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With the promotion of digital currency, how to effectively solve the authenticity, privacy and usability of digital currency issuance has been a key problem. Redactable signature scheme (RSS) can provide the verification of the integrity and source of the generated sub-documents and solve the privacy problem in digital currency by removing blocks from the signed documents. Unfortunately, it has not realized the consolidation of signed documents, which can not solve the problem of merging two digital currencies. Now, we introduce the concept of weight based on the threshold secret sharing scheme (TSSS) and present a redactable signature scheme with merge algorithm (RSS-MA) using the quasi-commutative accumulator. Our scheme can reduce the communication overhead by utilizing the merge algorithm when transmitting multiple digital currency signatures. Furthermore, this can effectively hide the scale of users' private monetary assets and the number of transactions between users. While meeting the three properties of digital currency issuance, in order to ensure the availability of digital currency after redacting, editors shall not remove the relevant identification information block form digital currency. Finally, our security proof and the analysis of efficiency show that RSS-MA greatly improves the communication and computation efficiency when transmitting multiple signatures.

Leukemic stem cells (LSCs) can acquire non-mutational resistance following drug treatment leading to therapeutic failure and relapse. However, oncogene-independent mechanisms of drug persistence in LSCs are incompletely understood, which is the primary focus of this study. We integrated proteomics, transcriptomics, and metabolomics to determine the contribution of STAT3 in promoting metabolic changes in tyrosine kinase inhibitor (TKI) persistent chronic myeloid leukemia (CML) cells. Proteomic and transcriptional differences in TKI persistent CML cells revealed BCR-ABL-independent STAT3 activation in these cells. While knockout of STAT3 inhibited the CML cells from developing drug-persistence, inhibition of STAT3 using a small molecule inhibitor sensitized the persistent CML cells to TKI treatment. Interestingly, given the role of phosphorylated STAT3 as a transcription factor, it localized uniquely to genes regulating metabolic pathways in the TKI-persistent CML stem and progenitor cells. Subsequently, we observed that STAT3 dysregulated mitochondrial metabolism forcing the TKI-persistent CML cells to depend on glycolysis, unlike TKI-sensitive CML cells, which are more reliant on oxidative phosphorylation. Finally, targeting pyruvate kinase M2, a rate-limiting glycolytic enzyme, specifically eradicated the TKI-persistent CML cells. By exploring the role of STAT3 in altering metabolism, we provide critical insight into identifying potential therapeutic targets for eliminating TKI-persistent LSCs.

Analyses of gene expression of subsurface bacteria and archaea provide insights into their physiological adaptations to in situ subsurface conditions. We examined patterns of expressed genes in hydrothermally heated subseafloor sediments with distinct geochemical and thermal regimes in Guaymas Basin, Gulf of California, Mexico. RNA recovery and cell counts declined with sediment depth, however, we obtained metatranscriptomes from eight sites at depths spanning between 0.8 and 101.9?m below seafloor. We describe the metabolic potential of sediment microorganisms, and discuss expressed genes involved in tRNA, mRNA, and rRNA modifications that enable physiological flexibility of bacteria and archaea in the hydrothermal subsurface. Microbial taxa in hydrothermally influenced settings like Guaymas Basin may particularly depend on these catalytic RNA functions since they modulate the activity of cells under elevated temperatures and steep geochemical gradients. Expressed genes for DNA repair, protein maintenance and circadian rhythm were also identified. The concerted interaction of many of these genes may be crucial for microorganisms to survive and to thrive in the Guaymas Basin subsurface biosphere.

Objective: Islet α cells input is essential for insulin secretion from β cells. The present study aims to investigate the association between 25-hydroxyvitamin D [25(OH)D] and islet function homeostasis in type-2 diabetes (T2D) patients. Methods: A total of 4670 T2D patients from seven communities in Shanghai, China were enrolled. The anthropometric indices, biochemical parameters, serum 25(OH)D, and islet function [including C-peptide (C-p) and glucagon] were measured. Results: The fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), glucagon, and C-p levels exhibited a significantly decreasing trend in T2D patients as the 25(OH)D levels increased. Next, the population was divided into two groups: abdominal obesity and non-abdominal obesity groups. After adjustment, the 25(OH)D level was found to be associated with HbA1c, glucagon, and homeostasis model assessment of β (HOMA-β) in the non-abdominal obesity group. There was a significant relationship between 25(OH)D and HbA1c, glucagon, HOMA-IR, baseline insulin or C-p in the abdominal obesity group. In the abdominal obesity group, the ordinary least squares (OLS) regression and quantile regression revealed that 25(OH) D was obviously associated with glucagon and fasting C-p levels. In the abdominal obesity group, the moderate analysis revealed a significant interaction effect of 25(OH)D and glucagon on C-p (P=0.0124). Furthermore, the conditional indirect effect of 25(OH)D on the glucagon/C-p ratio was significantly lower at 1 standard deviation (SD) below the mean (P=0.0002), and lower at the mean of the course of diabetes (P=0.0007). Conclusion: 25(OH)D was found to be negatively correlated to glucagon and C-p in T2D patients with abdominal obesity. The 25(OH)D influenced C-p in part by influencing glucagon. The effect of 25(OH)D on the glucagon/C-p ratio in T2D patients with abdominal obesity, in terms of islet homeostasis, is influenced by the course of diabetes.

Rheumatoid arthritis (RA) is a chronic autoimmune disease of unexplained causes. Its pathological features include synovial tissue hyperplasia, inflammatory cell infiltration in joint cavity fluid, cartilage bone destruction, and joint deformation. C–C motif chemokine ligand 3 (CCL3) belongs to inflammatory cell chemokine. It is highly expressed in inflammatory immune cells. Increasingly, studies have shown that CCL3 can promote the migration of inflammatory factors to synovial tissue, the destruction of bone and joint, angiogenesis, and participate in the pathogenesis of RA. These symptoms indicate that the expression of CCL3 is highly correlated with RA disease. Therefore, this paper reviews the possible mechanism of CCL3 in the pathogenesis of RA, which may provide some new insights for the diagnosis and treatment of RA.

Stem cell-based transplantation is a promising therapeutic approach for intervertebral disc degeneration (IDD). Current limitations of stem cells include with their insufficient cell source, poor proliferation capacity, low nucleus pulposus (NP)-specific differentiation potential, and inability to avoid pyroptosis caused by the acidic IDD microenvironment after transplantation. To address these challenges, embryo-derived long-term expandable nucleus pulposus progenitor cells (NPPCs) and esterase-responsive ibuprofen nano-micelles (PEG-PIB) were prepared for synergistic transplantation. In this study, we propose a biomaterial pre-modification cell strategy; the PEG-PIB were endocytosed to pre-modify the NPPCs with adaptability in harsh IDD microenvironment through inhibiting pyroptosis. The results indicated that the PEG-PIB pre-modified NPPCs exhibited inhibition of pyroptosis in vitro; their further synergistic transplantation yielded effective functional recovery, histological regeneration, and inhibition of pyroptosis during IDD regeneration. Herein, we offer a novel biomaterial pre-modification cell strategy for synergistic transplantation with promising therapeutic effects in IDD regeneration.

Rheumatoid arthritis (RA) is characterized by synovial inflammation, synoviocyte expansion and damage to cartilage and bone. We recently reported that peroxisome proliferator-activated receptor (PPAR)-γ inhibited the proliferation and activation of fibroblast-like synoviocytes (FLS), and was downregulated in RA synovial. In this study we investigated the role of PPAR-γ in RA and the underlying mechanisms. Adjuvant-induced arthritis (AIA) was induced in rats; from D15, AIA rats were orally administered pioglitazone (30 mg·kg−1·d−1) or rosiglitazone (4 mg·kg−1·d−1) for 14 days. Collagen-induced arthritis (CIA) was induced in wild-type and Ppar-γ+/−mice. We showed that the expression of PPAR-γ was significantly reduced, whereas that of TNF-α was markedly increased in human RA FLS. In CIA mice, knockdown of PPAR-γ expression (Ppar-γ+/−) aggravated the ankle inflammation. Similarly, T0070907 (a PPAR-γ antagonist) or si-PPAR-γpromoted the activation and inflammation of TNF-α-induced FLS in vitro. On the contrary, administration of PPAR-γ agonist pioglitazone or rosiglitazone, or injection of ad-Ppar-γinto the ankle of AIA rat in vivo induced overexpression of PPAR-γ, reduced the paw swelling and inflammation, and downregulated activation and inflammation of FLS in RA. Interesting, injection of ad-Ppar-γinto the ankle also reversed the ankle inflammation in Ppar-γ+/−CIA mice. We conducted RNA-sequencing and KEGG pathway analysis, and revealed that PPAR-γ overexpression was closely related to p53 signaling pathway in TNF-α-induced FLS. Co-IP study confirmed that p53 protein was bound to PPAR-γ in RA FLS. Taken together, PPAR-γ alleviates the inflammatory response of TNF-α-induced FLS by binding p53 in RA.

Acute liver injury (ALI) is a complex, life-threatening inflammatory liver disease, and persistent liver damage leads to rapid decline and even failure of liver function. However, the pathogenesis of ALI is still not fully understood, and no effective treatment has been discovered. Recent evidence shows that many circular RNAs (circRNAs) are associated with the occurrence of liver diseases. In this study we investigated the mechanisms of occurrence and development of ALI in lipopolysaccharide (LPS)-induced ALI mice. We found that expression of the circular RNA circDcbld2 was significantly elevated in the liver tissues of ALI mice and LPS-treated RAW264.7 cells. Knockdown of circDcbld2 markedly alleviates LPS-induced inflammatory responses in ALI mice and RAW264.7 cells. We designed and synthesized a series of hesperidin derivatives for circDcbld2, and found that hesperetin derivative 2a (HD-2a) at the concentrations of 2, 4, 8 μM effectively inhibited circDcbld2 expression in RAW264.7 cells. Administration of HD-2a (50, 100, 200 mg/kg. i.g., once 24 h in advance) effectively relieved LPS-induced liver dysfunction and inflammatory responses. RNA sequencing analysis revealed that the anti-inflammatory and hepatoprotective effects of HD-2a were mediated through downregulating circDcbld2 and suppressing the JAK2/STAT3 pathway. We conclude that HD-2a downregulates circDcbld2 to inhibit the JAK2/STAT3 pathway, thereby inhibiting the inflammatory responses in ALI. The results suggest that circDcbld2 may be a potential target for the prevention and treatment of ALI, and HD-2a may have potential as a drug for the treatment of ALI.

With the continuous advancement of remote sensing (RS) technology, RS ship detection plays a crucial role in ensuring maritime safety and the oceanic economy, but it also faces various challenges. Most existing RS ship detection methods typically apply deblurring processing to all input images before using a feature pyramid network (FPN) to detect ships of different sizes. However, this indiscriminate operation may cause image quality degradation due to excessive deblurring. Moreover, FPN has limitations in fully utilizing multigranularity features, which is particularly severe in RS ship detection tasks. These issues severely affect the accuracy of RS ship detection. To address these problems, this article proposes an effective feature augmentation network, 3WM-AugNet, based on the three-way decisions (3WDs) and multigranularity feature learning for RS ship detection. It consists of two modules: a blurred classification and deblurring module (BCDM) and a multigranularity feature augmentation module (MFAM). BCDM aims to combine 3WD and support vector machine (SVM) to design an image clarity classification algorithm and use the multi-temporal recurrent neural network (MT-RNN) algorithm to process the blurry images classified, effectively avoiding excessive deblurring of clear images. MFAM is used to enhance the richness and robustness of feature representations for ships of different sizes by introducing the bottom-up feature fusion layer and designing an adaptive coordinate attention module. Experimental results on three commonly used datasets, FGSD2021, HRSC2016, and UCAS-AOD, show that our proposed 3WM-AugNet achieves state-of-the-art performance in RS ship detection.

Chloride ion concentration is crucial for the reliability of stay cables, particularly when their protective covers are compromised. Previous studies have focused on the corrosion of single wires or cables over time, proposing estimation models that primarily consider corrosion duration while neglecting other significant factors. Addressing this gap, this paper establishes a corrosion damage model for stay cables considering time, temperature, humidity and inclination angle based on the diffusion characteristics of chloride ions. Firstly, We conducted accelerated corrosion experiments on stay cables in different environments to assess the characteristics of the spatial distribution of chloride ion concentrations within the cables and the mass loss characteristics of the wires. Secondly, a three-dimensional diffusion model for chloride ions in stay cables is proposed based on Fick's second law. A pivotal innovation of our research is the application of diverse machine learning techniques to explore how the diffusion coefficient of chloride ions is influenced by factors like time and environmental temperature, leading to the formulation of a sophisticated chloride ion diffusion model. Finally, by amalgamating this diffusion model with the established corrosion law for steel reinforcement, we devised a comprehensive corrosion damage evolution model for the steel wires of stay cables. The result demonstrates the anisotropic diffusion of chloride ions and its substantial correlation with the corrosion damage observed in steel wires. Notably, the PSO-BPNN method emerged as a highly accurate predictor for the diffusion coefficient of chloride ions. The model established in this paper considers a variety of influencing factors and accurately predicts the corrosion damage characteristics of stay cables, which makes an important contribution to improving the reliability of stay cables.

Given the corrosion protection failure of the cable-stayed bridge cable in the actual project, the impressed current cathodic protection (ICCP) technology was used to carry out the anti-corrosion tests from steel wire scale to cable scale, analyze the corrosion protection characteristics of steel wire ICCP, deduce the corrosion factor ICCP diffusion model, and reveal the space ICCP mechanism of the initial damaged cable. The analysis shows that ICCP can effectively inhibit the corrosive effect of steel wires and cables, and reduce the loss of mechanical properties of steel wires. Its protective efficiency increases with an increase in the absolute value of its protective potential and decreases with an increase in the dead load level. ICCP has a blocking effect on the diffusion of corrosion factors in the cable space, and the corrosion spatial distribution range, corrosion factor concentration, and diffusion coefficient of the initial damaged cable decrease significantly with the increase in the absolute value of the protection potential. The open circuit potential moves in a positive direction with the development of the corrosion process, and the blocking effect of corrosive factor diffusion is transformed from the joint participation by sacrificial anode cathodic protection and ICCP to the dominance of ICCP.

The article offers information related to embryo donation or double gamete donation whereby both egg and sperm have already combined to form an embryo and discusses how this composition of genetic material is given to the recipient or recipients.

A study was conducted to examine the market timing ability of commodity trading advisors (CTAs) using a set of return-based factors. Results reveal that CTAs are usually more skilled at market timing than discretionary CTAs, with the last one having slightly improved overall risk-adjusted performance.

AbstractThe dilatancy equation plays a significant role in establishing an elastoplastic constitutive model for soils. The rockfills will show strain-softening or strain-hardening behaviour according to the testing confining pressure and/or initial void ratio. Therefore, a new dilatancy equation for rockfill materials incorporating strain hardening and strain softening was studied. A series of triaxial compression tests on rockfills were carried out to investigate the material constants and applicability of the proposed dilatancy equation (PDE). The material constants Mc, β, aand cof the PDE were found to be independent of the initial void ratio and confining pressure. At the dilatancy point and critical state, the observed dilatancy of soils is zero, while the PDE was proved to fully meet these conditions. In addition, the PDE can well depict the trends of the observed dilatancy behaviour during the whole shearing, even though the dilatancy behaviour from the peak point to the critical state is difficult to be simulated for many existing equations. By comparing with three widely used dilatancy equations, the simulated strain-volume curves by a constitutive model using the PDE are significantly acceptable, no matter whether the rockfill is strain hardening or strain softening.

A survey of expatriates in China and Taiwan investigated the moderating role of cross-cultural differences and learning-teaching relation on the relations between expatriate training and effectiveness of training. Findings indicate that viewed needs for training significantly affect training effectiveness, which can be moderated by cross-cultural differences and learning-teaching fit.

Synthetic Aperture Radar (SAR) images are widely used in ship detection because of their all-weather and all-day imaging characteristics. However, there are two challenges for SAR ship detection. One is coherent speckle noise, causing ship confusion with similar objects and raising false alarms. The other is multi-scale ship detection, particularly in small ships, which suffers from insufficient accuracy. To address these challenges, this paper proposes a robust one-stage detector, S3MDet, for SAR ship detection with sequential three-way decisions (S3WDs) and multi-granularity. First, to effectively eliminate the interference of coherent speckle noise, a noise classification and denoising module (NCDM) S3WD-based is designed. This module can accurately classify the noise level of the image and only perform denoising on the images identified as noisy, avoiding unnecessary operations on noise-free images. Then, to solve the problem of multi-scale ship detection, a multi-granularity group attention module (MGAM) is designed to obtain a richer representation of multi-granularity features. This module adopts a multi-granularity group convolution structure and channel-wise attention weights to efficiently extract ship features of different scales from SAR images. Extensive experiments on four SAR ship datasets, including SAR-Ship-Dataset, HRSID, SSDD, and LS-SSDD-v1.0, validate the robustness of S3MDet, demonstrating that it achieves state-of-the-art performance. [ABSTRACT FROM AUTHOR]

ABSTRACTBackgroundThe CHA2DS2-VASc score is a guideline-recommended stroke risk stratification scheme for patients with atrial fibrillation (AF). Accurately calculating the CHA2DS2-VASc score and recognizing the stroke risk in AF patients is the foundation of optimal anticoagulation therapy. This survey aims to obtain a comprehensive understanding of perceptions and knowledge gaps on CHA2DS2-VASc scores among Chinese medical professionals for future education programs.MethodsA cross-sectional survey was conducted among clinicians, including cardiologists, neurologists, emergency physicians (EPs), general practitioners (GPs) and clinical pharmacists (CPs) using a self-administered questionnaire on the Chinese mainland. The survey contained 21 questions in combination with single-choice questions, multiple-choice questions, and an open-ended question, which was distributed online via e-mail or social media.ResultsA total of 562 participants (40.9% cardiologists, 19.2% neurologists, 8.5% EPs, 10.3% GPs, and 21.0% CPs) completed the survey. Most respondents across all specialties reported skills requiring improvements in the CHA2DS2-VASc score. In general, cardiologists, neurologists, and CPs had a relatively better understanding than GPs and EPs about the application of CHA2DS2-VASc score. Considering ‘H’ and ‘D’ components, more than 90% of respondents chose the correct answer in single-choice questions, whereas the correctness rate declined concerning detailed scoring criteria. Regarding ‘C,’ ‘A2,’ ‘S2,’ and ‘V’ components, partly correct answers were commonly observed in most multiple-choice questions. The majority of cardiologists believed themselves to be very familiar or at least familiar with the score and its components, while around 70% of EPs and GPs felt relatively unfamiliar with the CHA2DS2-VASc score. Mobile apps, AF guidelines and notebooks/handbooks were popular referencing scoring tools for respondents.ConclusionsChinese medical professionals, especially EPs and GPs, revealed a lack of knowledge and insufficient skills for CHA2DS2-VASc scores and their components. Improvements in the awareness of the CHA2DS2-VASc score and its detailed scoring criteria are urgently needed for Chinese medical professionals. Therefore, education programs concerning the introduction of stroke risk evaluation for AF patients and the development of referencing scoring tools are necessary.

Background: Epithelial-Mesenchymal Transition (EMT) and its reverse Mesenchymal-Epithelial Transition (MET) are essential for tumor cells metastasis. However, the effect of epigeneticmodifications on this transition is unclear. Objective: We aimed to explore the key histone modifications and hub genes of EMT/MET during ColorectalCancer (CRC) metastasis. Methods: The differentially expressed genes and differentially histone modified genes were identified.Based on the histone modification features, the up- and down-regulated genes were predicted by RandomForest algorithm. Through protein-protein interaction network and Cytoscape analysis, the hubgenes with histone modification changes were selected. GO, KEGG and survival analyses were performedto confirm the importance of the hub genes. Results: It was found that H3K79me3 plays an important role in EMT/MET. And the 200-300bp and400-500bp downstream of TSS may be the key regulatory regions of H3K79me3. Moreover, we foundthat the expression of the hub genes was down-regulated in EMT and then up-regulated in MET. Andthe changes of the hub genes expression were consistent with the changes of H3K79me3 signal in thespecific regions of the genome. Finally, the hub genes KRT8 and KRT18 were involved in the metastasisprocess and were significantly related to the survival time. Conclusion: H3K79me3 may be crucial for EMT/MET, and the hub genes KRT8 and KRT18 may bethe key genes in this process.

ABSTRACTThe present study attempts to explore the effective components, action targets, and potential mechanism of nightshade for colon cancer treatment. The relationship network diagram of ‘traditional Chinese medicine – component – target – disease’ was firstly constructed by employing network pharmacology. Experiments were conducted in vivo and in vitro to verify the influence of quercetin, the core effective component of nightshade, on colon cancer. Meanwhile, the regulatory effects of quercetin on core targets and main signaling pathways were determined. Based on the network diagram of ‘traditional Chinese medicine – component – target – disease’ and KEGG analysis, quercetin might exhibit certain effects on colon cancer treatment by regulating the biological behavior of core targets related to cell apoptosis in tumors including PIK3R1, PIK3CA, Akt1, and Akt2. Furthermore, quercetin has been demonstrated in vitro experiments to suppress the proliferation and migration of colon cancer cells whereas promote their apoptosis in a dose-dependent fashion. In vivo experiments indicate that quercetin had an antitumor effect on human colon cancer SW480 cells in nude mice bearing tumors. Furthermore, PIK3CA could bind to quercetin directly, which is validated by immunocoprecipitation. Therefore, the activation of PI3K/AKT phosphorylation was inhibited by quercetin and moreover the expressions of apoptotic proteins caspase-3 and Bcl2-Associated X protein (BAX) were up-regulated. In conclusion, the potential mechanism of nightshade lies in the activation of the PI3K/AKT signaling pathway inhibited by quercetin, thus promoting apoptosis of colon cancer cells for colon cancer treatment.

Proper regulation of p53 signaling is critical for the maintenance of hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs). The hematopoietic cell–specific mechanisms regulating p53 activity remain largely unknown. Here, we demonstrate that conditional deletion of acidic leucine-rich nuclear phosphoprotein 32B (ANP32B) in hematopoietic cells impairs repopulation capacity and postinjury regeneration of HSCs. Mechanistically, ANP32B forms a repressive complex with p53 and thus inhibits the transcriptional activity of p53 in hematopoietic cells, and p53 deletion rescues the functional defect in Anp32b-deficient HSCs. Of great interest, ANP32B is highly expressed in leukemic cells from patients with chronic myelogenous leukemia (CML). Anp32b deletion enhances p53 transcriptional activity to impair LSC function in a murine CML model and exhibits synergistic therapeutic effects with tyrosine kinase inhibitors in inhibiting CML propagation. In summary, our findings provide a novel strategy to enhance p53 activity in LSCs by inhibiting ANP32B and identify ANP32B as a potential therapeutic target in treating CML.

Objective: To explore the mechanism of herbal cake-partitioned moxibustion in Crohn disease (CD) treatment by observing the effect of herbal cake-partitioned moxibustion on protein expressions of colonic M2 macrophage marker CD206, AMP-activated protein kinase (AMPK) and tuberous sclerosis complex (TSC) 2. Methods: Twenty-six specific pathogen free male rats were randomly divided into a normal group, a model group and a herbal cake-partitioned moxibustion group. The CD model was prepared by enema with the mixture of 5% (W/V) 2,4,6-trinitrobenzene sulfonic acid (TNBS) and 50% ethanol at 2:1 (volume ratio). After the model was successfully prepared, rats in the herbal cake-partitioned moxibustion group received herbal cake-partitioned moxibustion at Qihai (CV 6) and bilateral Tianshu (ST 25). Hematoxylin-eosin (HE) staining was used to observe the histopathological changes of rat colon; immunohistochemical technique was used to detect the expression of colonic CD206 protein; Western blot, immunofluorescence, and real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) technologies were used to detect the protein and mRNA expressions of colonic AMPK and TSC2. Results: Compared with the normal group, rats in the model group showed damaged colonic mucosa, missing of the epithelial layer, thickened submucosa, vascular proliferation, massive infiltration of monocytes and lymphocytes, and cracked ulcers that reached the muscle layer. Rats in the herbal cake-partitioned moxibustion group showed reduced intestinal inflammation and healing intestinal epithelium ulcers. Compared with the normal group, rat colonic CD206 protein expression, and the protein and mRNA expressions of colonic AMPK and TSC2 were decreased in the model group (all P<0.01); compared with the model group, rat colonic CD206 protein expression was increased (P<0.01), as well as the protein and mRNA expressions of AMPK and TSC2 in the herbal cake-partitioned moxibustion (all P<0.05). Conclusion: Herbal cake-partitioned moxibustion can reduce intestinal inflammation in CD rats, increase colonic CD206 protein expression, and up-regulate the protein and mRNA expressions of colonic AMPK and TSC2.

Byline: Zhen-Yu. Li, Ying-Li. Dong, Yun. Feng, Zhen. Zhang, Xiao-Zhong. Cao Aims: Recently, the relationship between telomerase reverse transcriptase (TERT) polymorphisms and breast cancer risk has been investigated in several [...]

The abnormalities of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) are implicated in various autoimmune disorders and tumors. This study investigated the influence of TRAIL deficiency on Th17 cells and colonic microbiota in experimental colitis mouse model.

A meso-analysis method which is derived from the base force element method (BFEM) was proposed for recycled aggregate concrete (RAC). A simple algorithm was used to generate the convex recycled concrete aggregate (RCA) model. Uniaxial compression numerical simulations were carried out on the numerical specimens with different replacement rates of RCA. The model predictions were in a good agreement with the test results. The proposed method is very promising. It can totally predict the full stress-strain curve of RAC, as well as the failure process and failure mode, including strain softening and strain localization.

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Techniques for the reduction of the computational effort involved in solving continuous-state dynamic programs are presented. Conventional methods involve tensor product linear interpolants, which result in long computation times. Instead, cubic piecewise polynomial functions, such as tensor product cubic splines and multivariate Hermite polynomials, may be used to approximate the value function. The smoothness and improved accuracy of the higher-order functions lead to computational savings. The piecewise polynomial spline performs slightly better than the Hermite polynomials. Application to a stochastic 4-dimensional water supply reservoir problem indicates that the piecewise polynomial form also performs better than linear interpolation, which would normally solve the problem in two hours, by yielding a solution in less than a minute with the same level of accuracy.

The kinase FLT3 internal tandem duplication (FLT3-ITD) is related to poor clinical outcomes of acute myeloid leukemia (AML). FLT3 inhibitors have provided novel strategies for the treatment of FLT3-ITD-positive AML. But they are limited by rapid development of acquired resistance and refractory in monotherapy. Recent evidence shows that inducing the degradation of FLT3-mutated protein is an attractive strategy for the treatment of FLT3-ITD-positive AML, especially those with FLT3 inhibitor resistance. In this study we identified Wu-5 as a novel USP10 inhibitor inducing the degradation of FLT3-mutated protein. We showed that Wu-5 selectively inhibited the viability of FLT3 inhibitor-sensitive (MV4-11, Molm13) and -resistant (MV4-11R) FLT3-ITD-positive AML cells with IC50of 3.794, 5.056, and 8.386 μM, respectively. Wu-5 (1−10 μM) dose-dependently induced apoptosis of MV4-11, Molm13, and MV4-11R cells through the proteasome-mediated degradation of FLT3-ITD. We further demonstrated that Wu-5 directly interacted with and inactivated USP10, the deubiquitinase for FLT3-ITD in vitro (IC50value = 8.3 µM) and in FLT3-ITD-positive AML cells. Overexpression of USP10 abrogated Wu-5-induced FLT3-ITD degradation and cell death. Also, the combined treatment of Wu-5 and crenolanib produced synergistic cell death in FLT3-ITD-positive cells via the reduction of both FLT3 and AMPKα proteins. In support of this, AMPKα inhibitor compound C synergistically enhanced the anti-leukemia effect of crenolanib, while AMPKα activator metformin inhibited the anti-leukemia effect of crenolanib. In summary, we demonstrate that Wu-5, a novel USP10 inhibitor, can overcome FLT3 inhibitor resistance and synergistically enhance the anti-AML effect of crenolanib through targeting FLT3 and AMPKα pathway.

Affected by external environmental factors and evolution of dam performance, dam seepage behavior shows nonlinear time-varying characteristics. In this study, to predict and evaluate the long-term development trend and short-term fluctuation of the dam seepage behavior, two monitoring models were developed, one for the base flow effect and one for daily variation of dam seepage elements. In the first model, to avoid the influence of the time lag effect on the evaluation of seepage variation with the time effect component of seepage elements, the base values of the seepage element and the reservoir water level were extracted using the wavelet multi-resolution analysis method, and the time effect component was separated by the established base flow effect monitoring model. For the development of the daily variation monitoring model for dam seepage elements, all the previous factors, of which the measured time series prior to the dam seepage element monitoring time may have certain influence on the monitored results, were considered. Those factors that were positively correlated with the analyzed seepage element were initially considered to be the support vector machine (SVM) model input factors, and then the SVM kernel function-based sensitivity analysis was performed to optimize the input factor set and establish the optimized daily variation SVM model. The efficiency and rationality of the two models were verified by case studies of the water level of two piezometric tubes buried under the slope of a concrete gravity dam. Sensitivity analysis of the optimized SVM model shows that the influences of the daily variation of the upstream reservoir water level and rainfall on the daily variation of piezometric tube water level are processes subject to normal distribution.

ABSTRACTStreptococcus agalactiae(GBS) is an important pathogenic bacteria that infected both aquatic animals and human beings, causing huge economic loss. The increasing cases of antibiotic-resistant GBS impose challenges to treat such infection by antibiotics. Thus, it is highly demanded for the approach to tackle antibiotic resistance in GBS. In this study, we adopt a metabolomic approach to identify the metabolic signature of ampicillin-resistant GBS (AR-GBS) that ampicillin is the routine choice to treat infection by GBS. We find glycolysis is significantly repressed in AR-GBS, and fructose is the crucial biomarker. Exogenous fructose not only reverses ampicillin resistance in AR-GBS but also in clinic isolates including methicillin-resistant Staphylococcus aureus(MRSA) and NDM-1 expressing Escherichia coli. The synergistic effect is confirmed in a zebrafish infection model. Furthermore, we demonstrate that the potentiation by fructose is dependent on glycolysis that enhances ampicillin uptake and the expression of penicillin-binding proteins, the ampicillin target. Our study demonstrates a novel approach to combat antibiotic resistance in GBS.

Objective: Although relatively rare, adult immunoglobulin A vasculitis (IgAV) can lead to severe complications and longer hospitalization, and result in poor prognosis, when compared to childhood IgAV. Hence, early identification and prevention for patients prone to develop systemic involvement are essential. The purpose of this study was to explore the correlations of common serological markers with the development of systemic involvement in adult IgAV. Methods: A retrospective analysis was performed for adult IgAV patients, who were hospitalized in Wuhan Union Hospital between January 2016 and December 2019. A total of 259 patients were enrolled, and the pre-treatment serological markers were comprehensively assessed. Results: In the present study, 49.0% and 33.2% of patients developed renal and gastrointestinal (GI) involvement, respectively. Furthermore, the elevated levels of white blood cells count, D-Dimer (D-D), C-reactive protein (CRP) and neutrophil granulocyte ratio (NE%) >60% were significantly associated with GI involvement in the univariate analysis, while the decrease in high density lipoprotein level, and the elevated D-D and CRP levels were significantly associated with renal involvement (P<0.05). Moreover, a prediction model that combined multiple markers was established by performing a logistic regression analysis, and this presented a more favorable value of prediction than the individual serological markers. Conclusion: The present study suggests that common serological markers have close correlations with systemic involvement in adult IgAV, and that the establishment of a prediction model for systemic involvement may be helpful in facilitating personalized therapeutic strategies and clinical management for IgAV patients.

Nanotechnology has shown great promise in treating diverse diseases. However, developing nanomedicines that can cure autoimmune diseases without causing systemic immunosuppression is still quite challenging. Herein, we propose an all-in-one nanomedicine comprising an autoantigen peptide and CRISPR-Cas9 to restore specific immune tolerance by engineering dendritic cells (DCs) into a tolerogenic phenotype, which can expand autoantigen-specific regulatory T (Treg) cells. In brief, we utilized cationic lipid-assisted poly(ethylene glycol)-b-poly(lactide-co-glycolide) (PEG-PLGA) nanoparticles to simultaneously encapsulate an autoimmune diabetes-relevant peptide (2.5mi), a CRISPR-Cas9 plasmid (pCas9), and three guide RNAs (gRNAs) targeting costimulatory molecules (CD80, CD86, and CD40). We demonstrated that the all-in-one nanomedicine was able to effectively codeliver these components into DCs, followed by simultaneous disruption of the three costimulatory molecules and presentation of the 2.5mi peptide on the genome-edited DCs. The resulting tolerogenic DCs triggered the generation and expansion of autoantigen-specific Treg cells by presenting the 2.5mi peptide to CD4+T cells in the absence of costimulatory signals. Using autoimmune type 1 diabetes (T1D) as a typical disease model, we demonstrated that our nanomedicine prevented autoimmunity to islet components and inhibited T1D development. Our all-in-one nanomedicine achieved codelivery of CRISPR-Cas9 and the peptide to DCs and could be easily applied to other autoimmune diseases by substitution of different autoantigen peptides.

Tumor-infiltrating dendritic cells (TIDCs) are mostly immature and immunosuppressive, usually mediating immune inhibition. The utilization of cytosine-guanine oligodeoxynucleotides (CpG ODNs) to stimulate the activation of TIDCs has been demonstrated to be effective for improving antitumor immunity. However, a series of biological barriers has limited the efficacy of previous nanocarriers for delivering CpG to TIDCs. Herein, we developed a dual-sensitive dendrimer cluster-based nanoadjuvant for delivering CpG ODNs into TIDCs. We show that the tumor acidity triggers the rapid release of CpG conjugated polyamidoamine (PAMAM) dendrimers from the nanoadjuvant, thus facilitating its perfusion deep into tumors and phagocytosis by TIDCs. Thereafter, the reductive condition of the endolysosomes led to the subsequent release of CpG, which promotes the DCs activation and enhances antitumor immunotherapies. Programmable delivery of immune adjuvant efficiently overcomes the barriers for targeted delivery to TIDCs and provides a promising strategy for improving cancer immunotherapy.

Renal fibrosis is considered as the pathway of almost all kinds of chronic kidney diseases (CKD) to the end stage of renal diseases (ESRD). Ganoderic acid (GA) is a group of lanostane triterpenes isolated from Ganoderma lucidum, which has shown a variety of pharmacological activities. In this study we investigated whether GA exerted antirenal fibrosis effect in a unilateral ureteral obstruction (UUO) mouse model. After UUO surgery, the mice were treated with GA (3.125, 12.5, and 50 mg· kg−1·d−1, ip) for 7 or 14 days. Then the mice were sacrificed for collecting blood and kidneys. We showed that GA treatment dose-dependently attenuated UUO-induced tubular injury and renal fibrosis; GA (50 mg· kg−1·d−1) significantly ameliorated renal disfunction during fibrosis progression. We further revealed that GA treatment inhibited the extracellular matrix (ECM) deposition in the kidney by suppressing the expression of fibronectin, mainly through hindering the over activation of TGF-β/Smad signaling. On the other hand, GA treatment significantly decreased the expression of mesenchymal cell markers alpha-smooth muscle actin (α-SMA) and vimentin, and upregulated E-cadherin expression in the kidney, suggesting the suppression of tubular epithelial-mesenchymal transition (EMT) partially via inhibiting both TGF-β/Smad and MAPK (ERK, JNK, p38) signaling pathways. The inhibitory effects of GA on TGF-β/Smad and MAPK signaling pathways were confirmed in TGF-β1-stimulated HK-2 cell model. GA-A, a GA monomer, was identified as a potent inhibitor on renal fibrosis in vitro. These data demonstrate that GA or GA-A might be developed as a potential therapeutic agent in the treatment of renal fibrosis.

Thyroid hormones have a specific effect on glucose-induced insulin secretion from the pancreas. We aimed to investigate the association between euthyroid hormones and islet beta-cell function in general population and non-treated type 2 diabetes mellitus (T2DM) patients. A total of 5089 euthyroid participants (including 4601 general population and 488 non-treated T2DM patients) were identified from a cross-sectional survey on the prevalence of metabolic diseases and risk factors in East China from February 2014 to June 2016. Anthropometric indices, biochemical parameters, and thyroid hormones were measured. Compared with general population, non-treated T2DM patients exhibited higher total thyroxine (TT4) and free thyroxine (FT4) levels but lower ratio of free triiodothyronine (T3):T4 (P<0.01). HOMA-β had prominently negative correlation with FT4 and positive relationship with free T3:T4 in both groups even after adjusting for age, body mass index (BMI) and smoking. When analyzed by quartiles of FT4 or free T3:T4, there were significantly decreased trend of HOMA-β going with the higher FT4 and lower free T3:T4 in both groups. Linear regression analysis showed that FT4 but not FT3 and free T3:T4 was negatively associated with HOMA-β no matter in general population or T2DM patients, which was independent of age, BMI, smoking, hypertension and lipid profiles. FT4 is independently and negatively associated with islet beta-cell function in euthyroid subjects. Thyroid hormone even in reference range could play an important role in the function of pancreatic islets.

The effect of intercritical deformation on retained austenite and tensile performance of a low-carbon Si–Mn steel in modified quenching and bainitic partitioning processes was evaluated. The results showed that the intercritical deformation can play a positive role in stabilizing and refining the retained austenite, and possessed promising potential in balancing tensile strength and ductility of multiphase high-strength steels. The experimental low-carbon Si–Mn steel exhibited multiphase configuration comprising polygonal ferrite, granular bainite and granular structure after two different modified quenching and bainitic partitioning processes, and the bainitic ferrite laths got refined by intercritical deformation. The volume fraction of retained austenite in film-like and blocky morphology was increased from 11.5% to 13.9% due to applied intercritical deformation, and the larger amount of retained austenite provided the sufficient transformation-induced plasticity effect and resulted in enhanced work hardening degree; in response, enhanced ultimate tensile strength 1260 MPa and fracture elongation 22.1% were obtained, leading to increased product of strength and elongation in value of 27.7 GPa% compared to 20.8 GPa% of undeformed structure.

A novel rectangular tube with circumferential anti-symmetric local self-surface nanocrystallization (CALSSN) layouts is designed for energy absorption. The effects of stripe numbers on the energy absorption performance is investigated. Results reveal that the 8-stripe CALSSN model exhibits the best buckling modes, which is more regular and stable than the untreated ones. It is also found that the stripe numbers highly depend on the structural sizes, unsuitable stripes number may reduce the buckling stability and periodicity. Besides, five CALSSN models with stripe numbers from 6 to 10 are selected to find the optimized size which has the highest specific energy absorption (SEA). A new 7-stripe CALSSN model which has optimal buckling modes and energy absorption performance is achieved.

Studies have shown that the simultaneous regulation of tumor cell proliferation and the suppressive tumor immune microenvironment (TIME) could achieve better therapeutic effects. However, the targets of the proliferation and the TIME are different, which greatly limits the development of cancer therapy. A recent study found CD155, a highly expressed poliovirus receptor in melanoma cells and melanoma-infiltrating macrophages, functions as both an oncogene and immune checkpoint. Thus, it is supposed that targeting CD155 could bring dual therapeutic effects. Herein, we propose silencing the CD155 of melanoma cells and melanoma-infiltrating macrophages by a nanoparticle-delivered small interference RNA (siRNA) targeting CD155 (siCD155). We encapsulated siCD155 into cationic lipid-assisted nanoparticles (CLANsiCD155) and demonstrated that the intravenous injection of CLANsiCD155could efficiently deliver siCD155 into melanoma cells and melanoma-infiltrating macrophages. The downregulation of CD155 in melanoma cells directly inhibited their proliferation, and meanwhile, the downregulation of CD155 in melanoma-infiltrating macrophages increased the activation of NK cells and T cells. Owing to this dual effect, CLANsiCD155significantly inhibited the growth of B16-F10 melanoma. Our study suggests that nanoparticle-delivered siCD155 may be a simple but effective strategy for inhibiting tumor proliferation and reprogramming TIME.

In recent years, small nanoparticles (NPs) with a diameter of less than 10 nm have aroused considerable interest in biomedical applications. However, their intratumor performance, as well as the antitumor efficacy, has not been well understood due to their size-dependent pharmacokinetics, which presents a formidable challenge for delivering a comparable amount of different small NPs to tumor tissues. Utilizing the multistage delivery strategy, we construct G3-, G5-, and G7-iCluster delivery systems by using poly(amidoamine) (PAMAM) dendrimers of different generations (G3-, G5-, and G7-PAMAM) as building blocks. The iCluster nanoparticles showed comparable pharmacokinetics and similar initial tumor deposition due to their similarity in size and surface chemistry. After accumulating at a tumor site, individual small dendrimers were released, and thus, their intratumor performance was comparatively investigated. Our results indicated that a subtle change in generation markedly affects their intratumor activities. G5-iCluster outperformed G3-iCluster and G7-iCluster in the treatment efficacy in an orthotopic pancreatic tumor model. The mechanistic study revealed that G3-PAMAM showed reduced particle retention in tumor tissue due to its small size and weak cell internalization, while G7-PAMAM was much less penetrative because of its relatively large size and strong particle–cell interaction. In contrast, G5-PAMAM exhibited balanced tumor penetration, cell internalization, and tumor retention. Our finding highlights the huge influence of the subtle difference of small NPs in their intratumor performance.

Förster resonance energy transfer (FRET) is a well-established method for studying macromolecular interactions and conformational changes within proteins. Such a method normally uses fluorescent proteins or chemical-labeling methods which are often only accessible to surface-exposed residues and risk-disturbing target protein structures. Here, we demonstrate that the genetic incorporation of a synthetic fluorescent amino acid, L-(7-hydroxycoumarin-4-yl) ethylglycine (Cou) and natural endogenous fluorophore Tryptophan (Trp) residues of a protein could serve as an efficient FRET pair to monitor protein interactions, using the signaling transducer β-arrestin-1 as a model system. We used this technology to record the dynamic spectra in both binding and competition experiments of β-arrestin-1, the contribution of each specific phosphate in ternary complex formation, in a rapid and efficient manner. The determined Kdvalue for the association between the active arrestin and Fab30 is 0.68 μM in the three-component interaction system. Moreover, we were able to determine the contributions of the site 3 phospho-site and the site 6 phospho-site binding, each contributing to the high affinity ternary complex assembly as 2.7 fold and 15.5 fold, respectively, which were never determined before. These results thus highlighted the potential usage of this new method in measurement of the allosteric-induced enhanced affinity with small amount proteins and in a fast manner and in a complex system. Collectively, our newly developed Trp:Cou FRET system based on genetic expansion technology has extended the molecular toolboxes available for biochemical and structural biology studies.

To predict the performance of a rotary compressor and study the dynamic coupling characteristics of the valve, a three-dimensional dynamic model of the compressor is constructed in this paper. The model adopts the fluid–solid interaction method and the dynamic grid technique to achieve coupled reed valve motion. Meanwhile, to solve the problem of grid deformation caused by large deformation of the valve plate, a user-defined dynamic grid method is used to realize grid updating in the deformed area based on computational fluid dynamics method and the ideas of spring smoothing method. The model is validated with a cooling capacity error of 6.07% and an indicated power error of 2%. The stress, the displacement, the velocity and the pressure of the valve is analyzed. The flow characteristics and the dynamic characteristics of the valve plate obtained provide a reference for the design of the compressor.