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Photoimmunotherapy is a promising cancer treatment modality. While potent 1‐e− oxidative species are known to induce immunogenic cell death (ICD), they are also associated with unspecific oxidation and collateral tissue damage. This difficulty may be addressed by post‐generation radical reinforcement. Namely, non‐oxidative radicals are first generated and subsequently activated into powerful oxidative radicals to induce ICD. Here, we developed a photo‐triggered molecular donor (NPCD565) of nitrosoperoxycarbonate (ONOOCO2−), the first of its class to our knowledge, and further evaluated its feasibility for immunotherapy. Upon irradiation of NPCD565 by light within a broad spectral region from ultraviolet to red, ONOOCO2− is released along with a bright rhodamine dye (RD565), whose fluorescence is a reliable and convenient build‐in reporter for the localization, kinetics, and dose of ONOOCO2− generation. Upon photolysis of NPCD565 in 4T1 cells, damage‐associated molecular patterns (DAMPs) indicative of ICD were observed and confirmed to exhibit immunogenicity by induced maturation of dendritic cells. In vivo studies with a bilateral tumor‐bearing mouse model showcased the potent tumor‐killing capability of NPCD565 of the primary tumors and growth suppression of the distant tumors. This work unveils the potent immunogenicity of ONOOCO2−, and its donor (NPCD565) has broad potential for photo‐immunotherapy of cancer. [ABSTRACT FROM AUTHOR]

Photoimmunotherapy is a promising cancer treatment modality. While potent 1‐e− oxidative species are known to induce immunogenic cell death (ICD), they are also associated with unspecific oxidation and collateral tissue damage. This difficulty may be addressed by post‐generation radical reinforcement. Namely, non‐oxidative radicals are first generated and subsequently activated into powerful oxidative radicals to induce ICD. Here, we developed a photo‐triggered molecular donor (NPCD565) of nitrosoperoxycarbonate (ONOOCO2−), the first of its class to our knowledge, and further evaluated its feasibility for immunotherapy. Upon irradiation of NPCD565 by light within a broad spectral region from ultraviolet to red, ONOOCO2− is released along with a bright rhodamine dye (RD565), whose fluorescence is a reliable and convenient build‐in reporter for the localization, kinetics, and dose of ONOOCO2− generation. Upon photolysis of NPCD565 in 4T1 cells, damage‐associated molecular patterns (DAMPs) indicative of ICD were observed and confirmed to exhibit immunogenicity by induced maturation of dendritic cells. In vivo studies with a bilateral tumor‐bearing mouse model showcased the potent tumor‐killing capability of NPCD565 of the primary tumors and growth suppression of the distant tumors. This work unveils the potent immunogenicity of ONOOCO2−, and its donor (NPCD565) has broad potential for photo‐immunotherapy of cancer. [ABSTRACT FROM AUTHOR]

During deep-sea mining, heavy metal pollutants can cause contamination in the marine environment. In this paper, the multiphasic coupling model is established to describe the heavy metal migration process during deep-sea mining, which takes the effects of the convection–diffusion, adsorption–desorption, and sedimentation–resuspension of heavy metals in the aquatic environment into full consideration. Due to the advantages of the Lattice Boltzmann method, it is adopted to numerically solve the multiphasic coupling model and achieve the simulation of the heavy metal migration process during deep-sea mining. In addition, taking cadmium as an example, the concentration variations are discussed and analyzed in detail. Based on the established model and Lattice Boltzmann method, the concentration distribution of heavy metals can be accurately described to provide the reasonable bases for the evaluation of marine environmental protection. [ABSTRACT FROM AUTHOR]

An approximation scheme that combines approximate solutions with error estimators to accelerate the adaptive h‐refinement of the RWG‐based method of moments (MoM) with the electric field integral equation (EFIE) is presented. The scheme is effectively implemented by using the near‐field matrix to solve the approximate solution. Several conventional error estimators incorporated with the scheme are investigated. Compared to using the full MoM system, it significantly reduces the computational cost while maintaining the refinement effect. Numerical results indicate that the scheme could accelerate the adaptive refinement, yielding significant reductions in computational time and memory requirements. [ABSTRACT FROM AUTHOR]

The widespread occurrence of fowl adenovirus serotype 4 (FAdV-4)-induced hepatitis-hydropericardium syndrome (HHS) has led to significant economic losses for the poultry industry. A sensitive, accurate, and practical FAdV-4 diagnostic approach is urgently required to limit the incidence of the disease. In the present study, a practical method for detecting FAdV-4 was developed using the CRISPR/Cas13a system and recombinase-aided amplification. The approach was based on 37°C isothermal detection with visible results being achieved. The detection limit of the target gene with this approach was only 101 copies/μl, making it very sensitive and specific. Clinical samples fared well when tested with the Cas13a detection method. For identifying FAdV-4, this novel detection approach was found to be sensitive, specific, and effective. RESEARCH HIGHLIGHTS First study using the CRISPR/Cas13a-based lateral flow detection assay for FAdV-4 detection. The results can be observed by the naked eye. The developed assay could provide an alternative tool for detection of FAdV-4 with minimal equipment. [ABSTRACT FROM AUTHOR]

Porcine epidemic diarrhea virus (PEDV) infection causes severe diarrhea in pigs and can be fatal in newborn piglets. Exosomes are extracellular vesicles secreted by cells that transfer biologically active proteins, lipids, and RNA to neighboring or distant cells. Herein, the morphology, particle size, and secretion of exosomes derived from a control and PEDV-infected group are examined, followed by a proteomic analysis of the exosomes. The results show that the exosomes secreted from the Vero cells had a typical cup–shaped structure. The average particle size of the exosomes from the PEDV-infected group was 112.4 nm, whereas that from the control group was 150.8 nm. The exosome density analysis and characteristic protein determination revealed that the content of exosomes in the PEDV-infected group was significantly higher than that in the control group. The quantitative proteomics assays revealed 544 differentially expressed proteins (DEPs) in the PEDV-infected group's exosomes compared with those in the controls, with 236 upregulated and 308 downregulated proteins. The DEPs were closely associated with cellular regulatory pathways, such as the phosphatidylinositol–4,5–bisphosphate 3–kinase (PI3K)–protein kinase B (Akt) signaling pathway, extracellular matrix–receptor interaction, focal adhesion, and cytoskeletal regulation. These findings provide the basis for further investigation of the pathogenic mechanisms of PEDV and the discovery of novel antiviral targets. [ABSTRACT FROM AUTHOR]

Accumulating evidence shows HOOK1 disordered in human malignancies. However, the clinicopathological and biological significance of HOOK1 in renal cell carcinoma (RCC) remains rarely studied. In this study, the authors demonstrate that HOOK1 is downregulated in RCC samples with predicted poorer clinical prognosis. Mechanistically, HOOK1 inhibits tumor growth and metastasis via canonical TGF‐β/ALK5/p‐Smad3 and non‐canonical TGF‐β/MEK/ERK/c‐Myc pathway. At the same time, HOOK1 inhibits RCC angiogenesis and sunitinib resistance by promoting degradation of TNFSF13B through the ubiquitin‐proteasome pathway. In addition, HOOK1 is transcriptionally regulated by nuclear factor E2F3 in VHL dependent manner. Notably, an agonist of HOOK1, meletin, is screened and it shows antitumor activity more effectively when combined with sunitinib or nivolumab than it is used alone. The findings reveal a pivotal role of HOOK1 in anti‐cancer treatment, and identify a novel therapeutic strategy for renal cell carcinoma. [ABSTRACT FROM AUTHOR]

A record-breaking heavy rainfall event that occurred in Zhengzhou, Henan province during 19–21 July 2021 is simulated using the Weather Research and Forecasting Model, and the large-scale precipitation efficiency (LSPE) and cloud-microphysical precipitation efficiency (CMPE) of the rainfall are analyzed based on the model results. Then, the key physical factors that influenced LSPE and CMPE, and the possible mechanisms for the extreme rainfall over Zhengzhou are explored. Results show that water vapor flux convergence was the key factor that influenced LSPE. Water vapor was transported by the southeasterly winds between Typhoon In-Fa (2021) and the subtropical high, and the southerly flow of Typhoon Cempaka (2021), and converged in Zhengzhou due to the blocking by the Taihang and Funiu Mountains in western Henan province. Strong moisture convergence centers were formed on the windward slope of the mountains, which led to high LSPE in Zhengzhou. From the perspective of CMPE, the net consumption of water vapor by microphysical processes was the key factor that influenced CMPE. Quantitative budget analysis suggests that water vapor was mainly converted to cloud water and ice-phase particles and then transformed to raindrops through melting of graupel and accretion of cloud water by rainwater during the heavy precipitation stage. The dry intrusion in the middle and upper levels over Zhengzhou made the high potential vorticity descend from the upper troposphere and enhanced the convective instability. Moreover, the intrusion of cold and dry air resulted in the supersaturation and condensation of water vapor, which contributed to the heavy rainfall in Zhengzhou. [ABSTRACT FROM AUTHOR]

A series of acid–base-loaded γ-Al2O3 catalysts was applied as the catalysts for the isomerization of 3/4-methyl-tetrahydro phthalic anhydride. With a basic metal (K or Na) as the basic source and phosphorus (P) as the acid source, γ-Al2O3 was modified by equal volume immersion. NH3/CO2-TPD, XRD, TEM/EDS, BET, and TGA were used to analyze the catalysts, and 15%-K/Al2O3 and 10%-P/Al2O3 were determined as the most appropriate catalysts. The isomers were qualitatively and quantitatively analyzed using nuclear magnetic resonance (1H-NMR) and infrared spectroscopy (IR), and the reaction mechanism for the isomer formation was proposed. With 3-MTHPA as the substrate, the acid/base reaction temperature was 165/150 °C, the reaction time was 3 h and the amount of the catalyst added was 3%. A new type of continuous isomeric fixed-bed reactor was designed. The stability of the catalyst was tested, and the activity loss was 4.6–6.6% after 10 hours of operation. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to investigate the risk factors of left atrial (LA) or left atrial appendage (LAA) thrombi in patients with nonvalvular atrial fibrillation (NVAF) and to establish and validate relevant predictive models. It might improve thromboembolic risk stratification in patients with NVAF.Methods: This study retrospectively included 1210 consecutive patients with NVAF undergoing transesophageal echocardiography (TEE), of whom 139 patients had thrombi in LA or in LAA. Through literature review and the ten events per variable (10EPV) principle, 13 variables were finally identified for inclusion in multivariate analysis. Models were constructed by multivariate logistic stepwise regression and least absolute shrinkage and selection operator (lasso) regression.Results: After logistic regression, five variables (AF type, age, B-type natriuretic peptide, E/e' ratio, and left atrial diameter) were finally screened out as model 1. After Lasso regression, AF type, age, gender, B-type natriuretic peptide, E/e' ratio, left atrial diameter, and left ventricular ejection fraction were finally screened as model 2. After comparing the two models, the simpler model 1 was finally selected. The area under the ROC curve (AUC) of the model 1 was 0.865 (95% CI: 0.838-0.892), the Hosmer-Lemeshow test = 0.898, and the AUC = 0.861 after internal validation. The clinical decision curve showed that the new clinical prediction model could achieve a net clinical benefit when the expected threshold was between 0 and 0.6.Conclusion: This study constructed a new clinical prediction model of LA or LAA thrombi, with a higher discriminative degree than the CHADS2 and CHA2DS2-VASc scoring systems (AUC: 0.865 vs. 0.643; AUC: 0.865 vs 0.652). [ABSTRACT FROM AUTHOR]

Background and Objective: Postmenopausal women often require estrogen supplementation to improve menopausal and postmenopausal vasomotor symptoms and maintain hormonal balance. Conjugated equine estrogens extracted from the urine of pregnant mares are commonly used to provide this estrogen replacement therapy. The complex composition of this mixture of animal sulfated metabolites makes its bioanalysis challenging such that its detailed pharmacokinetics has not been fully characterized. The purpose of this work is to reveal the pharmacokinetic behavior of conjugated equine estrogens in healthy Chinese postmenopausal women by a parallel two-column LC–MS/MS method. Methods: An open-label study was carried out in 35 Chinese healthy postmenopausal women who received a single dose of Premarin® 0.625 mg. A high-throughput column-switching liquid chromatography-tandem mass spectrometry method was developed to determine four conjugated estrogens and two unconjugated estrogens formed by hydrolysis in vivo. The method multiplexes two high-performance liquid chromatography systems into one mass spectrometer and incorporates the positive/negative ion switching acquisition mode of mass spectrometry to significantly increase analysis efficiency. Pharmacokinetics was determined using non-compartmental methods. Results: Both conjugated and unconjugated estrogens can be analyzed simultaneously in a single run with an analysis time of 13.0 minutes in the column-switching liquid chromatography-tandem mass spectrometry method as opposed to 23.0 minutes in a single-column liquid chromatography-tandem mass spectrometry system. The exposures (maximum concentration and area under the curve) of estrone and equilin in Chinese women were higher than those in the North American women. Conclusions: The fully validated assay was successfully applied to a pharmacokinetic study in healthy postmenopausal Chinese women after oral administration of a conjugated equine estrogen tablet. This study suggests that Chinese postmenopausal women achieve the same level of unconjugated estrogens in plasma at a lower dose of conjugated equine estrogens than North American women. [ABSTRACT FROM AUTHOR]

The TDM of voriconazole which exhibits wide inter-individual variability is indispensable for treatment in clinic. In this study, a method that high-performance liquid chromatography tandem mass spectrometry cubed (HPLC-MS3) is first built and validated to quantify voriconazole in human plasma. The system is composed of Shimadzu Exion LCTM UPLC coupled with a Qtrap 5500 mass spectrometer. The separation of voriconazole is performed on a Poroshell 120 SB-C18 column at a flow rate of 0.8 mL/min remaining 7 min for each sample. The calibration curves are linear in the concentration range of 0.25–20 μg/mL. Intra-day and inter-day accuracies and precisions are within 8.0% at three concentrations, and the recoveries and matrix effect are all within accepted limits. In terms of stability, there is no significant degradation of voriconazole under various conditions. The HPLC-MS3 and HPLC-MRM (multiple reaction monitoring) methods are compared in 42 patients with Passing–Bablok regression and Bland–Altman plots, and the results show no significant difference between the two methods. However, HPLC-MS3 has a higher S/N (signal-to-noise ratio) and response than the MRM. Finally, the HPLC-MS3 assay is successfully applied to monitor the TDM (therapeutic drug monitoring) of voriconazole in human plasma, and this verifies that the dosing guidelines for voriconazole have been well implemented in the clinic and patients have received excellent treatment. [ABSTRACT FROM AUTHOR]

In this paper, the large deformation equilibrium equation of the plane arc-curved beam is derived based on the radius of curvature and tangent slope angle of the curved beam. The Jacobi elliptic function solutions of tangent slope angle and geometric configurations of a general curved beam and a curved beam between plates are given, in which the modulus p (or k) of elliptic functions is determined by the vertical external force η and boundary conditions. The nonlinear large deformation characteristics and geometric configurations of the curved beam with different initial installation angles (initial tangent slope angles of beam end) are analyzed in detail. The results show that the force–deformation curve of the curved beam has obvious platform stage, which means that the curved beam can store more energy and produce less reaction force compared with the ordinary elastic structure, and can be used as an energy-absorbing structure for the system subjected to repeated shocks. [ABSTRACT FROM AUTHOR]

• Four gene-intergenic FGF2 fusions were identified in 493 ICC samples. • The four non-canonical FGFR2 fusions can generate chimeric transcript. • The transcripts were characterized by exon17 of 5′ FGFR2 fusing with the exon2 of 3′ partner. • Combined with RNA-NGS, it may make up for omissions caused by DNA-NGS. Intrahepatic cholangiocarcinoma (ICC) is a fatal bile duct cancer with dismal prognosis and limited therapeutic options. FGFR family fusion have been identified in many diseases, and FGFR2 fusion is a validated oncogenic driver in ICC. At present, a variety of fusion forms have been reported, including gene-gene, gene-intergenic, and intergenic-intergenic fusion. Here, by performing RNA- and DNA-sequencing analysis, FGFR2 fusions were found in 10.1% of ICC, including 4 gene-intergenic fusions. We confirmed that the non-canonical rearrangements can generate chimeric transcripts, and used conventional splicing mechanism to explain the event. Our study provides possible target therapy for these 4 patients and possibility analysis scheme for similar situation. [ABSTRACT FROM AUTHOR]

Meropenem, a representative β‐lactam antibiotic, is widely used to treat complicated and serious infections. Therefore, it is of great significance to monitor the plasma drug concentration for individualized antimicrobial therapy. This study first describes the development and validation of high‐performance liquid chromatography–tandem mass spectrometry cubed method for monitoring meropenem in human plasma. Protein precipitation with methanol and a chromatographic analysis time of 7 min make this method simple and of high throughput. Meropenem was extracted from human plasma with recoveries >94.1%. Calibration curves were linear (R2 > 0.995) in the concentration range of 0.5–50 μg/mL. Overall accuracy and precision did not exceed 8.0% as well as no significant matrix effect was observed. The novelty of this method is that the triple‐stage mass spectrometry technology improves the selectivity and sensitivity. A comparison of the presented method and traditional liquid chromatography–tandem mass spectrometry method was assessed in 44 patients treated with meropenem and Passing–Bablok regression coefficients and Bland–Altman plots showed that no significant difference between the two methods. So the triple‐stage mass spectrometry method developed in this study is appropriate and practical for the monitor of meropenem in the daily clinical laboratory practice. [ABSTRACT FROM AUTHOR]

The design of the China Fusion Engineering Test Reactor (CFETR) device is one of the main tasks in the next stage of research on fusion energy in China. The CFETR divertor is a key in-vessel plasma-facing component, which will suffer from sputtering erosion and exfoliation caused by intense plasma bombardment, severe heat fluxes, and neutron irradiation. Due to neutron activation of in-vessel components, remote handling (RH) technology has been considered as one of the essential issues of the CFETR divertor. In this article, a new concept of an integral hybrid divertor blanket for the CFETR is proposed, which is feasible for installation and disassembly in CFETR vacuum vessel by RH. Dome is an important part of the CFETR divertor, which comprises 80 modules, and each module is composed of flat-type plasma-facing units (PFUs), steel supports (SSs), and RH compatible structures. Every Dome module is connected to the CFETR blanket by RH compatible structures. This article mainly carries out the conceptual design of Dome (option), degree of freedom (DOF) analysis, stability analysis, RH process planning, and flow field analysis of cooling scheme, which will provide a solid foundation for its subsequent thermal-hydraulic analysis. [ABSTRACT FROM AUTHOR]

Exosomes are nanoscale vesicles actively secreted by a variety of cells. They contain regulated microRNA (miRNA), allowing them to function in intercellular communication. In the present study, the role of exosomal miRNAs in porcine epidemic diarrhea virus (PEDV) infection was investigated using exosomes isolated from Vero cells infected with PEDV. The results of transmission electron microscopy observation showed that the exosomes are spherical in shape, uniform in size, and negatively stained in the membrane. Nanoparticle tracking analysis showed that the average exosome particle size is 130.5 nm. The results of miRNA sequencing showed that, compared with the control group, a total of 115 miRNAs are abnormally expressed in the exosomes of infected cells. Of these, 80 miRNAs are significantly upregulated and 35 miRNAs are significantly downregulated. Functional annotation analysis showed that the differentially expressed miRNAs are associated with PEDV infection through interaction with the cAMP, Hippo, TGF-beta, HIF-1, FoxO, MAPK, and Ras signaling pathways. Thus, our findings provide important information about the effects of PEDV infection on exosomal miRNA expression and will aid the search for potential anti-PEDV drug candidates. [ABSTRACT FROM AUTHOR]

Objectives: Most patients with progressive pseudorheumatoid dysplasia (PPRD) are initially misdiagnosed because of disease rarity and lack of awareness by most clinicians. The purpose of this study was to provide further early diagnostic options and potential treatment to patients with PPRD. Methods: A retrospective study was performed by collecting and organizing clinical manifestations, radiographic features, laboratory test results, genetic test outcome, treatment, and follow-up records of the patients with PPRD. Age of diagnosis and genotype-phenotype correlation were further analyzed. Results: Nine PPRD children with causative CCN6 mutation were included. There were 3 pairs of siblings and 1 patient from inbred family. Five patients were primarily misdiagnosed as juvenile idiopathic arthritis (JIA). The interval between onset of symptoms and definite diagnosis of 8 patients varied from 3.6 to 20 years. Symptoms at the onset included enlarged and stiff interphalangeal joints of the fingers, gait disturbance, or joint pain. Laboratory tests revealed normal range of inflammatory parameters. Radiographic findings disclosed different degrees of abnormal vertebral bodies and epiphyseal enlargement of the interphalangeal joints. After the treatment of calcitriol in 5 patients with low level 25-hydroxyvitamin D3 for around 1.25 years to 1.75 years, 2 patients kept stable, while 3 of them improved gradually. Conclusions: Combining the patient's family history, clinical features, normal inflammatory markers, and the characteristic radiographic findings, the clinical diagnosis of PPRD for the patients could be obtained at very early stage of the disease. The patients with PPRD carrying c.624dupA variant in CCN6 may have delayed onset. Underlying vitamin D deficiency should be sought and corrected in patients with PPRD. Key Points • Children with progressive pseudorheumatoid dysplasia (PPRD) are easily misdiagnosed with juvenile idiopathic arthritis (JIA). • PPRD is different from JIA with normal range of inflammatory parameters and abnormal vertebral bodies. • Underlying vitamin D deficiency should be sought and corrected in patients with PPRD. [ABSTRACT FROM AUTHOR]

Membrane–cytoskeleton interactions (MCIs) are mediated by actin-binding proteins (ABPs). Ezrin is a crucial ABP that links membranes to actin filaments during lamellipodia formation, cell polarization, and migration. We discuss the concept of MCI and the potential of ezrin as a druggable target for treating inflammatory diseases and cancers. [ABSTRACT FROM AUTHOR]

Levetiracetam is an antiepileptic drug that is primarily approved by the Food and Drug Administration for the treatment of focal and generalized seizures. This study describes the development and validation of a highly selective and sensitive liquid chromatography‐tandem mass spectrometry method with triple‐stage fragmentation to determine levetiracetam in epileptic patient serum. After simple protein precipitation, the analytes were separated on a short reversed‐phase column (Agilent Poroshell 120 SB‐C18 column, 4.6 × 50 mm, 2.7 μm) using isocratic elution with 25% 0.1% formic acid in water (solvent A) and 75% methanol (solvent B) at a flow rate of 0.8 ml/min. The linear range is 0.5–50 μg/mL (R2 > 0.99). All the validation data, such as lower limit of quantification, linearity, specificity, recoveries, matrix effects, and other parameters, fit the request of biological method validation guidance. Passing–Bablok regression coefficients demonstrated that there is no constant bias and no proportional bias between the liquid chromatography‐tandem mass spectrometry methods with triple‐stage fragmentation and liquid multiple reaction monitoring. Bland–Altman plot showed that the developed liquid chromatography‐tandem mass spectrometry method with triple‐stage fragmentation method is reliable and accurate to determine levetiracetam in human serum. [ABSTRACT FROM AUTHOR]

Human exposure to organic mercury (Hg) as methylmercury (MeHg) from seafood consumption is widely considered a health risk because pure methylmercury is extremely neurotoxic. In contrast, the clinical significance of Hg exposure from amalgam (AMG) dental restorations, the only other major nonoccupational source of Hg exposure, has long been debated. Here, we examined data from the two most recent National Health and Nutrition Examination Surveys (NHANES) on 14 181 subjects to assess the contributions of seafood consumption versus AMG to blood total mercury (THg), inorganic mercury (IHg), and methyl mercury (MeHg) and to urine creatinine corrected mercury (UTHg). All subjects were also classified as to their self-reported qualitative consumption of seafood (59% fish and 44% shellfish). Subjects with restorations were grouped into three groups (0) those without AMG (64.4%), (1) those with 1–5 dental AMG restorations (19.7%), (2) those with more than five AMG (16%). Seafood consumption increased total mercury in urine (UTHg) and total mercury (THg) and methyl mercury (MeHg) in blood, but unlike AMG, seafood did not increase blood inorganic mercury (IHg). Using stratified covariate (ANOVA) and multivariate (GLM) analyses revealed a strong correlation of blood (THg and IHg) and urine (UTHg) levels with the number of AMGs. In a subpopulation without fish consumption, having more than five AMG restorations raised blood THg (103%), IHg (221%), and urine UTHg (221%) over the group without AMG. The most striking difference was noted in classification by age: subjects under 6 years old with more than five AMG restorations had the highest blood IHg and urine UTHg among all age groups. Elevation of bivalent IHg on a large scale in children warrants urgent in-depth risk assessment with specific attention to genetic- and gender-associated vulnerabilities. [ABSTRACT FROM AUTHOR]

The chiral magnetic effect with a fluctuating chiral imbalance is more realistic in the evolution of quark-gluon plasma, which reflects the random gluonic topological transition. Incorporating this dynamics, we calculate the chiral magnetic current in response to space-time dependent axial gauge potential and magnetic field in AdS/CFT correspondence. In contrast to conventional treatment of constant axial chemical potential, the response function here is the AVV three-point function of the N = 4 super Yang-Mills at strong coupling. Through an iterative solution of the nonlinear equations of motion in Schwarzschild-AdS5 background, we are able to express the AVV function in terms of two Heun functions and prove its UV/IR finiteness, as expected for N = 4 super Yang-Mills theory. We found that the dependence of the chiral magnetic current on a non-constant chiral imbalance is non-local, different from hydrodynamic approximation, and demonstrates the subtlety of the infrared limit discovered in field theoretic approach. We expect our results enrich the understanding of the phenomenology of the chiral magnetic effect in the context of relativistic heavy ion collisions. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to develop a new method to treat the numerical singularity at the critical nodes of two skew coordinates, and optimize the leakage of micro herringbone grooved journal bearings (MHGJBs) with this method. Design/methodology/approach: A side leakage numerical algorithm is proposed by using the skew meshes with a virtual node (SMVN) method to evaluate the effects of groove angle, bank/groove ratio, groove depth and groove number on load capacity, friction and side leakage of MHGJB. Findings: The SMVN method is effective in treating the numerical singularity at the critical nodes of two skew coordinates. Besides, a group of optimized parameters of micro herringbone groove is obtained which can not only minimize the side leakage but also improve the load capacity and friction force. Originality/value: A virtual node method was proposed, which can significantly improve the calculation accuracy in the side leakage model. [ABSTRACT FROM AUTHOR]

Polymer dielectrics possessing the superiorities of easy processing and high power density are widely used in pulsed power and power electronics. However, the low energy storage density (Ue) of polymer dielectrics limits their application in the modern electronic industries. In this work, we present the sea-island structure multilayered composites based on polymethylmethacrylate (PMMA) matrix and polyvinylidene fluoride (PVDF) nanoparticles, which is constructed by the solution blending with typical solubility differences method and the layer-by-layer solution casting method. The PVDF/PMMA composite incorporated with high PVDF content is placed in the middle of the sandwich-structured composite as a non-traditional intermediate polarization layer. The PVDF/PMMA composite with low PVDF loading is placed in the outer layer to improve the insulating property of the composite. The results show that the PVDF/PMMA composites with inner and outer PVDF volume content of 30% and 10%, respectively, obtained an excellent dielectric constant value (εr ~ 4.35), which is 45% higher than that of PMMA (εr ~ 3). Meanwhile, the maximum Ue (~ 4.95 J cm−3) of the PVDF/PMMA composites at an electric field of 422.48 MV m−1 was obtained, which is 207% higher than that of PMMA (Ue ~ 1.61 J cm−3). The improved energy storage capability could be attributed to the introduction of highly polarizing particles, the increased number of heterogeneous interfaces, and the multilayered construction of composite. This work provides a strategy for the preparation of advanced all-organic dielectrics with a higher discharge energy density. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer-associated deaths accounting for 24% of all cancer deaths. As a crucial phase of tumor progression, lung cancer metastasis is linked to over 70% of these mortalities. In recent years, exosomes have received increasing research attention in their role in the induction of carcinogenesis and metastasis in the lung. In this review, recent studies on the contribution of exosomes to lung cancer metastasis are discussed, particularly highlighting the role of lung tumor-derived exosomes in immune system evasion, epithelial-mesenchymal transition, and angiogenesis, and their involvement at both the pre-metastatic and metastatic phases. The clinical application of exosomes as therapeutic drug carriers, their role in antitumor drug resistance, and their utility as predictive biomarkers in diagnosis and prognosis are also presented. The metastatic activity, a complex multistep process of cancer cell invasion, survival in blood vessels, attachment and subsequent colonization of the host's organs, is integrated with exosomal effects. Exosomes act as functional mediating factors in cell-cell communication, influencing various steps of the metastatic cascade. To this end, lung cancer cell-derived exosomes enhance cell proliferation, angiogenesis, and metastasis, regulate drug resistance, and antitumor immune activities during lung carcinogenesis, and are currently being explored as an important component in liquid biopsy assessment for diagnosing lung cancer. These nano-sized extracellular vesicles are also being explored as delivery vehicles for therapeutic molecules owing to their unique properties of biocompatibility, circulatory stability, decreased toxicity, and tumor specificity. The current knowledge of the role of exosomes highlights an array of exosome-dependent pathways and cargoes that are ripe for exploiting therapeutic targets to treat lung cancer metastasis, and for predictive value assessment in diagnosis, prognosis, and anti-tumor drug resistance. [ABSTRACT FROM AUTHOR]

Osteosarcoma is the most common type of bone malignancy, and the pathogenesis has not been entirely elucidated yet. An important deimination modification enzyme PADI4 (peptidylarginine deiminase 4) has attracted much attention in recent years for its important function in several kinds of human tumors. However, the role of PADI4 on osteosarcoma tumorigenesis remains largely unrevealed. Here, we first assessed the effect of PADI4 on osteosarcoma proliferation by the CCK8 method and colony formation assay. Ectopically expressing PADI4 positively regulates the colony formation capacity of both U2OS and Saos-2 cells. Furthermore, we explored the related mechanism and showed that PADI4 could stimulate Wnt/β-catenin and MEK/ERK signaling in both U2OS and Saos-2 cells. Then, we detected expression of PADI4 in human tissues of osteosarcoma and revealed that differential expression of PADI4 was associated with tumorigenesis of osteosarcoma. Last, we performed the in vivo experiment in nude mice and results also showed PADI4 could affect the tumor growth. In conclusion, this work revealed that PADI4 could upregulate the proliferation of osteosarcoma, mainly via the Wnt/β-catenin and MEK/ERK signaling pathway. This study gives us new insight into the regulation mechanism of osteosarcoma proliferation and highlights PADI4 as a promising target for osteosarcoma diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Purpose: This paper aims to explore the possibility of converting the nitrile butadiene rubber (NBR) water-lubricated bearing material into a self-lubricating bearing material by the action of polytetrafluoroethylene (PTFE) particles and water lubrication. Design/methodology/approach: A group of experimental studies was carried out on a ring-on-block friction test. The physical properties, tribological properties and interface structure of PTFE-NBR self-lubricating composites filled with different percentages of PTFE particles were investigated. Findings: The experimental results indicated that the reduction in friction and wear is a result of the formation of the lubricating film on the surface of the composites. The lubricating film was formed of a large amount of PTFE particles continuously supplied under water lubrication conditions and the PTFE particles here can greatly enhance the load capacity and lubrication performance. Originality/value: In this study, the tribological properties of PTFE particles added to the NBR water-lubricated bearing materials under water lubrication were investigated experimentally, and the research was carried out by a ring-on-block friction test. It is believed that this study can provide some guidance for the application of PTFE-NBR self-lubricating. Peer review: The peer review history for this article is available at: https://publons.com/publon/10.1108/ILT-05-2020-0187/ [ABSTRACT FROM AUTHOR]

Purpose: The tribological behavior, i.e. friction coefficient and wear rate, and vibration characteristics of the water-lubricated bearing was investigated. The water-lubricated bearing is made of three different materials, i.e. polyether-ether-ketone (PEEK), polyimide (PI) and nitrile-butadiene rubber (NBR). Design/methodology/approach: The tribological behavior was investigated experimentally on a specially designed test rig. Three vibration sensors were used to record the vibration of the bearing. Findings: The results indicated that the variation of friction coefficient with rotation speed agrees well with the trend of Stribeck curve. The tested friction coefficient of rubber bearing is higher than that of the other two bearings whether it is in the state of mixed-lubrication or hydrodynamic lubrication, and which causing a larger wear rate in rubber bearing. The PEEK bearing exhibits the best tribological properties due to it has smaller friction coefficient and wear rate. However, it can be found that the rubber bearing gives the minimum vibration acceleration, which means that the rubber bearing has the most potential to improve the stability of water-lubricated bearing rotor system. Originality/value: In this study, a group of experiment studies conducted on a specially designed test rig. The comprehensive performance, including friction coefficient, vibration acceleration and wear rate, of water-lubricated bearing with three different materials, i.e. PEEK, PI and NBR, was compared systematically. The experiment research may offer a reference for the selection of material in water-lubricated bearing in specific operating conditions. Peer review: The peer review history for this article is available at: https://publons.com/publon/10.1108/ILT-10-2019-0447/ [ABSTRACT FROM AUTHOR]

High-performance neuromorphic computing (i.e., brain-like computing) is envisioned to seriously demand optoelectronically integrated artificial neural networks (ANNs) in the future. Optoelectronic synaptic devices are critical building blocks for optoelectronically integrated ANNs. For the large-scale deployment of high-performance neuromorphic computing in the future, it would be advantageous to fabricate optoelectronic synaptic devices by using advanced silicon (Si) technologies. This calls for the development of Si-based optoelectronic synaptic devices. In this work we review the use of Si materials to make optoelectronic synaptic devices, which have either two-terminal or three-terminal structures. A series of important synaptic functionalities have been well mimicked by using these Si-based optoelectronic synaptic devices. We also present the outlook of using Si materials for optoelectronic synaptic devices. [ABSTRACT FROM AUTHOR]

The 1,2-diaza-4-phospholide (dp−) dipotassium ate complexes of chromium(II) {[(η1-N-3,5-tBu2dp)4Cr][(η5-(N,N,C,C,P))2-K(η1-O-THF)2]2} (5) and {[(η1-N-3,5-Ph2dp)4Cr][(η5-(N,N,C,C,P))2-K(η1-O-THF)2]2}∞ (6) were synthesized and characterized by X-ray single crystal structure analysis. Complex 5 with a near-square planar geometry at the chromium(II) ion was unambiguously characterized by the high field electron paramagnetic resonance (HF-EPR) technique and magnetic measurements, revealing that it is a field-induced single-molecule magnet (SMM). [ABSTRACT FROM AUTHOR]

As a transcriptional regulator of the classical binary regulatory system, PhoP plays an important role in the life activities of avian pathogenic Escherichia coli (APEC). In previous experiments, we found that the absence of phoP affects APEC biofilm formation and pathogenicity. To further explore the molecular mechanism of phoP regulation of these phenomena, the differentially expressed gene tolC was screened based on phoP-derived transcriptional data, and the specific sequence identity of the PhoP binding sequence was predicted by bioinformatics and verified by electrophoretic mobility shift assay (EMSA). The results showed that PhoP can directly bind to the tolC promoter. On this basis, tolC deletion and complementary strains were constructed. Biofilm formation was quantified by crystal violet staining and rdar morphology change was observed in these strains. Loss of tolC reduced biofilm formation. We also examined pathological changes in organ paraffin sections by challenging chicks with the strains. After loss of tolC, the clinical signs of pericarditis and liver and spleen enlargement in chicks were alleviated, and pathogenicity to the host cells was decreased. Additionally, quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed that tolC deletion downregulated secA/secB/secE/secY transcript levels, which are part of the type II secretion system secreting virulence effector element. These results indicate that tolC contributes to the phoP-mediated effect on APEC biofilm formation and pathogenicity. [ABSTRACT FROM AUTHOR]

Metastasis remains a notable issue in patients with newly diagnosed colorectal carcinomas (CRC). Although anti-angiogenic therapies target metastatic diseases, hypoxia-inducible factor-1 α (HIF-1α) and vascular endothelial growth factor (VEGF) status are routinely evaluated in primary tumors as metastatic sites are infrequently biopsied. The present study aimed to investigate the expression and significance of HIF-1α, VEGF and microvascular density (MVD) in primary tumors and corresponding metastatic CRC tissues. HIF-1α, VEGF and CD34 status were analyzed via immunohistochemistry analysis in 46 patients who underwent surgical resection of primary CRC (35 colon and 11 rectum) and matched metastases (lymph node and liver metastases) in Shandong Cancer Hospital. The association between selected biomarker status and clinicopathological characteristics was analyzed, and expression levels in primary tumors and corresponding metastases were compared. A total of 46 paired colorectal primary tumor and synchronous metastases samples were acquired for analysis using a standardized HIF-1α, VEGF and CD34 immunohistochemical procedure. The results demonstrated that the positive rates of HIF-1α and VEGF in primary CRC were 70 and 73.9%, respectively. HIF-1α (60.9%) and VEGF (58.7%) expression decreased in the lymph metastatic samples compared with primary CRC. Conversely, the level of MVD in primary tumors was significantly higher compared with metastatic tumors. No significant differences were demonstrated between HIF-1α and VEGF expression and the different clinicopathological features in primary CRC and corresponding metastases. Primary carcinomas and matched metastatic tissues demonstrated a moderate level of consistent immunoreactivity for HIF-1α and VEGF. HIF-1α, VEGF and CD34 were expressed in both primary tumors and corresponding metastases of CRC, suggesting that they may be involved in the development of metastasis. HIF-1α and VEGF expression in primary sites was consistent with that observed in metastases; however, it varied from that exhibited in MVD. The current analysis will improve the current understanding of the metastasis models and provide further evidence for evaluating the response to HIF-1α and VEGF inhibitors. [ABSTRACT FROM AUTHOR]

The function and susceptibility of various drugs are tested with renal proximal tubular epithelial cells; yet, replicating the morphology and kidneys function using the currently available in vitro models remains difficult. To overcome this difficulty, in the study presented in this paper, a device and a three-layer microfluidic chip were developed, which provides a simulated environment for kidney organs. This device includes two parts: (1) microfluidic drug concentration gradient generator and (2) a flow-temperature controlled platform for culturing of kidney cells. In chip study, renal proximal tubular epithelial cells (RPTECs) and peritubular capillary endothelial cells (PCECs) were screened with the drugs to assess the drug-induced nephrotoxicity. Unlike cells cultured in petri dishes, cells cultured in the microfluidic device exhibited higher performance in terms of both cell growth and drug nephrotoxicity evaluation. It is worth mentioning that a significant decrease in cisplatin-induced nephrotoxicity was found because of the intervention of cimetidine in the microfluidic device. In conclusion, the different in the cell performance between the microfluidic device and the petri dishes demonstrates the physiological relevance of the nephrotoxicity screening technology along with the microfluidic device developed in this study. Furthermore, this technology can also facilitate the development of reliable kidney drugs and serve as a useful and efficient test-bed for further investigation of the drug nephrotoxicity evaluation. [ABSTRACT FROM AUTHOR]

Background: Inflammation is one of the factors associated with prostate cancer. The cytokine tumor necrosis factor-alpha (TNF-α) plays an important role in inflammation. Several studies have focused on the association between TNF-α polymorphisms and prostate cancer development. Our meta-analysis aimed to estimate the association between TNF-α rs1800629 (− 308 G/A), rs361525 (− 238 G/A) and rs1799724 polymorphisms and prostate cancer risk. Methods: Eligible studies were identified from electronic databases (PubMed, Embase, Wanfang and CNKI) using keywords: TNF-α, polymorphism, prostate cancer, until Nov 15, 2019. Odds ratios (ORs) with 95% confidence intervals (CIs) were applied to determine the association from a quantitative point-of-view. Publication bias and sensitivity analysis were also applied to evaluate the power of current study. All statistical analyses were done with Stata 11.0 software. Results: Twenty-two different articles were included (22 studies about rs1800629; 8 studies for rs361525 and 5 studies related to rs1799724). Overall, no significant association was found between rs1800629 and rs1799724 polymorphisms and the risk of prostate cancer in the whole (such as: OR = 1.03, 95% CI = 0.92–1.16, P = 0.580 in the allele for rs1800629; OR = 0.95, 95% CI = 0.84–1.07, P = 0.381 in the allele for rs1799724). The rs361525 polymorphism also had no association with prostate cancer in the cases (OR = 0.93, 95% CI = 0.66–1.32, P = 0.684 in the allele) and ethnicity subgroup. The stratified subgroup of genotype method, however, revealed that the rs361525 variant significantly decreased the risk of prostate cancer in the Others (OR = 0.65, 95% CI = 0.47–0.89, P = 0.008, A-allele vs G-allele) and PCR-RFLP (OR = 2.68, 95% CI = 1.00–7.20, P = 0.050, AG vs GG or AA+AG vs GG) methods. Conclusions: In summary, the findings of the current meta-analysis indicate that the TNF-α rs1800629, rs361525 and rs1799724 polymorphisms are not correlated with prostate cancer development, although there were some pooled positive results. Further well-designed studies are necessary to form more precise conclusions. [ABSTRACT FROM AUTHOR]

Emerging data indicate that structural analogs of bisphenol A (BPA) such as bisphenol S (BPS), tetrabromobisphenol A (TBBPA), and bisphenol AF (BPAF) have been introduced into the market as substitutes for BPA. Our previous study compared in vitro testicular toxicity using murine C18-4 spermatogonial cells and found that BPAF and TBBPA exhibited higher spermatogonial toxicities as compared with BPA and BPS. Recently, we developed a novel in vitro three-dimensional (3D) testicular cell co-culture model, enabling the classification of reproductive toxic substances. In this study, we applied the testicular cell co-culture model and employed a high-content image (HCA)-based single-cell analysis to further compare the testicular toxicities of BPA and its analogs. We also developed a machine learning (ML)-based HCA pipeline to examine the complex phenotypic changes associated with testicular toxicities. We found dose- and time-dependent changes in a wide spectrum of adverse endpoints, including nuclear morphology, DNA synthesis, DNA damage, and cytoskeletal structure in a single-cell-based analysis. The co-cultured testicular cells were more sensitive than the C18 spermatogonial cells in response to BPA and its analogs. Unlike conventional population-averaged assays, single-cell-based assays not only showed the levels of the averaged population, but also revealed changes in the sub-population. Machine learning-based phenotypic analysis revealed that treatment of BPA and its analogs resulted in the loss of spatial cytoskeletal structure, and an accumulation of M phase cells in a dose- and time-dependent manner. Furthermore, treatment of BPAF-induced multinucleated cells, which were associated with altered DNA damage response and impaired cellular F-actin filaments. Overall, we demonstrated a new and effective means to evaluate multiple toxic endpoints in the testicular co-culture model through the combination of ML and high-content image-based single-cell analysis. This approach provided an in-depth analysis of the multi-dimensional HCA data and provided an unbiased quantitative analysis of the phenotypes of interest. [ABSTRACT FROM AUTHOR]

Transgelin-2 has been regarded as an actin-binding protein that induces actin gelation and regulates actin cytoskeleton. However, transgelin-2 has recently been shown to relax the myosin cytoskeleton of the airway smooth muscle cells by acting as a receptor for extracellular metallothionein-2. From a clinical perspective, these results support transgelin-2 as a promising therapeutic target for diseases such as cancer and asthma. The inhibition of transgelin-2 prevents actin gelation and thereby cancer cell proliferation, invasion, and metastasis. Conversely, the activation of transgelin-2 with specific agonists relaxes airway smooth muscles and reduces pulmonary resistance in asthma. Here, we review new studies on the biochemical properties of transgelin-2 and discuss their clinical implications for the treatment of immune, oncogenic, and respiratory disorders. Actin is a critical component of the cellular cytoskeleton and interacts with a plethora of actin-binding proteins. Transgelin-2 is an important actin-binding protein and misregulation of transgelin-2 may contribute to diseases such as cancer and asthma. Ezrin has emerged as an essential regulator of transgelin-2 in biological functions other than those involving actin. Specific targeting of transgelin-2 may result in a high potential to selectively and effectively regulate various diseases. [ABSTRACT FROM AUTHOR]

Therapeutic drug monitoring (TDM) is necessary in the clinical management of linezolid to improve its efficacy and reduce the risk of time- and dose-dependent toxicity. A novel and ultrahigh-throughput analytical method for the determination of linezolid in human plasma was developed based on direct analysis in real-time tandem mass spectrometry (DART-MS/MS) without chromatographic separation. After solid-phase extraction with Waters Oasis HLB, the linezolid and internal standard linezolid-d3 were detected by positive ion electrospray ionization followed by multiple reaction monitoring (MRM) of the transition at m/z 338.1 → 296.2 and 341.2 → 297.3, respectively. The use of DART-MS obviates the need for chromatographic separation and allowed determination of linezolid in a total run time of only 24 s per sample. The method was linear in the concentration range 0.20–25 μg mL−1 with intraday and interday precision <14.5% and accuracy ranging from −3.85% to 12.7%. The method was successfully applied to a pharmacokinetic study of linezolid in healthy male volunteers after oral administration of a 600 mg tablet. DART-MS/MS provides a rapid and sensitive method for the determination of linezolid that does not require chromatographic separation. It is eminently suitable to meet the high-throughput challenge of clinical TDM. [ABSTRACT FROM AUTHOR]

PhoP plays an important role as a transcriptional regulator in the two-component phoP/phoQ regulatory system, which is widely present in Gram-negative bacteria. In this study, we used DNA microarray-based technology to evaluate the role of phoP in biofilm formation in avian pathogenic Escherichia coli (APEC). Differences in gene transcription between APEC wild-type and phoP mutant strains were determined. Mutation of the phoP transcriptional regulator affects the expression profile of genes involved in processes such as flagellar assembly, ABC transporters, quorum sensing, and bacterial chemotaxis. Deletion of phoP in APEC reduced biofilm formation, as indicated by crystal violet staining and scanning electron microscopy (SEM). In addition, the phoP gene was found to be associated with changes in bacterial drug resistance and cell-membrane-related properties. This study shows that phoP plays an important regulatory role in APEC biofilm formation, and provides new insights into strategies for preventing and controlling APEC infection. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is one of the most serious neurodegenerative diseases with no effective treatment options available. The formation of insoluble amyloid fibrils of the hyperphosphorylated tau protein is intimately associated with AD, hence the tau protein has been a key target for AD drug development. In this work, hematoxylin was discovered as a dual functional compound, that is, acting in the inhibition of repeat domain of tau (tau-RD) protein fibrillogenesis and remodeling of pre-formed tau-RD fibrils in vitro. Meanwhile, hematoxylin was able to reduce the accumulation of tau-RD aggregates in Saccharomyces cerevisiae. Experimental and computational studies indicated that hematoxylin directly interacts with tau-RD protein through hydrophobic forces, hydrogen bonds, π -cation interactions, and π - π stackings. In addition, cellular viability assays showed that hematoxylin greatly reduced cytotoxicity induced by tau-RD aggregates. In summary, hematoxylin might be a promising candidate for further development as a potential therapeutic drug for AD patients. [ABSTRACT FROM AUTHOR]

• Microreactor broke the limitation of the kettle to achieve continuous D -A reaction. • Microchannel size of 0.8 mm can reach 100% conversion and selectivity in 8 min. • CFD simulations of MTHPA synthesis were built to validate the experimental results. We successfully carried out the D -A reaction of mixed C 5 and maleic anhydride in a Y-type microchannel reactor. The Y-type model established by CFD calculation was suitable for this reaction. The microreactor can optimize the operating conditions of the batch reactor and achieve a higher product conversion rate through homogeneous reactions. [ABSTRACT FROM AUTHOR]

• The weight of OVT target is about 1.85 t, which is suitable for the development of RH manipulator, reduces the weight and improves the reliability of RH maintenance. • RH channels, main bolt and main water pipe RH compatible structures are designed on the front face of the OVT target, realizing RH process planning. The OVT target can be easily removed or positioned with only slight rotation, realizing the reliable RH maintenance of front-face target and effectively improving RH maintenance efficiency. • Advanced materials are selected. KW has high recrystallization temperature and strong neutron irradiation resistance. ODS-Cu has good high-temperature performance and is an ideal high-temperature heat transfer material. The structural material is RAFM with neutron activation resistance. • The thermal-hydraulic analysis was carried out, which verified that the OVT target has heat removal ability to withstand heat flux of 20 MW/m2 and neutron radiation heat under 1.5 GW fusion power. • The work completed will promote the structural analysis and optimization of OVT. The divertor is a key in-vessel component of the China Fusion Engineering Test Reactor (CFETR), which is mainly used to remove high heat load and exclude particles. In addition, the CFETR divertor also needs to meet requirements of Remote handling (RH) maintenance due to activation of materials by neutrons. CFETR proposed the concept of hybrid divertor-blanket to meet the requirements mentioned above and improve tritium breeding ratio (TBR). The new concept cancels the cassette and adopts a separate structure. Space below the divertor is occupied by the breeding blanket to improve TBR, and targets are directly fixed on the breeding blanket to improve RH maintenance efficiency. The outer vertical target (OVT) is a high heat load component of the divertor, which needs to remove the heat flux of 20 MW/m2 and neutron radiation heat at 1.5 GW fusion power and meet the requirements of RH maintenance. The structure design, RH compatible structure design, RH process and thermal-hydraulic analysis of OVT are completed in this paper. The relevant design effectively reduces the weight and complexity of RH maintenance and improves RH efficiency of OVT. RH process for OVT proves to have great engineering feasibility. Advanced low activation materials are adopted for OVT. Thermal-hydraulic analysis verifies that OVT can remove heat flux of 20 MW/m2 and neutron radiation heat at 1.5 GW fusion power, which confirms the rationality of the cooling system and effectively prompts the structural analysis of OVT. [ABSTRACT FROM AUTHOR]

Aim: In this study, we investigated the role and mechanism of Salt-induced kinase 1 (SIK1) in regulation of hepatic glucose and lipid metabolism in a high-fat food (HFD) and streptozocin (STZ)-induced type 2 diabetes mellitus (T2DM) rat model. Methods: A diabetic rat model treated with HFD plus low-dose STZ was developed and was transduced to induce a high expression of SIK1 in vivo via a tail-vein injection of a recombinant adenoviral vector. The effects on hepatic glucogenetic and lipogenic gene expression, systemic metabolism and pathological changes were then determined. Results: In T2DM rats, SIK1 expression was reduced in the liver. Overexpression of SIK1 improved hyperglycaemia, hyperlipidaemia and fatty liver, reduced the expression of cAMP-response element binding protein (CREB)-regulated transcription co-activator 2 (CRTC2), phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase), pS577 SIK1, sterol regulatory element binding-protein-1c (SREBP-1c) and its target genes, including acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), and increased the expression of SIK1, pT182 SIK1 and pS171 CRTC2 in diabetic rat livers with the suppression of gluconeogenesis and lipid deposition. Conclusion: SIK1 plays a crucial role in the regulation of glucose and lipid metabolism in the livers of HFD/STZ-induced T2DM rats, where it suppresses hepatic gluconeogenesis and lipogenesis by regulating the SIK1/CRTC2 and SIK1/SREBP-1c signalling pathways. Strategies to activate SIK1 kinase in liver would likely have beneficial effects in patients with T2DM and nonalcoholic fatty liver disease (NAFLD). [ABSTRACT FROM AUTHOR]

Highlights • Simultaneous determination of Tα1 and rh-Tα1. • Alter the analytes charge ratio by adjusting pH. • Compared the pharmacokinetics of Tα1 and rh-Tα1. Abstract Thymosin α1 (Thymalfasin, Tα1) is a naturally occurring polypeptide widely used as an immune system enhancer for the treatment of HIV/AIDS, hepatitis B and C, and cancer. Recombinant human Tα1 (rh-Tα1) lacking N-terminal acetylation (NTA) displays similar biological activity to Tα1 and has completed phase III clinical trials in China. To compare the pharmacokinetics of rh-Tα1 and Tα1 and establish whether they undergo mutual transmutation in vivo , we developed a novel bioassay based on liquid chromatography–tandem mass spectrometry (LC–MS/MS) for the simultaneous determination of the two peptides in human plasma and urine. Sample preparation by protein precipitation using a mixture of methanol and perchloric acid was followed by HPLC on a Zorbax 300SB-C18 column (150 × 4.6 mm, 5 μm) maintained at 40 °C. Detection was by multiple reaction monitoring (MRM) of the precursor-to-product ion transitions at m/z 778.0→316.0 for Tα1, m/z 767.3→955.0 for rh-Tα1 and m/z 832.3→159.2 for the internal standard, eptifibatide. The method was linear in the range 2–100 ng/mL for both analytes with good accuracy and precision. High sample throughput was facilitated by inclusion of a parallel two-column chromatographic system. The method was successfully applied to a comparative pharmacokinetic study involving single subcutaneous injections of either Tα1 or rh-Tα1 to two groups of healthy male volunteers. The results indicate that rh-Tα1 undergoes NTA in vivo to form Tα1 but that Tα1 is not deacetylated to rh-Tα1. [ABSTRACT FROM AUTHOR]

This paper aims to recover a low-rank matrix and a sparse matrix from their superposition observed in additive white Gaussian noise by formulating a convex optimization problem with a non-separable non-convex regularization. The proposed non-convex penalty function extends the recent work of a multivariate generalized minimax-concave penalty for promoting sparsity. It avoids underestimation characteristic of convex regularization, which is weighted sum of nuclear norm and $\ell _1$ norm in our case. Due to the availability of convex-preserving strategy, the cost function can be minimized through forward-backward splitting. The performance of the proposed method is illustrated for both numerical simulation and hyperspectral images restoration. [ABSTRACT FROM AUTHOR]

Abstract Two severe hailstorms that occurred during spring in east China were simulated by the Weather Research and Forecasting model, version 3.9, with four bulk microphysics schemes. Despite some general similarities in the simulation results, the microphysical schemes produced many differences in the radar structure, surface precipitation, wind field, and the mass of hydrometeors. In particular, the Morrison (MOR) scheme produced the best prediction of the radar structure, while the Milbrandt–Yau two-moment (MY2) scheme produced the worst. The mass of ice-phase particles differed greatly in different schemes. An accumulation zone of supercooled rainwater was found in the WDM6 scheme. Analysis of the mass and heat budgets of hydrometeors revealed that embryos of hail were mainly formed through the collection of ice and rain (MOR) or conversion from graupel (MY2), and developed by collecting cloud droplets (MOR) or rainwater (MY2). Microphysical processes generally cooled the air at lower levels while warming it in the mid-upper troposphere. Based on the 1-km resolution results simulated by MOR and MY2, the growth mechanism of hailstones was analyzed preliminarily. Hail embryos were first formed at the upper edge of the upright main updraft, which could be regarded as the "embryo curtain", and developed through up–down cycling. To conclude, we present a conceptual model of the initial, developing, mature and dissipating stages of the two hailstorm cases. Highlights • The primary microphysical processes for the formation of hailstone were investigated. • Small hails and graupels were from the embryo curtain and re-enter the main updraft as a cycling growth. • A conceptual model of the initial, development, mature and dissipating stage of the hailstorm was given. [ABSTRACT FROM AUTHOR]

Cells are the most basic structural units that play vital roles in the functioning of living organisms. Analysis of the chemical composition and content of a single cell plays a vital role in ensuring precise investigations of cellular metabolism, and is a crucial aspect of lipidomic and proteomic studies. In addition, structural knowledge provides a better understanding of cell behavior as well as the cellular and subcellular mechanisms. However, single-cell analysis can be very challenging due to the very small size of each cell as well as the large variety and extremely low concentrations of substances found in individual cells. On account of its high sensitivity and selectivity, mass spectrometry holds great promise as an effective technique for single-cell analysis. Numerous mass spectrometric techniques have been developed to elucidate the molecular profiles at the cellular level, including electrospray ionization mass spectrometry (ESI-MS), secondary ion mass spectrometry (SIMS), laser-based mass spectrometry and inductively coupled plasma mass spectrometry (ICP-MS). In this review, the recent advances in single-cell analysis by mass spectrometry are summarized. The strategies of different ionization modes to achieve single-cell analysis are classified and discussed in detail. [ABSTRACT FROM AUTHOR]

Abstract Objective to find the Calycosin glycoside (CG) potential anti-inflammatory effect. The anti-inflammatory activity of CG was evaluated by lipopolysaccharide (LPS)-induced RAW 264.7 cells, and the IL-6, IL-1β, TNF-α and PGE2 level were measured by ELISA; NO levels in the culture media were determined using the Griess reaction. The iNOS and COX-2 mRNA expressions were measured by qRT-PCR and the phosphorylation of IκBα, p65, ERK, JNK, and p38 was determined by western blotting. The CG could markedly inhibit the productions of NO and PGE 2 and markedly inhibit the productions of TNF-α, IL-1β and IL-6. CG could suppress mRNA expression of iNOS, COX-2 and protein phosphorylation of IκBα, p65, ERK, JNK, and p38 in LPS-induced RAW 264.7 cells. These findings indicate that CG exhibited potent anti-inflammatory activity through the NF-κB and MAPK signal pathway, and as a potential therapeutic agent against inflammatory diseases. Highlights • CG could reverse the highly expressed COX-2, iNOS mRNA, IL-1β, IL-6 and TNF-α in LPS-treated cells. • The inhibitory effect of CG on iNOS expression was in a dose-dependent manner under a concentration of 12.5 μM. • CG at 100 μM could reduced LPS-induced p-IκB-α and p-p65 protein binding activity. • CG at 100 μM could reverse the LPS-induced increase of ERK, JNK, and p38 MAPKs in LPS models. [ABSTRACT FROM AUTHOR]

Arsenic is a well-known environmental carcinogen and an effective chemotherapeutic agent. The underlying mechanism of this dual-effect, however, is not fully understood. In this study, we applied mouse p53 +/+ and p53 −/− cells to examine the NFκB pathway and proinflammatory cytokines after arsenic treatment. Arsenic reduced cell viability and increased more apoptosis in the p53−/− cells as compared to p53+/+ cells, which was correlated with activation of SAPK/JNK, p38 MAPK, and AKT pathways. A transcriptional regulatory network analysis revealed that arsenic activated transcription regulatory elements E2F, Egr1, Trp53, Stat6, Bcl6, Creb2 and ATF4 in the p53+/+ cells, while in the p53−/− cells, arsenic treatment altered transcription factors NFκB, Pparg, Creb2, ATF4, and Egr1. We observed dynamic changes in phosphorylated NFκB p65 (p-NFκB p65) and phosphorylated IKKαβ (p-IKKαβ) in both genotypes from 4 h to 24 h after treatment, significant decreases of p-NFκB p65 and p-IKKαβ in the p53−/− cells, whereas increases of p-NFκB p65 and p-IKKαβ were observed in the p53+/+ cells. Our study confirmed the differential modulation of NFκB pathway by arsenic in the p53+/+ or p53−/− cells and this observation of the differential mechanism of cell death between the p53+/+ and p53−/− cells might be linked to the unique ability of arsenic to act as both a carcinogen and a chemotherapeutic agent. [ABSTRACT FROM AUTHOR]

Known endocrine disruptor bisphenol A (BPA) has been shown to be a reproductive toxicant in animal models. Its structural analogs: bisphenol S (BPS), bisphenol F (BPF), bisphenol AF (BPAF), and tetrabromobisphenol A (TBBPA) are increasingly being used in consumer products. However, these analogs may exert similar adverse effects on the reproductive system, and their toxicological data are still limited. This mini-review examined studies on both BPA and BPA analog exposure and reproductive toxicity. It outlines the current state of knowledge on human exposure, toxicokinetics, endocrine activities, and reproductive toxicities of BPA and its analogs. BPA analogs showed similar endocrine potencies when compared to BPA, and emerging data suggest they may pose threats as reproductive hazards in animal models. While evidence based on epidemiological studies is still weak, we have utilized current studies to highlight knowledge gaps and research needs for future risk assessments. [ABSTRACT FROM AUTHOR]

Bisphenol A is an endocrine disruptor that has been shown to have testicular toxicity in animal models. Its structural analog, including bisphenol S (BPS), bisphenol AF (BPAF), and tetrabromobisphenol A (TBBPA) have been introduced to the market as BPA alternatives. Previously, we developed high-content analysis (HCA) assays and applied machine learning to compare the testicular toxicity of BPA and its analogs in spermatogonial cells and testicular cell co-culture models. There are diverse cell populations in the testis to support spermatogenesis, but their cell type-specific toxicities are still not clear. The purpose of this study is to examine the selective toxicity of BPA, BPS), BPAF, and TBBPA on these testicular cells, including Sertoli cells, Leydig cells, and spermatogonia cells. We developed a high-content image-based single-cell analysis and measured a broad spectrum of adverse endpoints related to the development of reproductive toxicology, including cell number, nuclear morphology, DNA synthesis, cell cycle progression, early DNA damage response, cytoskeleton structure, DNA methylation status, and autophagy. We introduced an HCA index and spectrum to reveal multiple HCA parameters and observed distinct toxicity profiling of BPA and its analogs among three testicular types. The HCA spectrum shows the dynamic, chemical-specific, dose-dependent changes of each HCA parameter. Each chemical displayed a unique dose-dependent profile within each type of cell. All three types of cells showed the highest response to BPAF at 10 μM across all endpoints measured. BPAF targeted spermatogonial cell (C18) more significantly at 5 μM. BPS more likely targeted Sertoli cell (TM4) and Leydig cell (TM3) and less at spermatogonia cells. TBBPA targeted spermatogonia, Sertoli cells, and less at TM3 cells. BPA is mainly targeted at TM4, followed by TM3 cells, and less at spermatogonial cells. Most importantly, we observed that BPAF induced a dose-dependent increase in spermatogonia cells, not in Sertoli and Leydig cells. In summary, our current HCA assays revealed the cell-type-specific toxicities of BPA and its analogs in different testicular cells. Multinucleation induced by BPAF, along with increased DNA damage and synthesis at low doses, could possibly have a profound long-term effect on reproductive systems. • Image-based single-cell high content analysis (HCA) compared multiple adverse endpoints that related to testicular dysfunction after exposure to of BPA and its selected analogs. • Multiparametric HCA data revealed cell-type-specific toxicities of BPA and its analogs in different testicular cells. • Multinucleation induced by BPAF along with increased DNA damage and synthesis at low doses, could possibly have a profound long-term effect on reproductive systems. [ABSTRACT FROM AUTHOR]