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Abstract Decadal variations in near‐surface wind speed (NSWS) and their causes are poorly understood. We found that the decadal transition of winter NSWS in northern China (NC) was 10 years earlier than in southern China (SC), which could be linked to the changes in intensities of the eastward wave‐activity flux and Siberian High (SH) induced by the Warm Arctic‐Cold Eurasia (WACE) dipole pattern. From 1973 to 1990, the WACE pattern from positive to negative phases confined the eastward wave trains to high latitudes with a decreasing SH, inducing an NSWS reduction. From 1991 to 2000, the WACE strengthened from negative to positive phases, causing a decadal transition in NSWS first in NC. After 2000, accompanied by the strengthening of the positive WACE, the eastward wave trains propagated downstream to lower latitudes, the SH and the meridional pressure gradient enhanced. Therefore, the transition of decadal NSWS occurred in SC until 2000.

Photodynamic therapy (PDT) is considered as a promising anticancer approach, owning to its high efficiency and spatiotemporal selectivity. Ample evidence indicated that PDT can trigger immunogenic cell death by releasing antigens that activate immune cells to promote anti-tumor immunity. Nevertheless, the inherent nature of tumors and their complex heterogeneity often limits the efficiency of PDT, which can be overcome with a novel strategy of photo-immunotherapy (PIT) strategy. By exploring the principles of PDT induction and ICD enhancement, combined with other therapies such as chemotherapy or immune checkpoint blockade, the tailored solutions can be designed to address specific challenges of drug resistance, hypoxic conditions, and tumor immunosuppressive microenvironments (TIMEs), which enables targeted enhancement of systemic immunity to address most distant and recurrent cancers. The present article summarizes the specific strategies of PIT and discusses recent existing limitations. More importantly, we anticipate that the perspectives presented herein will help address the clinical translation challenges associated with PIT.

The research on developing a purification technology for 2,4-dichlorophenol (2,4-DCP) polluted water with high efficiency and the low energy consumption is crucial for achieving several Sustainable Development Goals (SDGs). In order to achieve these goals, MWCNTs-Pd/Fe nanocomposites were prepared by Fe nanoparticles modified with multi-walled carbon nanotubes (MWCNTs) and palladium (Pd) in the presence of ultrasonic irradiation. The MWCNTs-Pd/Fe nanocomposites were characterized by using Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), and X-Ray Diffraction (XRD), and others. Characterization results confirmed that the MWCNTs-Pd/Fe was successfully prepared, with the particle size of 80 nm and the specific surface area of 89.5 m2/g confirmed. We studied the reductive dechlorination of 2,4-Dichlorophenol (2,4-DCP) by MWCNTs-Pd/Fe nanocomposites under different conditions, and the optimized experimental results were found when the Pd loading was 0.4 %, the pH was 3, and the temperature was 30 °C. The phenol yield increased from 76.5 % (without ultrasonic irradiation) to 92.3 % (with ultrasonic irradiation) in 300 min and the 2,4-DCP removal rate reached 98.7 % under the optimal conditions. Therefore, ultrasonic irradiation enhanced the performance of MWCNTs-Pd/Fe nanocomposites for 2,4-DCP removal. We also established the degradation mechanism of chlorophenol by analyzing the intermediates, and proposed the degradation kinetics model. The degradation of 2,4-DCP followed the pseudo-first-order kinetics with the rate constant of 0.05988 min−1. Also, this study demonstrated the potential of using ultrasonic irradiation to improve the properties and recovery of MWCNTs-Pd/Fe nanocomposites, contributing to achievement of the Sustainable Development Goals (SDGs), including SDG-3, SDG-6.

Abstract Near‐surface wind speed (NSWS) over China shows multiple time‐scale changes at a centennial scale, but the contributions of internal variability (IV), anthropogenic forcing (ANT), and natural forcing (NAT) to those changes remain unknown. This study investigated the contributions of IV, ANT, and NAT to NSWS changes at a centennial scale. Results show that the NSWS changes were attributed mainly to IV. IV not only modulated the interannual changes in NSWS but also determined the interdecadal transition in NSWS. The relative contributions of IV to the interannual and decadal NSWS exceeded 75.0%. ANT contributed particularly to the long‐term reduction in NSWS; especially, it has contributed 55.0% of the reduction in NSWS since 1957, serving as the major contributor to the reduction in NSWS. NAT had a small‐to‐negligible effect on China's NSWS throughout the study period. This study enhances our understanding of NSWS changes at different time scales.

China has identified the synergistic reduction of pollution and carbon emissions as a crit ical component of its environmental protection and climate mitigation efforts. An assessment of this synergy can provide clarity on the strategic management of both air pollution and carbon emissions. Due to the extensive regional differences in China, the spatial effects of influencing factors on this synergy exhibit variation across different provinces. In this study, the reduction indexes of PM2.5 and CO2 were calculated based on their reduction bases, reduction efforts, and reduction stabilities across provinces. Then, the synergistic reduction effect was assessed using an exponential function with the PM2.5 reduction index as the base and the CO2 reduction index as the exponent. Next, the MGWR model was applied in order to analyze the influencing factors of the synergistic reduction effect, considering natural settings, socioeconomic conditions, and external emission impacts. Finally, the k-means clustering method was utilized to classify provinces into different categories based on the degree of impact of each influencing factor. The results indicated that air circulation, vegetation, tertiary industry ratio, and emission reduction efficiency are major impact indicators that have a positive effect. The topography and emissions from neighboring provinces have a statistically significant negative impact. The spatial influences of different factors exhibit a distribution trend characterized by a high-high cluster and a low-low cluster. A total of 31 provinces are divided into three categories, and suggestions on the corresponding category are proposed, to provide a scientific reference to the synergistic reduction of PM2.5 and CO2.

Bimetallic nanostructured catalysts have shown great promise in the areas of energy, environment and magnetics. Tunable composition and electronic configurations due to lattice strain at bimetal interfaces have motivated researchers worldwide to explore them industrial applications. However, to date, the fundamentals of the synthesis of lattice-mismatched bimetallic nanocrystals are still largely uninvestigated for most supported catalyst materials. Therefore, in this work, we have conducted a detailed review of the synthesis and structural characterization of bimetallic nanocatalysts, particularly for renewable energies. In particular, the synthesis of Pt, Au and Pd bimetallic particles in a liquid phase has been critically discussed. The outcome of this review is to provide industrial insights of the rational design of cost-effective nanocatalysts for sustainable conversion technologies.

This study is part of the preliminary research for the Chang’e 7 project in China. The Chang’e 7 project plans to drill to penetrate the lunar polar soil and collect lunar soil samples using a spiral groove structure. Ice in the cold environment of the lunar polar region is one of the important targets for sampling. In the vacuum environment of the lunar surface, icy soil samples are sensitive to ambient temperature and prone to solid–gas phase change as the temperature increases. To predict the temperature range of lunar soil samples, this study analyzed the effect of thermal parameters on the temperature rise of lunar soil particles and the drill using discrete element simulation. The parameters included in the thermal effect analysis included the thermal conductivity and specific heat capacity of the drilling tools and lunar soil particles. The simulation showed that the temperature of the icy lunar soil sample in the spiral groove ranged from −127.89 to −160.16 °C within the thermal parameter settings. The magnitude of the value was negatively correlated with the thermal conductivity and specific heat capacity of the lunar soil particles, and it was positively correlated with those of the drilling tools. The temperature variation in the drill bit ranged from −51.21 to −132 °C. The magnitude of the value was positively correlated with the thermal conductivity and specific heat capacity of the lunar soil particles and the thermal conductivity of the drilling tool.

Proper mitochondrial performance is imperative for the maintenance of normal neuronal function to prevent the development of neurodegenerative diseases. Persistent accumulation of damaged mitochondria plays a role in prion disease pathogenesis, which involves a chain of events that culminate in the generation of reactive oxygen species and neuronal death. Our previous studies have demonstrated that PINK1/Parkin-mediated mitophagy induced by PrP106−126 is defective and leads to an accumulation of damaged mitochondria after PrP106−126 treatment. Externalized cardiolipin (CL), a mitochondria-specific phospholipid, has been reported to play a role in mitophagy by directly interacting with LC3II at the outer mitochondrial membrane. The involvement of CL externalization in PrP106−126-induced mitophagy and its significance in other physiological processes of N2a cells treated with PrP106−126 remain unknown. We demonstrate that the PrP106−126 peptide caused a temporal course of mitophagy in N2a cells, which gradually increased and subsequently decreased. A similar trend in CL externalization to the mitochondrial surface was seen, resulting in a gradual decrease in CL content at the cellular level. Inhibition of CL externalization by knockdown of CL synthase, responsible for de novo synthesis of CL, or phospholipid scramblase-3 and NDPK-D, responsible for CL translocation to the mitochondrial surface, significantly decreased PrP106−126-induced mitophagy in N2a cells. Meanwhile, the inhibition of CL redistribution significantly decreased PINK1 and DRP1 recruitment in PrP106−126 treatment but had no significant decrease in Parkin recruitment. Furthermore, the inhibition of CL externalization resulted in impaired oxidative phosphorylation and severe oxidative stress, which led to mitochondrial dysfunction. Our results indicate that CL externalization induced by PrP106−126 on N2a cells plays a positive role in the initiation of mitophagy, leading to the stabilization of mitochondrial function.

The research on developing a purification technology for Cr(Ⅵ) polluted water with high efficiency and the low energy consumption is crucial for achieving several Sustainable Development Goals (SDGs). In order to achieve these goals, Fe3O4@SiO2-APTMS nanocomposites were prepared by Fe3O4 nanoparticles modified with silica and 3-aminopropyltrimethoxysilane in the presence of ultrasonic irradiation. The nanocomposites were characterized by TEM, FT-IR, VSM, TGA, BET, XRD, XPS and these analytic results proved that the nanocomposites were successfully prepared. The influential factors of Fe3O4@SiO2-APTMS on Cr(Ⅵ) adsorption have been explored and better experimental conditions have been obtained. The adsorption isotherm conformed to the Freundlich model. Pseudo-second-order kinetic model provided a better correlation for the experimental data compared to other kinetic models. Thermodynamic parameters for adsorption indicated that the adsorption of Cr(Ⅵ) was a spontaneous process. It was speculated that the adsorption mechanism of this adsorbent includes redox, electrostatic adsorption and physical adsorption. In summary, the Fe3O4@SiO2-APTMS nanocomposites were of great significance to human health and the remediation of heavy ion pollution, contributing to achievement of the Sustainable Development Goals (SDGs), including SDG-3, SDG-6.

Improving resource utilization efficiency is critical for achieving high yields and long-term agricultural development in arid and semi-arid settings. Using potato as the research material, a field trial was carried out from 2020 to 2022 in dryland agricultural areas of China, with two treatments of ridge planting with a furrow mulching straw pattern (SML) and flat planting without mulching (CK). The responses of the dryland potato yield, water use efficiency (WUE), and soil hydrothermal properties to the two cultivation patterns were investigated. The results indicated that during the potato reproductive period, the soil temperature of 0–25 cm in the SML treatment dropped by 0.70–0.83 °C, in comparison to CK; the ridge and furrow-covered belt, which showed a warming effect at 7:00 a.m. in the seedling stage (SD) and the budding stage (BP), was lower than CK in all the rest of the time, and also the planting belt on the ridge, which cooled down significantly at 14:00 a.m. and the performance varied between the years of 7:00 a.m. and 17:00 a.m. SML significantly decreased the water consumption before BP but significantly increased it after BP in the year of median water and mild drought, while the total amount of water consumed during the entire growing season did not differ significantly from CK’s. In the year of moderate drought, SML’s total water consumption was significantly less than that of CK, with the water consumption significantly lower before BP and after the tuber bulking stage (TB), but significantly higher from the BP to the TB. In three consecutive growing seasons, SML increased the yields by 9.72–41.67% and WUE by 4.62–11.14% compared with CK, with the yields significantly or positively connected with the average soil temperatures at the TB, the starch accumulation stage (SA), and the water consumption from the BP to the TB. Overall, partial straw mulching could be used as a cultivation technique to achieve sustainable agricultural development in dry farming areas.

Abstract A persistent accumulation of damaged mitochondria is part of prion disease pathogenesis. Normally, damaged mitochondria are cleared via a major pathway that involves the E3 ubiquitin ligase parkin and PTEN-induced kinase 1 (PINK1) that together initiate mitophagy, recognize and eliminate damaged mitochondria. However, the precise mechanisms underlying mitophagy in prion disease remain largely unknown. Using prion disease cell models, we observed PINK1-parkin-mediated mitophagy deficiency in which parkin depletion aggravated blocked mitochondrial colocalization with LC3-II-labeled autophagosomes, and significantly increased mitochondrial protein levels, which led to inhibited mitophagy. Parkin overexpression directly induced LC3-II colocalization with mitochondria and alleviated defective mitophagy. Moreover, parkin-mediated mitophagy was dependent on PINK1, since PINK1 depletion blocked mitochondrial Parkin recruitment and reduced optineurin and LC3-II proteins levels, thus inhibiting mitophagy. PINK1 overexpression induced parkin recruitment to the mitochondria, which then stimulated mitophagy. In addition, overexpressed parkin and PINK1 also protected neurons from apoptosis. Furthermore, we found that supplementation with two mitophagy-inducing agents, nicotinamide mononucleotide (NMN) and urolithin A (UA), significantly stimulated PINK1-parkin-mediated mitophagy. However, compared with NMN, UA could not alleviate prion-induced mitochondrial fragmentation and dysfunction, and neuronal apoptosis. These findings show that PINK1-parkin-mediated mitophagy defects lead to an accumulation of damaged mitochondria, thus suggesting that interventions that stimulate mitophagy may be potential therapeutic targets for prion diseases.

Abstract In view of the lack of long-term AOD (Aerosol Optical Depth) data, PSO (Particle Swarm Optimization) algorithm is introduced and joint used with NLSM (the nonlinear least square method) to improve visibility-AOD retrieval method, which is referred to as the PSO-M-Elterman model and significantly increases data available rate by 8% and correlation by about 20% with the true value in the experimental group. The mean absolute error, the proportion of the smaller absolute error and the root mean square error in the PSO-M-Elterman model experimental group are 0.0314 and 91.23%, 0.0509 respectively, which significantly outperforms other groups. The main increase of AOD was found in the eastern region (South China, East China, Central China) and Taklimakan with the trend coefficients of 2.67, 2.46, 2.13, and 1.45 (×10−3 yr−1) in recent 55 years, which may not be interpreted by the influence of relative humidity. Long-term change of AOD in east China is mainly caused by human activity, and the AOD is higher in cities with a larger population and more human activity. The PSO-M-Elterman model can maximize the advantage of visibility sequence length to obtain long-term AOD inversion results.

A conventional way to monitor severe convective weather is using the composite reflectivity of radar as an indicator. For oceanic areas without radar deployment, reconstruction from satellite data is useful. However, those reconstruction models built on a land dataset are not directly applicable to the ocean due to different underlying surfaces. In this study, we built reconstruction models based on U-Net (named STR-UNet) for different underlying surfaces (land, coast, offshore, and sea), and evaluated their applicability to the ocean. Our results suggest that the comprehensive use of land, coast, and offshore datasets should be more suitable for reconstruction in the ocean than using the sea dataset. The comprehensive performances (in terms of RMSE, MAE, POD, CSI, FAR, and BIAS) of the Land-Model, Coast-Model, and Offshore-Model in the ocean are superior to those of the Sea-Model, e.g., with RMSE being 5.61, 6.08, 5.06, and 7.73 in the oceanic area (Region B), respectively. We then analyzed the importance of different types of features on different underlying surfaces for reconstruction by using interpretability methods combined with physical meaning. Overall, satellite cloud-related features are most important, followed by satellite water-related features and satellite temperature-related features. For the transition of the model from land to coast, then offshore, the importance of satellite water-related features gradually increases, while the importance of satellite cloud-related features and satellite temperature-related features gradually decreases. It is worth mentioning that in the offshore region, the importance of satellite water-related features slightly exceeds the importance of satellite cloud-related features. Finally, based on the performance of the case, the results show that the STR-UNet reconstruction models we established can accurately reconstruct the shape, location, intensity, and range of the convective center, achieving the goal of detecting severe convective weather where a radar is not present.

Water ice is an important water source in lunar polar soil. Drilling and sampling lunar polar soil are important engineering tasks of lunar exploration. In view of the influence of temperature rise on the quality of samples obtained by drilling, the heat transfer and temperature rise in drilled ice-containing lunar soil were investigated. In this study, a thermal simulation model for drilling lunar soil was established based on the discrete element method (DEM). Simulations of the drilling temperature of lunar soil containing ice at 3–5% were performed assuming normal pressure and low temperature. After validating the feasibility and accuracy of the simulation method, the temperatures of the drilling tools and lunar soil were analyzed. Furthermore, drilling in a vacuum was simulated as well, and the results indicated that ice sublimation was negligible for reasonable drilling procedures in the current study.

This paper presents a detailed thermal simulation analysis of the drilling process for icy soil in the lunar polar region. The aim is to investigate the temperature changes that occur in the debris removal area during the drilling process. We developed a multi-level particle size simulation model that includes a thermal sieve based on geometric constraints to evaluate the influence of specific heat capacity and thermal conductivity on particle temperature. Using the central composite design method, we carried out the simulation test design and analyzed the average temperature difference of particles within and outside the range of the thermal sieve. The parameters of the discrete element model were determined by comparing the temperature of the debris removal zone in the lunar environment with the temperature simulated by the discrete element method. The results show that the thermal conductivity of the sieve ranges from 100 to 400 W/m, and the average temperature inside the thermal sieve is negatively related to the specific heat capacity. The temperature deviation of the chip removal area is ±10 °C, which is consistent with the temperature deviation observed in the lunar environment and the lunar icy regolith drilling test. Furthermore, the addition of the thermal sieve to the multi-stage particle size simulation modeling significantly reduces the calculation time by 86%. This reduction in computational time may potentially increase the efficiency of drilling operations in the future. Our study provides insights into the thermal behavior of lunar icy regolith during drilling, and proposes a numerical model of heat transfer with a thermal sieve that can effectively reduce computational time while ensuring accurate temperature calculations.

As the frozen soil in the South Pole region of the Moon is an important water resource, the operation of drilling and retrieving samples of the frozen soil in this region will be a crucial task for us to accomplish in future deep-space exploration. Thus, this paper investigated the effects of the increasing temperature and heat transfer between the drilling tools and the simulated lunar soil to minimize the degradation of the frozen soil samples during drilling due to the increased temperature. Specifically, the discrete element method was adopted and the heat transfer parameters of the discrete element particles were calibrated based on the equivalent heat transfer of the particle system. Moreover, a lunar soil particle system was developed for the simulations. Under the current working conditions with reasonable parameters, the maximum increase in the drill bit temperature was about 60 °C. Overall, the simulation results were consistent with the experimental results, and further analysis revealed that the flow of lunar soil can effectively take away thermal, which is also one of the reasons why the simulated lunar soil particles are in a high-temperature state at the front of the drilling tool.

Urban surface expansion affects land–atmosphere interactions as well as rainfall. Both the subregional area-averaged daily (DRAIN) and the subregional cumulative volumetric (VRAIN) rainfall amounts are important in this context for hydrological applications and management. Conducted at the city (Beijing, Shanghai, and Guangzhou), city cluster (Beijing–Tianjin–Hebei (BTH), the Yangtze River Delta (YRD), and the Pearl River Delta (PRD)), and national levels in China, numerical experiments were performed in this study using a regional climate model. The analysis revealed that urban-related changes in rainfall variability were more distinct for stronger rainfall among rainfalls of various intensity levels whereas changes in rainfall intensity were more pronounced for weaker rainfall. Furthermore, urban-induced changes in heavy storm rain were more prominent among rainfalls of various intensity levels, for which changes in the variability in DRAIN and VRAIN were more distinct than changes in their intensities, and exhibited marked subregional characteristics. The risk of heavy storm rain increased because of strengthened urban-induced DRAIN and VRAIN variability over Beijing, and urban areas of the YRD and China. However, the risk of heavy storm rain decreased because of decreased DRAIN and VRAIN variability and the reduced intensity of DRAIN over urban areas of Shanghai, nonurban areas of BTH, and nonurban and the entire areas of Guangzhou, the YRD, and the PRD. The urban-induced drying tendency in the lower troposphere and wetting tendency in the low–middle troposphere, and enhanced vertical motions played an important role in determining the changes in DRAIN and VRAIN in case of storm rain and heavy storm rain.

Abstract Background Mycobacterium bovis (M. bovis) is the principal causative agent of bovine tuberculosis; however, it may also cause serious infection in human being. Type I IFN is a key factor in reducing viral multiplication and modulating host immune response against viral infection. However, the regulatory pathways of Type I IFN signaling during M. bovis infection are not yet fully explored. Here, we investigate the role of Type I IFN signaling in the pathogenesis of M. bovis infection in mice. Methods C57BL/6 mice were treated with IFNAR1-blocking antibody or Isotype control 24 h before M. bovis infection. After 21 and 84 days of infection, mice were sacrificed and the role of Type I IFN signaling in the pathogenesis of M. bovis was investigated. ELISA and qRT-PCR were performed to detect the expression of Type I IFNs and related genes. Lung lesions induced by M. bovis were assessed by histopathological examination. Viable bacterial count was determined by CFU assay. Results We observed an abundant expression of Type I IFNs in the serum and lung tissues of M. bovis infected mice. In vivo blockade of Type I IFN signaling reduced the recruitment of neutrophils to the lung tissue, mediated the activation of macrophages leading to an increased pro-inflammatory profile and regulated the inflammatory cytokine production. However, no impact was observed on T cell activation and recruitment in the early acute phase of infection. Additionally, blocking of type I IFN signaling reduced bacterial burden in the infected mice as compared to untreated infected mice. Conclusions Altogether, our results reveal that Type I IFN mediates a balance between M. bovis-mediated inflammatory reaction and host defense mechanism. Thus, modulating Type I IFN signaling could be exploited as a therapeutic strategy against a large repertoire of inflammatory disorders including tuberculosis.

The C2H2-zinc finger proteins (ZFP) comprise a large family of transcription factors with various functions in biological processes. In maize, the function regulation of C2H2- zine finger (ZF) genes are poorly understood. We conducted an evolution analysis and functional prediction of the maize C2H2-ZF gene family. Furthermore, the ZmZFP126 gene has been cloned and sequenced for further favorable allelic variation discovery. The phylogenetic analysis of the C2H2-ZF domain indicated that the position and sequence of the C2H2-ZF domain of the poly-zinc finger gene are relatively conserved during evolution, and the C2H2-ZF domain with the same position is highly conserved. The expression analysis of the C2H2-ZF gene family in 11 tissues at different growth stages of B73 inbred lines showed that genes with multiple transcripts were endowed with more functions. The expression analysis of the C2H2-ZF gene in P1 and P2 inbred lines under drought conditions showed that the C2H2-ZF genes were mainly subjected to negative regulation under drought stress. Functional prediction indicated that the maize C2H2-ZF gene is mainly involved in reproduction and development, especially concerning the formation of important agronomic traits in maize yield. Furthermore, sequencing and correlation analysis of the ZmZFP126 gene indicated that this gene was significantly associated with the SDW-NAP and TDW-NAP. The analysis of the relationship between maize C2H2-ZF genes and C2H2-ZF genes with known functions indicated that the functions of some C2H2-ZF genes are relatively conservative, and the functions of homologous genes in different species are similar.

Accurate description of the mechanical properties for soft tissues can help surgeon predict the state during surgery. In unconfined compression tests (UCT) of soft tissue, a tiny force is typically applied to determine the starting position of compression. The preloading force will cause the obtained material parameters to deviate from the real parameters. In this paper, a novel elimination method was proposed to eliminate the effect of the preloading force. The effects of preloading force on mechanical response were analyzed by performing unconfined compression numerical tests. Different preloading force were applied in the simulation. The parameters obtained by traditional optimization method were defined as preloading material parameters. In the proposed method, an estimation model between the preloading material parameters and the preloading force was established to estimate real parameters. The proposed elimination method was verified by three sample diameters and material parameters. The results show that the material parameters obtained by proposed method are closer to the real parameters (estimated accuracy exceeds 97%). The proposed method can obtain more accurate constitutive model parameters, and eliminate the effect of preloading force.

Evidence of the gut microbiota influencing neurodegenerative diseases has been reported for several neural diseases. However, there is little insight regarding the relationship between the gut microbiota and prion disease. Here, using fecal samples of 12 prion-infected mice and 25 healthy controls, we analyzed the structure of the gut microbiota and metabolic changes by 16S rRNA sequencing and LC-MS–based metabolomics respectively as multi-omic analyses. Additionally, SCFAs and common amino acids were detected by GC–MS and UPLC respectively. Enteric changes induced by prion disease affected both structure and abundances of the gut microbiota. The gut microbiota of infected mice displayed greater numbers of Proteobacteria and less Saccharibacteria at the phylum level and more Lactobacillaceae and Helicobacteraceae and less Prevotellaceae and Ruminococcaceae at the family level. A total of 145 fecal metabolites were found to be significantly different in prion infection, and most (114) of these were lipid metabolites. Using KEGG pathway enrichment analysis, we found that 3 phosphatidylcholine (PC) compounds significantly decreased and 4 hydrophobic bile acids significantly increased. Decreases of 8 types of short-chain acids (SCFAs) and increases of Cys and Tyr and decreases of His, Trp, and Arg were observed in prion infection. Correlation analysis indicated that the gut microbiota changes observed in our study may have been the shared outcome of prion disease. These findings suggest that prion disease can cause significant shifts in the gut microbiota. Certain bacterial taxa can then respond to the resulting change to the enteric environment by causing dramatic shifts in metabolite levels. Our data highlight the health impact of the gut microbiota and related metabolites in prion disease.

Electric multiple unit is a modern transportation tool with high efficiency and large carrying capacity. Regarding its high speed, reliability requirement of the train is very important. As the main load bearing component of a train, the wheel is subjected to harsh working condition. Rolling contact between wheel and rail leads to wheel fatigue failure so that the fatigue reliability of wheel becomes one of the most attractive fields in electric multiple unit reliability study. This article proposed a fatigue reliability assessment method. It could obtain critical parts’ stress distribution efficiently through the force–stress relationship received by numerical simulation, so that it could assess wheel fatigue reliability under measured force–time spectrum. Also, multiaxial fatigue is considered in the method and the equivalent stress can be obtained by multiaxial model and fatigue experiment. Result of the case study shows that fatigue reliability of China Railway High-speed 5 wheel at 60,000 km mileage is 68%.

It is well-recognized that the gut microbiota (GM) is crucial for gut function, metabolism, and energy cycles. The GM also has effects on neurological outcomes via many mechanisms, such as metabolite production and the gut-brain axis. Emerging evidence has gradually indicated that GM dysbiosis plays a role in several neurological diseases, such as Parkinson's disease (PD), Alzheimer's disease, depression, and multiple sclerosis. Several studies have observed that PD patients generally suffer from gastrointestinal disorders and GM dysbiosis prior to displaying motor symptoms, but the specific link between the GM and PD is not clearly understood. In this review, we aim to summarize what is known regarding the correlation between the GM and PD pathologies, including direct, and indirect evidence.

The study of direct push sampling characteristics forms the theoretical basis for deep sampling tool design. In this paper, a ground test of the direct push sampling was carried out to analyze three influencing factors: tube diameter; friction coefficient; and soil plug length. Using the discrete element method software, EDEM, a lunar subsurface direct push sampling model was established. We propose a vortex structure of the particle displacement field in the sampling tube and establish a connection between the three influencing factors and the structure disturbance of the soil plug. The EDEM simulation revealed the microscopic mechanism of penetration sampling disturbance. The results show that the soil plug in the compressive state had a small disturbance and a high degree of sequence retention and that the internal stress was changed compared to that in the in-situ state. The structure disturbance of the soil plug in the stick-slip state was large, while the parts of the soil plug that are away from the center line of the tube were in disorder. In the center line of the tube, the in-situ sequence state was gradually restored with the increase in tube diameter or decrease in soil plug length. Increasing the friction coefficient would change the soil plug from the compression state to the stick-slip or adhesion state. In case of the stick-slip state or adhesion, reducing the diameter of the tube or increasing the length of the soil plug would change the soil plug from the stick-slip state or adhesion state to the compression state.

Background: The current diagnosis method for Creutzfeldt-Jakob disease (CJD) is post-mortem examination, so early detection of CJD has been historically problematic. Auxiliary detection of CJD based on changes in levels of components of the cerebrospinal fluid (CSF) has become a focus of research. In other neurodegenerative diseases such as Alzheimer's disease (AD), cell-free mitochondrial DNA (mtDNA) in the CSF of patients may serve as a biomarker that could facilitate early diagnosis and studies of the mechanisms underlying the disease.Methods: In this study, the cell-free mitochondrial DNA in the CSF of patients with sCJD and control patients was compared by digital droplet PCR.Results: The cell-free mitochondrial DNA copy number in the CSF of sCJD patients was significantly increased in comparison with that of the control group, and this difference was pathologically related to CJD.Conclusion: Therefore, we speculate that changes in cerebrospinal fluid mitochondrial DNA copy number play an important role in the study of CJD mechanism and diagnosis.

Mycobacterium bovis, the causative agent of tuberculosis in cattle and humans, infects host macrophages and induces endoplasmic reticulum stress (ERS), mitochondrial damage, and interleukin (IL)-1β production. The relationship between these phenotypes is yet to be elucidated. In this study, we investigated the role of ERS in mitochondrial damage and IL-1β production in macrophages during infection with a virulent M. bovis strain. We found that ERS activates the inflammasome via NOD-like receptor family, pyrin domain-containing 3 (NLRP3)-caspase-8 and that IFN-inducible protein absent in melanoma 2 (AIM2) triggered mitochondrial damage. ERS increased reactive oxygen species (ROS), which promoted translocation of the inflammasome to the mitochondria. NLRP3, but not AIM2, was involved in the ERS-induced cleavage of caspase-8 and Bid, leading to mitochondrial damage, which was required for the production of mature IL-1β. Our data suggest that ERS induces macrophages to produce mature IL-1β during infection with virulent M. bovis through a positive feedback loop between mitochondrial damage and inflammasome activation. To the best of our knowledge, this is the first evidence of the involvement of ERS and mitochondrial damage in inflammasome activation during M. bovis infection.

Prion diseases are a group of fatal and debilitating neurodegenerative diseases affecting humans and animal species. The conversion of a non-pathogenic normal cellular protein (PrPc) into an abnormal infectious, protease-resistant, pathogenic form prion protein scrapie (PrPSc), is considered the etiology of these diseases. PrPSc accumulates in the affected individual’s brain in the form of extracellular plaques. The molecular pathways leading to neuronal cell death in prion diseases are still unclear. The free radical damage, oxidative stress and mitochondrial dysfunction play a key role in the pathogenesis of the various neurodegenerative disorders including prion diseases. The brain is very sensitive to changes in the redox status. It has been demonstrated that PrPc behaves as an antioxidant, while the neurotoxic prion peptide PrPSc increases hydrogen peroxide toxicity in the neuronal cultures leading to mitochondrial dysfunction and cell death. The nuclear factor erythroid 2-related factor 2 (NRF2) is an oxidative responsive pathway and a guardian of lifespan, which protect the cells from free radical stress-mediated cell death. The reduced glutathione, a major small molecule antioxidant present in all mammalian cells, and produced by several downstream target genes of NRF2, counterbalances the mitochondrial reactive oxygen species (ROS) production. In recent years, it has emerged that the ubiquitin-binding protein, p62-mediated induction of autophagy, is crucial for NRF2 activation and elimination of mitochondrial dysfunction and oxidative stress. The current review article, focuses on the role of NRF2 pathway in prion diseases to mitigate the disease progression.

A recovery of near-surface wind speed (SWS) in the last decade has been reported over China; nevertheless, the contributions of large-scale ocean-atmosphere circulations (LOACs) to the SWS changes are rarely investigated. In this study, the turning point (TP) of the terrestrial stilling was validated over eastern China for 1979–2017. Furthermore, a forward stepwise regression algorithm was used to assess the contribution of LOACs to SWS changes. The results revealed that the TP of the SWS reversal occurred in approximately 2011 during the study period. Mean annual and seasonal SWSs exhibited decreases before the TP, with the largest decrease in spring (–0.134 ± 0.014 m s ^−1 decade ^−1 ), while SWSs increased after the TP, most strongly in autumn (0.377 ± 0.053 m s ^−1 decade ^−1 ). The SWS decrease before the TP and increase after the TP were caused by the decreasing and increasing frequencies of strong windy days (>75th percentile of SWS), respectively. The effects of LOACs on the long-term changes of SWS were pronounced. The contributions of LOACs to the decreasing and increasing trends of SWSs were >60.0%, with the exception of autumn. The projected SWSs exhibited increases in the near-term (2021–2040) for the low-emission scenarios (e.g. Shared Socioeconomic Pathway 245). For the mid-term and long-term projections, the SWSs still displayed a downward trend, which was mainly attributed to the reduction of strong windy days. Consequently, the present SWS recovery in the recent decade may be only expected to last for a short amount of time before winds start decreasing again.

A global terrestrial stilling in recent decades has been reported, but the centennial-scale changes in global terrestrial near-surface wind speed (NSWS) and the potential contributing factors are yet to be revealed. Consequently, in this study, centennial-scale changes in global terrestrial NSWS are investigated based on Coupled Model Intercomparison Project phase 6 datasets, and that the potential factors causing those changes are detected. The results show that the global annual mean NSWS increased from 1850 to 1967 (+0.0045 m s ^−1 decade ^−1 , p < 0.01), with significant increases in North America, Europe, Africa, and South Asia. However, the NSWS decreased from 1968 to 2014 (−0.0044 m s ^−1 decade ^−1 , p < 0.01), significantly so in the mid-to-high latitudes of the Northern Hemisphere. The seasonal mean NSWS also increased before the 1960s and decreased thereafter. However, the NSWS over South America and most of Southern Africa increased during the study period. The changes in NSWS were caused mainly by changes in the number of strong windy days. The increase in NSWS from 1850 to 1967 could be attributed to internal variability, and the decrease in NSWS from 1968 to 2014 could be attributed to natural, aerosol, and greenhouse-gas forcings. However, internal variability acted mainly to increase the NSWS from 1968 to 2014, and so it is suggested that the contributions of external forcings to the global terrestrial stilling after the 1960s were considerable.

Understanding future changes in global terrestrial near-surface wind speed (NSWS) in specific global warming level (GWL) is crucial for climate change adaption. Previous studies have projected the NSWS changes; however, the changes of NSWS with different GWLs have yet to be studied. In this paper, we employ the Max Planck Institute Earth System Model large ensembles to evaluate the contributions of different GWLs to the NSWS changes. The results show that the NSWS decreases over the Northern Hemisphere (NH) mid-to-high latitudes and increases over the Southern Hemisphere (SH) as the GWL increases by 1.5 °C–4.0 °C relative to the preindustrial period, and that these characteristics are more significant with the stronger GWL. The probability density of the NSWS shifts toward weak winds over NH and strong winds over SH between the current climate and the 4.0 °C GWL. Compared to 1.5 °C GWL, the NSWS decreases −0.066 m s ^−1 over NH and increases +0.065 m s ^−1 over SH with 4.0 °C GWL, especially for East Asia and South America, the decrease and increase are most significant, which reach −0.21 and +0.093 m s ^−1 , respectively. Changes in the temperature gradient induced by global warming could be the primary factor causing the interhemispheric asymmetry of future NSWS changes. Intensified global warming induces the reduction in Hadley, Ferrell, and Polar cells over NH and the strengthening of the Hadley cell over SH could be another determinant of asymmetry changes in NSWS between two hemispheres.

The mechanism by which microRNAs (miRNAs) modulate innate immunity and autophagy has not been fully elucidated in Mycobacterium bovis (M. bovis) infections. In this study, we identified that miR-199a inhibited key innate immune responses and autophagy in murine macrophages infected with M. bovis. Using ex vivo and in vitro approaches we show that the expression of miR-199a was significantly increased during M. bovis infection. Furthermore, miR-199a suppressed autophagy and interferon-β (IFN-β) production by directly targeting TANK-binding kinase 1 (TBK1) mRNA in both J774a.1 and BMDM cells. Upregulation of miR-199a or TBK1 silencing (siTBK1) inhibited maturation of autophagosomes and increased M. bovis survival. Our results demonstrate that, by targeting of TBK1, miR-199a modulates innate immune responses and promote the intracellular survival and growth of M. bovis.

Prion diseases are fatal neurological disorders affecting various mammalian species including humans. Lack of proper diagnostic tools and non-availability of therapeutic remedies are hindering the control strategies for prion diseases. MicroRNAs (miRNAs) are abundant endogenous short non-coding essential RNA molecules that negatively regulate the target genes after transcription. Several biological processes depend on miRNAs, and altered profiles of these miRNAs are potential biomarkers for various neurodegenerative diseases, including prion diseases. Autophagic flux degrades the misfolded prion proteins to reduce chronic endoplasmic reticulum stress and enhance cell survival. Recent evidence suggests that specific miRNAs target and regulate the autophagic mechanism, which is critical for alleviating cellular stress. miRNAs-mediated regulation of these specific proteins involved in the autophagy represents a new target with highly significant therapeutic prospects. Here, we will briefly describe the biology of miRNAs, the use of miRNAs as potential biomarkers with their credibility, the regulatory mechanism of miRNAs in major neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and prion diseases, degradation pathways for aggregated prion proteins, the role of autophagy in prion diseases. Finally, we will discuss the miRNAs-modulated autophagic flux in neurodegenerative diseases and employ them as potential therapeutic intervention strategy in prion diseases.

Prion diseases are neurodegenerative disorders characterized by the accumulation of misfolded prion protein, spongiform changes in the brain, and brain inflammation as a result of the wide-spread activation of microglia. Autophagy is a highly conserved catabolic process for the clearance of cytoplasmic components, including protein aggregates and damaged organelles; this process also eliminates pathological PrPSc as it accumulates during prion infection. The NALP3 inflammasome is a multiprotein complex that is a component of the innate immune system and is responsible for the release of pro-inflammatory cytokines. Our previous study showed that the neurotoxic prion peptide PrP106-126 induces NALP3 inflammasome activation and subsequent IL-1β release in microglia. Autophagy is involved in the regulation of the immune responses and inflammation in many diseases including neurodegenerative diseases. However, the relationship between autophagy and NALP3 inflammasome in prion diseases has not been investigated. In this study, we demonstrated that the processing and release of mature IL-1β is significantly enhanced by the inhibition of autophagy. Conversely, gene-silencing of the NALP3 inflammasome promotes autophagy. Suppression of TRIF or TLR4 by siRNA attenuated PrP106-126-induced autophagy, which is indicating that the TLR4-TRIF signaling pathway is involved in PrP106-26-induced autophagy. Caspase 1 directly cleaved TRIF to diminish TLR-4-TRIF mediated autophagy. Our findings suggest that the inhibition of autophagy by NALP3 inflammasome is probably mediated by activated Caspase-1-induced TRIF cleavage. This is the first study reporting that the NALP3 inflammasome complex negatively regulates autophagy in response to PrP106-126 stimulation in microglia, and partly explains the mechanism of autophagy inhibition by Caspase-1 in PrP106-126-induced BV2 cell activation. Our findings suggest that autophagy up-regulation and inhibition of Caspase-1 may protect against prion-induced neuroinflammation and accelerate misfolded protein degradation and are potential therapeutic approaches for prion diseases.

Tuberculosis (TB) is one of the most fatal infectious diseases and a leading cause of mortality, with 95% of these deaths occurring in developing countries. The causative agent, Mycobacterium tuberculosis (Mtb), has a well-established ability to circumvent the host’s immune system for its intracellular survival. microRNAs (miRNAs) are small, non-coding RNAs having an important function at the post-transcriptional level and are involved in shaping immunity by regulating the repertoire of genes expressed in immune cells. It has been established in recent studies that the innate immune response against TB is significantly regulated by miRNAs. Moreover, differential expression of miRNA in Mtb infection can reflect the disease progression and may help distinguish between active and latent TB infection (LTBI). These findings encouraged the application of miRNAs as potential biomarkers. Similarly, active participation of miRNAs in modulation of autophagy and apoptosis responses against Mtb opens an exciting avenue for the exploitation of miRNAs as host directed therapy (HDT) against TB. Nanoparticles mediated delivery of miRNAs to treat various diseases has been reported and this technology has a great potential to be used in TB. In reality, this exploitation of miRNAs as biomarkers and in HDT is still in its infancy stage, and more studies using animal models mimicking human TB are advocated to assess the role of miRNAs as biomarkers and therapeutic targets. In this review, we attempt to summarize the recent advancements in the role of miRNAs in TB as immune modulator, miRNAs’ capability to distinguish between active and latent TB and, finally, usage of miRNAs as therapeutic targets against TB.

Mycobacterium avium subspecies paratuberculosis (MAP) persistently survive and replicate in mononuclear phagocytic cells by adopting various strategies to subvert host immune response. Interleukin-10 (IL-10) upregulation via inhibition of macrophage bactericidal activity is a critical step for MAP survival and pathogenesis within the host cell. Mitogen-activated protein kinase p38 signaling cascade plays a crucial role in the elevation of IL-10 and progression of MAP pathogenesis. The contribution of microRNAs (miRNAs) and their influence on the activation of macrophages during MAP pathogenesis are still unclear. In the current study, we found that miRNA-27a-3p (miR-27a) expression is downregulated during MAP infection both in vivo and in vitro. Moreover, miR-27a is also downregulated in toll-like receptor 2 (TLR2)-stimulated murine macrophages (RAW264.7 and bone marrow-derived macrophage). ELISA and real-time qRT-PCR results confirm that overexpression of miR-27a inhibited MAP-induced IL-10 production in macrophages and upregulated pro-inflammatory cytokines, while miR-27a inhibitor counteracted these effects. Luciferase reporter assay results revealed that IL-10 and TGF-β-activated protein kinase 1 binding protein 2 (TAB 2) are potential targets of miR-27a. In addition, we demonstrated that miR-27a negatively regulates TAB 2 expression and diminishes TAB 2-dependent p38/JNK phosphorylation, ultimately downregulating IL-10 expression in MAP-infected macrophages. Furthermore, overexpression of miR-27a significantly inhibited the intracellular survival of MAP in infected macrophages. Our data show that miR-27a augments antimicrobial activities of macrophages and inhibits the expression of IL-10, demonstrating that miR-27a regulates protective innate immune responses during MAP infection and can be exploited as a novel therapeutic target in the control of intracellular pathogens, including paratuberculosis.

Prion diseases are a group of infectious diseases characterized by multiple neuropathological changes, yet the mechanisms that preserve function and protect against prion-associated neurodegeneration are still unclear. We previously reported that the repressor element 1-silencing transcription factor (REST) alleviates neurotoxic prion peptide (PrP106-126)-induced toxicity in primary neurons. Here we confirmed the findings of the in vitro model in 263K infected hamsters, an in vivo model of prion diseases and further showed the relationships between REST and related signaling pathways. REST was depleted from the nucleus in prion infected brains and taken up by autophagosomes in the cytoplasm, co-localizing with LC3-II. Importantly, downregulation of the Akt–mTOR and at least partially inactivation of LRP6-Wnt-β-catenin signaling pathways correlated with the decreased levels of REST in vivo in the brain of 263K-infected hamsters and in vitro in PrP106-126-treated primary neurons. Overexpression of REST in primary cortical neurons alleviated PrP106-126 peptide-induced neuronal oxidative stress, mitochondrial damage and partly inhibition of the LRP6-Wnt-β-catenin and Akt–mTOR signaling. Based on our findings, a model of REST-mediated neuroprotection in prion infected animals is proposed, with Akt–mTOR and Wnt-β-catenin signaling as the key pathways. REST-mediated neuronal survival signaling could be explored as a viable therapeutic target for prion diseases and related neurodegenerative diseases.

Mycobacterium bovis (M. bovis) is the pathogen of animals and humans that can replicate in the phagosomes of myeloid cells. Cytosolic detection of bacterial products plays a crucial role in initiating the innate immune response, including autophagy activation and interferon-β (IFN-β) release. Although IFN-β release and autophagy activation have been reported during mycobacterium infection, the mechanisms underlying remains poorly defined. Here, we demonstrated that IFN-β release increases in macrophages exposed to M. bovis and this requires the activation of the DNA sensor of interferon-γ inducible protein 204 (IFI204). Knockdown of the IFI204 in immortalized and primary murine macrophages blocked IFN-β production and autophagy marker LC3 expression. Thus, our results indicate that the IFI204 is an important sensor for innate immune responses of M. bovis infection.

Prion diseases are neurodegenerative pathologies characterized by the accumulation of a protease-resistant form of the cellular prion protein named prion protein scrapie (PrPSc) in the brain. PrPSc accumulation in the endoplasmic reticulum (ER) result in a dysregulated calcium (Ca2+) homeostasis and subsequent initiation of unfolded protein response (UPR) leading to neuronal dysfunction and apoptosis. The molecular mechanisms for the transition between adaptation to ER stress and ER stress-induced apoptosis are still unclear. Mitogen-activated protein kinases (MAPKs) are serine/threonine protein kinases that rule the signaling of many extracellular stimuli from plasma membrane to the nucleus. However the identification of numerous points of cross talk between the UPR and MAPK signaling pathways may contribute to our understanding of the consequences of ER stress in prion diseases. Indeed the MAPK signaling network is known to regulate cell cycle progression and cell survival or death responses following a variety of stresses including misfolded protein response stress. In this article, we review the UPR signaling in prion diseases and discuss the triad of MAPK signaling pathways. We also describe the role played by MAPK signaling cascades in Alzheimer’s (AD) and Parkinson’s disease (PD). We will also overview the mechanisms of cell death and the role of MAPK signaling in prion disease progression and highlight potential avenues for therapeutic intervention.

Animal mycobacterioses are among the most important zoonoses worldwide. These are generally caused by either Mycobacterium tuberculosis (MTB), M. bovis (MBO) or M. avium (MAV). To test the hypothesis that different species of pathogenic mycobacteria isolated from varied anatomic locations or animal species differ in virulence and pathogenicity, we performed experiments with three mycobacteria strains (NTSE-3(MTB), NTSE-4(MBO) and NTSE-5 (MAV)) obtained from animal species. Spoligotyping analysis was used to confirm both MTB and MBO strains while the MAV strain was confirmed by 16s rDNA sequencing. BALB/c mice were intranasally infected with the three strains at low and high CFU doses to evaluate variations in pathogenicity. Clinical and pathological parameters were assessed. Infected mice were euthanized at 80 days post-inoculation (dpi). Measures of lung and body weights indicated that the MBO infected group had higher mortality, more weight loss, higher bacterial burden and more severe lesions in lungs than the other two groups. Cytokine profiles showed higher levels of TNF-α for MBO versus MTB, while MAV had the highest amounts of IFN-β in vitro and in vivo. In vitro levels of other cytokines such as IL-1β, IL-10, IL-12, IL-17, and IFN-β showed that Th1 cells had the strongest response in MBO infected mice and that Th2 cells were inhibited. We found that the level of virulence among the three isolates decreased in the following order MBO>MTB>MAV.

Abstract:Mycobacterium bovis (M. bovis) is highly adapted to macrophages and has developed multiple mechanisms to resist intracellular assaults. However, the host cells in turn deploy a multipronged defense mechanism to control bacterial infection. Endoplasmic reticulum (ER) stress-mediated apoptosis is one such primary defense mechanism. However the role of interferon regulatory factor 3 (IRF3) between ER stress and apoptosis during M. bovis infection is unknown. Here, we demonstrate that M. bovis effectively induced apoptosis in murine macrophages. Caspase-12, caspase-9 and caspase-3 were activated over a 48 h infection period. The splicing of XBP-1 mRNA and the level of phosphorylation of eIF2α, indicators of ER stress, significantly increased at early time points after M. bovis infection. The expansion of the ER compartment, a morphological hallmark of ER stress, was observed at 6 h. Pre-treatment of Raw 264.7 cells with 4-PBA (an ER stress-inhibitor) reduced the activation of the ER stress indicators, caspase activation and its downstream poly (ADP-ribose) polymerase (PARP) cleavage, phosphorylation of TBK1 and IRF3 and cytoplasmic co-localization of STING and TBK1. M. bovis infection led to the interaction of activated IRF3 and cytoplasmic Bax leading to mitochondrial damage. Role of IRF3 in apoptosis was further confirmed by blocking this molecule with BX-795 that showed significant reduction expression of caspase-8 and caspase-3. Intracellular survival of M. bovis increased in response to 4-PBA and BX-795. These findings indicate that STING-TBK1-IRF3 pathway mediates a crosstalk between ER stress and apoptosis during M. bovis infection, which can effectively control intracellular bacteria.

Mycobacterium bovis (M. bovis) is a member of the Mycobacterium tuberculosis (Mtb) complex causing bovine tuberculosis (TB) and imposing a high zoonotic threat to human health. Kallikreins (KLKs) belong to a subgroup of secreted serine proteases. As their role is established in various physiological and pathological processes, it is likely that KLKs expression may mediate a host immune response against the M. bovis infection. In the current study, we report in vivo and in vitro upregulation of KLK12 in the M. bovis infection. To define the role of KLK12 in immune response regulation of murine macrophages, we produced KLK12 knockdown bone marrow derived macrophages (BMDMs) by using siRNA transfection. Interestingly, the knockdown of KLK12 resulted in a significant downregulation of autophagy and apoptosis in M. bovis infected BMDMs. Furthermore, we demonstrated that this KLK12 mediated regulation of autophagy and apoptosis involves mTOR/AMPK/TSC2 and BAX/Bcl-2/Cytochrome c/Caspase 3 pathways, respectively. Similarly, inflammatory cytokines IL-1β, IL-6, IL-12 and TNF-α were significantly downregulated in KLK12 knockdown macrophages but the difference in IL-10 and IFN-β expression was non-significant. Taken together, these findings suggest that upregulation of KLK12 in M. bovis infected murine macrophages plays a substantial role in the protective immune response regulation by modulating autophagy, apoptosis and pro-inflammatory pathways. To our knowledge, this is the first report on expression and the role of KLK12 in the M. bovis infection and the data may contribute to a new paradigm for diagnosis and treatment of bovine TB.

Nilotinib, a tyrosine kinase inhibitor, has been studied extensively in various tumor models; however, no information exists about the pharmacological action of nilotinib in bacterial infections. Mycobacterium bovis (M. bovis) and Mycobacterium avium subspecies paratuberculosis (MAP) are the etiological agents of bovine tuberculosis and Johne’s disease, respectively. Although M. bovis and MAP cause distinct tissue tropism, both of them infect, reside, and replicate in mononuclear phagocytic cells of the infected host. Autophagy is an innate immune defense mechanism for the control of intracellular bacteria, regulated by diverse signaling pathways. Here we demonstrated that nilotinib significantly inhibited the intracellular survival and growth of M. bovis and MAP in macrophages by modulating host immune responses. We showed that nilotinib induced autophagic degradation of intracellular mycobacterium occurred via the inhibition of PI3k/Akt/mTOR axis mediated by abelson (c-ABL) tyrosine kinase. In addition, we observed that nilotinib promoted ubiquitin accumulation around M. bovis through activation of E3 ubiquitin ligase parkin. From in-vivo experiments, we found that nilotinib effectively controlled M. bovis growth and survival through enhanced parkin activity in infected mice. Altogether, our data showed that nilotinib regulates protective innate immune responses against intracellular mycobacterium, both in-vitro and in-vivo, and can be exploited as a novel therapeutic remedy for the control of M. bovis and MAP infections.

Transcription factors play a significant role during the symptomatic onset and progression of prion diseases. We previously showed the immunomodulatory and nuclear factor of activated T cells’ (NFAT) suppressive effects of an immunosuppressant, FK506, in the symptomatic stage and an antibiotic, minocycline, in the pre-symptomatic stage of prion infection in hamsters. Here we used for the first time, a combinatory FK506+minocycline treatment to test its transcriptional modulating effects in the symptomatic stage of prion infection. Our results indicate that prolonged treatment with FK506+minocycline was effective in alleviating astrogliosis and neuronal death triggered by misfolded prions. Specifically, the combinatory therapy with FK506+minocycline lowered the expression of the astrocytes activation marker GFAP and of the microglial activation marker IBA-1, subsequently reducing the level of pro-inflammatory cytokines interleukin 1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α), and increasing the levels of anti-inflammatory cytokines IL-10 and IL-27. We further found that FK506+minocycline treatment inhibited mitogen-activated protein kinase (MAPK) p38 phosphorylation, NF-kB nuclear translocation, caspase expression, and enhanced phosphorylated cAMP response element-binding protein (pCREB) and phosphorylated Bcl2-associated death promoter (pBAD) levels to reduce cognitive impairment and apoptosis. Interestingly, FK506+minocycline reduced mitochondrial fragmentation and promoted nuclear factor–erythroid2-related factor-2 (NRF2)-heme oxygenase 1 (HO-1) pathway to enhance survival. Taken together, our results show that a therapeutic cocktail of FK506+minocycline is an attractive candidate for prolonged use in prion diseases and we encourage its further clinical development as a possible treatment for this disease.

Cyclic GMP-AMP synthase (cGAS) is an important cytosolic DNA sensor that plays a crucial role in triggering STING-dependent signal and inducing type I interferons (IFNs). cGAS is important for intracellular bacterial recognition and innate immune responses. However, the regulating effect of the cGAS pathway for bone marrow-derived dendritic cells (BMDCs) during Mycobacterium bovis (M. bovis) infection is still unknown. We hypothesized that the maturation and activation of BMDCs were modulated by the cGAS/STING/TBK1/IRF3 signaling pathway. In this study, we found that M. bovis promoted phenotypic maturation and functional activation of BMDCs via the cGAS signaling pathway, with the type I IFN and its receptor (IFNAR) contributing. Additionally, we showed that the type I IFN pathway promoted CD4+ T cells’ proliferation with BMDC during M. bovis infection. Meanwhile, the related cytokines increased the expression involved in this signaling pathway. These data highlight the mechanism of the cGAS and type I IFN pathway in regulating the maturation and activation of BMDCs, emphasizing the important role of this signaling pathway and BMDCs against M. bovis. This study provides new insight into the interaction between cGAS and dendritic cells (DCs), which could be considered in the development of new drugs and vaccines against tuberculosis.

The impacts of urban surface expansion, based on satellite-derived data displaying urban surface expansion in China at different spatial scales from 1980 to 2016, were investigated using nested dynamical downscaling methods with the Weather Research and Forecasting (WRF) regional climate model at a 3.3-km resolution over a city and city cluster scale. Urban-related warming, based on daily mean surface air temperature at 2 m (SAT), calculated from the averages of four time records each day (00, 06, 12, and 18 h UTC, T4) and averages of SAT maximum (Tmax) and minimum (Tmin) (Txn), was evaluated. Differences in urban-related warming contributions calculated using T4 and Txn were small, whereas annual mean SAT and trends calculated using Txn were respectively and significantly larger and smaller than those calculated using T4 over Guangzhou and Shenzhen, excluding the trends over middle-northern Shenzhen. The differences in annual mean SAT calculated using T4 and Txn are attributed to nonlinear or asymmetric variations with time for the diurnal cycle of SAT. Meanwhile, differences in trends between T4 and Txn are interpreted as a strong trend for Tmin and a weak one for Tmax, which mitigated the trend for Txn. The impacts on the evaluations of urban-related warming contributions calculated from different methods were the largest over the areas classified as urban surfaces in both time periods (U2U), especially during intense urban-surface-expansion periods between 2000 and 2016. The subregional performances in the changes in annual mean SAT, trends, and urban-related warming are attributed to urban-surface-expansion, which induced varied changes in the diurnal cycle due to asymmetric warming during the daytime and nighttime over different subregions.

It is widely accepted that different strains of Mycobacterium tuberculosis have variable degrees of pathogenicity and induce different immune responses in infected hosts. Similarly, different strains of Mycobacterium bovis have been identified but there is a lack of information regarding the degree of pathogenicity of these strains and their ability to provoke host immune responses. Therefore, in the current study, we used a mouse model to evaluate various factors involved in the severity of disease progression and the induction of immune responses by two strains of M. bovis isolated from cattle. Mice were infected with both strains of M. bovis at different colony-forming unit (CFU) via inhalation. Gross and histological findings revealed more severe lesions in the lung and spleen of mice infected with M. bovis N strain than those infected with M. bovis C68004 strain. In addition, high levels of interferon-γ (IFN-γ), interleukin-17 (IL-17), and IL-22 production were observed in the serum samples of mice infected with M. bovis N strain. Comparative genomic analysis showed the existence of 750 single nucleotide polymorphisms and 145 small insertions/deletions between the two strains. After matching with the Virulence Factors Database, mutations were found in 29 genes, which relate to 17 virulence factors. Moreover, we found an increased number of virulent factors in M. bovis N strain as compared to M. bovis C68004 strain. Taken together, our data reveal that variation in the level of pathogenicity is due to the mutation in the virulence factors of M. bovis N strain. Therefore, a better understanding of the mechanisms of mutation in the virulence factors will ultimately contribute to the development of new strategies for the control of M. bovis infection.

Human tuberculosis remains a huge global public health problem with an estimated 1/3rd of the population being infected. Defensins are antibacterial cationic peptides produced by a number of cell types, most notably neutrophil granulocytes and epithelial cells. All three defensin types (α-, β-, and θ-defensins) have antibacterial activities, mainly through bacterial membrane permeabilization. Defensins are effective against Gram-negative and Gram-positive bacteria including mycobacteria and are active both intra- and extracellularly. Mycobacterial resistance has never been demonstrated although the mprF gene encoding resistance in Staphylococcus aureus is present in the Mycobacterium tuberculosis genome. In addition to their antibacterial effect, defensins are chemoattractants for macrophages and neutrophils. There are many cases for their use for therapy or prophylaxis in tuberculosis as well. In conclusion, we propose that there is considerable scope and potential for exploring their use as therapeutic/prophylactic agents and more comprehensive survey of defensins from different species and their bioactivity is timely.

Mycobacterium bovis is the causative agent of tuberculosis in a wide range of mammals, including humans. Macrophages are the first line of host defense. They secrete proinflammatory cytokines, such as interleukin-1 beta (IL-1β), in response to mycobacterial infection, but the underlying mechanisms by which human macrophages are activated and release IL-1β following M. bovis infection are poorly understood. Here we show that the 'nucleotide binding and oligomerization of domain-like receptor (NLR) family pyrin domain containing 7 protein' (NLRP7) inflammasome is involved in IL-1β secretion and caspase-1 activation induced by M. bovis infection in THP-1 macrophages. NLRP7 inflammasome activation promotes the induction of pyroptosis as well as the expression of tumor necrosis factor alpha (TNF-α), Chemokine (C-C motif) ligand 3 (CCL3) and IL-1β mRNAs. Thus, the NLRP7 inflammasome contributes to IL-1β secretion and induction of pyroptosis in response to M. bovis infection in THP-1 macrophages.

Tuberculosis (TB) is a major health threat to the human population worldwide. The etiology of the disease is Mycobacterium tuberculosis (Mtb), a highly successful intracellular pathogen. It has the ability to manipulate the host immune response and to make the intracellular environment suitable for its survival. Many studies have addressed the interactions between the bacteria and the host immune cells as involving many immune mediators and other cellular players. Interferon-β (IFN-β) signaling is crucial for inducing the host innate immune response and it is an important determinant in the fate of mycobacterial infection. The role of IFN-β in protection against viral infections is well established and has been studied for decades, but its role in mycobacterial infections remains much more complicated and debatable. The involvement of IFN-β in immune evasion mechanisms adopted by Mtb has been an important area of investigation in recent years. These advances have widened our understanding of the pro-bacterial role of IFN-β in host–pathogen interactions. This pro-bacterial activity of IFN-β appears to be correlated with its anti-inflammatory characteristics, primarily by antagonizing the production and function of interleukin 1β (IL-1β) and interleukin 18 (IL-18) through increased interleukin 10 (IL-10) production and by inhibiting the nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome. Furthermore, it also fails to provoke a proper T helper 1 (Th1) response and reduces the expression of major histocompatibility complex II (MHC-II) and interferon-γ receptors (IFNGRs). Here we will review some studies to provide a paradigm for the induction, regulation, and role of IFN-β in mycobacterial infection. Indeed, recent studies suggest that IFN-β plays a role in Mtb survival in host cells and its downregulation may be a useful therapeutic strategy to control Mtb infection.