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Abstract Complicated associations between multiplexed environmental factors and aging are poorly understood. We manipulated aging using multidimensional metrics such as phenotypic age, brain age, and brain volumes in the UK Biobank. Weighted quantile sum regression was used to examine the relative individual contributions of multiplexed environmental factors to aging, and self-organizing maps (SOMs) were used to examine joint effects. Air pollution presented a relatively large contribution in most cases. We also found fair heterogeneities in which the same environmental factor contributed inconsistently to different aging metrics. Particulate matter contributed the most to variance in aging, while noise and green space showed considerable contribution to brain volumes. SOM identified five subpopulations with distinct environmental exposure patterns and the air pollution subpopulation had the worst aging status. This study reveals the heterogeneous associations of multiplexed environmental factors with multidimensional aging metrics and serves as a proof of concept when analyzing multifactors and multiple outcomes.

Objective: To develop machine learning-based prediction models for all-cause and premature mortality among the middle-aged and elderly population in China. Method: Adults aged 45 years or older at baseline of 2011 from the China Health and Retirement Longitudinal Study (CHARLS) were included. The stacked ensemble model was built utilizing five selected machine learning algorithms. These models underwent training and testing using the CHARLS 2011–2015 cohort (derivation cohort) and subsequently underwent external validation using the CHARLS 2015–2018 cohort (validation cohort). SHapley Additive exPlanations (SHAP) was introduced to quantify the importance of risk factors and explain machine learning algorithms. Result: In derivation cohort, a total of 10,677 subjects were included, 478 died during the follow-up. The stacked ensemble model demonstrated the highest efficacy in terms of its discrimination capability for predicting all-cause mortality and premature death, with an AUC[95 % CI] of 0.826[0.792–0.859] and 0.773[0.725–0.821], respectively. In validation cohort, the corresponding AUC[95 % CI] were 0.803[0.743–0.864] and 0.791[0.719–0.863], respectively. Risk factors including age, sex, self-reported health, activities of daily living, cognitive function, ever smoker, levels of systolic blood pressure, Cystatin C and low density lipoprotein were strong predictors for both all-cause mortality and premature death. Conclusion: Stacked ensemble models performed well in predicting all-cause and premature death in this Chinese cohort. Interpretable techniques can aid in identifying significant risk factors and non-linear relationships between predictors and mortality.

Abstract Background The meticulous selection of appropriate vaccine adjuvants is crucial for optimizing immune responses. Traditionally, pemphigus vulgaris (PV), an autoimmune disorder, has been modelled using complete Freund's adjuvant (CFA). In this study, we aimed to discern potential variations in immune responses elicited by Toll‐like receptor (TLR) ligands as compared to CFA. Methods A comprehensive investigation was conducted, comparing the effects of these adjuvants in conjunction with ovalbumin or desmoglein‐3. Flow cytometry was employed to analyse distinct cell subsets, while enzyme‐linked immunosorbent assay quantified antigen‐specific antibodies and cytokine levels. Histological examination of harvested skin tissues and transcriptome analysis of skin lesions were performed to identify differentially expressed genes. Results TLR ligands demonstrated efficacy in inducing PV‐like symptoms in wild‐type mice, in contrast to CFA. This underscored the substantial impact of the adjuvant on self‐antigen tolerance. Furthermore, we proposed an enhanced method for establishing a PV model through adoptive transfer, substituting CFA with TLR ligands. Our results revealed that in contrast to the perception that CFA being the most potent immunopotentiator reported, CFA promoted regulatory T cells (Treg), follicular regulatory T cells and IL‐10‐producing neutrophils, whereas TLR ligands downregulated CCL17 and IL‐10. This suggested potential implications for the recruitment and activation of Treg subsets. While B cell and CD8+ T cell responses exhibited similarity, CFA induced less activation in dendritic cell subsets. A novel mouse model of PV and systemic comparison of immunostimulatory effects of adjuvants were provided by this study. Conclusions The systematic comparison of CFA and TLR ligands shed light on the distinctive properties of these adjuvants, presenting innovative mouse models for the investigation of pemphigus. This study significantly contributes to adjuvant research and advances our understanding of PV pathogenesis. Key points/highlights Immunization with desmoglein 3 and Toll‐like receptor (TLR) ligands effectively induces pemphigus symptoms in wild‐type mice, whereas complete Freund's adjuvant (CFA) fails. TLR ligands heightened the autoreactivity of donor cells in the adoptive transfer pemphigus model. CFA promoted regulatory T cells and IL‐10‐producing neutrophils, whereas TLR ligands downregulated CCL17 and IL‐10, leading to more effective immune responses.

Abstract The blood urea nitrogen to albumin ratio (BAR) has been demonstrated as a prognostic factor in sepsis and respiratory diseases, yet its role in severe coronary heart disease (CHD) remains unexplored. This retrospective study, utilizing data from the Medical Information Mart for Intensive Care-IV database, included 4254 CHD patients, predominantly male (63.54%), with a median age of 74 years (IQR 64–83). Primary outcomes included in-hospital, 28-day and 1-year all-cause mortality after ICU admission. The Kaplan–Meier curves, Cox regression analysis, multivariable restricted cubic spline regression were employed to assess association between BAR index and mortality. In-hospital, within 28-day and 1-year mortality rates were 16.93%, 20.76% and 38.11%, respectively. Multivariable Cox proportional hazards analysis revealed associations between the increased BAR index and higher in-hospital mortality (HR 1.11, 95% CI 1.02–1.21), 28-day mortality (HR 1.17, 95% CI 1.08–1.27) and 1-year mortality (HR 1.23, 95% CI 1.16–1.31). Non-linear relationships were observed for 28-day and 1-year mortality with increasing BAR index (both P for non-linearity

The accurate modeling of multi-temporal correlation of photovoltaic stations output is important to achieve the precise power system reliability. However, the existing studies is mainly focused on the hourly temporal correlation between adjacent interval outputs of photovoltaic station. In this paper, a novel multi-temporal correlation modeling method for photovoltaic station output is proposed by using an improved nonparametric disaggregation (INPD) technique, and the multi-temporal characteristic representing the interactive correlation between the total daily output and hourly temporal outputs are deeply explored. Moreover, a three-stage sampling method for the INPD based power system reliability evaluation is further presented considering the multi-temporal correlation of photovoltaic stations output, which includes 1) the random sampling of daily photovoltaic station output; 2) the random disaggregation of daily output to the hourly temporal outputs and 3) the random sampling of power device. Finally, several numerical tests are conducted for a modified IEEE-RTS79 to validate the proposed method.

Currently, commercial cellular public networks such as 4G/5G have been widely deployed in China. In addition to serving general public customers, they are extensively used in the electric power industry for electricity information acquisition and distribution automation telemetry, as well as other non-control-related businesses. Simultaneously, power grid companies are actively studying and deploying electric power wireless private networks for bearing high-security control-related businesses such as distribution grid dispatching and distributed energy control. Electric power wireless private networks utilize dedicated spectrum resources, which operate on narrow individual carrier channels with numerous carriers in a discrete manner. These spectral characteristics indicate that electric power wireless private networks require unique system designs that are different from those of commercial cellular networks. Although some proposals have been proposed in relevant research, a unified and mature technical specification for electric power wireless private networks has not yet been established. This paper introduces the development history of electric power wireless private networks and power grid business requirements, with a specific emphasis on system design and key technologies, including frame structure and numerology, massive discrete carrier aggregation, spectrum sensing, security and isolation. We presented a comprehensive analysis and suggestions for these key technologies. Finally, we discuss future research on technological evolution. This study offers indications for an electric power wireless private network ecosystem.

The rail transit system plays a crucial role in modern transportation. With the increasing demand for clean and green energy in the transport sector, its energy system is expected to achieve low-carbon and highly efficient energy utilization in rail transit. However, the gradual development of the rail transport energy system has led to an increase in its complexity, and the rising difficulty of system assessment has faced the limitations of traditional assessment methods. Hence, it is essential to develop effective assessment methods. This paper begins by providing a systematic review of the development status of Reliability, Availability, Maintainability and Safety (RAMS) assessment and analyzing the shortcomings of traditional RAMS assessment technology in the context of rail transit energy systems. Subsequently, based on the four fundamental properties of RAMS, it summarizes the current state of key assessment technologies in the field of rail transit. Moreover, the paper delves into the challenges and potential solutions concerning the implementation of RAMS assessment technology for rail transit energy systems. Finally, the paper offers an outlook on the future development of RAMS assessment for rail transport energy systems. By comprehensively analyzing these aspects, the paper aims to contribute valuable insights into optimizing the rail transit energy system, promoting its sustainable and efficient operation in the context of clean and green energy utilization.

To address the need for multivalent vaccines against Coronaviridae that can be rapidly developed and manufactured, we compared antibody responses against SARS-CoV, SARS-CoV-2, and several variants of concern in mice immunized with mRNA-lipid nanoparticle vaccines encoding homodimers or heterodimers of SARS-CoV/SARS-CoV-2 receptor-binding domains. All vaccine constructs induced robust anti-RBD antibody responses, and the heterodimeric vaccine elicited an IgG response capable of cross-neutralizing SARS-CoV, SARS-CoV-2 Wuhan-Hu-1, B.1.351 (beta), and B.1.617.2 (delta) variants.

The properties of thermal sprayed WC based cermet coatings are limited by their structural defects, especially corrosion resistance. This article studied the influence of vacuum sealing with silicone resin on the long-term corrosion resistance of HVOF sprayed WC-Cr3C2-Ni coating in 3.5 wt.% NaCl solution. The surface morphologies of the unsealed and sealed coatings show the high compatibility between sealant and WC-Cr3C2-Ni coating. Benefiting from the block of sealant in defects, the sealed coating presents lower corrosion current density (5.843 × 10−8 A cm−2) after long-term corrosion than the unsealed coating (1.776 × 10−7 A cm−2). Owing to the vacuum treatment, sealant adequately penetrates and remains inside the WC-Cr3C2-Ni coating, and inhibits the growth of corrosion pits on the sealed coating surface. The vacuum sealing with silicone resin effectively hinders the diffusion of corrosion solution, and provides practicable strategy to improve the corrosion resistance of the coatings.

The bioactivity of tea polysaccharides (TPs) has been widely reported, but studies to date have focused on green tea. Some human health investigations have implied that black tea may possess potential antidiabetic effects, but less is known about their potential role and related antidiabetic mechanism. The present study was, therefore, conducted to investigate the chemical properties and antidiabetic activity of TPs from black tea. Monosaccharide composition revealed that Alduronic acid (77.8 mol%) considerably predominated in the fraction. TP conformation analysis indicated that three components in TPs were all typical of high-branching structures. Oral administration of TPs could effectively alleviate fasting blood glucose in type 2 diabetes mellitus (T2D) mice, with the values 23.6 ± 1.42, 19.6 ± 2.25, and 16.4 ± 2.07 mmol/L in the 200, 400, and 800 mg/kg·BW groups, respectively. Among these TPs groups, the 800 mg/kg·BW groups significantly decreased by 37.88% when compared with the T2D+water group (p < 0.05). Further studies demonstrated that TP treatment upregulated the expression of p-Akt/p-PI3K (p < 0.001). Additionally, TP treatment significantly promoted glucose transporter protein 2 (GLUT2) translocation in the liver (p < 0.001). These findings suggest that TPs from black tea protect against T2D by activating PI3K/Akt/GLUT2 signaling and might serve as a novel therapeutic candidate for T2D.

Berberine (BBR) as one of the most effective natural products has been increasingly used to treat various chronic diseases due to its immunosuppressive/tolerogenic activities. However, it is unknown if BBR can be applied without abrogating the efforts of vaccination. Here we show that priming of CD8+ T cells in the presence of BBR lead to improved central memory formation (Tcm) with substantially reduced effector proliferation, primarily orchestrated through activation of AMPK and Stat5. Tcm derived from vaccinated mice fed with BBR were able to adoptively transfer protective immunity to naïve recipients. Vaccination of BBR-fed mice conferred better memory protection against infection without losing immediate effector efficacy, suggesting appreciable benefits from using BBR in vaccination. Thus, our study may help to lay the groundwork for mechanistic understanding of the immunomodulatory effects of natural products and their potential use as adjuvant that allows the design of novel vaccines with more desirable properties.

In order to explore the mechanism of the influence of Sn contents on the relevant properties of Cu–Sn alloys, the structure, elasticity, electronic, and thermal properties of Cu–Sn alloys doped with different proportions of Sn (3.125 at%, 6.25 at%, and 9.375 at%) were established using the first-principles calculation based on density functional theory. Firstly, their lattice constants and Sn concentration comply with Vegard’s Law. From the mixing enthalpy, it can be seen that Sn atoms can be firmly dissolved in the Cu matrix, and the structure is most stable when the Sn content is 3.125 at%. In addition, the introduction of mismatch strain characterized their solid solution strengthening effect. The elastic and electronic properties showed that when the Sn content is 6.25 at%, the Cu–Sn alloy has the best plasticity and the highest elastic anisotropy; when the Sn content is 3.125 at%, the Cu–Sn alloy is the most stable and has stronger bulk and shear modulus, which was mainly due to a stronger Cu-Cu covalent bond. Finally, the Debye temperature, thermal conductivity, and melting point were calculated. It is estimated that the thermal conductivity of Cu–Sn alloy is relatively good when the Sn content is low.

The long non-coding RNA, Negative Regulator of Antiviral Response (NRAV) has been identified as a participant in both respiratory virus replication and immune checkpoints, however, its involvement in pan-cancer immune regulation and prognosis, particularly those of hepatocellular carcinoma (HCC), remains unclear. To address this knowledge gap, we analyzed expression profiles obtained from The Cancer Genome Atlas (TCGA) database, comparing normal and malignant tumor tissues. We found that NRAV expression is significantly upregulated in tumor tissues compared to adjacent nontumor tissues. Kaplan-Meier (K-M) analysis revealed the prognostic power of NRAV, wherein overexpression was significantly linked to reduced overall survival in a diverse range of tumor patients. Furthermore, noteworthy associations were observed between NRAV, immune checkpoints, immune cell infiltration, genes related to autophagy, epithelial-mesenchymal transition (EMT), pyroptosis, tumor mutational burden (TMB), and microsatellite instability (MSI) across different cancer types, including HCC. Moreover, NRAV upregulation expression was associated with multiple pathological stages by clinical observations. Furthermore, our investigation revealed a substantial elevation in the expression of NRAV in both HCC tumor tissues and cells compared to normal tissues and cells. The inhibition of NRAV resulted in the inhibition of cell proliferation, migration, and invasion in HCC cells, while also influencing the expression of CD274 (PD-L1) and CD44, along with various biomarkers associated with EMT, autophagy, and pyroptosis. The aforementioned results propose NRAV as a promising prognostic biomarker for HCC. [ABSTRACT FROM AUTHOR]

In this study, an enclosed cooling slope channel (ECSC) was used to produce a semi-solid slurry of the 7075 aluminum alloy. The effects of the pouring temperature and the rate of cooling water on the microstructure of the semi-solid slurry were studied. The microstructure, solidification behavior, mechanical properties, and fracture mechanism of rheological squeeze casting (Rheo-SC) and liquid squeeze casting (LSC) samples were compared. The results indicate that lowering the pouring temperature and increasing the rate of cooling water can refine the crystals of the semi-solid slurry. The best process is a pouring temperature of 670 °C and a rate of cooling water of 200 L/h. The microstructure of the LSC samples was made up of coarse dendritic crystals, but the microstructure of the Rheo-SC samples was made up of almost spherical primary α1-Al and refined secondary α2-Al under this method. The ultimate tensile strength, yield strength, and elongation of the Rheo-SC samples were 238 MPa, 151 MPa, and 5.2%, respectively, which were 10%, 10.5%, and 44.4% higher than those of the LSC sample. The key factor contributing to the increased performance of the Rheo-SC samples is the combination of decreased casting flaws, strengthened grain refinement, and improved segregation.

Abstract We have recently described Pz-1, a benzimidazole-based type-2 RET and VEGFR2 inhibitor. Based on a kinome scan, here we show that Pz-1 is also a potent (IC50

This paper presents the performance analysis of CentiSpace low earth orbit (LEO) experiment satellites. Distinguishing them from other LEO navigation augmentation systems, the co-time and co-frequency (CCST) self-interference suppression technique is employed in CentiSpace to mitigate significant self-interference caused by augmentation signals. Consequently, CentiSpace exhibits the capability of receiving navigation signals from the Global Navigation Satellite System (GNSS) while simultaneously broadcasting augmentation signals within the same frequency bands, thus ensuring excellent compatibility for GNSS receivers. CentiSpace is a pioneering LEO navigation system to successfully complete in-orbit verification of this technique. Leveraging the on-board experiment data, this study analyzes the performance of space-borne GNSS receivers equipped with self-interference suppression and evaluates the quality of navigation augmentation signals. The results show that CentiSpace space-borne GNSS receivers are capable of covering more than 90% visible GNSS satellites and the precision of self-orbit determination is at the centimeter level. Furthermore, the quality of augmentation signals meets the requirements outlined in the BDS interface control documents. These findings underscore the potential of the CentiSpace LEO augmentation system for the establishment of global integrity monitoring and GNSS signal augmentation. Moreover, these results contribute to subsequent research on LEO augmentation techniques.

Identifying the geographical origins of white tea is of significance because the quality and price of white tea from different production areas vary largely from different growing environment and climatic conditions. In this study, we used near-infrared spectroscopy (NIRS) with white tea (n = 579) to produce models to discriminate these origins under different conditions. Continuous wavelet transform (CWT), min-max normalization (Minmax), multiplicative scattering correction (MSC) and standard normal variables (SNV) were used to preprocess the original spectra (OS). The approaches of principal component analysis (PCA), linear discriminant analysis (LDA) and successive projection algorithm (SPA) were used for features extraction. Subsequently, identification models of white tea from different provinces of China (DPC), different districts of Fujian Province (DDFP) and authenticity of Fuding white tea (AFWT) were established by K-nearest neighbors (KNN), random forest (RF) and support vector machine (SVM) algorithms. Among the established models, DPC-CWT-LDA-KNN, DDFP-OS-LDA-KNN and AFWT-OS-LDA-KNN have the best performances, with recognition accuracies of 88.97%, 93.88% and 97.96%, respectively; the area under curve (AUC) values were 0.85, 0.93 and 0.98, respectively. The research revealed that NIRS with machine learning algorithms can be an effective tool for the geographical origin traceability of white tea.

Abstract Background Although observational epidemiological studies have found that smoking is positively associated with risk of rheumatoid arthritis (RA), assessing the causality of this relationship has remained elusive because conventional observational studies are susceptible to bias such as confounding and reverse causation. Here, we applied the Mendelian randomization (MR) approach to examine the potential causal relationship between smoking and risk of RA. Methods Summary statistics data for RA were obtained from a meta-analysis of genome-wide association studies (GWAS), including 14,361 RA cases and 43,923 controls of European ancestry. The instrumental variables (IV) and the genetic association estimates for smoking initiation and lifetime smoking were obtained from a GWAS meta-analysis including 1,232,091 individuals and a GWAS of 462,690 individuals of European ancestry, respectively. MR analyses were performed using the inverse-variance weighted (IVW) method and supplemented with the weighted-median method. Potential pleiotropy was assessed using the MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test and MR-Egger regression. Sensitivity analyses were further performed to test the robustness of the association. Results We found that compared with never smokers, genetic predisposition to smoking initiation was positively associated with risk of RA (odds ratio (OR) = 1.32, 95% confidence interval (CI) = 1.15–1.52, P = 9.17 × 10−5 using the IVW method). Similarly, genetically predicted lifetime smoking was associated with an increased risk of RA (OR = 1.55, 95% CI = 1.13–2.14, P = 0.007). Sensitivity analyses using alternative MR methods and different sets of IVs produced similar results, suggesting the robustness of our findings. Conclusions These results provide support for a causal association between smoking and increased risk of RA. Further studies are warranted to explain the underlying mechanisms of smoking in the development of RA.

Raffinose synthetase (RS) is a key enzyme in the process of raffinose (Raf) synthesis and is involved in plant development and stress responses through regulating Raf content. As a sweetener, Raf makes an important contribution to the sweet taste of white tea. However, studies on the identification, analysis and transcriptional regulation of CsRSs (Camellia sinensis RS genes) are still lacking. In this study, nine CsRSs were identified from the tea plant (Camellia sinensis) genome database. The CsRSs were classified into five groups in the phylogenetic tree. Expression level analysis showed that the CsRSs varied in different parts of the tea plant. Transcriptome data showed that CsRSs could respond to persistent drought and cold acclimation. Except for CsRS5 and CsRS9, the expression pattern of all CsRSs increased at 12 h and decreased at 30 h during the withering process of white tea, consistent with the change trend of the Raf content. Furthermore, combining yeast one-hybrid assays with expression analysis, we found that CsDBB could potentially regulate the expression of CsRS8. Our results provide a new perspective for further research into the characterization of CsRS genes and the formation of the white tea flavour.

Treatment of full-thickness articular cartilage defects with exposure of subchondral bone often seen in osteoarthritic conditions has long been a great challenge, especially with a focus on the feasibility of in situ cartilage regeneration through minimally invasive procedures. Osteoblasts that situate in the subchondral bone plate may be considered a potentially vital endogenous source of cells for cartilage resurfacing through direct reprogramming into chondrocytes. Microarray-based gene expression profiles were generated to compare tissue-specific transcripts between subchondral bone and cartilage of mice and to assess age-dependent differences of chondrocytes as well. On osteoblast cell lines established from mouse proximal tibial subchondral bone, sequential screening by co-transduction of transcription factor (TF) genes that distinguish chondrocytes from osteoblasts reveals a shortlist of potential reprogramming factors exhibiting combined effects in inducing chondrogenesis of subchondral bone osteoblasts. A further combinatorial approach unexpectedly identified two 3-TF combinations containing Sox9 and Sox5 that exhibit differences in reprogramming propensity with the third TF c-Myc or Plagl1, which appeared to direct the converted chondrocytes toward either a superficial or a deeper zone phenotype. Thus, our approach demonstrates the possibility of converting osteoblasts into two major chondrocyte subpopulations with two combinations of three genes (Sox9, Sox5, and c-Myc or Plagl1). The findings may have important implications for developing novel in situ regeneration strategies for the reconstruction of full-thickness cartilage defects.

Groundwater protection is essential for global sustainable development. Due to the lack of motivation among farmers to build harmless disposal facilities for livestock excrement, there is a huge challenge surrounding groundwater protection, which also threatens the achievement of the UN Sustainable Development Goal (SDG) 6: “clean water and sanitation”. Aiming to improve the groundwater protection behavior (GPB) of farmers, this study involved the following approach: (1) the use of rural China as a case area; (2) an exploration of the theoretical mechanisms and quantitative impacts of cooperatives as a way to encourage farmers to build harmless disposal facilities for livestock excrement; (3) a discussion about improvement strategies to increase the possibility of farmers building harmless disposal facilities for livestock excrement. The study highlighted the following findings: (1) compared to farmers who did not participate in cooperatives, farmers who were in cooperatives were 1.18% more likely to build harmless disposal facilities for livestock excrement; (2) compared to the basic scenario, the probability of farmers building harmless disposal facilities for livestock excrement could be increased by 50~1300%. The results of this study could help to provide a reference for the introduction of policies to protect groundwater, as well as an experiential reference for the achievement of the UN SDGs 3 and 6.

Sarcodon aspratus is a popular edible fungus for its tasty flavour and can be used as a dietary supplement for its functional substances. This study was conducted to evaluate the potential health benefits of Sarcodon aspratus polysaccharides (SAFP) on water immersion and restraint stress (WIRS)-induced gastric ulcer in rats. The results indicated that SAFP could decrease myeloperoxidase (MPO) activity and plasma corticosterone levels, as well as enhance Prostaglandin E2 (PGE2) and Nitrate/nitrite (NOx) concentration in rats. Furthermore, SAFP significantly attenuated the stress damage, inflammation, pathological changes and gastric mucosal lesion in rats. Moreover, high-throughput pyrosequencing of 16S rRNA suggested that SAFP modulated the dysbiosis of gut microbiota by enhancing the relative abundance of probiotics, decreasing WIRS-triggered bacteria proliferation. In summary, these results provided the evidence that SAFP exerted a beneficial effect on a WIRS-induced gastric ulcer via blocking the TLR4 signaling pathway and activating the Nrf2 signaling pathway. Notably, SAFP could modulate the WIRS-induced dysbiosis of gut microbiota. Thus, SAFP might be explored as a natural gastric mucosal protective agent in the prevention of gastric ulcers and other related diseases in the food and pharmaceutical industries.

Summary: The NLRP3 inflammasome, a critical component of the innate immune system, induces caspase-1 activation and interleukin (IL)-1β maturation in response to microbial infection and cellular damage. However, aberrant activation of the NLRP3 inflammasome contributes to the pathogenesis of several inflammatory disorders, including cryopyrin-associated periodic syndromes, Alzheimer’s disease, type 2 diabetes, and atherosclerosis. Here, we identify the receptor for activated protein C kinase 1 (RACK1) as a component of the NLRP3 complexes in macrophages. RACK1 interacts with NLRP3 and NEK7 but not ASC. Suppression of RACK1 expression abrogates caspase-1 activation and IL-1β release in response to NLRP3- but not NLRC4- or AIM2-activating stimuli. This RACK1 function is independent of its ribosomal binding activity. Mechanistically, RACK1 promotes the active conformation of NLRP3 induced by activating stimuli and subsequent inflammasome assembly. These results demonstrate that RACK1 is a critical mediator for NLRP3 inflammasome activation.

The spatial variance of target scattering characteristic would introduce severe impact on the imaging results under the wide aperture for bistatic synthetic aperture radar (BSAR) with navigation satellites. If the isotropic point scattering mechanisms are adopted in image formation processing, the signal-to-noise ratio (SNR) of the image will decrease in such case. Therefore, it is necessary to study the corresponding compensation processing to improve the image SNR. This study proposes an adaptive imaging algorithm to compensate for the spatial variance caused by the target scattering in wide aperture of the system. By using experimental equipment of the research group, the echo data of 1600 s from the scene was collected and processed. Comparing strong scattering area imaging results before and after adaptive phase compensation, the focusing performance is improved. Also thus, the feasibility of wide aperture BSAR imaging based on navigation satellite was verified preliminarily.

It is important that bacterium can coordinately deliver several effectors into host cells to disturb the cellular progress during infection, however, the precise role of effectors in host cell cytosol remains to be resolved. In this study, we identified a new bacterial virulence effector from pathogenic Edwardsiella piscicida, which presents conserved crystal structure to thioredoxin family members and is defined as a thioredoxin-like protein (Trxlp). Unlike the classical bacterial thioredoxins, Trxlp can be translocated into host cells, mimicking endogenous thioredoxin to abrogate ASK1 homophilic interaction and phosphorylation, then suppressing the phosphorylation of downstream Erk1/2- and p38-MAPK signaling cascades. Moreover, Trxlp-mediated inhibition of ASK1-Erk/p38-MAPK axis promotes the pathogenesis of E. piscicida in zebrafish larvae infection model. Taken together, these data provide insights into the mechanism underlying the bacterial thioredoxin as a virulence effector in downmodulating the innate immune responses during E. piscicida infection.

Schedulers can compress the schedule of construction projects by overlapping design and construction activities. However, overlapping may induce increased total cost with the decrease of duration. To solve the concurrency-based time-cost tradeoff problem effectively, this paper demonstrates an overlapping optimization algorithm that identifies an optimal overlapping strategy with exact overlap rates and generates the required duration at the minimum cost. The method makes use of overlapping strategy matrix (OSM) to illustrate the dependency relationships between activities. This method then optimizes the genetic algorithm (GA) to compute an overlapping strategy with exact overlap rates by means of overlapping and crashing. This paper then proposes an integrated framework of genetic algorithm and building information modeling (BIM) to prove the practice feasibility of theoretical research. The study is valuable to practitioners because the method allows establishing a compressed schedule which meets the limited budget within the contract duration. This article is also significant to researchers because it can compute the optimal scheduling strategy with exact overlap rates, crashing degree, and resources expeditiously. The usability and validity of the optimized method are verified by a test case in this paper.

Concomitant inhibition of MAPK and PI3K signaling pathways has been recognized as a promising strategy for cancer therapy, which effectively overcomes the drug resistance of MAPK signaling pathway-related inhibitors. Herein, we report the scaffold-hopping generation of a series of 1H-pyrazolo[3,4-d]pyrimidine dual ERK/PI3K inhibitors. Compound 32d was the most promising candidate, with potent inhibitory activities against both ERK2 and PI3Kα which displays superior anti-proliferative profiles against HCT116 and HEC1B cancer cells. Meanwhile, compound 32d possessed acceptable pharmacokinetic profiles and showed more efficacious anti-tumor activity than GDDC-0980 and the corresponding drug combination (BVD-523 + GDDC-0980) in HCT-116 xenograft model, with a tumor growth inhibitory rate of 51% without causing observable toxic effects. All the results indicated that 32d was a highly effective anticancer compound and provided a promising basis for further optimization towards dual ERK/PI3K inhibitors.

Inflammatory caspase-11/4/5 recognize cytosolic LPS from invading Gram-negative bacteria and induce pyroptosis and cytokine release, forming rapid innate antibacterial defenses. Since extracellular or vacuole-constrained bacteria are thought to rarely access the cytoplasm, how their LPS are exposed to the cytosolic sensors is a critical event for pathogen recognition. Hemolysin is a pore-forming bacterial toxin, which was generally accepted to rupture cell membrane, leading to cell lysis. Whether and how hemolysin participates in non-canonical inflammasome signaling remains undiscovered. Here, we show that hemolysin-overexpressed enterobacteria triggered significantly increased caspase-4 activation in human intestinal epithelial cell lines. Hemolysin promoted LPS cytosolic delivery from extracellular bacteria through dynamin-dependent endocytosis. Further, we revealed that hemolysin was largely associated with bacterial outer membrane vesicles (OMVs) and induced rupture of OMV-containing vacuoles, subsequently increasing LPS exposure to the cytosolic sensor. Accordingly, overexpression of hemolysin promoted caspase-11 dependent IL-18 secretion and gut inflammation in mice, which was associated with restricting bacterial colonization in vivo. Together, our work reveals a concept that hemolysin promotes noncanonical inflammasome activation via liberating OMVs for cytosolic LPS sensing, which offers insights into innate immune surveillance of dysregulated hemolysin via caspase-11/4 in intestinal antibacterial defenses.

This paper sets to analyze the application of coal liquefaction residue for the purpose of building waterproof replacing polyurethane waterproof coating. We adopt the method of using coal liquefaction residue 01, 05 and 07 to replace the group B in polyurethane waterproof coating. When mixed in certain ratios, we conducted analysis on the waterproof performance. It is our finding that replacing group B in waterproof coating with coal liquefaction residue improves the performance of the coating when applied for building waterproof. In conclusion, in terms of building waterproof, substituting coal liquefaction residue for group B in water proof coating improves the building waterproof performance.

G protein-coupled receptors (GPCRs), the largest family of targets for approved drugs, are rarely targeted for cancer treatment, except for certain endocrine and hormone-responsive tumors. Limited knowledge regarding GPCR expression in cancer cells likely has contributed to this lack of use of GPCR-targeted drugs as cancer therapeutics. We thus undertook GPCRomic studies to define the expression of endoGPCRs (which respond to endogenous molecules such as hormones, neurotransmitters and metabolites) in multiple types of cancer cells. Using TaqMan qPCR arrays to quantify the mRNA expression of ∼340 such GPCRs, we found that human chronic lymphocytic leukemia (CLL) cells/stromal cells associated with CLL, breast cancer cell lines, colon cancer cell lines, pancreatic ductal adenocarcinoma (PDAC) cells, cancer associated fibroblasts (CAFs), and PDAC tumors express 50 to >100 GPCRs, including many orphan GPCRs (which lack known physiologic agonists). Limited prior data exist regarding the expression or function of most of the highly expressed GPCRs in these cancer cells and tumors. Independent results from public cancer gene expression databases confirm the expression of such GPCRs. We propose that highly expressed GPCRs in cancer cells (for example, GPRC5A in PDAC and colon cancer cells and GPR68 in PDAC CAFs) may contribute to the malignant phenotype, serve as biomarkers and/or may be novel therapeutic targets for the treatment of cancer.

Many bacterial pathogens inject effectors directly into host cells to target a variety of host cellular processes and promote bacterial dissemination and survival. Identifying the bacterial effectors and elucidating their functions are central to understanding the molecular pathogenesis of these pathogens. Edwardsiella piscicida is a pathogen with a wide host range, and very few of its effectors have been identified to date. Here, based on the genes significantly regulated by macrophage infection, we identified 25 intracellular translocation-positive candidate effectors, including all five previously reported effectors, namely EseG, EseJ, EseH, EseK, and EvpP. A subsequent secretion analysis revealed diverse secretion patterns for the 25 effector candidates, suggesting that multiple transport pathways were involved in the internalization of these candidate effectors. Further, we identified two novel type VI secretion system (T6SS) putative effectors and three outer membrane vesicles (OMV)-dependent putative effectors among the candidate effectors described above, and further analyzed their contribution to bacterial virulence in a zebrafish model. This work demonstrates an effective approach for screening bacterial effectors and expands the effectors repertoire in E. piscicida.

Novel the bilayered electrospun biosheet with rapid cell mimiciking and proliferative efficacy will be suitable for wound healing application. The optimized concentration of gelatin (G) and sodium alginate (A) biosheet with nanofibrous Poly (3-hydroxybutyric acid) (P) as a bilayered elctrospun matrix through electrospinning. The engineered GAP bilayered biosheet involves tissue formation at extra cellular matrix (ECM) which further characterized its function in vitro and invivo. Here we fabricated GAP which exhibit better physiochemical properties, biological and mechanical properties with superior prosomes it enhance air passable at skin wounds. The Bilayered biosheet matrix possess better biocompatibility, cell adherence, fructuous and cell to cell interactions evaluated using cell lines. Furthermore, GAP bilayered matrix regulates growth factors to attain maximum wound closure efficiency during invivo. Thus, the fabricated GAP electrospun biosheet would be a possible wound dressing for skin wound applications. [ABSTRACT FROM AUTHOR]

The olfactory system receives extensive serotonergic inputs from the dorsal raphe, a nucleus involved in control of behavior, regulation of mood, and modulation of sensory processing. Although many studies have investigated how serotonin modulates the olfactory bulb, few have focused on the anterior piriform cortex (aPC), a region important for olfactory learning and encoding of odor identity and intensity. Specifically, the mechanism and functional significance of serotonergic modulation of the aPC remain largely unknown. Here we used pharmacologic, optogenetic, and fiber photometry techniques to examine the serotonergic modulation of neural activity in the aPC in vitro and in vivo. We found that serotonin (5-HT) reduces the excitability of pyramidal neurons directly via 5-HT2C receptors, phospholipase C, and calcium-activated potassium (BK) channels. Furthermore, endogenous serotonin attenuates odor-evoked calcium responses in aPC pyramidal neurons. These findings identify the mechanism underlying serotonergic modulation of the aPC and shed light on its potential role. [ABSTRACT FROM AUTHOR]

G protein-coupled receptors (GPCRs), the largest family of targets for approved drugs, are rarely targeted for cancer treatment, except for certain endocrine and hormoneresponsive tumors. Limited knowledge regarding GPCR expression in cancer cells likely has contributed to this lack of use of GPCR-targeted drugs as cancer therapeutics. We thus undertook GPCRomic studies to define the expression of endoGPCRs (which respond to endogenous molecules such as hormones, neurotransmitters and metabolites) in multiple types of cancer cells. Using TaqMan qPCR arrays to quantify the mRNA expression of ~340 such GPCRs, we found that human chronic lymphocytic leukemia (CLL) cells/stromal cells associated with CLL, breast cancer cell lines, colon cancer cell lines, pancreatic ductal adenocarcinoma (PDAC) cells, cancer associated fibroblasts (CAFs), and PDAC tumors express 50 to >100 GPCRs, including many orphan GPCRs (which lack known physiologic agonists). Limited prior data exist regarding the expression or function of most of the highly expressed GPCRs in these cancer cells and tumors. Independent results from public cancer gene expression databases confirm the expression of such GPCRs. We propose that highly expressed GPCRs in cancer cells (for example, GPRC5A in PDAC and colon cancer cells and GPR68 in PDAC CAFs) may contribute to the malignant phenotype, serve as biomarkers and/or may be novel therapeutic targets for the treatment of cancer. [ABSTRACT FROM AUTHOR]

To evaluate the environmental effectiveness of the control measures for atmospheric pollution in Shijiazhuang of China, a large-scale controlling experiment for emission sources of atmospheric pollutants (i.e., a temporary emission control action, TECA) was designed and implemented during November 1, 2016 to January 9, 2017. Under the unfavorably meteorological conditions, the mean concentrations of PM2.5, PM10, SO2, NO2, and chemical species (Si, Al, Ca2+, Mg2+) in PM2.5 during the control action and heating period (CAHP) still decreased by 15%, 26%, 5%, 19%, 30.3%, 4.5%, 47.0% and 45.2%, respectively, compared to the no control action and heating period (NCAHP); indicating that the control measures of atmospheric pollution in Shijiazhuang were effective and was in a right direction. Overall, the effects of control measures in suburbs were better than those in urban area, especially for the control effects of particulate matters sources. The control effects for emission sources of carbon monoxide (CO) were not apparent during the TECA period, especially in suburbs, which is likely due to the increasing usage of domestic coal in suburbs along with the temperature decreasing. The results of PMF analysis showed that crustal dust, secondary sources, vehicle emissions, coal combustion and industrial emissions were major PM2.5 sources. Compared to the whole year, the contributions of coal combustion to PM2.5 increased significantly during the CAHP and after control action (ACA); while the contribution proportions of crustal dust and vehicle emissions to PM2.5 decreased apparently during the CAHP. The contribution concentrations and proportions of crustal dust and vehicle emissions to PM2.5 during the CAHP also decreased significantly compared to ACA. The pollutant's emission sources during the CAHP were in effective control, especially for crustal dust and vehicles. While the necessary coal heating for cold winter and the unfavorably meteorological conditions had an offset effect on the control measures for emission sources to some extent. Meanwhile, our results also illustrated that the discharge of pollutants was still enormous even under such strict control measures. The backward trajectory and potential source contribution function (PSCF) analysis in the light of atmospheric pollutants suggested that the potential sources-areas mainly concentrated in surrounding regions of Shijiazhuang, i.e., south of Hebei, north of Henan and Shanxi. The regional nature of the atmospheric pollution in Northern China Plain revealed that there is an urgent need for making cross-boundary control policy except for local control-measures given the high background level of pollutants. The TECA is an important practical exercise but it can't be advocated as the normalized control measures for atmospheric pollution in China. The direct cause of atmospheric pollution in China is the emission of pollutants exceeds the air environment's self-purification capacity, and the essential reason is unreasonable and unhealthy pattern for economic development of China. [ABSTRACT FROM AUTHOR]