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Abstract Background Peste des Petits Ruminants (PPR) is a world organization for animal health (WOAH) notifiable and economically important transboundary, highly communicable viral disease of small ruminants. PPR virus (PPRV) belongs to the genus Morbillivirus of the family Paramyxoviridae. Aim The present cross-sectional epidemiological investigation was accomplished to estimate the apparent prevalence and identify the risk factors linked with peste des petits ruminants (PPR) in the previously neglected northern border regions of Pakistan. Method A total of 1300 samples (serum = 328; swabs = 972) from 150 flocks/herds were compiled from sheep (n = 324), goats (n = 328), cattle (n = 324), and buffaloes (n = 324) during 2020–2021 and tested using ELISA for detection of viral antibody in sera or antigen in swabs. Results An overall apparent prevalence of 38.7% (504 samples) and an estimated true prevalence (calculated by the Rogan and Gladen estimator) of 41.0% (95% CI, 38.0–44 were recorded in the target regions. The highest apparent prevalence of 53.4% (85 samples) and the true prevalence of 57.0%, 95% Confidence Interval (CI) were documented in the Gilgit district and the lowest apparent prevalence of 53 (25.1%) and the true prevalence of 26.0%, 95% Confidence Interval (CI), 19.0–33.0) was reported in the Swat district. A questionnaire was designed to collect data about associated risk factors that were put into a univariable logistic regression to decrease the non-essential assumed risk dynamics with a P-value of 0.25. ArcGIS, 10.8.1 was used to design hotspot maps and MedCalc’s online statistical software was used to calculate Odds Ratio (OR). Some of the risk factors significantly different (P

The microstructure, grain size, dislocation density, and crystal texture of a material vary owing to prestraining due to external forces. These changes directly affect the corrosion behavior of the material, thereby affecting the structural integrity and service life of the equipment. Thus, this study investigated the impact of 0 %–25 % prestrain on the microstructure and corrosion properties of Incoloy 840, a nickel-based alloy steel. This research explored the relationship between the grain size, low-angle grain boundaries, geometrically necessary dislocation density, dislocation distribution, and corrosion properties. When the prestrain was less than 20 %, the material had fewer defects, and the corrosion performance was influenced by the grain size and low-angle grain boundaries. The highest corrosion resistance was observed with a prestrain of 20 %. Conversely, higher prestrain levels increased the number of defects and dislocation density, thereby rupturing the passivation film and reducing the corrosion resistance of the material.

Abstract Background Recent research indicates a positive correlation between DEP structural domain‐containing 1B (DEPDC1B) and the cell cycle in various tumors. However, the role of DEPDC1B in the infiltration of the tumor immune microenvironment (TIME) remains unexplored. Methods We analyzed the differential expression and prognostic significance of DEPDC1B in colon adenocarcinoma (COAD) using the R package “limma” and the Gene Expression Profiling Interactive Analysis (GEPIA) website. Gene set enrichment analysis (GSEA) was employed to investigate the functions and interactions of DEPDC1B expression in COAD. Cell Counting Kit‐8 (CCK‐8) assays and colony formation assays were utilized to assess the proliferative function of DEPDC1B. Correlations between DEPDC1B expression and tumor‐infiltrating immune cells, immune checkpoints, tumor mutational burden (TMB), and microsatellite instability (MSI) status were examined using Spearman correlation analysis and CIBERSORT. Results DEPDC1B was highly expressed in COAD. Elevated DEPDC1B expression was associated with lower epithelial‐to‐mesenchymal transition (EMT) and TNM stages, leading to a favorable prognosis. DEPDC1B mRNA was prominently expressed in COAD cell lines. CCK‐8 and colony formation assays demonstrated that DEPDC1B inhibited the proliferation of COAD cells. Analysis using the CIBERSORT database and Spearman correlation revealed that DEPDC1B correlated with four types of tumor‐infiltrating immune cells. Furthermore, high DEPDC1B expression was linked to the expression of PD‐L1, CTLA4, SIGLEC15, PD‐L2, TMB, and MSI‐H. High DEPDC1B expression also indicated responsiveness to anti‐PD‐L1 immunotherapy. Conclusions DEPDC1B inhibits the proliferation of COAD cells and positively regulates the cell cycle, showing a positive correlation with CCNB1 and PBK expression. DEPDC1B expression in COAD is associated with tumor‐infiltrating immune cells, immune checkpoints, TMB, and MSI‐H in the tumor immune microenvironment. This suggests that DEPDC1B may serve as a novel prognostic marker and a potential target for immunotherapy in COAD.

[INLINE:1] Previous studies have reported upregulation of heme oxygenase-1 in different central nervous system injury models. Heme oxygenase-1 plays a critical anti-inflammatory role and is essential for regulating cellular redox homeostasis. Metformin is a classic drug used to treat type 2 diabetes that can inhibit ferroptosis. Previous studies have shown that, when used to treat cardiovascular and digestive system diseases, metformin can also upregulate heme oxygenase-1 expression. Therefore, we hypothesized that heme oxygenase-1 plays a significant role in mediating the beneficial effects of metformin on neuronal ferroptosis after spinal cord injury. To test this, we first performed a bioinformatics analysis based on the GEO database and found that heme oxygenase-1 was upregulated in the lesion of rats with spinal cord injury. Next, we confirmed this finding in a rat model of T9 spinal cord compression injury that exhibited spinal cord nerve cell ferroptosis. Continuous intraperitoneal injection of metformin for 14 days was found to both upregulate heme oxygenase-1 expression and reduce neuronal ferroptosis in rats with spinal cord injury. Subsequently, we used a lentivirus vector to knock down heme oxygenase-1 expression in the spinal cord, and found that this significantly reduced the effect of metformin on ferroptosis after spinal cord injury. Taken together, these findings suggest that metformin inhibits neuronal ferroptosis after spinal cord injury, and that this effect is partially dependent on upregulation of heme oxygenase-1.

Abstract Purpose To investigate the influence of β-arrestin2 on the docetaxel resistance in castration-resistant prostate cancer (CRPC) and elucidate the underlying molecular mechanisms. Methods PC3 and DU145 cells with stable β-arrestin2 overexpression and C4-2 cells with stable β-arrestin2 knockdown, were constructed via using lentivirus and puromycin selection. MTT and colony formation assays were carried out to investigate the effect of β-arrestin2 expression on the docetaxel resistance of CRPC cells. Glycolysis analysis was used to assess the glycolytic capacity modulated by β-arrestin2. GO enrichment analysis, gene set enrichment analysis and Spearman correlation test were carried out to explore the potential biological function and mechanism via using public data from GEO and TCGA. The expressions of PKM2, Phospho-PKM2, Phospho-ERK1/2 and hnRNP A1 were detected by western blot. Functional blocking experiments were carried out to confirm the roles of PKM2 and hnRNP A1 in the regulation of β-arrestin2’s biological functions via silencing PKM2 or hnRNP A1 expression in cells with stable β-arrestin2 overexpression. Finally, nude mice xenograft models were established to confirm the experimental results of cell experiments. Results β-Arrestin2 significantly decreased the sensitivity of CRPC cells to docetaxel stimulation, through enhancing the phosphorylation and expression of PKM2. Additionally, β-arrestin2 increased PKM2 phosphorylation via the ERK1/2 signaling pathway and induced PKM2 expression in a post-transcriptional manner through an hnRNP A1-dependent PKM alternative splicing mechanism, rather than by inhibiting its ubiquitination degradation. Conclusion Our findings indicate that the β-arrestin2/hnRNP A1/PKM2 pathway could be a promising target for treating docetaxel-resistant CRPC.

Abstract Background Canine distemper virus (CDV) is one of the most contagious and lethal viruses known to the Canidae, with a very broad and expanding host range. Autophagy serves as a fundamental stabilizing response against pathogens, but some viruses have been able to evade or exploit it for their replication. However, the effect of autophagy mechanisms on CDV infection is still unclear. Results In the present study, autophagy was induced in CDV-infected Vero cells as demonstrated by elevated LC3-II levels and aggregation of green fluorescent protein (GFP)-LC3 spots. Furthermore, CDV promoted the complete autophagic process, which could be determined by the degradation of p62, co-localization of LC3 with lysosomes, GFP degradation, and accumulation of LC3-II and p62 due to the lysosomal protease inhibitor E64d. In addition, the use of Rapamycin to promote autophagy promoted CDV replication, and the inhibition of autophagy by Wortmannin, Chloroquine and siRNA-ATG5 inhibited CDV replication, revealing that CDV-induced autophagy facilitated virus replication. We also found that UV-inactivated CDV still induced autophagy, and that nucleocapsid (N) protein was able to induce complete autophagy in an mTOR-dependent manner. Conclusions This study for the first time revealed that CDV N protein induced complete autophagy to facilitate viral replication.

In order to investigate the influence of fracture attitude variation on the permeability of fractures in deep rock mass under natural crustal stresses, based on the permeability law of a single fracture obeying the law of negative exponential change, the theoretical formula of coefficient of permeability of fractures with variable attitude subjected to 3D stresses is proposed. The Lagrange multiplier method is applied to analyze the change of variable attitude on fracture permeability, and influence factors and sensibility of fracture permeability with or without infillings are also analyzed. Statistic law of crustal stress in Chinese mainland is taken as an example, and the variable laws of the permeability of fractures in rock mass with depth and fracture attitude are analyzed. The results show that (1) the permeability of fractures in rock mass is obviously influenced by the attitude of fractures. For shallow rock mass, under the condition of the maximum principle stress distribution in the horizontal direction, the permeability of fractures gradually decreases with the increasing dip angle of fractures; but with the increasing depth, when the depth is more than 200 m and the strike of fracture is roughly consistent with the direction of large or medium principal stress, the permeability of fractures can increase with the increasing dip angle of fractures, especially the strike of fractures perpendicular to the direction of the minimum principle stress. For deep rock mass, the permeability of fracture is very weak, and the impact of fracture attitude change on its permeability is very slight. (2) For fractures with infillings, the change of elastic modulus ratio of rock block to infillings and Poisson’s ratio of infillings have little effect on fracture permeability. The conclusions can be used for reference for further investigating the variation of deep rock permeability characteristics.

Exploring metallic microfibers with an excellent combination of high strength and ductility is a challenge for structural applications under extreme conditions. In this work, a heterogeneous gradient structure was introduced into CoCrFeNi high-entropy alloy (HEA) microfibers via thermomechanical processing. The annealed CoCrFeNi microfiber displays an ultrahigh yield strength of ∼ 1 GPa, an ultimate tensile strength of 1.45 GPa, and an outstanding uniform elongation of 75% at 150 K. These excellent properties originate from the ultrafine grains and heterogeneous gradient structure, as well as the activation of multiple deformation mechanisms including deformation twins, dense dislocations, stacking faults, Lomer-Cottrell locks, phase transformation and 9R phase. Our work not only suggests that HEA microfibers have great potential for structural applications in cryogenic environments, but also sheds light on the design of advanced multi-component metallic microfibers with superior mechanical properties.

Abstract Background Gliomas are the most frequent type of central nervous system tumor, accounting for more than 70% of all malignant CNS tumors. Recent research suggests that the hyaluronan-mediated motility receptor (HMMR) could be a novel potential tumor prognostic marker. Furthermore, mounting data has highlighted the important role of ceRNA regulatory networks in a variety of human malignancies. The complexity and behavioural characteristics of HMMR and the ceRNA network in gliomas, on the other hand, remained unknown. Methods Transcriptomic expression data were collected from TCGA, GTEx, GEO, and CGGA database.The relationship between clinical variables and HMMR was analyzed with the univariate and multivariate Cox regression. Kaplan–Meier method was used to assess OS. TCGA data are analyzed and processed, and the correlation results obtained were used to perform GO, GSEA, and ssGSEA. Potentially interacting miRNAs and lncRNAs were predicted by miRWalk and StarBase. Results HMMR was substantially expressed in gliomas tissues compared to normal tissues. Multivariate analysis revealed that high HMMR expression was an independent predictive predictor of OS in TCGA and CGGA. Functional enrichment analysis found that HMMR expression was associated with nuclear division and cell cycle. Base on ssGSEA analysis, The levels of HMMR expression in various types of immune cells differed significantly. Bioinformatics investigation revealed the HEELPAR-hsa-let-7i-5p-RRM2 ceRNA network, which was linked to gliomas prognosis. And through multiple analysis, the good predictive performance of HELLPAR/RRM2 axis for gliomas patients was confirmed. Conclusion This study provides multi-layered and multifaceted evidence for the importance of HMMR and establishes a HMMR-related ceRNA (HEELPAR-hsa-let-7i-5p-RRM2) overexpressed network related to the prognosis of gliomas.

This paper presents a backpropagation neural network (BPNN) approach based on the sparse autoencoder (SAE) for short-term water demand forecasting. In this method, the SAE is used as a feature learning method to extract useful information from hourly water demand data in an unsupervised manner. After that, the extracted information is employed to optimize the initial weights and thresholds of the BPNN. In addition, to enhance the effectiveness of the proposed method, data reconstruction is implemented to create suitable samples for the BPNN, and the early stopping method is employed to overcome the BPNN overfitting problem. Data collected from a real-world water distribution system are used to verify the effectiveness of the proposed method, and a comparison with the BPNN and other BPNN-based methods which integrate the BPNN with particle swarm optimization (PSO) and the mind evolutionary algorithm (MEA), respectively, is conducted. The results show that the proposed method can achieve fairly accurate and stable forecasts with a 2.31% mean absolute percentage error (MAPE) and 320 m3/h root mean squared error (RMSE). Compared with the BPNN, PSO–BPNN and MEA–BPNN models, the proposed method gains MAPE improvements of 5.80, 3.33 and 3.89%, respectively. In terms of the RMSE, promising improvements (i.e., 5.27, 2.73 and 3.33%, respectively) can be obtained. HIGHLIGHTS To enhance the performance of the BPNN, the SAE is introduced to extract useful features in an unsupervised manner.; An effective framework which integrates the BPNN with the SAE and early stopping technique is proposed for water demand forecasting.; The proposed method is verified by comparing with the BPNN and similar methods which integrate the BPNN with PSO and the MEA, respectively.;

Abstract Anti-CD38 monoclonal antibodies (mAbs), daratumumab, and isatuximab have represented a breakthrough in the treatment of multiple myeloma (MM). Recently, CD38-based mAbs were expected to achieve increasing potential beyond MM, which encouraged us to develop new anti-CD38 mAbs to meet clinical needs. In this study, we developed a novel humanized anti-CD38 antibody, FTL004, which exhibited enhanced pro-apoptotic ability and negligible binding to red blood cells (RBCs). FTL004 presented a better ability to induce direct apoptosis independent of Fc-mediated cross-linking against lymphoma and MM cell lines as well as primary myeloma cells derived from MM patients. For instance, FTL004 induced RPMI 8226 cells with 55% early apoptosis cells compared with 20% in the isatuximab-treated group. Of interest, FTL004 showed ignorable binding to CD38 on human RBCs in contrast to tumor cells, even at concentrations up to 30 μg/mL. Furthermore, with an engineered Fc domain, FTL004 displayed stronger antibody-dependent cellular cytotoxicity (ADCC) against CD38+ malignant cells. In vivo MM and non-Hodgkin lymphoma tumor xenograft models showed that FTL004 possessed an effective anti-tumor effect. Cryo-electron microscopy structure resolved two epitope centers of FTL004 on CD38: one of which was unique while the other partly overlapped with that of isatuximab. Taken together, FTL004 distinguishes it from other CD38 targeting mAbs and represents a potential candidate for the treatment of MM and non-Hodgkin lymphoma.

The “do not eat me” signaling pathway is extremely active in tumor cells, providing a means for these cells to elude macrophage phagocytosis and escape immune surveillance. Representative markers of this pathway, such as CD47 and CD24, are highly expressed in numerous tumors. The interaction of SIRPα with CD47 reduces the accumulation of non-myosin ⅡA on the cell membrane. The combination of CD24 and Siglec10 ultimately leads to the recruitment of SHP-1 or SHP-2 to reduce signal transduction. Both of them weaken the ability of macrophages to engulf tumor cells. Blocking the mutual recognition between CD47-SIRPα or CD24-Siglec10 using large molecular proteins or small molecular drugs represents a promising avenue for tumor immunotherapy. Doing so can inhibit signal transduction and enhance macrophage clearance rates of cancer cells. In this paper, we summarize the characteristics of the drugs that affect the “do not eat me” signaling pathway via classical large molecular proteins and small molecule drugs, which target the CD47-SIRPα and CD24-Siglec10 signaling pathways, which target the CD47-SIRPα and CD24-Siglec10 signaling pathways. We expect it will offer insight into the development of new drugs centered on blocking the “do not eat me” signaling pathway.

Accurately assessing the risk of flash floods is a fundamental prerequisite for defending against flash flood disasters. The existing methods for assessing flash flood risk are constrained by unclear key factors and challenges in elucidating disaster mechanisms, resulting in less-than-ideal early warning effectiveness. This article is based on official statistics of flash flood disaster data from 2017 to 2021. It selects eight categories of driving factors influencing flash floods, such as rainfall, underlying surface conditions, and human activities. Subsequently, a geographical detector is utilized to analyze the explanatory power of each driving factor in flash flood disasters, quantifying the contribution of each factor to the initiation of flash flood; the flash flood potential index (FFPI) was introduced to assess the risk of flash flood disasters in China, leading to the construction of a comprehensive assessment framework for flash flood risk. The results indicate that (1) Flash floods are generally triggered by multiple factors, with rainfall being the most influential factor, directly causing flash floods. Soil type is the second most influential factor, and the combined effects of multiple factors intensify the risk of flash floods. (2) The southeastern, southern, and southwestern regions of China are considered high-risk areas for flash floods, with a high danger level, whereas the northwestern, northern, and northeastern plain regions exhibit a lower danger level. The above research results provide reference and guidance for the prevention and control of flash flood disasters.

Effect of annealing treatment on deep drawing behavior of hot-rolled Q235 carbon steel/410/304 stainless steel three-layer composite plate was investigated. Deep drawability of the unannealed composite plates exhibits a sharp difference for various contact surfaces with the die. The limit drawing ratio (LDR) of the composite plate with the carbon steel contacting the die is 1.75, while it is 1.83 with the stainless steel contacting the die due to the different mechanical responses to the tensile stress at the corner of the die. After annealing at 900°C for 2 h, however, the deep drawabilities of the composite plates both for various contact surfaces with the die are significantly improved and becomes almost identical, which are attributed to the stress relief, the enhanced ductility and the improved interface bonding strength of the hot-rolled component plates during annealing.

Seneca Valley Virus (SVV), a member of the Picornaviridae family, is an emerging porcine virus that can cause vesicular disease in pigs. However, the immune evasion mechanism of SVV remains unclear, as does its interaction with other pathways. STING (Stimulator of interferon genes) is typically recognized as a critical factor in innate immune responses to DNA virus infection, but its role during SVV infection remains poorly understood. In the present study, we observed that STING was degraded in SVV-infected PK-15 cells, and SVV replication in the cells was affected when STING was knockdown or overexpressed. The STING degradation observed was blocked when the SVV-induced autophagy was inhibited by using autophagy inhibitors (Chloroquine, Bafilomycin A1) or knockdown of autophagy related gene 5 (ATG5), suggesting that SVV-induced autophagy is responsible for STING degradation. Furthermore, the STING degradation was inhibited when reticulophagy regulator 1 (FAM134B), a reticulophagy related receptor, was knocked down, indicating that SVV infection induces STING degradation via reticulophagy. Further study showed that in eukaryotic translation initiation factor 2 alpha kinase 3 (PERK)/activating transcription factor 6 (ATF6) deficient cells, SVV infection failed to induce reticulophagy-medaited STING degradation, indicating that SVV infection caused STING degradation via PERK/ATF6-mediated reticulophagy. Notably, blocking reticulophagy effectively hindered SVV replication. Overall, our study suggested that SVV infection resulted in STING degradation via PERK and ATF6-mediated reticulophagy, which may be an immune escape strategy of SVV. This finding improves the understanding of the intricate interplay between viruses and their hosts and provides a novel strategy for the development of novel antiviral drugs.

With the increase in the occupancy ratio of bridges and the speed of trains, the probability of trains being located on bridges during earthquakes increases, and the risk of derailment increases. To investigate the influence of unequal-height piers on the dynamic response of high-speed railway train bridge systems, a seismic action model of high-speed train–track–bridge dynamic systems was established based on the in-house code using the finite element method and multi-body dynamics method. It is found that (1) compared to equal-height piers, the peak lateral dynamic response of unequal-height piers (with gradually increasing pier heights) decreases, while the peak vertical dynamic response increases; (2) the peak lateral dynamic response of unequal-height piers (with a steep increase in pier height) increases sharply, while the peak vertical dynamic response decreases; and (3) the safety indicators of equal-height piers are significantly superior to the two unequal-height pier operating conditions.

A hybrid model based on the mind evolutionary algorithm is proposed to predict hourly water demand. In the hybrid model, hourly water demand data are first reconstructed to generate appropriate samples so as to represent the characteristics of time series effectively. Then, the mind evolutionary algorithm is integrated into a back propagation neural network (BPNN) to improve prediction performance. To investigate the application potential of the proposed model in hourly water demand forecasting, real hourly water demand data were applied to evaluate its prediction performance. In addition, the performance of the proposed model was compared with a traditional BPNN model and another hybrid model where the genetic algorithm (GA) is used as an optimization algorithm for BPNN. The results show that the proposed model has a satisfactory prediction performance in hourly water demand forecasting. On the whole, the proposed model outperforms all other models involved in the comparisons in both prediction accuracy and stability. These findings suggest that the proposed model can be a novel and effective tool for hourly water demand forecasting. HIGHLIGHTS A unified framework is developed to select input variables for an hourly water demand forecasting model.; Mind evolutionary algorithm, a novel and powerful optimization algorithm, is used to obtain the optimal initial weights and thresholds for the back propagation neural network.; A hybrid model coupling mind evolutionary algorithm and back propagation neural network is proposed to predict hourly water demand.;

DNA methylation mediated by DNA methyltransferase is an important epigenetic process that regulates gene expression in mammals, which plays a key role in silencing certain genes, such as tumor suppressor genes, in cancer, and it has become a promising therapeutic target for cancer treatment. Similar to other epigenetic targets, DNA methyltransferase can also be modulated by chemical agents. Four agents have already been approved to treat hematological cancers. In order to promote the development of a DNA methyltransferase inhibitor as an anti-tumor agent, in the current review, we discuss the relationship between DNA methylation and tumor, the anti-tumor mechanism, the research progress and pharmacological properties of DNA methyltransferase inhibitors, and the future research trend of DNA methyltransferase inhibitors.

BackgroundIntracranial aneurysm (IA) causes more than 80% of nontraumatic subarachnoid hemorrhages (SAHs). The mechanism of ferroptosis involved in IA formation remains unclear. The roles played by competitive endogenous RNA (ceRNA) regulation networks in many diseases are becoming clearer. The goal of this study was to understand more fully the ferroptosis-related ceRNA regulation network in IA.Materials and methodsTo identify differentially expressed genes (DEGs), differentially expressed miRNAs (DEMs), and differentially expressed lncRNAs (DELs) across IA and control samples, the GEO datasets GSE122897 and GSE66239 were downloaded and analyzed with the aid of R. Ferroptosis DEGs were discovered by exploring the DEGs of ferroptosis-related genes of the ferroptosis database. Potentially interacting miRNAs and lncRNAs were predicted using miRWalk and StarBase. Enrichment analysis was also performed. We utilized the STRING database and Cytoscape software to identify protein-protein interactions and networks. DAB-enhanced Prussian blue staining was used to detect iron in IA tissues.ResultsIron deposition was evident in IA tissue. In all, 30 ferroptosis DEGs, 5 key DEMs, and 17 key DELs were screened out for constructing a triple regulatory network. According to expression regulation of DELs, DEMs, and DEGs, a hub triple regulatory network was built. As the functions of lncRNAs are determined by their cellular location, PVT1-hsa-miR-4644-SLC39A14 ceRNA and DUXAP8-hsa-miR-378e/378f-SLC2A3 ceRNA networks were constructed.ConclusionCeRNA (PVT1-hsa-miR-4644-SLC39A14 and DUXAP8-hsa-miR-378e/378f-SLC2A3) overexpression networks associated with ferroptosis in IA were established.

BackgroundSeveral studies have suggested that anti-silencing function 1 B (ASF1B) can serve as a good potential marker for predicting tumor prognosis. But the values of ASF1B in gliomas have not been elucidated and further confirmation is needed.MethodsTranscriptomic and clinical data were downloaded from The Cancer Genome Atlas database (TCGA), genotypic tissue expression (GTEx), and the Chinese Gliomas Genome Atlas database (CGGA). Univariate and multivariate Cox regression analyses were used to investigate the link between clinical variables and ASF1B. Survival analysis was used to assess the association between ASF1B expression and overall survival (OS). The relationship between ASF1B expression and OS was studied using survival analysis. To investigate the probable function and immunological infiltration, researchers used gene ontology (GO) analysis, gene set enrichment analysis (GSEA), and single-sample GSEA (ssGSEA).ResultsIn glioma tissues, ASF1B expression was considerably higher than in normal tissues. The survival analysis found that increased ASF1B expression was linked with a poor prognosis in glioma patients. ASF1B demonstrated a high diagnostic value in glioma patients, according to a Receiver Operating Characteristic (ROC) analysis. ASF1B was found to be an independent predictive factor for OS in a Cox regression study (HR = 1.573, 95% CI: 1.053–2.350, p = 0.027). GO, KEGG, and GSEA functional enrichment analysis revealed that ASF1B was associated with nuclear division, cell cycle, m-phase, and cell cycle checkpoints. Immuno-infiltration analysis revealed that ASF1B was positively related to Th2 cells, macrophages, and aDC and was negatively related to pDC, TFH, and NK CD56 bright cells.ConclusionA high level of ASF1B mRNA expression was correlated with a poor prognosis in glioma patients in this study, implying that it could be a reliable prognostic biomarker for glioma patients.

Abstract Our previous study demonstrated that azithromycin could promote alternatively activated (M2) macrophages under lupus conditions in vitro, which might be beneficial for lupus treatment. Thus, the aim of this study was to further confirm whether azithromycin can drive M2 polarisation in lupus and ultimately alleviate systemic lupus erythematosus (SLE) in vivo. Lymphocyte-derived DNA (ALD-DNA)-induced mice (induced lupus model) and MRL-Fas lpr mice (spontaneous lupus model) were both used in the experiment. First, we observed symptoms of lupus by assessing the levels of serum anti-dsDNA antibodies and serum creatinine and renal pathology. We found that both murine models showed increased levels of serum anti-dsDNA antibodies and creatinine, enhanced glomerular fibrosis and cell infiltration, basement membrane thickening and elevated IgG deposition. After azithromycin treatment, all these medical indexes were alleviated, and kidney damage was effectively reversed. Next, macrophage polarisation was assessed in the spleen and kidneys. Macrophage infiltration in the spleen was notably decreased after azithromycin treatment in both murine models, with a remarkably elevated proportion of M2 macrophages. In addition, the expression of interleukin (IL)-1, IL-6, tumour necrosis factor (TNF)-α, inducible nitric oxide synthase (iNOS), CD86, toll-like receptor (TLR)2 and TLR4 was extremely downregulated, while the expression of transforming growth factor (TGF)-β, arginase-1 (Arg-1), chitinase-like 3 (Ym-1), found in inflammatory zone (Fizz-1) and mannose receptor (CD206) was significantly upregulated in the kidneys after azithromycin treatment. Taken together, our results indicated for the first time that azithromycin could alleviate lupus by promoting M2 polarisation in vivo. These findings exploited the newly discovered potential of azithromycin, a conventional drug with verified safety, affordability and global availability, which could be a novel treat-to-target strategy for SLE via macrophage modulation.

Foot-and-mouth disease (FMD) is one of the most contagious livestock diseases in the world, posing a constant global threat to the animal trade and national economies. The chemokine C-X-C motif chemokine ligand 13 (CXCL13), a biomarker for predicting disease progression in some diseases, was recently found to be increased in sera from mice infected with FMD virus (FMDV) and to be associated with the progression and severity of the disease. However, it has not yet been determined which cells are involved in producing CXCL13 and the signaling pathways controlling CXCL13 expression in these cells. In this study, the expression of CXCL13 was found in macrophages and T cells from mice infected with FMDV, and CXCL13 was produced in bone-marrow-derived macrophages (BMDMs) by activating the nuclear factor-kappaB (NF-κB) and JAK/STAT pathways following FMDV infection. Interestingly, CXCL13 concentration was decreased in sera from interleukin-10 knock out (IL-10-/-) mice or mice blocked IL-10/IL-10R signaling in vivo after FMDV infection. Furthermore, CXCL13 was also decreased in IL-10-/- BMDMs and BMDMs treated with anti-IL-10R antibody following FMDV infection in vitro. Lastly, it was demonstrated that IL-10 regulated CXCL13 expression via JAK/STAT rather than the NF-κB pathway. In conclusion, the study demonstrated for the first time that macrophages and T cells were the cellular sources of CXCL13 in mice infected with FMDV; CXCL13 was produced in BMDMs via NF-κB and JAK/STAT pathways; and IL-10 promoted CXCL13 expression in BMDMs via the JAK/STAT pathway.

Abstract This study is a meta-analysis aimed at pooling reported data and clarifying the association between circulating level of interleukin-18 and systemic lupus erythematosus (SLE). We searched medical databases including Medline/Pubmed, Embase, Scopus, The Cochrane Library, and Web of Science thoroughly to obtain all related articles published before July 15th, 2020. We pooled computed standardized mean difference (SMD) and its 95% confidence interval using STATA 13.0 and exhibited in the form of forest graph. Meta-regression and subgroup analysis were also performed to explore the source of heterogeneity. Publication bias was first evaluated by the symmetry of the funnel plot and then Egger’s linear regression test. Thirty eligible studies from eighteen regions were finally included and the relevant data from these studies were pooled. The analysis results displayed that SLE patients showed a significantly higher level of circulating IL-18 level in comparison with healthy controls (SMD = 1.56, 95% CI [1.20–1.93]; I2 = 94.9%, p

A cost-effective approach which consists of cyclic heat treatment (CHT) and annealing is used to refine the coarse lamellar structure of as-cast Ti-6Al-4V alloy. The coarse lamellar microstructure was significantly refined after the CHT process, α lamellae were broken up while the original orientations of α lamellae were maintained. After annealing treatment, a basketweave microstructure was achieved in Ti-6Al-4V alloy, and the formation of globular α grains was observed. The microstructure refinement mechanisms during CHT and annealing are mainly considered to be break-up of lamellar structure and static recrystallization. The room temperature mechanical properties of Ti-6Al-4V alloy were significantly improved. The microhardness of Ti-6Al-4V alloy increased from 306 HV to 402 HV. The values of yield strength (YS) and ultimate tensile strength (UTS) increased from 734 MPa and 740 MPa to 911 MPa and 1010 MPa, respectively. The value of ductility increased from 1.1 % to 3.3 %.

Systemic lupus erythematosus (SLE) is an autoimmune disease that is accompanied with autoantibody production and inflammation. Other features of SLE pathogenesis include iron accumulation, oxidative stress, and lipid peroxidation, which are also major biochemical characteristics of ferroptosis, a novel non-apoptotic regulated form of cell death. To date, ferroptosis has been demonstrated to be an important driver of lupus progression, and several ferroptosis inhibitors have therapeutic effect in lupus-prone mice. Given the emerging link between ferroptosis and SLE, it can be postulated that ferroptosis is an integral component in the vicious cycle of immune dysfunction, inflammation, and tissue damage in SLE pathogenesis. In this review, we summarize the potential links between ferroptosis and SLE, with the aim of elucidating the underlying pathogenic mechanism of ferroptosis in lupus, and providing a new promising therapeutic strategy for SLE.

African swine fever (ASF), caused by the African swine fever virus (ASFV), is an acute, deadly, infectious disease of domestic pigs and wild boars and has a tremendous negative socioeconomic impact on the swine industry. ASF is a notifiable disease to the World Organization for Animal Health (OIE). Currently, no effective vaccine or treatment against ASF is available. Early detection and rapid diagnosis are potentially significant to control ASF spread with the emerging ASFV mutant strains and non-classical symptoms. In this study, we developed a real-time recombinase-aid amplification (RAA) assay to detect the ASFV genome rapidly. Thirty samples were detected using commercial lysis buffer for DNA extraction and equipped with a portable testing instrument. The results showed that the sensitivity of RAA was 103 copies per reaction at 95% probability in 9 min at 39°C. The method was universally specific for three strains of ASFV, and there was no cross-reaction with other pathogens, including foot-and-mouth disease virus (FMDV), classical swine fever virus (CSFV), porcine reproductive and respiratory syndrome virus (PRRSV), porcine circovirus 2 (PCV2), pseudorabies virus (PRV), and porcine parvovirus (PPV). The coefficient of variation (C.V) of repetitive experiments was 0%, and the coincidence rate was 100% compared to the real-time qPCR. 123 field samples were detected by the real-time RAA assay, and the results showed that the clinical coincidence rate of the real-time RAA assay was 98% compared to the real-time qPCR assay. The advantages of this method were as follows: the extraction of DNA can be performed on site, the DNA template is directly used, a small battery-powered instrument is easily available, and the on-site diagnostic process is finished within an hour. These suggest that this assay could be used to detect different genotypes of ASFV and play a vital role in the control of ASF.

Background: The liver and skin are the most common organs involved in Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Drug reactions rarely affect both organs concurrently. The clinical features, risk factors, and prognostic markers of drug-induced liver injury (DILI) in patients with SJS/TEN are not well studied. Materials and Methods: The clinical features, risk factors, and prognostic markers of DILI in patients with SJS/TEN hospitalized at the dermatology department of our hospital from January 2009 to December 2018 were retrospectively analyzed. Results: A total of 298 patients with SJS/TEN were enrolled in this study. Of them, 40 had liver injury and the rest served as control. Causative drugs mainly included antipodagrics (xanthine oxidase inhibitors occupying 100% among antipodagrics), anticonvulsants (dibenzazepine occupying 76.92% among anticonvulsants), and traditional Chinese medicines. There was a statistically significant difference between the patients with liver injury and the control group in the history of liver disease, diabetes, and hyperlipidemia (P < 0.05). Nine of the 40 patients with liver injury died. High serum total bilirubin and creatinine levels were significantly associated with poor prognosis of DILI in patients with SJS/TEN (P < 0.05). Conclusion: DILI usually occurs in patients with SJS/TEN. Pre-existing liver disease, diabetes, and hyperlipidemia are independent risk factors for DILI in patients with SJS/TEN. High serum total bilirubin and creatinine levels may be useful prognostic markers for DILI in patients with SJS/TEN.

Foot-and-mouth disease (FMD) is an acute contagious disease of cloven-hoofed animals such as cattle, pigs, and sheep. Current emergency FMD vaccines are of limited use for early protection because their protective effect starts 7 days after vaccination. Therefore, antiviral drugs or additives are used to rapidly stop the spread of the virus during FMD outbreaks. Manganese (Mn2+) was recently found to be an important substance necessary for the host to protect against DNA viruses. However, its antiviral effect against RNA viruses remains unknown. In this study, we found that Mn2+ has antiviral effects on the FMD virus (FMDV) both in PK15 cells and mice. The inhibitory effect of Mn2+ on FMDV involves NF-κB activation and up-regulation of interferon-stimulated genes. Animal experiments showed that Mn2+ can be highly effective in protecting C57BL/6N mice from being infected with FMDV. Overall, we suggest Mn2+ as an effective antiviral additive for controlling FMDV infection.

Compared with primary and local tumor, metastasis is more difficult to resect completely and remain the leading cause of death associated with solid tumors. It is therefore pressing to develop effective strategies to prevent and suppress tumor metastasis in its early stages. Heparanase overexpression is significantly associated with increased malignancy and metastasis. Here, we develop a novel heparanase degradable heparin-based microcarrier, HBMA, for specific staining, targeting, and inhibiting tumor cells with high metastatic potential. HBMA is fabricated through self-assembling of three components, positively charged fluorescent gold nanoclusters (KG-AuNCs), heparin polymers (HP), and antisense miRNA-21 oligonucleotides (AM-21), with each component playing multiple roles. Results of confocal microscopy and flow cytometry show that this agent has an excellent capability to label metastatic tumor cells with high selectivity. On the therapeutic side, the results of cell viability assay, wound healing assay, and plate colony formation assay verify that HBMA induces a significant inhibition effect towards the proliferation and migration of the selectively target tumor cells. The heparanase responsive AM-21 delivery, the specific staining, and the efficient tumor cell activity suppression highlight HBMA as a promising cancer theranostic agent to prevent tumor metastasis.

Baiyangdian lake, the largest fresh lake on the Haihe Basin in North China, has attracted wide attention on account of the distinguished ecological water bodies in Xiong’an New Area. Although remarkable achievements have been made in pollution control in Baiyangdian lake, the problem facing the overall water environment remains serious. The complex pollutant sources, drastic pollutant flux changes, and the unclear impact of the role of pollutants pose great challenges to the water quality, water environment management, and long-term restoration of the ecological environment. Here, the potential pollution sources, their contribution ratio, and the influence of the pollution load of different sources on the water quality in the priority source areas of Baiyangdian lake are discussed in detail based on collected and existing monitoring data. It is proven that the primary pollution sources of for nitrogen, phosphorus, and organic pollutants are from agricultural and rural non-point source pollution; the load contribution rates exceed 50%, of which the contribution rate to the total phosphorus load reaches 73.37%. The total load contribution of runoff to the three pollutants was small, although the contribution of soil erosion to total nitrogen was 22.95%. The contribution of point source pollution to COD was high, with a rate of 22.33%. In order to ensure the environmental quality of Baiyangdian lake, it is obligatory to strengthen the control of agricultural and rural pollution discharge and to standardize the pollution discharge of livestock and poultry breeding. This study provides a helpful support for protecting the water ecology of the national Xiong’an New Area.

TiAl alloy is a high temperature structural material with excellent comprehensive properties in the range of 750–900 °C. However, its engineering application is limited by its poor plasticity and hot working properties at room temperature. Based on the above background, a novel three-phase Ti-40Al-6V-1Cr-0.3Ni (at.%) alloy was designed and fabricated in the present study. The as-cast ingot was subjected to near-isothermal forging, and the thermoplastic deformation behavior, microstructure evolution and mechanical properties were systematically studied. Near-isothermal forging shows excellent forming capability, and the forging disk is flawless without cracking. The core of the forging disk shows the greatest degree of deformation, and the microstructure is composed of fine equiaxed grains and residual (α2/γ) lamellae. The hardness of the B2 phase and the hardness difference between the B2 phase and γ phase are reduced by the Cr and V elements added in the alloy. The wrought alloy exhibits excellent mechanical properties at room temperature and elevated temperature, respectively. The uniform fine microstructure, low nanohardness of the B2 and γ phase and the property matching of each phase can be accounted for the excellent mechanical properties.

To determine the anisotropic mechanical characteristics of carbonaceous slate at the Jinman Mine located in Lancang River Gorge, China, uniaxial compression, acoustic emission (AE) monitoring, and scanning electron microscopy (SEM) tests were conducted. The results show that stress loading directions and bedding effects have a significant impact on strain characteristics. The deformation of slate undergoes compaction, elastic, damage accumulation, and failure stages, and there are significant differences in strain paths. The mechanical properties of grey and carbonaceous slate have significant features, and variations of these properties of carbonaceous slate are more than that of grey slate. The discrete degree is significantly related to the direction of stress loading and different types of slate structures. The AE response intensity is related to the loading mode and slate type. A sudden increase in the AE cumulative ring number near peak stress indicates instability and rupture and is a precursor of rock rupture. The failure patterns and fracture characteristics are significantly correlated to the layered structure of the slate. Slates subjected to vertical loading and parallel loading conditions are dominated by shear fracture and tensile fracture, respectively. The peak strains of gray and carbonaceous slate correspond to brittle failure. The SEM tests indicate that slate samples subjected to parallel loading primarily show a tensile failure compared with slate samples subjected to vertical loading, with fractured sections being of lesser roughness, and scattered fractures and sections being smooth without obvious protrusions or cracks.

DDR1 has been identified as a cancer‐associated receptor tyrosine kinase that is highly expressed in several malignancies relative to normal tissues. Clinically approved multi‐kinase inhibitors, such as nilotinib, inhibit DDR1‐mediated tumor growth in xenograft models, suggesting DDR1 might be a potential target for cancer treatments. Here, we employed an antibody‐based strategy with a novel anti‐DDR1 antibody‐drug conjugate (ADC) for colon carcinoma treatment. We developed T4H11‐DM4, an ADC targeting DDR1 which carries the tubulin inhibitor payload DM4. Immunohistochemical analysis of a tissue microarray containing 100 colon cancer specimens revealed that DDR1 was highly expressed in 81% of tumor tissues. Meanwhile, high expression of DDR1 was associated with poor survival in patients. In vitro, T4H11‐DM4 exhibited potent anti‐proliferative activity with half maximal inhibitory concentration (IC50) values in the nanomolar range in a panel of colon cancer cell lines. In vivo, the antitumor efficacy of T4H11‐DM4 was evaluated in three colon cancer cell lines expressing different levels of DDR1. T4H11‐DM4 achieved complete tumor regression at doses of 5 and 10 mg·kg−1 in HT‐29 and HCT116 tumor models. Moreover, a correlation between in vivo efficacy of T4H11‐DM4 and the levels of DDR1 expression on the cell surface was observed. Tumor cell proliferation was caused by the induction of mitotic arrest, indicating that the antitumor effect in vivo was mediated by DM4. In addition, T4H11‐DM4 was efficacious in oxaliplatin‐resistant colon cancer models. In exploratory safety studies, T4H11‐DM4 exhibited no overt toxicities when multi‐doses were administered at 10 mg·kg−1 into BALB/c nude mice or when a single dose up to 50 mg·kg−1 was administered into BALB/c mice. Overall, our findings highlight the potential of DDR1‐targeted ADC and may facilitate the development of a new effective therapeutic strategy for colon cancer.

Repeat-associated non-ATG translation of dipeptide repeat proteins (DPRs) contributes to disease manifestation in FTD/ALS associated with the hexanucleotide repeat expansion of the C9ORF72 gene. Here the authors show that a transgenic mouse line expressing poly-PR28 in neurons displays some signs of neuronal loss that mirrors that seen in the disease.

Previous studies have demonstrated that exercise facilitates recovery from ischemia. However, the mechanisms need to be further elucidated. The current investigation was designed to study the effect of voluntary exercise on cerebral ischemia and discuss possible mechanisms usingmiddle cerebral artery occlusion model. Rats were randomly allocated to three groups: control, middle cerebral artery occlusion, and middle cerebral artery occlusion plus exercise. The middle cerebral artery occlusion plus exercise group was preconditioned by three weeks of voluntary wheel running prior to surgery. The accelerated rotarod test was employed to evaluate motor performance. Infarct volumes were analyzed to detect the neuroprotective effect of voluntary exercise. Brain-derived neurotrophic factor, Bax, Bcl-2, and caspase-3 protein expressions were measured by Western blot. Behavior evaluation showed the middle cerebral artery occlusion plus exercise group achieved significantly longer time on a rotarod than the unexercised group. Additionally, voluntary exercise reduced cerebral infarction and increased brain derived neurotrophic factor expression. Exercise down-regulated the apoptotic Bax/Bcl-2 ratio and caspase-3 protein expression. Results indicate that voluntary wheel running promote hippocampal brain derived neurotrophic factor and inhibit cell apoptosis in ischemia-induced impairment.

The economic loss caused by frequent flood disasters poses a great threat to China’s economic prosperity. This study analyzes the driving factors of flood-related economic losses in China. We used the extended Kaya identity to establish a factor decomposition model and the logarithmic mean Divisia index decomposition method to identify five flood-related driving effects for economic loss: demographic effect, economic effect, flash flood disaster control effect, capital efficiency effect, and loss-rainfall effect. Among these factors, the flash flood disaster control effect most obviously reduced flood-related economic losses. Considering the weak foundation of flash flood disaster prevention and control in China, non-engineering measures for flash flood prevention and control have been implemented since 2010, achieving remarkable results. Influenced by these measures, the loss-rainfall effect also showed reduction output characteristics. The demographic, economic, and capital efficiency effects showed incremental effect characteristics. China’s current economic growth leads to an increase in flood control pressure, thus explaining the incremental effect of the economic effect. This study discusses the relationship between flood-related economic loss and flash flood disaster prevention and control in China, adding value for the adjustment and formulation of future flood disaster prevention policies.

Rabies is a lethal zoonotic disease caused by lyssaviruses, such as rabies virus (RABV), that results in nearly 100% mortality once clinical symptoms appear. There are no curable drugs available yet. RABV contains five structural proteins that play an important role in viral replication, transcription, infection, and immune escape mechanisms. In the past decade, progress has been made in research on the pathogenicity of RABV, which plays an important role in the creation of new recombinant RABV vaccines by reverse genetic manipulation. Here, we review the latest advances on the interaction between RABV proteins in the infected host and the applied development of rabies vaccines by using a fully operational RABV reverse genetics system. This article provides a background for more in-depth research on the pathogenic mechanism of RABV and the development of therapeutic drugs and new biologics.

Microtubules composed of α/β tubulin heterodimers are an essential part of the cytoskeleton of eukaryotic cells and are widely regarded as targets for cancer chemotherapy. IC261, which is discovered as an ATP-competitive inhibitor of serine/threonine-specific casein kinase 1 (CK1), has shown its inhibitory activity on microtubule polymerization in recent studies. However, the structural information of the interaction between tubulin and IC261 is still unclear. Here, we provided a high-resolution (2.85 Å) crystal structure of tubulin and IC261 complex, revealed the intermolecular interaction between tubulin and IC261, and analyzed the structure–activity relationship (SAR). Subsequently, the structure of tubulin-IC261 complex was compared with tubulin-colchicine complex to further elucidate the novelty of IC261. Furthermore, eight optimal candidate compounds of new IC261-based microtubule inhibitors were obtained through molecular docking studies. In conclusion, the co-crystal structure of tubulin-IC261 complex paves a way for the design and development of microtubule inhibitor drugs.

The microstructure and microtexture evolution of the as-cast Ti-6Al-4V alloy with an initial lamellar microstructure was investigated in the temperature range of 900–1050 °C and the low strain rate range of 10−3–10−1 s−1. In the ranges 900–950 °C and 10−3–10−2 s−1, globularization of the α lamellar structure took place; the initial α {0001} texture softened, and the {0001} texture rotated to the transverse direction. Additionally, the increasing strain rate led to more randomization. The globularization process was considered to be continuous dynamic recrystallization (CDRX). At strain rates higher than 10−2 s−1 and temperatures between 900 and 950 °C, flow instabilities occurred. In the β range, dynamic recrystallization (DRX) occurred at a temperature of 1050 °C and a strain rate of 10−3 s−1.

The structural optimization of the internal structure of parts based on three-dimensional (3D) printing has been recognized as being important in the field of mechanical design. The purpose of this paper is to present a creation of a unit structure-performance database based on the selective laser melting (SLM), which contains various structural units with different functions and records their structure and performance characteristics so that we can optimize the internal structure of parts directly, according to the database. The method of creating the unit structure-performance database was introduced in this paper and several structural units of the unit structure-performance database were introduced. The bow structure unit was used to show how to create the structure-performance database of the unit as an example. Some samples of the bow structure unit were designed and manufactured by SLM. These samples were tested in the WDW-100 compression testing machine to obtain their performance characteristics. After this, the paper collected all data regarding unit structure parameters, weight, performance characteristics, and other data; and, established a complete set of data from the bow structure unit for the unit structure-performance database. Furthermore, an aircraft part was reconstructed conveniently to be more lightweight according to the unit structure-performance database. Its weight was reduced by 36.8% when compared with the original structure, while the strength far exceeded the requirements.

The purpose of this paper is to present a new design method of lightweight parts fabricated by selective laser melting (SLM) based on the “Skin-Frame” and to explore the influence of fabrication defects on SLM parts with different sizes. Some standard lattice parts were designed according to the Chinese GB/T 1452-2005 standard and manufactured by SLM. Then these samples were tested in an MTS Insight 30 compression testing machine to study the trends of the yield process with different structure sizes. A set of standard cylinder samples were also designed according to the Chinese GB/T 228-2010 standard. These samples, which were made of iron-nickel alloy (IN718), were also processed by SLM, and then tested in the universal material testing machine INSTRON 1346 to obtain their tensile strength. Furthermore, a lightweight redesigned method was researched. Then some common parts such as a stopper and connecting plate were redesigned using this method. These redesigned parts were fabricated and some application tests have already been performed. The compression testing results show that when the minimum structure size is larger than 1.5 mm, the mechanical characteristics will hardly be affected by process defects. The cylinder parts were fractured by the universal material testing machine at about 1069.6 MPa. These redesigned parts worked well in application tests, with both the weight and fabrication time of these parts reduced more than 20%.