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Urban eco-efficiency (EE) refers to the ability of a city to balance economic growth with environmental protection through the optimal use of resources and environmental management, reflecting the city’s performance in sustainable development. Quantitative EE analysis is a crucial evaluation criterion for measuring the process of sustainable development (SD). To assess the current state of sustainable development in China, this study employs the slacks-based super efficiency model (Super-SBM) to measure the the urban eco-efficiency in China (CUEE) of 284 cities. The study utilizes Kernel Density Estimation (KDE) and Spatial Autocorrelation Analysis (SAA) to investigate the fundamental patterns of CUEE in terms of inter-city differences and relationships. Complex Network Analysis (CNA) and Link Prediction methods are applied to examine the characteristics and future trends of the CUEE network. Additionally, Geodetector and Geographically Weighted Regression (GWR) are used to analyze the influencing factors of CUEE. The findings are as follows: Overall CUEE is relatively low but shows a steady increase. The spatial association network of CUEE is becoming more complex, with increasing association strengths. The Chengdu-Chongqing Economic Circle (CCEC) is expected to further enhance its spatial association strength and may emerge as a new core area. The effectiveness of the interactions among selected factors is greater than that of individual factors. Degree centrality (X1) is identified as a core explanatory factor influencing CUEE, showing a positive correlation with CUEE. Scientific expenditure (X5) is also positively correlated with CUEE. Local fiscal budget expenditure (X3), industrial output value of foreign-invested enterprises (X7), and total cargo transportation volume (X9) are negatively correlated with CUEE. The analytical framework and research conclusions of this study offer valuable insights into the development of urban ecological efficiency in China and provide constructive recommendations for promoting sustainable urban development.

Abstract Transmembrane protein 52B (TMEM52B), a newly identified tumor‐related gene, has been reported to regulate various tumors, yet its role in nasopharyngeal carcinoma (NPC) remains unclear. Transcriptomic analysis of NPC cell lines reveals frequent overexpression of TMEM52B, and immunohistochemical results show that TMEM52B is associated with advanced tumor stage, recurrence, and decreased survival time. Depleting TMEM52B inhibits the proliferation, migration, invasion, and oncogenesis of NPC cells in vivo. TMEM52B encodes two isoforms, TMEM52B‐P18 and TMEM52B‐P20, differing in their N‐terminals. While both isoforms exhibit similar pro‐oncogenic roles and contribute to drug resistance in NPC, TMEM52B‐P20 differentially promotes metastasis. This functional discrepancy may be attributed to their distinct subcellular localization; TMEM52B‐P18 is confined to the cytoplasm, while TMEM52B‐P20 is found both at the cell membrane and in the cytoplasm. Mechanistically, cytoplasmic TMEM52B enhances AKT phosphorylation by interacting with phosphoglycerate kinase 1 (PGK1), fostering NPC growth and metastasis. Meanwhile, membrane‐localized TMEM52B‐P20 promotes E‐cadherin ubiquitination and degradation by facilitating its interaction with the E3 ubiquitin ligase NEDD4, further driving NPC metastasis. In conclusion, the TMEM52B‐P18 and TMEM52B‐P20 isoforms promote the metastasis of NPC cells through different mechanisms. Drugs targeting these TMEM52B isoforms may offer therapeutic benefits to cancer patients with varying degrees of metastasis.

Creatine is a naturally occurring derivative of an amino acid commonly utilized in functional foods and pharmaceuticals. Nevertheless, the current industrial synthesis of creatine relies on chemical processes, which may hinder its utilization in certain applications. Therefore, a biological approach was devised that employs whole-cell biocatalysis in the bacterium Corynebacterium glutamicum, which is considered safe for use in food production, to produce safe-for-consumption creatine. The objective of this study was to identify a guanidinoacetate N-methyltransferase (GAMT) with superior catalytic activity for creatine production. Through employing whole-cell biocatalysis, a gamt gene from Mus caroli (Mcgamt) was cloned and expressed in C. glutamicum ATCC 13032, resulting in a creatine titer of 3.37 g/L. Additionally, the study employed a promoter screening strategy that utilized nine native strong promoters in C. glutamicum to enhance the expression level of GAMT. The highest titer was achieved using the P1676 promoter, reaching 4.14 g/L. The conditions of whole-cell biocatalysis were further optimized, resulting in a creatine titer of 5.42 g/L. This is the first report of successful secretory creatine expression in C. glutamicum, which provides a safer and eco-friendly approach for the industrial production of creatine.

Objective: This study aimed to investigate the mechanism that Lactobacillus murinus (L. murinus) alleviated lung inflammation induced by polycyclic aromatic hydrocarbons (PAHs) exposure based on metabolomics. Methods: Female mice were administrated with PAHs mix, L. murinus and indoleacrylic acid (IA) or indolealdehyde (IAId). Microbial diversity in feces was detected by 16 S rRNA gene sequencing. Non-targeted metabolomics analysis in urine samples and targeted analysis of tryptophan metabolites in serum by UPLC-Orbitrap-MS and short-chain fatty acids (SCFA) in feces by GC-MS were performed, respectively. Flow cytometry was used to determine T helper immune cell differentiation in gut and lung tissues. The levels of IgE, IL-4 and IL-17A in the bronchoalveolar lavage fluid (BALF) or serum were detected by ELISA. The expressions of aryl hydrocarbon receptor (Ahr), cytochrome P450 1A1 (Cyp1a1) and forkheadbox protein 3 (Foxp3) genes and the histone deacetylation activity were detected by qPCR and by ELISA in lung tissues, respectively. Results: PAHs exposure induced lung inflammation and microbial composition shifts and tryptophan metabolism disturbance in mice. L. murinus alleviated PAHs-induced lung inflammation and inhibited T helper cell 17 (Th17) cell differentiation and promoted regulatory T cells (Treg) cell differentiation. L. murinus increased the levels of IA and IAId in the serum and regulated Th17/Treg imbalance by activating AhR. Additionally, L. murinus restored PAHs-induced decrease of butyric acid and valeric acid which can reduce the histone deacetylase (HDAC) level in the lung tissues, enhancing the expression of the Foxp3 gene and promoting Treg cell differentiation. Conclusion: our study illustrated that L. murinus alleviated PAHs-induced lung inflammation and regulated Th17/Treg cell differentiation by regulating host tryptophan metabolism and SCFA levels. The study provided new insights into the reciprocal influence between gut microbiota, host metabolism and the immune system, suggesting that L. murinus might have the potential as a novel therapeutic strategy for lung diseases caused by environmental pollution in the future.

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes multi-organ damage, which includes hepatic dysfunction, as observed in over 50% of COVID-19 patients. Angiotensin I converting enzyme (peptidyl-dipeptidase A) 2 (ACE2) is the primary receptor for SARS-CoV-2 entry into host cells, and studies have shown the presence of intracellular virus particles in human hepatocytes that express ACE2, but at extremely low levels. Consequently, we asked if hepatocytes might express receptors other than ACE2 capable of promoting the entry of SARS-CoV-2 into cells. To address this question, we performed a genome-wide CRISPR-Cas9 activation library screening and found that Asialoglycoprotein receptor 1 (ASGR1) promoted SARS-CoV-2 pseudovirus infection of HeLa cells. In Huh-7 cells, simultaneous knockout of ACE2 and ASGR1 prevented SARS-CoV-2 pseudovirus infection. In the immortalized THLE-2 hepatocyte cell line and primary hepatic parenchymal cells, both of which barely expressed ACE2, SARS-CoV-2 pseudovirus could successfully establish an infection. However, after treatment with ASGR1 antibody or siRNA targeting ASGR1, the infection rate significantly dropped, suggesting that SARS-CoV-2 pseudovirus infects hepatic parenchymal cells mainly through an ASGR1-dependent mechanism. We confirmed that ASGR1 could interact with Spike protein, which depends on receptor binding domain (RBD) and N-terminal domain (NTD). Finally, we also used Immunohistochemistry and electron microscopy to verify that SARS-CoV-2 could infect primary hepatic parenchymal cells. After inhibiting ASGR1 in primary hepatic parenchymal cells by siRNA, the infection efficiency of the live virus decreased significantly. Collectively, these findings indicate that ASGR1 is a candidate receptor for SARS-CoV-2 that promotes infection of hepatic parenchymal cells.

Abstract Using about 73,000 individuals’ data in China, this research, for the first time, analyzes the impact of labor transfer (LT) caused by foreign product demand (FPD) on human capital investment. Two-stage least squares estimation with the instrumental variable is applied and produced three findings. First, the FPD-LT model illustrates that with FPD increasing, more labor transfers from the agricultural sector to the non-agricultural sector. Second, working in the non-agricultural sector requires higher-level skills than in the agricultural sector. LT from agricultural sector to non-agricultural sector motivates people to invest more in human capital and promotes gender equality in human capital investment. Third, labor transferring from the agricultural sector to the non-agricultural sector enhances individuals’ income, leading to the increase of children’s human capital investments. The better-educated people make greater investment in their children’s human capital, exacerbating intergenerational inequality.

The increasing concern over climate change has spurred significant interest in exploring the potential of microalgae for wastewater treatment. Among the various types of industrial wastewaters, high-salinity NH4+-N wastewater stands out as a common challenge. Investigating microalgae’s resilience to NH4+-N under high-salinity conditions and their efficacy in NH4+-N utilization is crucial for advancing industrial wastewater microalgae treatment technologies. This study evaluated the effectiveness of employing nitrogen-efficient microalgae, specifically Oocystis lacustris, for NH4+-N removal from saline wastewater. The results revealed Oocystis lacustris’s tolerance to a Na2SO4 concentration of 5 g/L. When the Na2SO4 concentration reached 10 g/L, the growth inhibition experienced by Oocystis lacustris began to decrease on the 6th day of cultivation, with significant alleviation observed by the 7th day. Additionally, the toxic mechanism of saline NH4+-N wastewater on Oocystis lacustris was analyzed through various parameters, including chlorophyll-a, soluble protein, oxidative stress indicators, key nitrogen metabolism enzymes, and microscopic observations of algal cells. The results demonstrated that when the Oocystis lacustris was in the stationary growth phase with an initial density of 2 × 107 cells/L, NH4+-N concentrations of 1, 5, and 10 mg/L achieved almost 100% removal of the microalgae on the 1st, 2nd, and 4th days of treatment, respectively. On the other hand, saline NH4+-N wastewater minimally impacted photosynthesis, protein synthesis, and antioxidant systems within algal cells. Additionally, NH4+-N within the cells was assimilated into glutamic acid through glutamate dehydrogenase-mediated pathways besides the conventional pathway involving NH4+-N conversion into glutamine and assimilation amino acids.

Diabetic foot ulcers, a common complication of diabetes mellitus, significantly impact patients’ quality of life and impose a substantial economic burden on healthcare systems. However, the currently used treatments are associated with various challenges and the traditionally used dressings lack functional efficacy. Oxidative stress is believed to play a vital role in diabetic wound healing. Therefore, nicotinamide mononucleotide (NMN), which is known for its antioxidant properties, offers the potential to accelerate the wound-healing process. Here, a thermosensitive composite hydrogel was synthesized by mixing Pluronic F127 and Pluronic F68 with an antibacterial component chitosan. The hydrogel exhibited favorable properties including a stable structure, appropriate solid–liquid phase change, loose porosity, slow-release, antibacterial properties, and biocompatibility. In vitro experiments demonstrated that the NMN-loaded temperature-sensitive hydrogel effectively promoted cell proliferation, migration, and angiogenesis and exhibited antioxidant activity. In diabetic thickness skin defect models, NMN-loaded temperature-sensitive hydrogel treatment significantly accelerated wound healing by promoting collagen synthesis, angiogenesis, and increased expression of vascular endothelial growth factor and transforming growth factor- β1. In summary, NMN-loaded temperature-sensitive hydrogel can promote diabetic wound healing in a simple, economical, effective, and safe manner, with potential application in treating diabetic wounds.

Objective In the aging world, the depression of older adults has aroused great concern. It brings detrimental side effects to old adults and the sustainability of society. The information and communication technologies have reshaped how people live among which the Internet has gained much popularity in the senior community. This study aims to explore the association between Internet use and depression in older adults. Methods This study applied a representative national dataset (China Longitudinal Aging Social Survey, CLASS 2018) to examine by conducting regression analysis. Inspired by the social capital theory, we further examined the mediating role of general social networks (as a general concept) and specific networks (family and friend networks) in reducing depression. All calculations and analyses were conducted by STATA. Results (a) Internet use significantly reduces depressive symptoms among Chinese older adults; (b) internet use enhances social network support for Chinese older adults; and (c) social networks in general and family networks and friend networks in specific all play a mediating role between internet use and depression symptoms. Conclusion This work proved that internet use could reduce depression levels in older adults in China, and social networks, including family networks and friend networks, have a mediation role in the relationship between internet use and depression in older adults in China. Combined with the Chinese social context, we explained that the existence of an empty-nest elderly community in Chinese society and the emphasis on kinship in Chinese tradition may be the reasons. Based on the main findings, tailor-made suggestions for addressing depression issues among older adults were discussed.

Abstract In the complex tasks environment, efficient state feature learning is a key factor to improve the performance of the agent’s policy. When encountering a similar new environment, reinforcement learning agents usually need to learn from scratch. However, humans naturally have a common sense of the environment and are able to use prior knowledge to extract environmental state features. Although the prior knowledge may not be fully applicable to the new environment, it is able to speed up the learning process of the state feature. Taking this inspiration, we propose an artificial potential field-based reinforcement learning (APF-RL) method. The method consists of an artificial potential field state feature abstractor (APF-SA) and an artificial potential field intrinsic reward model (APF-IR). The APF-SA can introduce human knowledge to accelerate the learning process of the state feature. The APF-IR can generate an intrinsic reward to reduce the invalid exploration and guide the learning of the agent’s policy. We conduct experiments on PySC2 with different mini-games. The experimental results show that the APF-RL method achieves improvement in the learning efficiency compared to the benchmarks.

Acquired immunodeficiency syndrome (AIDS) cannot be completely cured, mainly due to the existence of a latent HIV-1 reservoir. However, our current understanding of the molecular mechanisms underlying the establishment and maintenance of HIV-1 latent reservoir is not comprehensive. Here, using a genome-wide CRISPR-Cas9 activation library screening, we identified E3 ubiquitin ligase F-box protein 34 (FBXO34) and the substrate of FBXO34, heterogeneous nuclear ribonucleoprotein U (hnRNP U) was identified by affinity purification mass spectrometry, as new host factors related to HIV-1 latent maintenance. Overexpression of FBXO34 or knockout of hnRNP U can activate latent HIV-1 in multiple latent cell lines. FBXO34 mainly promotes hnRNP U ubiquitination, which leads to hnRNP U degradation and abolishment of the interaction between hnRNP U and HIV-1 mRNA. In a latently infected cell line, hnRNP U interacts with the ReV region of HIV-1 mRNA through amino acids 1-339 to hinder HIV-1 translation, thereby, promoting HIV-1 latency. Importantly, we confirmed the role of the FBXO34/hnRNP U axis in the primary CD4+ T lymphocyte model, and detected differences in hnRNP U expression levels in samples from patients treated with antiretroviral therapy (ART) and healthy people, which further suggests that the FBXO34/hnRNP U axis is a new pathway involved in HIV-1 latency. These results provide mechanistic insights into the critical role of ubiquitination and hnRNP U in HIV-1 latency. This novel FBXO34/hnRNP U axis in HIV transcription may be directly targeted to control HIV reservoirs in patients in the future.

The massive and rapid transmission of SARS-CoV-2 has led to the emergence of several viral variants of concern (VOCs), with the most recent one, B.1.1.529 (Omicron), which accumulated a large number of spike mutations, raising the specter that this newly identified variant may escape from the currently available vaccines and therapeutic antibodies. Using VSV-based pseudovirus, we found that Omicron variant is markedly resistant to neutralization of sera from convalescents or individuals vaccinated by two doses of inactivated whole-virion vaccines (BBIBP-CorV). However, a homologous inactivated vaccine booster or a heterologous booster with protein subunit vaccine (ZF2001) significantly increased neutralization titers to both WT and Omicron variant. Moreover, at day 14 post the third dose, neutralizing antibody titer reduction for Omicron was less than that for convalescents or individuals who had only two doses of the vaccine, indicating that a homologous or heterologous booster can reduce the Omicron escape from neutralizing. In addition, we tested a panel of 17 SARS-CoV-2 monoclonal antibodies (mAbs). Omicron resists seven of eight authorized/approved mAbs, as well as most of the other mAbs targeting distinct epitopes on RBD and NTD. Taken together, our results suggest the urgency to push forward the booster vaccination to combat the emerging SARS-CoV-2 variants.

In the current global crisis of antibiotic resistance, delivery systems are emerging to combat resistant bacteria in a more efficient manner. Despite the significant advances of antibiotic nanocarriers, many challenges like poor biocompatibility, premature drug release, suboptimal targeting to infection sites and short blood circulation time are still challenging. To achieve targeted drug delivery and enhance antibacterial activity, here we reported a kind of pH-responsive nanoparticles by simply self-assembly of an amphiphilic poly(ethylene glycol)-Schiff-vancomycin (PEG-Schiff-Van) prodrug and free Van in one drug delivery system. The acid-liable Schiff base furnished the PEG-Schiff-Van@Van with good storage stability in the neutral environment and susceptible disassembly in response to faintly acidic condition. Notably, on account of the combination of physical encapsulation and chemical conjugation of vancomycin, these nanocarriers with favorable biocompatibility and high drug loading capacity displayed a programmed drug release behavior, which was capable of rapidly reaching high drug concentration to effectively kill the bacteria at an early period and continuously exerting an bacteria-sensitive effect whenever needed over a long period. In addition, more Schiff-base moieties within the PEG-Schiff-Van@Van nanocarriers may also make great contributions on promoting the antimicrobial activity. Using this strategy, this system was designed to have programmable structural destabilization and sequential drug release due to changes in pH that were synonymous with bacterial infection sites, thereby presenting prominent antibacterial therapy both in vitro and in vivo. This work represents a synergistic strategy on offering important guidance to rational design of multifunctional antimicrobial vehicles, which would be a promising class of antimicrobial materials for potential clinical translation.

The clinical treatment of AML is dominated by ''7 + 3'' therapy, but it often shows great toxicity and limited therapeutic efficacy in application. Therefore, it is urgent to develop novel therapeutic strategies to achieve safe and efficient treatment of AML. Small-molecule inhibitors have the characteristics of high specificity, low off-target toxicity and remarkable therapeutic effect, and are receiving more and more attention in tumor therapy. In this study, we screened a library of 1972 FDA-approved small molecular compounds for those that induced the inflammatory death of AML cells, among which the TLR8 agonist Motolimod (MTL) showed stronger anti-AML activity in the animal model but slight affection on normal lymphocytes in control mice. In terms of mechanism, cellular experiments in AML cell lines proved that TLR8 and LKB1/AMPK are the key distinct mechanisms for MTL triggered caspase-3-dependent cell death and the expression of a large number of inflammatory factors. In conclusion, our findings identified the immunoactivator MTL as a single agent exerting significant anti-AML activity in vitro and in vivo, with strong potential for clinical translation.

The social contact rate has influenced the transmission of COVID-19, with more social contact resulting in more contagion cases. We chose 18 countries with the most confirmed cases in the first 200 days after the Wuhan lockdown. This was the first study using the dynamic social contact rate to simulate the epidemic under diverse restriction policies over 500 days since the COVID-19 outbreak. The developed General Dynamic Model suggested that the probability of contagion ranged from 12.52% to 39.39% in the epidemic. The geometric mean of the social contact rates differed from 18.21% to 96.00% between countries. The restriction policies in developed economies were 3.5 times more efficient than in developing economies. We compare the effectiveness of different policies for disease prevention and discuss the influence of policy adjustment frequency for each country. Maintaining the tightest restriction or alternate tightening and loosening restrictions was recommended, with each having an average 72.45% and 79.78% reduction in maximum active cases, respectively.

Infrared small target detection (IRSTD) is widely used in many fields such as detection and guidance systems and is of great research importance. However, small targets in infrared images are typically small, blurry, feature-poor, and prone to being overwhelmed by noisy backgrounds, posing a significant challenge for IRSTD. In this paper, we propose a thermodynamics-inspired multi-feature network (TMNet) for the IRSTD task, which extracts richer and more essential semantic features of infrared targets through cross-layer and multi-scale feature fusion, along with the assistance of a thermodynamics-inspired super-resolution branch. Specifically, it consists of an attention-directed feature cross-aggregation encoder (AFCE), a U-Net backbone decoder, and a thermodynamic super-resolution branch (TSB). In the shrinkage path, the original encoder structure is reconstructed as AFCE, which contains two depth-weighted multi-scale attention modules (DMA) and a cross-layer feature fusion module (CFF). The DMA and CFF modules achieve self-feature-guided multi-scale feature fusion and cross-layer feature interaction by utilizing semantic features from different stages in the encoding process. In thermodynamics, the difference in the formation of different heat between particles leads to heat transfer between objects, which inspired us to analogize the feature extraction process of gradually focusing the network’s attention to an infrared target under the constraints of the loss function to the process of heat transfer. On the expansion path, the TSB module incorporates the Hamming equation of thermodynamics to mine infrared detail features through heat transfer-inspired high-resolution feature representations while assisting the low-resolution branch to learn high-resolution features. We conduct extensive experiments on the publicly available NUAA-SIRSST dataset and find that the proposed TMNet exhibits excellent detection performance in both pixel-level and object-level metrics. This discovery provides us with a relatively dependable guideline for formulating network designs aimed at IRSTD.

A soft, or continuum, robot has great potential in many practical fields with confined space, such as manufacturing system, electrical industry and other, due to its flexibility and benign bending attribute. However, its innate nonlinear dynamics and infinite degrees of freedom pose challenges both in modeling and control. How to build a proper model, which can be used to analyze the characteristics of soft robots, and how to design a robustly stabilized controller, are still open issues. In this work, we build a model for cable-driven continuum robots using a piecewise constant-curvature method. An improved state parameterization is proposed to avoid singularities, which produce pathological behaviors mainly on straight configurations of continuum robots. Then, a novel disturbance-rejection control framework is proposed with a tailored sliding mode controller to achieve stabilized control. Aiming at better robustness, we lump all system uncertainties, including unmodeled dynamics, unknown external disturbances, and unknown parameter variations, together as an extended state of the system. A linear extended state observer is then proposed to estimate the total uncertainties online, enabling compensation for their negative effects. Stability analysis and numerical simulations are carried out to show the feasibility and effectiveness of the proposed approaches.

Lidocaine, a potent local anesthetic, is clinically used in nerve block and pain management. However, due to its short half-life, repeated administration is required. For this reason, here we designed and prepared a lidocaine-encapsulated polylactic acid-glycolic acid (Lidocaine@PLGA) microcapsule with ultrasound responsiveness to relieve the sciatica nerve pain. With a premixed membrane emulsification strategy, the fabricated lidocaine-embedded microcapsules possessed uniform particle size, good stability, injectability, and long-term sustained release both in vitro and in vivo. More importantly, Lidocaine@PLGA microcapsules had the function of ultrasonic responsive release, which made the drug release controllable with the effect of on-off administration. Our research showed that using ultrasound as a trigger switch could promote the rapid release of lidocaine from the microcapsules, achieving the dual effects of long-term sustained release and short-term ultrasound-triggered rapid release, which can enable the application of ultrasound-responsive Lidocaine@PLGA microcapsules to nerve root block and postoperative pain relief.

BackgroundThe differential diagnosis between autoimmune encephalitis and low-grade diffuse astrocytoma remains challenging. We aim to develop a quantitative model integrating radiomics and spatial distribution features derived from MRI for discriminating these two conditions.MethodsIn our study, we included 188 patients with confirmed autoimmune encephalitis (n = 81) and WHO grade II diffuse astrocytoma (n = 107). Patients with autoimmune encephalitis (AE, n = 59) and WHO grade II diffuse astrocytoma (AS, n = 79) were divided into training and test sets, using stratified sampling according to MRI scanners. We further included an independent validation set (22 patients with AE and 28 patients with AS). Hyperintensity fluid-attenuated inversion recovery (FLAIR) lesions were segmented for each subject. Ten radiomics and eight spatial distribution features were selected via the least absolute shrinkage and selection operator (LASSO), and joint models were constructed by logistic regression for disease classification. Model performance was measured in the test set using the area under the receiver operating characteristic (ROC) curve (AUC). The discrimination performance of the joint model was compared with neuroradiologists.ResultsThe joint model achieved better performance (AUC 0.957/0.908, accuracy 0.914/0.840 for test and independent validation sets, respectively) than the radiomics and spatial distribution models. The joint model achieved lower performance than a senior neuroradiologist (AUC 0.917/0.875) but higher performance than a junior neuroradiologist (AUC 0.692/0.745) in the test and independent validation sets.ConclusionThe joint model of radiomics and spatial distribution from a single FLAIR could effectively classify AE and AS, providing clinical decision support for the differential diagnosis between the two conditions.

Summary: The SARS-CoV-2 variants B.1.617.1 (Kappa) contain multiple mutations in the spike protein. However, the effect of B.1.617.1 lineage-related mutants on viral infectivity and inactivated-virus vaccine efficacy remains to be defined. We therefore constructed 12 B.1.617.1-related pseudoviruses and systematically studied the effects of mutations on virus infectivity and neutralization resistance to convalescent and inactivated virus vaccine sera. Our results show that the B.1.617.1 variant exhibited both higher infectivity and neutralization resistance in sera at 1 or 3 months after vaccination of 28 individuals and at 14 and 200 days after discharge of 15 convalescents. Notably, 89% of vaccines and 100% of the convalescent serum samples showed more than 2.5-fold reduction in neutralization against one single mutation: E484Q. Besides, we found a significant decrease in neutralizing activity in convalescent patients and BBIBP-CorV vaccines for B.1.1.529. These findings demonstrate that inactivated-virus vaccination or convalescent sera showed reduced, but still significant, neutralization against the B.1.617.1 variant.

BackgroundPrevious studies have shown that metabolic syndrome (MetS) is associated with increased systemic inflammation and cardiac mortality in elderly subjects. However, information on the association of inflammation markers with cardiac adverse remodeling is limited in the elderly with MetS. Therefore, we investigated whether the inflammatory marker neutrophil/lymphocyte ratio (NLR) is associated with the cardiac adverse remodeling in Chinese elderly with MetS.MethodsA total of 1,087 hospitalized Chinese elderly (aged ≥ 65 years) with MetS were collected retrospectively. The cross-sectional data of echocardiography and clinical parameters were compared among quartile NLR groups.ResultsIn the elderly with MetS, higher quartile NLR (≥3.83) was found to be associated with male gender, older age, lower estimated glomerular filtration rate (eGFR), and cardiac left ventricular (LV) dilatation (all p

Abstract There is limited information on the association of body mass index (BMI) with left ventricular (LV) remodeling corresponding to severity of reduced lung function in patients with chronic obstructive pulmonary disease (COPD). Therefore, we investigated whether BMI is associated with cardiac atrial and ventricular dimensions according to severity of lung functional impairment in Chinese COPD elderly. A total of 563 hospitalized COPD patients with lung function impairment and 184 patients with non-COPD (aged 65–92 years) were collected retrospectively in a cross-sectional study in a university affiliated tertiary hospital in China. BMI and cardiac echocardiographic parameters were compared according to severity of lung functional impairment in COPD patients. BMI was 22.9 ± 3.9 kg/m2 in COPD patients, 24.0 ± 4.1 kg/m2 in non-COPD patients respectively. Reduced BMI, LV mass index, LV wall thickness and left atrial diameter, and dilated right ventricle (RV) existed in COPD patients with severe lung dysfunction as compared the COPD patients with mild to moderate lung functional reduction and non-COPD patients (P 0.05). Logistic regression analysis showed that low BMI (BMI

Abstract Ubiquitination-dependent DNA damage response (DDR) signals play a critical role in the cellular choice of DNA damage repair pathways. Human DNA helicase RecQL4 participates in DNA replication and repair, and loss of RecQL4 is associated with autosomal recessive genetic disorders characterized by genomic instability features. In an earlier study, RecQL4 was isolated as a stable complex that contained two ubiquitin ligases of the N-end rule (UBR1 and UBR2). However, it is unknown whether or not RecQL4 ubiquitination status is critical for its DNA repair function. Here, we report that RecQL4 directly interacts with RNF8 (a RING finger ubiquitin E3 ligase), and both co-localize at DNA double-strand break (DSB) sites. Our findings indicate that RNF8 ubiquitinates RecQL4 protein mainly at the lysine sites of 876, 1048, and 1101, thereby facilitating the dissociation of RecQL4 from DSB sites. RecQL4 mutant at ubiquitination sites had a significantly prolonged retention at DSBs, which hinders the recruitment of its direct downstream DSB repair proteins (CtIP & Ku80). Interestingly, reduced DSB repair capacity observed in RecQL4 depleted cells was restored only by the reconstitution of wild-type RecQL4, but not the ubiquitination mutant. Additionally, RecQL4 directly interacts with WRAP53β that is known to recruit RNF8 to DSBs and WRAP53β enhances the association of RecQL4 with RNF8. WRAP53β silencing resulted in a nearly diminished recruitment of RNF8 to DSBs and in a greatly attenuated dissociation of RecQL4 from the DSB sites. Collectively, our study demonstrates that the ubiquitination event mediated by RNF8 constitutes an essential component for RecQL4’s function in DSB repair.

In the digital era, the contradiction between regional urban development and land ecological protection is still prominent. Clarifying the relationship and internal interaction logic among digital economy (DE), new-type urbanization (NU), and land ecology (LE) is of great significance to the region’s sustainable development. Based on theoretical analysis, this study examines the relationship among DE, NU, and LE in the Yangtze River Delta through spatial analysis and empirical test with the city data from 2011 to 2020. The study found that: (1) The overall development level of DE–NU–LE in the Yangtze River Delta shows a steady upward trend, the development level of DE and NU lags behind LE, and the convergence trend among them gradually strengthened. (2) The DE-NE-LE and the coupling coordination have different and complex spatial and temporal dynamic evolution characteristics. The ability for coordinated development is enhanced continuously, which presents a typical pattern of “high in the east and low in the west”. (3) The DE has a lasting role in promoting the development of the NU and LE, while the support and stimulation of NU and LE for DE needs to be strengthened. The relationship between the NU and LE shows a mutually restricted trend. (4) The DE has a significant “siphon effect”. While NU and LE both have significant positive spatial spillover effects, which can promote the coordinated development of surrounding cities. This study deepens the understanding of DE–NU–LE coordinated development, and provides a new perspective for sustainable urban development and alleviating land conflicts.

The issue of how the external integration and internal sharing of big data influence organizational innovation has attracted extensive attention worldwide. The existing literature rarely addresses the relationship between big data integration/sharing and organizational innovation from the strategic perspective at a higher level. Consequently, in this study, big data integration and sharing were employed as external and internal influencing factors to explore the origin of organizational innovation from the perspective of the mediating role of strategic learning and the moderating role of market responsiveness. Simultaneously, an online questionnaire survey was conducted to gather data from 237 research staff working in Chinese firms. The empirical analysis indicated that big data integration and sharing promoted organizational innovation. Specifically, strategic learning played a partial mediating role in the correlation between big data integration/sharing and its innovative capability. Moreover, the innovation-promoting degree of big data integration varied among organizations with market response levels. This study has specific theoretical and managerial implications.

The extensive development of digital business in the countryside has had explicit and implicit influences on farmers' production, lifestyle and cognitive mode and has had an impact on their sense of economic gain (SEG). This study aims to determine whether digital business penetration (DBP) improves farmers' SEG in traditional villages in western China, and if significant, this study seeks to determine the mechanism. Based on questionnaire responses from 343 farmers, the empirical results indicate the principle in three ways. First, farmers' SEG grows with business digitization, especially in traditional minority villages. Second, farmers' entrepreneurial orientation (EO) partially mediates DBP's positive effect on SEG. Third, farmers' market response capacity (MRC) plays a positive moderating role, which indicates that in comparison with farmers who have a lower response to market changes, farmers who have a higher response to market changes have a higher SEG promoted by DBP. Furthermore, DBP's impact on farmers' SEG is upgraded throughout their EO, boosted by their MRC. Thus, farmers' MRC is a significant influencing factor for improving their entrepreneurial intention, enhancing their attitude toward digitization and increasing their SEG.

With the tendency toward economic and strategy decoupling between China and the United States and amidst the anti-globalization trend, enterprises are facing unprecedented challenges and opportunities. In this study, we reveal how the agile intuition (AI) of top managers with respect to the external environment affects enterprise innovation behavior (IB) based on the cognition-behavior framework. Strategic learning (SL) is considered a moderator, and knowledge sharing (KS) is considered a mediator. The survey sample consists of 305 managers from 47 enterprises in China during the COVID-19 period. The empirical results show that top management agile intuition significantly promotes enterprise IB; knowledge sharing (KS) partially mediates the relationship between top manager AI and enterprise IB; and SL suppresses the promotion effect of top manager AI on enterprise IB to a certain extent, hindering blind innovation. In a surprising result, we find that strategic guidance by an external consultant does not significantly affect the enterprise IB in China.

High-fat (HF) diet-induced neuroinflammation and cognitive decline in humans and animals have been associated with microbiota dysbiosis via the gut-brain axis. Our previous studies revealed that excretory-secretory products (ESPs) derived from the larval Echinococcus granulosus (E. granulosus) function as immunomodulators to reduce the inflammatory response, while the parasitic infection alleviates metabolic disorders in the host. However, whether ESPs can improve cognitive impairment under obese conditions remain unknown. This study aimed to investigate the effects of E. granulosus-derived ESPs on cognitive function and the microbiota-gut-brain axis in obese mice. We demonstrated that ESPs supplementation prevented HF diet-induced cognitive impairment, which was assessed behaviorally by nest building, object location, novel object recognition, temporal order memory, and Y-maze memory tests. In the hippocampus (HIP) and prefrontal cortex (PFC), ESPs suppressed neuroinflammation and HF diet-induced activation of the microglia and astrocytes. Moreover, ESPs supplementation improved the synaptic ultrastructural impairments and increased both pre- and postsynaptic protein levels in the HIP and PFC compared to the HF diet-treated group. In the colon, ESPs reversed the HF diet-induced gut barrier dysfunction, increased the thickness of colonic mucus, upregulated the expression of zonula occludens-1 (ZO-1), attenuated the translocation of bacterial endotoxins, and decreased the colon inflammation. Notably, ESPs supplementation alleviated the HF diet-induced microbiota dysbiosis. After clarifying the role of antibiotics in obese mice, we found that broad-spectrum antibiotic intervention abrogated the effects of ESPs on improving the gut microbiota dysbiosis and cognitive decline. Overall, the present study revealed for the first time that the parasite-derived ESPs alleviate gut microbiota dysbiosis and improve cognitive impairment induced by a high-fat diet. This finding suggests that parasite-derived molecules may be used to explore novel drug candidates against obesity-associated neurodegenerative diseases.

In the network operation and management of rail transit systems, the occurrence of unexpected events causes damage to the network structure, further hindering regional accessibility performance and the function of the system. This study is based on the rail transit operation schedules in 2009, 2013, 2016, 2019 and 2022. We construct a directional weighted rail transit time network (RNNT) with train operation time as the weight, compare the betweenness centrality, sum of the shortest time path and entropy importance, etc., and quantitatively measure the network accessibility, connectivity and its resilience evolution. The results show that the current rail transportation network in China has a “small-world” effect, and there are a few stations with strong connections. The most densely distributed intervals of travel times between pairs of nodes changes from [440, 445] to [207, 210]. The fastest and best-performing disturbance to network connectivity and accessibility performance are both caused by the betweenness disturbance strategy. When the network connectivity remains 80% effective, the ratio of failed nodes under the static betweenness centrality strategy decreases from 3.96% in 2009 to 2.31% in 2022, with weaker connections between node pairs, and their network resilience diminishes. When the network accessibility remains 80% effective, the ratio of failed nodes under the static (dynamic) betweenness centrality strategy increases from 0.13% (0.13%) in 2009 to 0.20% (0.23%) in 2022. Therefore, the rail transit network can protect the corresponding rail stations based on the station ranking of the above strategies, and this research is beneficial to rail transit network protection and structure optimization.

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) cannot be completely eliminated because of existence of the latent HIV-1 reservoir. However, the facts of HIV-1 latency, including its establishment and maintenance, are incomplete. FKBP3, encoded by the FKBP3 gene, belongs to the immunophilin family of proteins and is involved in immunoregulation and such cellular processes as protein folding. In a previous study, we found that FKBP3 may be related to HIV-1 latency using CRISPR screening. In this study, we knocked out the FKBP3 gene in multiple latently infected cell lines to promote latent HIV-1 activation. We found that FKBP3 could indirectly bind to the HIV-1 long terminal repeat through interaction with YY1, thereby recruiting histone deacetylase 1/2 to it. This promotes histone deacetylation and induces HIV-1 latency. Finally, in a primary latent cell model, we confirmed the effect of FKBP3 knockout on the latent activation of HIV-1. Our results suggest a new mechanism for the epigenetic regulation of HIV-1 latency and a new potential target for activating latent HIV-1. IMPORTANCE The primary reason why AIDS cannot be completely cured is the existence of a latent HIV-1 reservoir. Currently, the facts of HIV-1 latency, including its establishment and maintenance, are incomplete. Using a CRISPR library in our earlier screening of genes related to HIV-1 latency, we identified FBKP3 as a candidate gene related to HIV-1 latency. Therefore, in this mechanistic study, we first confirmed the HIV-1 latency-promoting effect of FKBP3 and determined that FKBP3 promotes histone deacetylation by recruiting histone deacetylase 1/2 to the HIV-1 long terminal repeat. We also confirmed, for the first time, that FKBP3 can act as a transcription factor (TF) recruitment scaffold and participate in epigenetic regulation of HIV-1 latency. These findings suggest a new mechanism for the epigenetic regulation of HIV-1 latency and a new potential target for activating latent HIV-1.

The contact form of the orbiting scroll and Oldham’s coupling plays an important role in improving the operation stability of the scroll compressor. In this study, the kinematic simulation of key moving parts such as the orbiting scroll and Oldham’s coupling was carried out under the condition of low speed, and the reason for the impact between Oldham’s coupling and the orbiting scroll was revealed. Results showed that the clearance between the moving pairs causes the orbiting scroll to have a slight rotation tendency and causes the impact between Oldham’s coupling and the orbiting scroll. The angular velocity of the orbiting scroll in the x-axis direction can effectively characterize this impact. The impact of the Oldham’s coupling convex key on the mainframe keyway is more severe than that on the keyway of the orbiting scroll. By optimizing the structure of the convex key of Oldham’s coupling, the contact form between Oldham’s coupling and the orbiting scroll is improved, and the starting acceleration of the orbiting scroll is reduced by 53%, which greatly improved the working stability of the scroll compressor.

Excessive wear of gears will not only cause noise and vibration in the transmission system, but also reduce transmission efficiency and accuracy in severe cases, causing irreversible losses to the transmission system. It is desirable to develop a micro-gear unit model for evaluating the wear process and predicting the failure time of large gear units (such as wind turbine gear units), reducing losses due to sudden failures. Based on the Buckingham pi-theorem of dimensional analysis and Hertz formula, the similarity ratio of each parameter of the gear wear process was proposed. The maximum equivalent stress is calculated by establishing the FEM model and comparing it with the theoretical contact stress calculated by the Hertz formula, and the results were relatively consistent. Two pairs of gear friction and wear experiments with similar parameters were carried out to compare the wear evolution performance of two similar gears. The friction performance process of the test gears was observed by particle counter and analytical ferrograph. The results show that the friction and wear processes of the two groups of gears with similar parameters have a certain correlation, which was consistent with the proposed similarity model. The similarity model combined with the observation results of abrasive particles has a certain application value for the evaluation of the wear state of the transmission system.

This study evaluates the impact of policy intensity on overcapacity using 55 listed photovoltaic (PV) firms from 2011 to 2019 in China. We divide PV industrial chain into three segments, which are upstream, midstream, and downstream. Results show that China’s PV industry is diminishing returns to scale with low level of capacity utilization (20%). The enhancement of policy intensity can significantly promote overcapacity, but its impact varies in different policies and different enterprises. Fiscal subsidy has the largest positive effect in promoting overcapacity, followed by tax preference and land support. For three segments of PV industrial chain, fiscal subsidy, land support, and tax preference play a significant role in promoting overcapacity in each segment; the increase in financial support exacerbates overcapacity in midstream. The present study also tests the effectiveness of an important PV policy posed by the Chinese government in 2013. The results show that the policy is inefficient in the short term. Nevertheless, it promotes the development of PV industry in the long term. It takes a long time to reduce positive effect of policies on overcapacity. This study provides a guide for the government to make comprehensive use of different policies.

The discovery of artemisinin (ART) for malaria treatment won the 2015 Nobel Prize in Medicine, which inspired the rediscovery and development of ART for the treatment of other diseases including cancer. In this study, we investigated the potential therapeutic effect of ART and dihydroartemisinin (DHA) on multiple myeloma (MM) cells including primary MM cells and in 5TMM3VT mouse model. Both in vitro and in vivo experiments showed that DHA might be a more promising anti-MM agent with significantly improved efficacy compared to ART. Mechanistic analyses suggested that DHA activated the mitochondrial apoptotic pathway by interacting with ferrous (Fe2+) ions and oxygen to produce reactive oxygen species (ROS). Intriguingly, DHA could reverse the upregulated expression of B-cell lymphoma 2 (Bcl-2) protein, a typical mitochondrial apoptotic marker, induced by dexamethasone (Dexa) in MM. We further demonstrated that DHA treatment could overcome Dexa resistance and enhance Dexa efficacy in MM. Additionally, DHA combined with Dexa resulted in increased ROS production and cytochrome C translocation from the mitochondria to the cytoplasm, resulting in alterations to the mitochondrial membrane potential and caspase-mediated apoptosis. In summary, our study demonstrated that DHA was superior to ART in MM treatment and overcame Dexa resistance both in vitro and in vivo, providing a promising therapeutic strategy for MM therapy.

HIV-1 inserts its proviral DNA into the infected host cells, by which HIV proviral DNA can then be duplicated along with each cell division. Thus, provirus cannot be eradicated completely by current antiretroviral therapy. We have developed an innovative strategy to silence the HIV provirus by targeted DNA methylation on the HIV promoter region. We genetically engineered a chimeric DNA methyltransferase 1 composed of designed zinc-finger proteins to become ZF2 DNMT1. After transient transfection of the molecular clone encoding this chimeric protein into HIV-1 infected or latently infected cells, efficient suppression of HIV-1 expression by the methylation of CpG islands in 5′-LTR was observed and quantified. The effective suppression of HIV in latently infected cells by ZF2-DNMT1 is stable and can last through about 40 cell passages. Cytotoxic caused by ZF2-DNMT1 was only observed during cellular proliferation. Taken together, our results demonstrate the potential of this novel approach for anti-HIV-1 therapy. Keywords: HIV-1, methylation, zinc finger, chimeric protein, DNMT1, gene therapy

MAPKAPK2 (MK2), the direct substrate of p38 MAPK, has been well-acknowledged as an attractive drug target for cancer therapy. However, few studies have assessed the functions of it in multiple myeloma (MM). In the present study, MK2 expression of MM patients was analyzed by gene expression profiling (GEP) and array-based comparative genomic hybridization (aCGH). Several experiments in vitro including MTT assay, Western blot and flow cytometry analysis were performed to identify the function of MK2 in MM. In addition, we conducted mouse survival experiments to explain the effects of MK2 on MM in vivo. mRNA level of MK2 and chromosomal gain of MK2 locus in MM cells significantly increased compared to normal samples. Furthermore, MM patients with high expression of MK2 were associated with a poor outcome. Follow-up studies showed that MK2 exerted a remarkably positive effect on MM cell proliferation and drug-resistance. Further exploration focusing on MK2 inhibitor IV revealed its inhibitory action on MM growth and drug-resistance, as well as improving survival in mouse models. In addition, a combination of MK2 inhibitor IV and the key MM therapeutic agents including bortezomib, doxorubicin, or dexamethasone facilitated curative effects on inhibiting MM cell proliferation. Taken together, our study reveals the clinical relevance of MK2 inhibition in MM and demonstrates that targeting MK2 may afford a new therapeutic approach to MM.

The immune response relies on the integration of cell-intrinsic processes with cell-extrinsic cues. During infection, B cells vacate the marrow during emergency granulopoiesis but return upon restoration of homeostasis. Here we report a novel glycosylation-mediated crosstalk between marrow B cells and hematopoietic progenitors. Human B cells secrete active ST6GAL1 sialyltransferase that remodels progenitor cell surface glycans to suppress granulopoiesis. In mouse models, ST6GAL1 from B cells alters the sialylation profile of bone marrow populations, and mature IgD+ B cells were enriched in sialylated bone marrow niches. In clinical multiple myeloma, ST6GAL1 abundance in the multiple myeloma cells negatively correlated with neutrophil abundance. These observations highlight not only the ability of medullary B cells to influence blood cell production, but also the disruption to normal granulopoiesis by excessive ST6GAL1 in malignancy.

The ability of droplet digital PCR (ddPCR) to accurately determine the concentrations of amplifiable targets makes it a promising platform for measuring copy number alterations (CNAs) in genomic biomarkers. However, its application to clinical samples, particularly formalin-fixed paraffin-embedded specimens, will require strategies to reliably determine CNAs in DNA of limited quantity and quality. When applied to cancerous tissue, those methods must also account for global genetic instability and the associated probability that the abundance(s) of one or more chosen reference loci do not represent the average ploidy of cells comprising the specimen. Here we present an experimental design strategy and associated data analysis tool that enables accurate determination of CNAs in a panel of biomarkers using multiplexed ddPCR. The method includes strategies to optimize primer and probes design to cleanly segregate droplets in the data output from reaction wells amplifying multiple independent templates, and to correct for bias from artifacts such as DNA fragmentation. We demonstrate how a panel of reference loci can be used to determine a stable CNA-neutral benchmark. These innovations, when taken together, provide a comprehensive strategy that can be used to reliably detect biomarker CNAs in DNA extracted from either frozen or FFPE tissue biopsies.

Non-human primates have emerged as an important resource for the study of human disease and evolution. The characterization of genomic variation between and within non-human primate species could advance the development of genetically defined non-human primate disease models. However, non-human primate specific reagents that would expedite such research, such as exon-capture tools, are lacking. We evaluated the efficiency of using a human exome capture design for the selective enrichment of exonic regions of non-human primates. We compared the exon sequence recovery in nine chimpanzees, two crab-eating macaques and eight Japanese macaques. Over 91% of the target regions were captured in the non-human primate samples, although the specificity of the capture decreased as evolutionary divergence from humans increased. Both intra-specific and inter-specific DNA variants were identified; Sanger-based resequencing validated 85.4% of 41 randomly selected SNPs. Among the short indels identified, a majority (54.6%-77.3%) of the variants resulted in a change of 3 base pairs, consistent with expectations for a selection against frame shift mutations. Taken together, these findings indicate that use of a human design exon-capture array can provide efficient enrichment of non-human primate gene regions. Accordingly, use of the human exon-capture methods provides an attractive, cost-effective approach for the comparative analysis of non-human primate genomes, including gene-based DNA variant discovery.