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Abstract This study investigates the impact of long-term water immersion on the mechanical and hydrochemical properties of cemented calcareous soil, emphasizing the critical role of carbonate content in mechanical performance. Utilizing hydrochemical analysis and triaxial testing, the research revealed that prolonged immersion disrupts the acid-base balance of the solution, resulting in an increased concentration of ions and chemicals. Significant dissolution of carbonates and soluble minerals occurs, which reacts with carbon dioxide to generate bicarbonate ions, thereby elevating the alkalinity of the soaking solution. Additionally, the gradual dissolution of clay minerals compromises the cementitious structure, leading to particle reorientation and interlocking. The study quantitatively assesses the changes in soil properties, demonstrating a substantial reduction in soil cohesion by up to 86.1% and an increase in the internal friction angle by 37.5%. Furthermore, the gradual dissolution of clay minerals compromises the cementitious structure, resulting in particle reorientation and interlocking that contribute to the observed mechanical changes. The findings underscore the importance of understanding the effects of extended immersion on the stability and engineering applicability of cemented calcareous soils.

Ectopic transplantation of the hand remains a rare, innovative yet valuable operation in select cases of trauma and amputation. We aim to describe a novel technique of complex hand reconstruction using a two‐stage ectopic implantation of the contralateral upper limb. A male patient with a near complete avulsion amputation of the right upper limb at the level of the mid‐forearm and a crushing injury to his left hand was admitted after a farming accident. The right palm was ectopically transplanted to the left lower limb and both upper limbs underwent debridement with vacuum assisted dressings (VACs). There was eventual dieback of the left thumb, ring and little finger with a large palmar soft tissue defect that was eventually reconstructed using segments of the ectopically transplanted limb in two separate operations. The patient made an uneventful postoperative recovery and managed to regain protective sensation and gross motor function of his reconstructed hand.

ObjectiveTo explore the value of dual-accelerated simultaneous multi-slice (SMS) imaging in diffusion tensor imaging (DTI) of glioma.MethodsThirty-four patients with glioma who underwent magnetic resonance imaging (MRI) in our hospital from January 2022 to March 2023 were randomly selected. The results of dual-accelerated SMS-DTI and conventional DTI were retrospectively analyzed. All patients were scanned using a uMR790 3.0T MRI scanner, and the scanning technicians followed a predefined sequence to ensure consistency in scan parameters. The images were subjectively evaluated using a Likert 5-point scoring system. Objective evaluation was performed by measuring the required values of the images with b-value = 1000 s/mm2, primarily measuring the signal intensity in the tumor region and the contralateral normal brain white matter region. The standard deviation values were used to calculate the signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) in the same encoding direction as the background noise. The number of generated fiber pathways, fractional anisotropy (FA), and mean diffusivity (MD) were measured and analyzed using post-processing software. The relative FA (rFA) and relative MD (rMD) were calculated.ResultsThe results of conventional DTI and SMS-accelerated DTI were compared. In terms of subjective evaluation, including overall image quality, tumor edge clarity, and magnetic sensitivity artifacts, both techniques showed no significant differences, indicating comparable diagnostic performance in anatomical visualization. In terms of objective evaluation and quantitative parameter measurement, there were statistically significant differences in SNR and CNR values, with slightly lower values in the dual-accelerated SMS-DTI compared with conventional DTI, a significant reduction in scanning time can be achieved through a slight loss in image quality. The number of fiber pathways and the rFA and rMD values did not show typical differences between the two techniques. The correlation between these measures was highly similar, with no significant differences observed.ConclusionThe application of dual-accelerated simultaneous multi-slice imaging in DTI of glioma is feasible.

Abstract Understanding the complex relationships between enzyme sequence, folding stability and catalytic activity is crucial for applications in industry and biomedicine. However, current enzyme assay technologies are limited by an inability to simultaneously resolve both stability and activity phenotypes and to couple these to gene sequences at large scale. Here we present the development of enzyme proximity sequencing, a deep mutational scanning method that leverages peroxidase-mediated radical labeling with single cell fidelity to dissect the effects of thousands of mutations on stability and catalytic activity of oxidoreductase enzymes in a single experiment. We use enzyme proximity sequencing to analyze how 6399 missense mutations influence folding stability and catalytic activity in a D-amino acid oxidase from Rhodotorula gracilis. The resulting datasets demonstrate activity-based constraints that limit folding stability during natural evolution, and identify hotspots distant from the active site as candidates for mutations that improve catalytic activity without sacrificing stability. Enzyme proximity sequencing can be extended to other enzyme classes and provides valuable insights into biophysical principles governing enzyme structure and function.

Based on the factor endowment theory and the agriculture-induced technological innovation theory, this study examines the impact of high-standard farmland construction (HFC) on agricultural ecological efficiency (AEE) and sustainable agricultural development. Using empirical data from 30 provinces in China between 2005 and 2022, it explores how high-standard farmland construction techniques can enhance AEE, considering factor endowment preferences and geographical characteristics. Empirical research indicates that high-standard farmland significantly enhances AEE, particularly in the eastern region, the main grain-producing areas, and the regions with less geographical fluctuation. Additionally, agricultural innovations, capital accumulation, and land circulation reinforce the benefits of such construction, whereas labor mobility has a moderating effect. Quantile regression analyses show that the impact of HFC on AEE initially increases and then diminishes, potentially due to inadequate post-management and maintenance. Consequently, the study recommends that the government enhance policy support and supervision for high-standard farmland projects, integrate agricultural technology with capital accumulation, optimize human resource allocation, guide labor mobility, and reform land transfer systems to boost AEE and sustainability.

Late spring coldness (LSC) is the main limiting factor threatening wheat yield and quality stability. Optimal nutrient management is beneficial in mitigating the harms of LSC by improving wheat root physiology. This study proposed a nutrient management strategy that postponed the application of phosphorus (P) and potassium (K), effectively strengthening wheat’s defense against LSC. This experiment used the winter cultivar “Yannong19” (YN 19) as plant material for two consecutive years (2021–2022 and 2022–2023). Two fertilizer treatments were used: traditional P and K fertilizers application (R1: base fertilizer: jointing fertilizer = 10:0) and postponed P and K fertilizers application (R2: base fertilizer: jointing fertilizer = 5:5); wheat plants at the anther connective formation stage shifted to temperature-controlled phytotrons for normal (T0, 11 °C/4 h) and low temperatures (T1, 4 °C/4 h; T2, −4 °C/4 h) as treatments of LSC. The results showed that under low temperature (LT) treatment, compared with R1, the R2 treatment increased the concentrations of osmotic adjustment substances (soluble sugars and soluble protein contents by 6.2–8.7% and 3.0–8.9%), enhanced activities of antioxidant enzymes (superoxide dismutase, peroxidase and catalase activities by 2.2–9.1%, 6.2–9.7% and 4.2–8.4%), balanced the hormone concentrations (increased IAA and GA3 contents by 2.8–17.5% and 10.4–14.1% and decreased ABA contents by 7.2–14.3%), and reduced the toxicity (malondialdehyde, hydrogen peroxide content and O2·− production rate by 5.7–12.4%, 17.7–22.8% and 19.1–19.1%) of the cellular membranes. Furthermore, the wheat root physiology in R2 significantly improved as the root surface area and dry weight increased by 5.0–6.6% and 4.7–6.6%, and P and K accumulation increased by 7.4–11.3% and 12.2–15.4% compared to R1, respectively. Overall, the postponed application of P and K fertilizers enhanced the physiological function of the root system, maintained root morphology, and promoted the accumulation of wheat nutrients under the stress of LSC.

This study examines the effects of digital financial inclusion on non-farm employment of rural labor and the mediating mechanism of innovation and entrepreneurship activity using China Family Panel Studies (CFPS) and the provincial index of digital financial inclusion. Through the empirical test of the Probit model and mediation effect model, we found that: firstly, digital financial inclusion can promote non-farm employment of rural labor, with the level of digitalization having the most significant impact; secondly, by encouraging innovation and entrepreneurial activity, digital financial inclusion can promote non-farm employment of rural labor; thirdly, the driving effect of digital financial inclusion on non-farm employment of rural labor is more pronounced among the unmarried, eastern region, and male labor. Therefore, we should improve the construction of rural digital infrastructure and accelerate the development of inclusive rural finance to promote more diversified non-farm employment options for “disadvantaged groups”; encourage and support innovation at the government level, and create a favorable atmosphere for innovation and entrepreneurship. Simultaneously, farmers’ digital literacy and financial knowledge should be improved so that more can adopt and take advantage of digital financial inclusion.

The digital economy has become an important driver for stimulating economic growth. The digital economy has now widely penetrated the fields of economy and society, providing new opportunities for the development of urban-rural integration. Based on panel data for 30 provinces in China from 2011 to 2020, this study constructed an index system for the integration of the digital economy and the development of urban–rural areas and conducted a systematic measurement analysis. Additionally, we used a two-step system of GMM estimation to analyze the impact of the digital economy on the development of urban-rural integration. The findings demonstrate the significant imbalance paradox of China’s digital economy development, which is shown in a gradient where the eastern region is higher than the center and the central region is higher than the west. Urban-rural integration levels in China fluctuate and display geographical variance, typically displaying high levels in the east and low levels in the west. Urban-rural integration is significantly encouraged by the digital economy, yet it varies in variability between different areas and dimensions. Additionally, rural human capital moderates the favorable effects of the digital economy on urban-rural integration. As a result, in order to achieve the integrated development of urban and rural areas, it is imperative to fully exploit the active role of the digital economy, better support the development of rural revitalization, bridge the “digital divide” between urban and rural development, and build a strong foundation for the formation of a digital urban-rural integrated development pattern with urban and rural areas and common construction and sharing.

This study conducts a comprehensive analysis of China’s digital village construction, emphasizing its role in rural organizational governance, from bureaucracies to self-governance bodies to market forces and social organizations. Utilizing sample data from 30 provinces from 2014 to 2020, the study dissects the dynamics and diversity of multi-level governance in bolstering agroecological efficiency (AEE). Notable insights include a significant positive correlation between digital villages and AEE. However, it wanes in an “inverted U” pattern beyond a digital development index of 0.8. Furthermore, rural bureaucrats and self-governing entities independently advance AEE, while market forces and social organizations require enhancement. These findings contribute to the field of digital village construction and inform sustainable agricultural strategies in developing nations.

Miscommunications between air traffic controllers (ATCOs) and pilots in air traffic control (ATC) may lead to catastrophic aviation accidents. Thanks to advances in speech and language processing, automatic speech recognition (ASR) is an appealing approach to prevent misunderstandings. To allow ATCOs and pilots sufficient time to respond instantly and effectively, the ASR systems for ATC must have both superior recognition performance and low transcription latency. However, most existing ASR works for ATC are primarily concerned with recognition performance while paying little attention to recognition speed, which motivates the research in this article. To address this issue, this article introduces knowledge distillation into the ASR for Mandarin ATC communications to enhance the generalization performance of the light model. Specifically, we propose a simple yet effective lightweight strategy, named Target-Swap Knowledge Distillation (TSKD), which swaps the logit output of the teacher and student models for the target class. It can mitigate the potential overconfidence of the teacher model regarding the target class and enable the student model to concentrate on the distillation of knowledge from non-target classes. Extensive experiments are conducted to demonstrate the effectiveness of the proposed TSKD in homogeneous and heterogeneous architectures. The experimental results reveal that the generated lightweight ASR model achieves a balance between recognition accuracy and transcription latency.

Abstract Sparse multiobjective optimization problems are common in practical applications. Such problems are characterized by large-scale decision variables and sparse optimal solutions. General large-scale multiobjective optimization problems (LSMOPs) have been extensively studied for many years. They can be well solved by many excellent custom algorithms. However, when these algorithms are used to deal with sparse LSMOPs, they often encounter difficulties because the sparse nature of the problem is not considered. Therefore, aiming at sparse LSMOPs, an algorithm based on multiple sparse detection is proposed in this paper. The algorithm applies an adaptive sparse genetic operator that can generate sparse solutions by detecting the sparsity of individuals. To improve the deficiency of sparse detection caused by local detection, an enhanced sparse detection (ESD) strategy is proposed in this paper. The strategy uses binary coefficient vectors to integrate the masks of nondominated solutions. Essentially, the mask is globally and deeply optimized by coefficient vectors to enhance the sparsity of the solutions. In addition, the algorithm adopts an improved weighted optimization strategy to fully optimize the key nonzero variables to balance exploration and optimization. Finally, the proposed algorithm is named MOEA-ESD and is compared to the current state-of-the-art algorithm to verify its effectiveness.

Abstract Lipotoxicity induced by the overload of lipid in the liver, especially excess free cholesterol (FC), has been recognized as one of driving factors in the transition from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH). MicroRNA (miR)-379-5p has been reported to play regulatory roles in hepatic triglyceride homeostasis, but the relationship of miR-379-5p and hepatic cholesterol homeostasis has never been touched. In the current study, we found that hepatic miR-379-5p levels were decreased obviously in NAFLD patients and model mice compared with their controls. Moreover, miR-379-5p was discovered to be able to inhibit intracellular FC accumulation and alleviate mitochondrial damage induced by palmitic acid (PA) in vitro. Furthermore, overexpression of miR-379-5p in HFHC-fed db/db mice could reduce the level of hepatic total cholesterol (TC) and FC, and ameliorate hepatic injury reflected by the lower serum alanine aminotransferase (ALT) and aspartate transaminase (AST). Subsequently, by combining spectrometry (MS) and luciferase assay, we identified miR-379-5p suppressed STAT1 through transcriptional and translational regulation. Finally, we confirmed that STAT1 was a transcriptional factor of HMGCS1. In conclusion, miR-379-5p inhibits STAT1 expression and regulates cholesterol metabolism through the STAT1/HMGCS1 axis, suggesting miR-379-5p might be applied to improve lipotoxicity in the future.

Aristolochic acids (AAs) have long been considered as a potent carcinogen due to its nephrotoxicity. Aristolochic acid I (AAI) reacts with DNA to form covalent aristolactam (AL)–DNA adducts, leading to subsequent A to T transversion mutation, commonly referred as AA mutational signature. Previous research inferred that AAs were widely implicated in liver cancer throughout Asia. In this study, we explored whether AAs exposure was the main cause of liver cancer in the context of HBV infection in mainland China. Totally 1256 liver cancer samples were randomly retrieved from 3 medical centers and a refined bioanalytical method was used to detect AAI–DNA adducts. 5.10% of these samples could be identified as AAI positive exposure. Whole genome sequencing suggested 8.41% of 107 liver cancer patients exhibited the dominant AA mutational signature, indicating a relatively low overall AAI exposure rate. In animal models, long-term administration of AAI barely increased liver tumorigenesis in adult mice, opposite from its tumor-inducing role when subjected to infant mice. Furthermore, AAI induced dose-dependent accumulation of AA–DNA adduct in target organs in adult mice, with the most detected in kidney instead of liver. Taken together, our data indicate that AA exposure was not the major threat of liver cancer in adulthood.

Abstract Safe, effective, and economical vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are needed to achieve adequate herd immunity and end the pandemic. We constructed a novel SARS-CoV-2 vaccine, CoVac501, which is a self-adjuvanting peptide vaccine conjugated with Toll-like receptor 7 (TLR7) agonists. The vaccine contains immunodominant peptides screened from the receptor-binding domain (RBD) and is fully chemically synthesized. It has been formulated in an optimized nanoemulsion formulation and is stable at 40 °C for 1 month. In non-human primates (NHPs), CoVac501 elicited high and persistent titers of protective neutralizing antibodies against multiple RBD mutations, SARS-CoV-2 original strain, and variants (B.1.1.7 and B.1.617.2). Specific peptides booster immunization against the B.1.351 variant has also been shown to be effective in improving protection against B.1.351. Meanwhile, CoVac501 elicited the increase of memory T cells, antigen-specific CD8+ T-cell responses, and Th1-biased CD4+ T-cell immune responses in NHPs. Notably, at an extremely high SARS-CoV-2 challenge dose of 1 × 107 TCID50, CoVac501 provided near-complete protection for the upper and lower respiratory tracts of cynomolgus macaques.

Long-landing Events (LLEs) can occur as a result of pilot’s improper operation, resulting in shorter available runways and higher operating costs. The LLE can be effectively pinpointed by analyzing data from the Quick Access Recorder (QAR), which records all of the pilot’s operations during takeoff and landing. Traditionally, domain experts inspect LLEs by manually setting thresholds on uni-dimensional data. However, they cannot detect effectively the defects caused by the pilot’s maneuvering technique because the potential mutual information between different features in the large amount of data is not considered. This paper proposes a data-driven LLE detection and causation analysis workflow, which can automatically mine and analyze the mutual information, to overcome the existing problems. Firstly, a dataset is established based on the extracted QAR data from 2002 flights, considering the landing phase of the aircraft. Subsequently, this paper proposes a Hybrid Feature Selection (HFS) method for selecting features that are highly correlated with LLEs in both supervised and unsupervised ways. A categorical Light Gradient Boosting Machine (LGBM) with a Bayesian optimization (LGBMBO) model is used to determine the performance improvement. Furthermore, the model is visualized to analyze the marginal effect of key parameters for the LLEs by using SHapley Additive exPlanations (SHAP). The experimental results demonstrate that our model reduces computational cost and achieves better performance. Additionally, this paper demonstrates that LLEs can be avoided during the landing phase by maintaining the appropriate descent speed, aircraft altitude, and descent angle.

Abstract The extreme instability of mRNA makes the practical application of mRNA‐based vaccines heavily rely on efficient delivery system and cold chain transportation. Herein, a DNA‐based nanomachine, which achieves programmed capture, long‐term storage without cryopreservation, and efficient delivery of mRNA in cells, is developed. The polythymidine acid (Poly‐T) functionalized poly(N‐isopropylacrylamide) (DNA‐PNIPAM) is synthesized and assembled as the central compartment of the nanomachine. The DNA‐PNIPAM nano‐assembly exhibits reversible thermal‐responsive dynamic property: when lower than the low critical solution temperature (LCST, ≈32 °C) of PNIPAM, the DNA‐PNIPAM transforms into extension state to expose the poly‐T, facilitating the hybridization with polyadenylic acid (Poly‐A) tail of mRNA; when higher than LCST, DNA‐PNIPAM re‐assembles and achieves an efficient encapsulation of mRNA. It is remarkable that the DNA‐PNIPAM nano‐assembly realizes long‐term storage of mRNA (≈7 days) at 37 °C. Biodegradable 2‐hydroxypropyltrimethyl ammonium chloride chitosan is assembled on the outside of DNA‐PNIPAM to facilitate the endocytosis of mRNA, RNase‐H mediating mRNA release occurs in cytoplasm, and efficient mRNA translation is achieved. This work provides a new disign principle of nanosystem for mRNA delivery.

BackgroundLow fertility and adverse pregnancy outcomes are commonly observed in women with chronic kidney disease (CKD). However, a causal relationship between low fertility and adverse pregnancy outcomes with CKD remains unclear. Besides, whether mild kidney dysfunction can affect fertility and pregnancy still needs exploration. Hence, this study aimed to investigate the causal effect of kidney damage on fertility and pregnancy using Mendelian randomization (MR).MethodsWe first used two-sample MR to examine the effects of kidney damage on fertility and pregnancy. Next, we introduced the Bayesian model averaging MR analysis to detect major causal relationships and render the results robust. The genetic instruments and outcome data were derived from various large genome-wide association studies.ResultsAdverse pregnancy outcomes: Our analyses supported a suggestive causal effect of CKD and estimated glomerular filtration rate (eGFR) rapid on stillbirth, with CKD having an odds ratio (OR) of 1.020 [95% confidence interval (CI) 1.002 to 1.038] and eGFR rapid having an OR of 1.026 (95% CI 1.004-1.048). We also discovered a suggestive causal effect of eGFR on spontaneous abortion, with an OR of 2.63 (95% CI 1.269 to 5.450). Moreover, increased urinary albumin-to-creatinine ratio (UACR) was regarded as a potential risk factor for pre-eclampsia (OR = 1.936; 95% CI 1.065 to 3.517) and gestational hypertension (OR = 1.700; 95% CI 1.002 to 2.886). Fertility assessment: The results indicated that eGFR and UACR had a suggestive causal relationship with the anti-Müllerian hormone level (eGFR beta: 1.004; UACR beta: 0.405).ConclusionsOur study used MR to demonstrate a suggestive causal relationship between kidney damage and fertility and pregnancy. We reported that mild kidney dysfunction might be a risk factor for reduced fertility and adverse pregnancy outcomes. Dynamic renal detection may help preserve fertility and reduce the risk of pregnancy loss.

To solve the tracking control problem for nonaffine systems, an online design method was developed by using the action dependent heuristic dynamic programming (ADHDP) structure.Firstly, the tracking control problem for the unknown nonaffine system was transformed into the error regulation problem.Then, the ADHDP tracking controller was designed and the online learning method was adopted to synchronize the system control with the training of action networks and critic networks, so that the desired trajectory could be tracked by the system state.Finally, a simulation example was given to verify the effectiveness of the proposed method.

Abstract To investigate the value of the star-VIBE sequence in dynamic contrast-enhanced magnetic resonance imaging of esophageal carcinoma under free breathing conditions. From February 2019 to June 2020, 60 patients with esophageal carcinoma were prospectively enrolled to undergo dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with the K-space golden-angle radial stack-of-star acquisition scheme (star-VIBE) sequence (Group A) or conventional 3D volumetric-interpolated breath-hold examination (3D-VIBE) sequence (Group B), completely randomized grouping. The image quality of DCE-MRI was subjectively evaluated at five levels and objectively evaluated according to the image signal-to-noise ratio (SNR) and contrast-noise ratio (CNR). The DCE-MRI parameters of volume transfer constant (Ktrans), rate constant (Kep) and vascular extracellular volume fraction (Ve) were calculated using the standard Tofts double-compartment model in the post-perfusion treatment software TISSUE 4D (Siemens). Each group included 30 randomly selected cases. There was a significant difference in subjective classification between the groups (35.90 vs 25.10, p = 0.009). The study showed that both the SNR and CNR of group A were significantly higher than those of group B (p = 0.004 and 0.05). The star-VIBE sequence can be applied in DCE-MRI examination of esophageal carcinoma, which can provide higher image quality than the conventional 3D-VIBE sequence in the free breathing state.

Background Various tumors are insensitive to immune checkpoint blockade (ICB) therapy. Toll-like receptors (TLRs) establish the link between innate and adaptive immunity, which can assist T-cell activation and serve as promising targets for combination to enhance ICB therapy. Here, we aimed to improve efficacy for anti-programmed death ligand 1 (PD-L1) therapy by developing a PD-L1/TLR7 dual-targeting nanobody-drug conjugate (NDC), based on the PD-L1 nanobodies and TLR7 agonist we developed.Methods PD-L1 nanobodies were obtained by phage display screening and identified through T-cell activation bioassay, in vivo imaging and quantitative biodistribution study. Immune activation and PD-L1-inducing of TLR7 agonists were evaluated in diverse innate cell models. We constructed PD-L1/TLR7 dual-targeting NDCs by chemically coupling PD-L1 nanobodies and TLR7 agonists. The antitumor effect was evaluated via several murine or humanized solid tumor models. Immunophenotyping, immune cell depletion, tumor rechallenge, RNA sequencing and PD-L1-deficient models were combined to determine the mechanism for NDCs function. The dynamics of the in vivo behaviors of NDCs were assessed based on multiorgan changes in PD-L1 levels.Results The screened PD-L1 nanobodies were characterized as tumor-targeting and alleviated T-cell immunosuppression. The TLR7 agonists induced broad innate immune responses and intratumoral PD-L1 expression on antigen-presenting cells (APCs), and its antitumor effect was dependent on intratumoral delivery. The combination of TLR7 agonists and PD-L1 nanobodies activated both innate and adaptive immunity and upregulated PD-L1-related signaling pathways. After coupling to form dual-targeting NDCs, TLR7 agonists and PD-L1 nanobodies exerted synergistic antitumor effects and safety in either ‘hot’ or ‘cold’ tumor and early or advanced tumor models, reshaped the tumor immune microenvironment and induced antitumor immune memory. CD8+ T cells and natural killer cells were the main effector cells for NDCs to function. NDCs can promote PD-L1 expression on intratumoral APCs and tumor cells, and subsequently achieve targeted enrichment in tumors. Moreover, the efficacy of NDCs is biased toward dependence on host expression of PD-L1.Conclusions The novel PD-L1/TLR7 dual-targeting NDC exhibited potent efficacy against heterogeneous tumors through orchestrating innate and adaptive immunity, which could act as a promising strategy to improve ICB therapy and shows prospects for clinical development.

Person re-identification plays an important role in the construction of the smart city. A reliable person re-identification system relieves users from the inefficient work of identifying the specific individual from enormous numbers of photos or videos captured by different surveillance devices. The most existing methods either focus on local discriminative features without global contextual information or scatter global features while ignoring the local features, resulting in ineffective attention to irregular pedestrian zones. In this article, a novel Transformer-CNN Coupling Network (TCCNet) is proposed to capture the fluctuant body region features in a heterogeneous feature-aware manner. We employ two bridging modules, the Low-level Feature Coupling Module (LFCM) and the High-level Feature Coupling Module (HFCM), to improve the complementary characteristics of the hybrid network. It is significantly helpful to enhance the capacity to distinguish between foreground and background features, thereby reducing the unfavorable impact of cluttered backgrounds on person re-identification. Furthermore, the duplicate loss for the two branches is employed to incorporate semantic information from distant preferences of the two branches into the resulting person representation. The experiments on two large-scale person re-identification benchmarks demonstrate that the proposed TCCNet achieves competitive results compared with several state-of-the-art approaches. The mean Average Precision (mAP) and Rank-1 identification rate on the MSMT17 dataset achieve 66.9% and 84.5%, respectively.

A new 70Mn–25Ni–5Cr (wt. %) filler with no traditional melting-point depressants (MPDs) of Si/B was used for transient liquid phase (TLP) bonding a directionally solidified (DS) superalloy based on Ni3Al intermetallic compound (IMC) at 1150 °C, a pressure of 2 MPa for 10–120 min. Experimental results show that the joint can be divided into 3 zones, isothermally solidified zone (ISZ), athermally solidified zone (ASZ) and diffusion-affected zone (DAZ), which was similar to microstructure of typical TLP joint bonded by Ni based filler. The joint microstructures were mainly composed of γ-Ni, γ′-Ni3(Al, Ta), MC and M23C6 carbides. Besides, in the ISZ, due to the enrichment of Al, which diffused from the base metal (BM), strip-shaped Ni(Mn, Al) phases formed in such region. The ASZ included γ-Ni and compounds of “equiaxed Ni(Mn, Al) + acicular Ni3Ta” owing to the composition segregation during the later stage of solidification. Moreover, as the bonding time increased, the volume fraction of Ni(Mn, Al) and MC carbides decreased owing to homogenization of alloying elements. After bonding for 120 min, sufficient isothermal solidification (IS) of filler can also decrease segregation of Mn/Al in front of the S/L interface and the Ni(Mn, Al)+Ni3Ta compounds were eliminated almost. Thus, the highest tensile strength was 816.9 MPa of the TLP joint of 120 min, which has been equivalent to that of BM (812 MPa). However, due to the existence of a few residual large MC carbides in the joint, which can induce the stress concentration and decreased the ductility of the joints, the highest joint elongation of 4.4% was only about 40% of the BM.

In order to deal with the problems of background mixing, pedestrian blur and pedestrian multi-scale in pedestrian tunnels, we proposed an improved faster region based convolution neural network (IF-RCNN) pedestrian detection method, which uses deep CNN to automatically extract features from pictures instead of traditional manual design features. In this paper, an improved region proposal network (RPN) structure is proposed to solve the multi-scale problem of pedestrians in tunnel. The anchor size in RPN network is further improved in the face of pedestrian images in tunnels with small total pixels. Meanwhile, feature fusion technology is introduced to the algorithm to output the features of different convolution layers. The image is fused to enhance the detection performance of blurred and occluded pedestrians in tunnel. Experimental results show that IF-RCNN algorithm has better detection performance in tunnel data set and VOC2007 data set.

Non-alcoholic fatty liver disease (NAFLD) is a chronic metabolic disease manifested in hepatic steatosis, inflammation, fibrosis, etc., which affects over one-quarter of the population around the world. Since no effective therapeutic drugs are available to cope with this widespread epidemic, the functional research of genes with altered expression during NAFLD helps understand the pathogenesis of this disease and the development of new potential therapeutic targets for drugs. In the current work, we discovered via the analysis of the Gene Expression Omnibus (GEO) dataset that cysteine sulfinic acid decarboxylase (CSAD) decreased significantly in NAFLD patients, which was also confirmed in multiple NAFLD mouse models (HFD-fed C57BL/6J, db/db and HFHFrHC-fed C57BL/6J mice). Next, CSAD’s function in the progression of NAFLD was explored using AAV-mediated liver-directed gene overexpression in an HFD-fed mouse model, where the overexpression of CSAD in the liver could alleviate NAFLD-associated pathologies, including body weight, liver/body weight ratio, hepatic triglyceride and total cholesterol, and the degree of steatosis. Mechanically, we found that the overexpression of CSAD could increase the expression of some genes related to fatty acid β-oxidation (Acad1, Ppara, and Acox1). Furthermore, we also detected that CSAD could improve mitochondrial injury in vitro and in vivo. Finally, we proposed that the effect of CSAD on lipid accumulation might be independent of the taurine pathway. In conclusion, we demonstrated that CSAD is involved in the development of NAFLD as a protective factor, which suggested that CSAD has the potential to become a new target for drug discovery in NAFLD.

Aims: Acute myeloid leukemia (AML) is an aggressive hematologic neoplasm, in which relapse due to drug resistance is the main cause for treatment failure and the disease progression. In this study, we aimed to investigate the molecular mechanism of KDM4C-dependent MALAT1/miR-328-3p/CCND2 axis in cytarabine (Ara-C) resistance in the context of AML. Methods: Bioinformatics analysis was performed to predict the targeting relationships among KDM4C, MALAT1, miR-328-3p, and CCND2 in AML, which were validated with chromatin immunoprecipitation and dual-luciferase reporter assay. Methylation-specific polymerase chain reaction was conducted to detect the methylation of MALAT1 promoter. After conducting gain- and loss-of-function assays, we investigated the effect of KDM4C on cell Ara-C resistance. A NOD/SCID mouse model was established to further investigate the roles of KDM4C/MALAT1/miR-328-3p/CCND2 in Ara-C resistant AML cells. Results: KDM4C expression was upregulated in AML. KDM4C upregulation promoted the demethylation in the promoter region of MALAT1 to increase its expression, MALAT1 targeted and inhibited miR-328-3p expression, enhancing the Ara-C resistance of HL-60/A. miR-328-3p targeted and suppressed the expression of CCND2 in HL-60/A to inhibit the Ara-C resistance. Mechanistically, KDM4C regulated miR-328-3p/CCND2 through MALAT1, resulting in Ara-C resistance in AML. Findings in an in vivo xenograft NOD/SCID mouse model further confirmed the contribution of KDM4C/MALAT1/miR-328-3p/CCND2 in the Ara-C resistant AML. Conclusion: Our study demonstrated that KDM4C may up-regulate MALAT1 expression, which decreases the expression of miR-328-3p. The downregulation of miR-328-3p increased the level of CCND2, which induced the Ara-C resistance in AML.

Wireless Sensor Networks (WSNs) are built upon tens to thousands of sensor nodes dispersed across a geographical area. Most sensor nodes have limited on-board resources, such as limited computing capabilities and limited power. These issues can reduce the reliability of the sensor nodes, which, in turn, affects the robustness of the WSN as a whole. One of the components that can be affected is the data transmission system of the sensor nodes. We propose a reliable transport layer protocol that uses a combination of redundant packets and probabilistic transmission to ensure reliable transmission of data while maintaining the efficiency of the network. The proposed protocol does not require acknowledgement packets, such as the transmission control protocol (TCP) and yet its efficiency is similar to that of the user datagram protocol (UDP). In this paper, we explain the proposed protocol and demonstrate how it can achieve 7% improvements in reliability while maintaining 77% efficiency compared to UDP.

In recent years, the Wi-Fi-based indoor positioning technology has become a research hotspot. This technology mainly locates the indoor Wi-Fi based on the received signal strength indicator (RSSI) signals. The most popular Wi-Fi positioning algorithm is the k-nearest neighbors (KNN) algorithm. Due to the excessive amount of RSSI data, clustering algorithms are generally adopted to classify the data before KNN positioning. However, the traditional clustering algorithms cannot maintain data integrity after the classification. To solve the problem, this paper puts forward an improved public c-means (IPC) clustering algorithm with high accuracy in indoor environment, and uses the algorithm to optimize the fingerprint database. After being trained in the database, all fingerprint points were divided into several classes. Then, the range of each class was determined by comparing the cluster centers. To optimize the clustering effect, the points in the border area between two classes were allocated to these classes simultaneously, pushing up the positioning accuracy in this area. The experimental results show that the IPC clustering algorithm achieved better accuracy with lighter computing load than FCM clustering and k-means clustering, and could be coupled with KNN or FS-KNN to achieve good positioning effect.

Internet of Things (IoT) is digitizing the world, and indoor positioning is one of the important applications of them. Indoor positioning refers to the realization of positioning in the indoor environment. The recent research on indoor positioning focuses on Wi-Fi-based methods since GPS cannot achieve the desired effect. A core algorithm in those methods is the K nearest neighbor (KNN) search. In this paper, we proposed an improved indoor positioning algorithm named IpKNN with better accuracy and efficiency. The IpKNN mainly includes two parts. The first part is to use the proposed clustering algorithm to classify the data set, which can improve the computational efficiency. The second part is to improve the positioning accuracy by using the proposed KNN algorithm. The proposed algorithm can achieve high precision and low consumption, and the experiment results also proved it.

A series of novel indolone derivatives were synthesized and evaluated for their binding affinities toward MDM2 and MDMX. Some compounds showed potent MDM2 and moderate MDMX activities. Among them, compound A13 exhibited the most potent affinity toward MDM2 and MDMX, with a Ki of 0.031 and 7.24 μM, respectively. A13 was also the most potent agent against HCT116, MCF7, and A549, with IC50 values of 6.17, 11.21, and 12.49 μM, respectively. Western blot analysis confirmed that A13 upregulated the expression of MDM2, MDMX, and p53 by Western blot analysis. These results indicate that A13 is a potent dual p53-MDM2 and p53-MDMX inhibitor and deserves further investigation.

Ubiquitin-protein ligase E3A (UBE3A) has dual functions as a E3 ubiquitin-protein ligase and coactivator of nuclear hormone receptors. Mutations or deletions of the maternally inherited UBE3A gene cause Angelman syndrome. Here, we performed transcriptome profiling in the hippocampus of Ube3am+/p+ and Ube3am–/p+ mice, and determined that the expression of the retinoic acid (RA) signalling pathway was downregulated in Ube3a-deficient mice compared to WT mice. Furthermore, we demonstrated that UBE3A directly interacts with RARα and may function as a coactivator of the nuclear receptor RARα to participate in the regulation of gene expression. Loss of UBE3A expression caused the downregulation of the expression of RA-related genes, including Erbb4, Dpysl3, Calb1, Pten, and Arhgap5 in Ube3am–/p+ mice brain tissues. This work revealed a new role for UBE3A in regulating retinoic acid (RA) signalling downstream genes and hopefully to shed light on the potential drug target of AS.

Lung adenocarcinoma (LUAD) is caused by multiple biological factors. Therefore, it will be more meaningful to study the prognosis from the perspective of omics integration. Given the significance of epigenetic modification and immunity in tumorigenesis and development, we tried to combine aberrant methylation and tumor infiltration CD8 T cell-related genes to build a prognostic model, to explore the key biomarkers of early-stage LUAD. On the basis of RNA-seq and methylation microarray data downloaded from The Cancer Genome Atlas (TCGA), differentially expressed genes and aberrant methylated genes were calculated with “DEseq2” and “ChAMP” packages, respectively. A Chi-square test was performed to obtain methylation driver genes. Weighted correlation network analysis (WGCNA) was utilized to mine cancer biomarkers related to CD8 T cells. With the consequences of univariate Cox proportional hazards analysis and least absolute shrinkage and selection operator (LASSO) COX regression analysis, the prognostic index based on 17 methylation driver genes (ZNF677, FAM83A, TRIM58, CLDN6, NKD1, NFE2L3, FKBP5, ITGA5, ASCL2, SLC24A4, WNT3A, TMEM171, PTPRH, ITPKB, ITGA2, SLC6A17, and CCDC81) and four CD8 T cell-related genes (SPDL1, E2F7, TK1, and TYMS) was successfully established, which could make valuable predictions for the survival risk of patients with early-stage LUAD.

Objectives: MicroRNAs (miRNAs) have been demonstrated to contribute to carcinogenesis; however, their association with tumor chemoresistance is not fully understood. In this study we aimed to investigate the molecular mechanisms involved in resistance to taxane-based chemotherapy in lung adenocarcinoma (LAD).Methods: We established paclitaxel-resistant A549 cells (A549/PTX) and docetaxel-resistant H1299 cells (H1299/DTX). In order to hit the mark, we employed multiple methods including qRT-PCR, western blotting analysis, loss/gain-of-function analysis, luciferase assays, drug sensitivity assays, animal experiment, wound-healing assay, and invasion assay.Results: Bioinformatics analysis and a luciferase reporter assay revealed that secreted frizzled-related protein 1 (SFRP1) is a direct target of miR-1260b. By qRT-PCR analysis, we found that miR-1260b was significantly upregulated in taxane-resistant cells as compared to parental cells. Suppression of miR-1260b reversed the chemoresistance of human LAD cells to taxanes both in vitro and in vivo, whereas ectopic miR-1260b expression decreased the sensitivity of parental LAD cell lines to taxanes. Downregulation of miR-1260b expression inactivated the Wnt signaling pathway and reversed the epithelial-mesenchymal transition (EMT) phenotype of taxane-resistant LAD cells. In clinical tumor tissue samples, high miR-1260b expression was detected in tumors of non-responding patients treated with taxane-based chemotherapy and was associated with low SFRP1 expression and poor prognosis.Conclusions: Our findings reveal that targeting of the miR-1260b/SFRP1/Wnt signaling axis might provide a novel strategy for overcoming chemotherapy resistance in LAD.

The aim of this paper is to provide a systematic route of information retrieval from a knowledge-based database (or domain knowledge) through a dialog system of natural language interaction. The application is about a comprehensive building at a university, with classrooms, laboratory rooms, meeting rooms, research rooms and offices, and is to present related information the user asks for. First, the domain knowledge is expressed with predicate expressions based on the ontology structure; then the vocabulary is presented distributedly with word embedding enhanced with the domain knowledge; queries from the user are then converted into the intent (general) and slot elements (specific) with the help of trained recurrent neural network (RNN). The system works smoothly. The key point is integrating the two methods of knowledge-based and data-driven natural language processing into one system, and the domain knowledge is in the central part which is incorporated into the word embedding to make it specifically fit the natural language in this application.

In the present study, α-tocopherol succinate (TOS) conjugated dextran (Dex-TOS) was synthesized and characterized by fourier transform infrared (FT-IR) spectroscopy, 1H nuclear magnetic resonance (1H NMR), dynamic light scattering (DLS) and fluorescence spectroscopy. Dex-TOS could form nanoscaled micelles in aqueous medium. The critical micelle concentration (CMC) is 0.0034 mg/mL. Doxorubicin (Dox) was selected as a model drug. Dox-loaded Dex-TOS (Dex-TOS/Dox) micelles were prepared by a dialysis method. The size of Dex-TOS/Dox micelles increased from 295 to 325 nm with the Dox-loading content increasing from 4.21% to 8.12%. The Dex-TOS/Dox micelles were almost spherical in shape, as determined by transmission electron microscopy (TEM). In vitro release demonstrated that Dox release from the micelles was in a sustained manner for up to 96 h. The cellular uptake of Dex-TOS/Dox micelles in human nasopharyngeal epidermoid carcinoma (KB) cells is an endocytic process determined by confocal laser scanning microscopy (CLSM). Moreover, Dex-TOS/Dox micelles exhibited comparable cytotoxicity in contrast with doxorubicin hydrochloride. These results suggested that Dex-TOS micelles could be a promising carrier for drug delivery.

Exposure to aristolochic acid I (AAI) can lead to aristolochic acid nephropathy (AAN), Balkan endemic nephropathy (BEN) and urothelial cancer. The induction of hepatic CYP1A, especially CYP1A2, was considered to detoxify AAI so as to reduce its nephrotoxicity. We previously found that baicalin had the strong ability to induce CYP1A2 expression; therefore in this study, we examined the effects of baicalin on AAI toxicity, metabolism and disposition, as well as investigated the underlying mechanisms. Our toxicological studies showed that baicalin reduced the levels of blood urea nitrogen (BUN) and creatinine (CRE) in AAI-treated mice and attenuated renal injury induced by AAI. Pharmacokinetic analysis demonstrated that baicalin markedly decreased AUC of AAI in plasma and the content of AAI in liver and kidney. CYP1A induction assays showed that baicalin exposure significantly increased the hepatic expression of CYP1A1/2, which was completely abolished by inhibitors of the Aromatic hydrocarbon receptor (AhR), 3ʹ,4ʹ-dimethoxyflavone and resveratrol, in vitro and in vivo, respectively. Moreover, the luciferase assays revealed that baicalin significantly increased the luciferase activity of the reporter gene incorporated with the Xenobiotic response elements recognized by AhR. In summary, baicalin significantly reduced the disposition of AAI and ameliorated AAI-induced kidney toxicity through AhR-dependent CYP1A1/2 induction in the liver.

Low solubility, tissue accumulation, and toxicity are chief obstacles to developing triptolide derivatives, so a better understanding of the pharmacokinetics and toxicity of triptolide derivatives will help with these limitations. To address this, we studied pharmacokinetics and toxicity of (5R)-5-hydroxytriptolide (LLDT-8), a novel triptolide derivative immunosuppressant in a conditional knockout (KO) mouse model with liver-specific deletion of CYP450 reductase. Compared to wild type (WT) mice, after LLDT-8 treatment, KO mice suffered severe testicular toxicity (decreased testicular weight, spermatocytes apoptosis) unlike WT mice. Moreover, KO mice had greater LLDT-8 exposure as confirmed with elevated AUC and Cmax, increased drug half-life, and greater tissue distribution. γ-H2AX, a marker of meiosis process, its localization and protein level in testis showed a distinct meiosis block induced by LLDT-8. RNA polymerase II (Pol II), an essential factor for RNA storage and synapsis in spermatogenesis, decreased in testes of KO mice after LLDT-8 treatment. Germ-cell line based assays confirmed that LLDT-8 selectively inhibited Pol II in spermatocyte-like cells. Importantly, the analysis of androgen receptor (AR) related genes showed that LLDT-8 did not change AR-related signaling in testes. Thus, hepatic CYP450s were responsible for in vivo metabolism and clearance of LLDT-8 and aggravated testicular injury may be due to increased LLDT-8 exposure in testis and subsequent Pol II reduction.

MicroRNAs (miRNAs) are a class of small non-coding RNAs, which direct post-transcriptional gene silencing (PTGS) and function in a vast range of biological events including cancer development. Most miRNAs pair to the target sites through seed region near the 5' end, leading to mRNA cleavage and/or translation repression. Here, we demonstrated a miRNA-induced dual regulation of heme oxygenase-1 (HO-1) via seed region and non-seed region, consequently inhibited tumor growth of NSCLC. We identified miR-1254 as a negative regulator inhibiting HO-1 translation by directly targeting HO-1 3'UTR via its seed region, and suppressing HO-1 transcription via non-seed region-dependent inhibition of transcriptional factor AP-2 alpha (TFAP2A), a transcriptional activator of HO-1. MiR-1254 induced cell apoptosis and cell cycle arrest in human non-small cell lung carcinoma (NSCLC) cells by inhibiting the expression of HO-1, consequently suppressed NSCLC cell growth. Consistently with the in vitro studies, mouse xenograft studies validated that miR-1254 suppressed NSCLC tumor growth in vivo. Moreover, we found that HO-1 expression was inversely correlated with miR-1254 level in human NSCLC tumor samples and cell lines. Overall, these findings identify the dual inhibition of HO-1 by miR-1254 as a novel functional mechanism of miRNA, which results in a more effective inhibition of oncogenic mRNA, and leads to a tumor suppressive effect.

Diabetic cardiomyopathy (DCM) is a common and severe complication of diabetes and results in high mortality. It is therefore imperative to develop novel therapeutics for the prevention or inhibition of the progression of DCM. Oxidative stress is a key mechanism by which diabetes induces DCM. Hence, targeting of oxidative stress-related processes in DCM could be a promising therapeutic strategy. To date, a number of studies have shown beneficial effects of several natural products on the attenuation of DCM via an antioxidative mechanism of action. The aim of the present review is to provide a comprehensive and concise overview of the previously reported antioxidant natural products in the inhibition of DCM progression. Clinical trials of the antioxidative natural products in the management of DCM are included. In addition, discussion and perspectives are further provided in the present review.

Road transport is recognized as having a negative impact on the environment. Policy has focused on replacement of the internal combustion engine (ICE) with less polluting forms of technology, including battery electric and fuel cell electric powertrains. However, progress is slow and both battery and fuel cell based vehicles face considerable commercialization challenges. To understand these challenges, a review of current electric battery and fuel cell electric technologies is presented. Based on this review, this paper proposes a battery electric vehicle (BEV) where components are sized to take into account the majority of user requirements, with the remainder catered for by a trailer-based demountable intelligent fuel cell range extender. The proposed design can extend the range by more than 50% for small BEVs and 25% for large BEVs (the extended range of vehicles over 250 miles), reducing cost and increasing efficiency for the BEV. It enables BEV manufacturers to design their vehicle battery for the most common journeys, decreases charging time to provide convenience and flexibility to the drivers. Adopting a rent and drop business model reduces the demand on the raw materials, bridging the gap in the amount of charging (refueling) stations, and extending the lifespan for the battery pack.

In order to understand the molecular mechanisms of Bifidobacterium infantis thymidine kinase/nucleoside analogue ganciclovir (BI-TK/GCV) treatment system which was proven to exhibit sustainable anti-tumor growth activity and induce apoptosis in bladder cancer, a proteomic approach of isobaric tags for relative and absolute quantification (iTRAQ), followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used. 192 down-regulated and 210 up-regulated proteins were identified after treatment with BI-TK/GCV system in Sprague-Dawley (SD) rats. Western blot analysis and immunohistochemistry analysis confirmed that Peroxiredoxin-I (Prx-I) was significantly down-regulated in bladder cancer after treatment. Prx-I silencing by transfection of Prx-I shRNA significantly suppressed growth, promoted apoptosis and regulated the cell cycle in T24 cells and reduced the phospho-NF-κB p50 and p65 protein expression which revealed the links between Prx-I and NF-κB pathway implied by Ingenuity pathway analysis (IPA). These findings yield new insights into the therapy of bladder cancer, revealing Prx-I as a new therapeutic target and indicating BI-TK/GCV system as a prospective therapy by down-regulation of Prx-I through NF-κB signaling pathway.