contrasts between fluids affect oscillations of the droplet in a complicated way. Particularly, sufficiently large densities of the core or the host lead to the disappearance of the out-of-phase mode. The thin shell approximation predicts well the oscillation of the compound droplet when the shell is thin.
In this paper, we present a method for generating a copula by composing two arbitrary n-dimensional copulas via a vector of bivariate functions, where the resulting copula is named as the multivariate composite copula. A necessary and sufficient condition on the vector guaranteeing the composite function to be a copula is given, and a general approach to construct the vector satisfying this necessary and sufficient condition via bivariate copulas is provided. The multivariate composite copula proposes a new framework for the construction of flexible multivariate copula from existing ones, and it also includes some known classes of copulas. It is shown that the multivariate composite copula has a clear probability structure, and it satisfies the characteristic of uniform convergence as well as the reproduction property for its component copulas. Some properties of multivariate composite copulas are discussed. Finally, numerical illustrations and an empirical example on financial data are provided to show the advantages of the multivariate composite copula, especially in capturing the tail dependence.
Carrier-based unmanned aerial aircraft (UAV) structure is subjected to severe tensile load during takeoff, especially the drawbar, which affects its fatigue performance and structural safety. However, the complex structural features pose great challenges for the engineering design. Considering this situation, a structural design, fatigue analysis, and parameters optimisation joint working platform are urgently needed to solve this problem. In this study, numerical analysis of strain fatigue is carried out based on the laboratory fatigue failure of the carrier-based aircraft drawbar. Taking the sensitivity of drawbar parameters to stress and life into account and optimum design of drawbar with fatigue life as a target using the parametric method, this study also includes cutting-edge parameters of milling cutters, structural details of the drawbar and so on. Then an experimental design is applied using the Latin hypercube sampling method, and a surrogate model based on RBF neural network is established. Lastly, a multi-island genetic algorithm is introduced for optimisation. The results show that the error between the obtained optimal solution and simulation is 0.26%, while the optimised stress level is reduced by 15.7%, and the life of the drawbar is increased by 122%.
The aim of this study was to investigate risk factors and psychological stress of health-care workers (HCWs) with coronavirus disease 2019 (COVID-19) in a nonfrontline clinical department.
Methods:
Data of 2 source patients and all HCWs with infection risk were obtained in a department in Wuhan from January to February 2020. A questionnaire was designed to evaluate psychological stress of COVID-19 on HCWs.
Results:
The overall infection rate was 4.8% in HCWs. Ten of 25 HCWs who contacted with 2 source patients were diagnosed with confirmed COVID-19 (8/10) and suspected COVID-19 (2/10). Other 2 HCWs were transmitted by other patients or colleagues. Close care behaviors included physical examination (6/12), life nursing (4/12), ward rounds (4/12), endoscopic examination (2/12). Contacts fluctuated from 1 to 24 times and each contact was short (8.1 min ± 5.6 min). HCWs wore surgical masks (11/12), gloves (7/12), and isolation clothing (3/12) when providing medical care. Most HCWs experienced a mild course with 2 asymptomatic infections, taking 9.8 d and 20.9 d to obtain viral shedding and clinical cure, respectively. Psychological stress included worry (58.3%), anxiety (83.3%), depression (58.3%), and insomnia (58.3%).
Conclusions:
Close contact with COVID-19 patients and insufficient protection were key risk factors. Precaution measures and psychological support on COVID-19 is urgently required for HCWs.
In the alloy materials, their mechanical properties mightly rely on the compositions and concentrations of chemical elements. Therefore, looking for the optimum elemental concentration and composition is still a critical issue to design high-performance alloy materials. Traditional alloy designing method via “trial and error” or domain experts’ experiences is barely possible to solve the issue. Here, we propose a “composition-oriented” method combined machine learning to design the Cu–Zn alloys with the high strengths, high ductility, and low friction coefficient. The method of separate training for each attribute label is used to study the effects of elemental concentrations on the mechanical properties of Cu–Zn alloys. Moreover, the elemental concentrations of new Cu–Zn alloys with the good mechanical properties are predicted by machine learning. The current results reveal the vital importance of the “composition-oriented” design method via machine learning for the development of high-performance alloys in a broad range of elemental compositions.
Identifying risk factors and mortality of individuals with Alzheimer’s disease (AD) could have important implications for the clinical management of AD.
Objective:
This pilot study aimed to examine the overall mortality of AD patients over a 10-year surveillance period in Shanghai, China. This study is an extension of our previous investigation on mortality of neurodegenerative diseases.
Methods:
One hundred and thirty-two AD patients recruited from the memory clinics of two hospitals in Shanghai in 2007 were followed up until December 31, 2017 or death, representing a follow-up period of up to 10 years. Overall standardized mortality ratios (SMRs) were calculated, and predictors for survival at recruitment were estimated.
Results:
Sixty-seven patients had died by December 31, 2017, and the SMR at 10 years of follow-up was 1.225 (95% confidence interval 0.944–1.563). Employing Cox’s proportional hazard modeling, lower Mini-Mental State Examination score, and comorbid diabetes predicted poor survival in this cohort.
Conclusion:
This pilot study suggests a similar survival trend of patients with AD compared to the general population in Shanghai urban region. Poor cognitive status and comorbid diabetes had a negative impact on the survival of AD patients.
Bismuth (Bi)-based photocatalytic materials are widely used in the field of photocatalytic degradation of wastewater. In this study, β-Bi2O3/BiOBr heterojunction photocatalysts were prepared by an in situ chemical transformation method. BiOBr molecules are arrayed to cross each other to form a pore around β-Bi2O3. The prepared photocatalyst had a large specific surface area and excellent adsorption and photocatalytic properties. The β-Bi2O3/BiOBr with a molecular ratio of 11.1% had the highest catalytic activity. The result of a degradation experiment, performed with Rhodamine B (RhB) as the target pollutant, revealed that the degradation rate reached 99.85% after 25 min under visible light irradiation. The pore structure can adsorb contaminants and the heterojunction facilitates the separation of photogenerated electron–hole pairs to enhance the photocatalytic properties. The high adsorption performance and heterojunction achieved higher photocatalytic efficiency. This semiconductor photocatalyst with high adsorption performance provides a new approach to control water pollution.
Although the streaked optical pyrometer (SOP) system has been widely adopted in shock temperature measurements, its reliability has always been of concern. Here, two calibrated Planckian radiators with different color temperatures were used to calibrate and verify the SOP system by comparing the two calibration standards using both multi-channel and single-channel methods. A high-color-temperature standard lamp and a multi-channel filter were specifically designed for the measurement system. To verify the reliability of the SOP system, the relative deviation between the measured data and the standard value of less than 5% was calibrated out, which demonstrates the reliability of the SOP system. Furthermore, a method to analyze the uncertainty and sensitivity of the SOP system is proposed. A series of laser-induced shock experiments were conducted at the ‘Shenguang-II’ laser facility to verify the reliability of the SOP system for temperature measurements at tens of thousands of kelvin. The measured temperature of the quartz in our experiments agreed fairly well with previous works, which serves as evidence for the reliability of the SOP system.
In this paper a one-dimensional numerical study on the nonlinear behaviour of an electrically charged jet of Oldroyd-B viscoelastic, Taylor–Melcher leaky dielectric liquid is carried out. The effect of surface charge level, axial wavenumber and finite conductivity on the nonlinear evolution of the jet is investigated. Different structures including beads-on-a-string with/without satellite droplets, quasi-spikes and spikes are detected, and their domains in the plane of the non-dimensional axial wavenumber and the electrical Bond number are illustrated. The underlying mechanisms in the formation of the structures are examined. It is found that tangential electrostatic force plays a key role in the formation of a quasi-spike structure. Decreasing liquid conductivity may lead to a decrease in the size of satellite droplets or even the complete removal of them from a beads-on-a-string structure, induce the transition from a beads-on-a-string to a quasi-spike structure or postpone the appearance of a spike. On the other hand, finite conductivity has little influence on filament thinning in a beads-on-a-string structure, owing to the fact that the electrostatic forces are of secondary importance compared with the capillary force. The difference between the finite conductivity, large conductivity and other cases is elucidated. An experiment is carried out to observe spike structures.
Swelling deformation tests of Kunigel bentonite and its sand mixtures were performed in distilled water and NaCl solution. The salinity of NaCl solution has a significant impact on the swelling properties of bentonite, but not on its surface structure. The surface structure was characterized using the fractal dimension Ds. Based on the fractal dimension, a unique curve of the em–pe relationship (em is the void ratio of montmorillonite and pe is the effective stress) at full saturation was introduced to express the swelling deformation of bentonite–sand mixtures. In mixtures with a large bentonite content, the swelling deformation always followed the em–pe relationship. In mixtures with a small bentonite content, when the effective stress reached a threshold, the void ratio of montmorillonite em deviated from the unique em–pe curve due to the appearance of a sand skeleton. The threshold of vertical pressure for mixtures in different solutions and the maximum swelling strains were estimated using the em–pe relationship. The good agreement between estimates and experimental data suggest that the em–pe relationship might be an alternative method for predicting the swelling deformation of bentonite–sand mixtures in salt solution.
In situ X-raydiffraction measurements on almandine, (Fe0.86Mg0.07Mn0.07)3Al2Si3O12, were performed using a heating diamond-anvil cell instrument with synchrotron radiation at Beijing Synchrotron Radiation Facilityup to 27.7 GPa and 533 K. The pressure-volume-temperature data were fitted to a third-order Birch-Murnaghan equation of state. The isothermal bulk modulus of K0 = 177±2 GPa, a temperature derivative of the bulk modulus of (∂K/∂T)P= –0.032±0.016 GPaK–1 and a thermal expansion coefficient (α0) of (3.1±0.7)×10–5 K–1 were obtained. This is the first time that the temperature derivative of the bulk modulus of almandine has been determined at high pressure and high temperature. Combining these results with previous results, the compositional dependence of the bulk modulus, thermal expansion, and temperature derivative of the bulk modulus are discussed.
Kawasaki disease, which is characterised by systemic vasculitides accompanied by acute fever, is regularly treated by intravenous immunoglobulin to avoid lesion formation in the coronary artery; however, the mechanism of intravenous immunoglobulin therapy is unclear. Hence, we aimed to analyse the global expression profile of serum exosomal proteins before and after administering intravenous immunoglobulin.
Methods
Two-dimensional electrophoresis coupled with mass spectrometry analysis was used to identify the differentially expressed proteome of serum exosomes in patients with Kawasaki disease before and after intravenous immunoglobulin therapy.
Results
Our analysis revealed 69 differential protein spots in the Kawasaki disease group with changes larger than 1.5-fold and 59 differential ones in patients after intravenous immunoglobulin therapy compared with the control group. Gene ontology analysis revealed that the acute-phase response disappeared, the functions of the complement system and innate immune response were enhanced, and the antibacterial humoral response pathway of corticosteroids and cardioprotection emerged after administration of intravenous immunoglobulin. Further, we showed that complement C3 and apolipoprotein A-IV levels increased before and decreased after intravenous immunoglobulin therapy and that the insulin-like growth factor-binding protein complex acid labile subunit displayed reverse alteration before and after intravenous immunoglobulin therapy. These observations might be potential indicators of intravenous immunoglobulin function.
Conclusions
Our results show the differential proteomic profile of serum exosomes of patients with Kawasaki disease before and after intravenous immunoglobulin therapy, such as complement C3, apolipoprotein A-IV, and insulin-like growth factor-binding protein complex acid labile subunit. These results may be useful in the identification of markers for monitoring intravenous immunoglobulin therapy in patients with Kawasaki disease.
Tungstate based phosphors have efficient absorption in the UV region and can be used for UV-pumped light emitting. For novel and effective materials and synthesis methods in this system, a series of Eu3+ and Tb3+ co-doped NaY(WO4)2 phosphors have been synthesized via the molten salt method. The powder X-ray diffraction (PXRD) patterns, scanning electronic microscope (SEM), and photoluminescent spectra have been characterized for the prepared samples. The results show the flux (NaCl) not only decreases the reaction temperature (700–900 °C) than the normal solid state synthesis (∼1000 °C), but also controls the morphology of the products. The shape and size of products can be changed simply and effectively by the reaction conditions, such as temperature and heating time. It is also found that the emission colors of the samples can be tuned from red to green by simply adjusting the doping concentrations of Eu3+ and Tb3+ ions under the same wave length excitation, which has potential applications for multi-color display and illumination as a single-component phosphor.
The CMP challenges for advanced technology nodes are discussed. Global and local uniformity challenges and their cumulative effects are presented. Uniformity improvements for advanced node integration were achieved through slurry, pad and platen optimization, innovative integration schemes, the reduction of incoming variation and the reduction of cumulative effects. We discuss reduction of typical CMP defect types. Defects resulting from simple mechanisms (foreign material, polish residues) and those resulting from chemical and physical interactions (corrosion, chemical attack, scratches, physical migration) and strategies for control are studied. Defectivity reduction measures include new post-CMP clean chemicals, new slurries and pads and reduction of incoming defectivity. Finally we discuss an observed tradeoff between good defectivity and good uniformity.
SG-III laser facility is now the largest laser driver for inertial confinement fusion research in China. The whole laser facility can deliver 180 kJ energy and 60 TW power ultraviolet laser onto target, with power balance better than 10%. We review the laser system and introduce the SG-III laser performance here.