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Abstract Background Neural stem cells (NSCs) are considered to be the most promising cell type for cell replacement therapy in neurodegenerative diseases. However, their low neuronal differentiation ratio impedes their application in such conditions. Elucidating the molecular mechanism of NSC differentiation may provide the necessary experimental basis for expanding their application. Previous studies have indicated that POU3F4 can induce neuronal differentiation of NSCs, this study aims to underly the possible exact mechanism of POU3F4 on the NSC differentiation and development. Methods NSCs were isolated and cultured from the hippocampus of neonatal mice. The frozen hippocampal sections were prepared for immunohistochemical staining. Synaptic development was assessed using electron microscopy. High-throughput sequencing was employed to analyze the gene expression profile following the overexpression of Brn4. Gene expression levels were determined through Western blotting and qRT-PCR. Cell cycle and differentiation were evaluated using flow cytometry and immunofluorescent staining. Results It was found that POU3F4 promoted the neuronal differentiation of hippocampal NSCs and synapse development, and inhibited NSC proliferation. POU3F4-deficient mice exhibited impairments in learning and memory. RNA sequencing and ChIP assays confirmed that Gli1 was downstream of POU3F4. Loss and gain function experiments indicated that Gli1 mediated POU3F4 promoting neuronal differentiation and synapse development. Forced expression of Gli1 in hippocampus improved learning and memory function of animal models. Conclusions The results suggest that POU3F4 and Gli1 promote neuronal differentiation and synaptic development of NSCs, and that Gli1 partially mediates the effects of POU3F4. Graphical abstract

Abstract Background Chronological age (CA) does not reflect individual variation in the aging process. However, existing biological age predictors are mostly based on European populations and overlook the widespread nonlinear effects of clinical biomarkers. Methods Using data from the prospective Dongfeng-Tongji (DFTJ) cohort of elderly Chinese, we propose a physiological aging index (PAI) based on 36 routine clinical biomarkers to measure aging progress. We first determined the optimal level of each biomarker by restricted cubic spline Cox models. For biomarkers with a U-shaped relationship with mortality, we derived new variables to model their distinct effects below and above the optimal levels. We defined PAI as a weighted sum of variables predictive of mortality selected by a LASSO Cox model. To measure aging acceleration, we defined ΔPAI as the residual of PAI after regressing on CA. We evaluated the predictive value of ΔPAI on cardiovascular diseases (CVD) in the DFTJ cohort, as well as nine major chronic diseases in the UK Biobank (UKB). Results In the DFTJ training set (n = 12,769, median follow-up: 10.38 years), we identified 25 biomarkers with significant nonlinear associations with mortality, of which 11 showed insignificant linear associations. By incorporating nonlinear effects, we selected CA and 17 clinical biomarkers to calculate PAI. In the DFTJ testing set (n = 15,904, 5.87 years), PAI predict mortality with a concordance index (C-index) of 0.816 (95% confidence interval, [0.796, 0.837]), better than CA (C-index = 0.771 [0.755, 0.788]) and PhenoAge (0.799 [0.784, 0.814]). ΔPAI was predictive of incident CVD and its subtypes, independent of traditional risk factors. In the external validation set of UKB (n = 296,931, 12.80 years), PAI achieved a C-index of 0.749 (0.746, 0.752) to predict mortality, remaining better than CA (0.706 [0.702, 0.709]) and PhenoAge (0.743 [0.739, 0.746]). In both DFTJ and UKB, PAI calibrated better than PhenoAge when comparing the predicted and observed survival probabilities. Furthermore, ΔPAI outperformed any single biomarker to predict incident risks of eight age-related chronic diseases. Conclusions Our results highlight the potential of PAI and ΔPAI as integrative biomarkers to evaluate aging acceleration and facilitate the development of targeted intervention strategies for healthy aging.

Abstract As a fundamental unit for packaging genomic DNA into chromatin, the eukaryotic nucleosome core comprises a canonical octamer with two copies for each histone, H2A, H2B, H3, and H4, wrapped around with 147 base pairs of DNA. While H3 and H4 share structure-fold with archaeal histone-like proteins, the eukaryotic nucleosome core and the complete nucleosome (the core plus H1 histone) are unique to eukaryotes. To explore whether the eukaryotic nucleosome can assemble in prokaryotes and to reconstruct the possible route for its emergence in eukaryogenesis, we developed an in vivo system for assembly of nucleosomes in the model bacterium, Escherichia coli, and successfully reconstituted the core nucleosome, the complete nucleosome, and unexpectedly the non-canonical (H3-H4)4 octasome. The core and complete nucleosomes assembled in E. coli exhibited footprints typical of eukaryotic hosts after in situ micrococcal nuclease digestion. Additionally, they caused condensation of E. coli nucleoid. We also demonstrated the stable formation of non-canonical (H3-H4)2 tetrasome and (H3-H4)4 octasomes in vivo, which are suggested to be ‘fossil complex’ that marks the intermediate in the progressive development of eukaryotic nucleosome. The study presents a unique platform in a bacterium for in vivo assembly and studying the properties of non-canonical variants of nucleosome.

Abstract Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB) are neurodegenerative disorders characterized by the accumulation of α-synuclein aggregates. α-synuclein forms droplets via liquid-liquid phase separation (LLPS), followed by liquid-solid phase separation (LSPS) to form amyloids, how this process is physiologically-regulated remains unclear. β-synuclein colocalizes with α-synuclein in presynaptic terminals. Here, we report that β-synuclein partitions into α-synuclein condensates promotes the LLPS, and slows down LSPS of α-synuclein, while disease-associated β-synuclein mutations lose these capacities. Exogenous β-synuclein improves the movement defects and prolongs the lifespan of an α-synuclein-expressing NL5901 Caenorhabditis elegans strain, while disease-associated β-synuclein mutants aggravate the symptoms. Decapeptides targeted at the α-/β-synuclein interaction sites are rationally designed, which suppress the LSPS of α-synuclein, rescue the movement defects, and prolong the lifespan of C. elegans NL5901. Together, we unveil a Yin-Yang balance between α- and β-synuclein underlying the normal and disease states of PD and DLB with therapeutical potentials.

The presented work proposes that the self-assembly of amphiphilic compounds in Xiaoqu Baijiu occurs at the distillation and condensation stage of Chinese Baijiu production for the first time. Such phenomena have similitude with the self-assembly nano-particles conducted by evaporation and condensation approaches. Hydrogen-bonding interactions prompting the formation of molecular clusters in the system. Herein, we characterized the variation of dipole moment, hydrogen bond strength, and cluster morphology in Xiaoqu Baijiu, based on electrochemical impedance spectroscopy, Raman spectroscopy, atomic force microscopy, and molecular dynamics simulation. The effects of major aroma substances on the self-assembly of Xiaoqu Baijiu were fully investigated, it turns out ethyl lactate had the strongest effect on resulting in self-assembled clusters.

Abstract Background High-altitude cerebral edema (HACE) is considered an end-stage acute mountain sickness (AMS) that typically occurs in people after rapid ascent to 2500 m or more. While hypoxia is a fundamental feature of the pathophysiological mechanism of HACE, emerging evidence suggests that inflammation serves as a key risk factor in the occurrence and development of this disease. However, little is known about the molecular mechanism underlying their crosstalk. Methods A mouse HACE model was established by combination treatment with hypobaric hypoxia exposure and lipopolysaccharides (LPS) stimulation. Lactylated-proteomic analysis of microglia was performed to reveal the global profile of protein lactylation. Molecular modeling was applied to evaluate the 3-D modeling structures. A combination of experimental approaches, including western blotting, quantitative real-time reverse transcriptionpolymerase chain reaction (qRT-PCR), and enzyme-linked immunosorbent assay (ELISA), confocal microscopy and RNA interference, were used to explore the underlying molecular mechanisms. Results We found that hypoxia exposure increased the lactate concentration and lactylation in mouse HACE model. Moreover, hypoxia aggravated the microglial neuroinflammatory response in a lactate-dependent manner. Global profiling of protein lactylation has shown that a large quantity of lysine-lactylated proteins are induced by hypoxia and preferentially occur in protein complexes, such as the NuRD complex, ribosome biogenesis complex, spliceosome complex, and DNA replication complex. The molecular modeling data indicated that lactylation could affect the 3-D theoretical structure and increase the solvent accessible surface area of HDAC1, MTA1 and Gatad2b, the core members of the NuRD complex. Further analysis by knockdown or selectively inhibition indicated that the NuRD complex is involved in hypoxia-mediated aggravation of inflammation. Conclusions These results revealed a comprehensive profile of protein lactylation in microglia and suggested that protein lysine lactylation plays an important role in the regulation of protein function and subsequently contributes to the neuroinflammatory response under hypoxic conditions.

In order to obtain high performance cement-based grouting materials for mining and expand the application of staple fiber in the field of full-length anchorage, Utilizing ultrafine silica cement as the binder material, with the addition of accelerator, expansion agent, and polycarboxylate superplasticizer as additives, a single-factor experiment was conducted to investigate the influence of polypropylene fibers (PPF) content on the mechanical properties, pumpability, bleeding, setting time, volume shrinkage, and microstructure of cement-based grouting materials. For ultrafine cement-based slurries modified with PPF selected as anchor materials, the mechanical load bearing properties and acoustic emission characteristics of the full-length anchoring system were studied under similar pull-out condition. The results revealed that PPF content significantly impacted the slurry characteristics and mechanical property of ultrafine cement grouting materials. It notably enhanced the compressive performance and material toughness while shortening the initial setting time and reducing fluidity. Particularly, there was a positive correlation between flexural strength and PPF content. When the PPF content was 0.1%, the comprehensive performance of composite grouting material S1 was optimal. The compressive strength of the hardened specimens at 3 d and 28 d was 60.1 MPa and 83.7 MPa, respectively, which is 23.4% and 23.2% higher than the reference group S0 without PPF. Microscopic characterizations including XRD, SEM, and FTIR confirmed that the suitable PPF not only facilitated hydration reaction but also improved internal cracks within the hardened body. It acted as a bridge, transferred stress, and delayed crack propagation. Pull-out tests indicated that the mechanical property, residual bearing capacity, and maximum deformation of the full-length anchoring system based on this composite grouting material were significantly enhanced. The maximum pull-out strength was 1.356 times the reference group S0, and the occurrence of acoustic emission events was delayed. It improved the stability of roadway surrounding rocks, providing valuable insights for the similar full-length anchoring applications.

IntroductionThe quantitative distribution of grain size of sediments could imply the hydrodynamic conditions as well as terrestrial material composition; and thus, it is indicative of sea-level fluctuations, regional sources and climate changes. The environmentally sensitive components extracted from grain size data serve as excellent indicators of the sedimentary environment and monsoon intensity.Material and methodsThe drilling data from the shelf margin of the northwestern Qiongdongnan Basin provide an excellent opportunity for studying hydrodynamics and climate change in the Quaternary South China Sea (SCS). The 49 obtained samples of Quaternary sediments are primarily composed of clay and silt, with a low sand content. The environmentally sensitive components are extracted from the sediment samples, based on multiple attempts including grain size-standard deviation, the end-member modelling analysis and the principal component factor analysis methods.ResultsThe increased grain size as supplemented by ratios of rolling movement on the sediment probability accumulation curves indicate enhanced hydrodynamic conditions in the Quaternary northwestern SCS. The alternative indicators of the Quaternary East Asian monsoon are obtained after a comprehensive comparative analysis. The changes in the content of the grain size components of 5.21-6.72 μm and 27.4-35.3 μm are used as the proxy indicators for the Quaternary East Asian summer and winter monsoon of the NW-SCS, respectively. It is likely indicated that the East Asian winter monsoon remarkably strengthened since 1.3 Ma but reached its maximum intensity around 0.8 Ma. During this period, the magnitude of both climatic temperature and sea-level fluctuations are significant, thus, the coarse-grained component increased at falling or low sea-level stages.DiscussionThe grain size characteristics of the Quaternary shelf margin sediments are indicative of hydrodynamic conditions, source-sink systems and environmental monsoon climate changes in the northwestern SCS.

Abstract Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer and its prognosis remains poor. Although growing numbers of studies have verified the involvement of circular RNAs (circRNAs) in various cancer types, their specific functions in ICC remain elusive. Herein, a circRNA, circUGP2 is identified by circRNA sequencing, which is downregulated in ICC tissues and correlated with patients’ prognosis. Moreover, circUGP2 overexpression suppresses tumor progression in vitro and in vivo. Mechanistically, circUGP2 functions as a transcriptional co‐activator of PURB over the expression of ADGRB1. It can also upregulate ADGRB1 expression by sponging miR‐3191‐5p. As a result, ADGRB1 prevents MDM2‐mediated p53 polyubiquitination and thereby activates p53 signaling to inhibit ICC progression. Based on these findings, circUGP2 plasmid is encapsulated into a lipid nanoparticle (LNP) system, which has successfully targeted tumor site and shows superior anti‐tumor effects. In summary, the present study has identified the role of circUGP2 as a tumor suppressor in ICC through regulating ADGRB1/p53 axis, and the application of LNP provides a promising translational strategy for ICC treatment.

The O-GlcNAc transferase (OGT) is an essential enzyme that mediates protein O-GlcNAcylation, a unique form of posttranslational modification of many nuclear and cytosolic proteins. Recent studies observed increased OGT and O-GlcNAcylation levels in a broad range of human cancer tissues compared to adjacent normal tissues, indicating a universal effect of OGT in promoting tumorigenesis. Here, we show that OGT is essential for tumor growth in immunocompetent mice by repressing the cyclic GMP-AMP synthase (cGAS)-dependent DNA sensing pathway. We found that deletion of OGT (Ogt−/−) caused a marked reduction in tumor growth in both syngeneic mice tumor models and a genetic mice colorectal cancer (CRC) model induced by mutation of the Apc gene (Apcmin). Pharmacological inhibition or genetic deletion of OGT induced a robust genomic instability (GIN), leading to cGAS-dependent production of the type I interferon (IFN-I) and IFN-stimulated genes (ISGs). As a result, deletion of Cgas or Sting from Ogt−/− cancer cells restored tumor growth, and this correlated with impaired CD8+ T-cell-mediated antitumor immunity. Mechanistically, we found that OGT-dependent cleavage of host cell factor C1 (HCF-1) is required for the avoidance of GIN and IFN-I production in tumors. In summary, our results identify OGT-mediated genomic stability and activate cGAS-STING pathway as an important tumor-cell-intrinsic mechanism to repress antitumor immunity.

Abstract In recent years, cancer immunotherapy has undergone a transformative shift toward personalized and targeted therapeutic strategies. Bacteria‐derived outer membrane vesicles (OMVs) have emerged as a promising and adaptable platform for cancer immunotherapy due to their unique properties, including natural immunogenicity and the ability to be engineered for specific therapeutic purposes. In this review, a comprehensive overview is provided of state‐of‐the‐art techniques and methodologies employed in the engineering of versatile OMVs for cancer immunotherapy. Beginning by exploring the biogenesis and composition of OMVs, unveiling their intrinsic immunogenic properties for therapeutic appeal. Subsequently, innovative approaches employed to engineer OMVs are delved into, ranging from the genetic engineering of parent bacteria to the incorporation of functional molecules. The importance of rational design strategies is highlighted to enhance the immunogenicity and specificity of OMVs, allowing tailoring for diverse cancer types. Furthermore, insights into clinical studies and potential challenges utilizing OMVs as cancer vaccines or adjuvants are also provided, offering a comprehensive assessment of the current landscape and future prospects. Overall, this review provides valuable insights for researchers involved in the rapidly evolving field of cancer immunotherapy, offering a roadmap for harnessing the full potential of OMVs as a versatile and adaptable platform for cancer treatment.

Abstract The development of efficient methodologies for the controlled manufacture of specific stereoisomers bearing quaternary stereocenters has prompted advances in a variety of scientific disciplines including pharmaceutical chemistry, materials science, and chemical biology. However, complete control of the absolute and relative stereochemical configurations of alkyne derivatives remains an unmet synthetic challenge. Herein, a Ni/Cu dual‐catalyzed asymmetric propargylic substitution reaction is presented to produce propargylated products with all‐carbon quaternary stereocenters in high yields with significant diastereo‐ and enantioselectivities (up to >20:1 dr, >99% ee). The synthesis of all stereochemical variants of methohexital, a widely used sedative‐hypnotic drug, exemplifies the efficacy of dual‐catalyzed stereodivergent propargylation.

Business credit supply entails a firm providing credit to its customers as a means to gain a competitive edge. The advent of the digital economy has brought about profound changes in business practices. In this context, it becomes crucial to examine how the digital economy impacts the business credit supply of enterprises. This study employs a theoretical framework to derive insights and carries out an empirical analysis using the City Digital Economy Development Index spanning from 2008 to 2021, along with data from A-share listed companies in Shanghai and Shenzhen. The objective is to explore the influence of the digital economy on corporate business credit supply and its underlying mechanisms. The findings reveal that the digital economy can enhance corporate business credit supply by reducing the incidence of bad debt, thus enabling companies to extend more credit to their customers. This research contributes empirical evidence for understanding the microeconomic impact of the digital economy, while also providing theoretical insights to advance the development of the digital economy and optimize the allocation of financial resources, thereby alleviating corporate financing constraints.

In response to the inadequacy of existing defense methods for backdoor attacks in federated learning to effectively remove embedded backdoor features from models, while simultaneously reducing the accuracy of the primary task, a federated learning backdoor defense method called ContraFL was proposed, which utilized contrastive training to disrupt the clustering process of backdoor samples in the feature space, thereby rendering the global model classifications in federated learning independent of the backdoor trigger features.Specifically, on the server side, a trigger generation algorithm was developed to construct a generator pool to restore potential backdoor triggers in the training samples of the global model.Consequently, the trigger generator pool was distributed to the participants by the server, where each participant added the generated backdoor triggers to their local samples to achieve backdoor data augmentation.Experimental results demonstrate that ContraFL effectively defends against various backdoor attacks in federated learning, outperforming existing defense methods.

Abstract Aloperine (ALO), a quinolizidine‐type alkaloid isolated from a natural Chinese herb, has shown promising antitumor effects. Nevertheless, its common mechanism of action and specific target remain elusive. Here, it is demonstrated that ALO inhibits the proliferation and migration of non‐small cell lung cancer cell lines in vitro and the tumor development in several mouse tumor models in vivo. Mechanistically, ALO inhibits the fusion of autophagosomes with lysosomes and the autophagic flux, leading to the accumulation of sequestosome‐1 (SQSTM1) and production of reactive oxygen species (ROS), thereby inducing tumor cell apoptosis and preventing tumor growth. Knockdown of SQSTM1 in cells inhibits ROS production and reverses ALO‐induced cell apoptosis. Furthermore, VPS4A is identified as a direct target of ALO, and the amino acids F153 and D263 of VPS4A are confirmed as the binding sites for ALO. Knockout of VPS4A in H1299 cells demonstrates a similar biological effect as ALO treatment. Additionally, ALO enhances the efficacy of the anti‐PD‐L1/TGF‐β bispecific antibody in inhibiting LLC‐derived subcutaneous tumor models. Thus, ALO is first identified as a novel late‐stage autophagy inhibitor that triggers tumor cell death by targeting VPS4A.

Abstract Targeted delivery of glutamine metabolism inhibitors holds promise for cholangiocarcinoma therapy, yet effective delivery vehicles remain a challenge. This study reports the development of a biomimetic nanosystem, termed R‐CM@MSN@BC, integrating mesoporous organosilicon nanoparticles with reactive oxygen species‐responsive diselenide bonds for controlled release of the glutamine metabolism inhibitor bis‐2‐(5‐phenylacetamido‐1,3,4‐thiadiazol‐2‐yl) ethyl sulfide (BPTES) and the photosensitizer Ce6. Erythrocyte membrane coating, engineered with Arg‐Gly‐Asp (RGD) peptides, not only enhanced biocompatibility but also improved tumor targeting and tissue penetration. Upon laser irradiation, R‐CM@MSN@BC executed both photodynamic and glutamine‐metabolic therapies, inducing necroptosis in tumor cells and triggering significant immunogenic cell death. Time‐of‐flight mass cytometry analysis revealed that R‐CM@MSN@BC can remodel the immunosuppressive tumor microenvironment by polarizing M1‐type macrophages, reducing infiltration of M2‐type and CX3CR1+ macrophages, and decreasing T cell exhaustion, thereby increasing the effectiveness of anti‐programmed cell death ligand 1 immunotherapy. This strategy proposed in this study presents a viable and promising approach for the treatment of cholangiocarcinoma.

Lipids are components of cytomembranes that are involved in various biochemical processes. High-altitude hypoxic environments not only affect the body’s energy metabolism, but these environments can also cause abnormal lipid metabolism involved in the hypoxia-induced cognitive impairment. Thus, comprehensive lipidomic profiling of the brain tissue is an essential step toward understanding the mechanism of cognitive impairment induced by hypoxic exposure. In the present study, mice showed reduced new-object recognition and spatial memory when exposed to hypobaric hypoxia for 1 day. Histomorphological staining revealed significant morphological and structural damage to the hippocampal tissue, along with prolonged exposure to hypobaric hypoxia. Dynamic lipidomics of the mouse hippocampus showed a significant shift in both the type and distribution of phospholipids, as verified by spatial lipid mapping. Collectively, a diverse and dynamic lipid composition in mice hippocampus was uncovered, which deepens our understanding of biochemical changes during sustained hypoxic exposure and could provide new insights into the cognitive decline induced by high-altitude hypoxia exposure.

Abstract Using updated National Health and Nutrition Examination Survey (NHANES) follow-up data, and a large nationwide representative sample of adult U.S. citizens, the aim of this study was to explore the relationship between dietary flavonol intake, all-cause and cause-specific mortality risks. In this prospective cohort study based on NHANES (2007–2008, 2009–2010, and 2017–2018), a total of 11,679 participants aged 20 years and above were evaluated. The amount and type of food taken during a 24-h dietary recall were used to estimate dietary flavonol intake, which includes total flavonol, isorhamnetin, kaempferol, myricetin, and quercetin. Each analysis of the weighted data was dealt with in accordance with the NHANES reporting requirements' intricate stratification design. The Cox proportional risk regression model or Fine and Gray competing risks regression model were applied to evaluate all-cause and cause-specific mortality risks, respectively. The follow-up period was calculated using the time interval between the baseline and the death date or December 31, 2019 (whichever occurs first). Each data analysis was performed between October 1, 2023, and October 22, 2023. Dietary flavonol intake included total flavonol, isorhamnetin, kaempferol, myricetin, and quercetin. Up to December 31, 2019, National Death Index (NDI) mortality data were used to calculate mortality from all causes as well as cause-specific causes. A total of 11,679 individuals, which represents 44,189,487 U.S. non-hospitalized citizens, were included in the study; of these participants, 49.78% were male (n = 5816), 50.22% were female (n = 5, 863); 47.56% were Non-Hispanic White (n = 5554), 18.91% were Non-Hispanic Black (n = 2209), 16.23% were Mexican American (n = 1895), and 17.30% were other ethnicity (n = 2021); The mean [SE] age of the sample was 46.93 [0.36] years, with a median follow-up of 7.80 years (interquartile range, 7.55–8.07 years). After adjusting covariates, Cox proportional hazards models and fine and gray competing risks regression models for specific-cause mortality demonstrated that total flavonol intake was associated with all-cause (HR 0.64, 95% CI 0.54–0.75), cancer-specific (HR 0.45, 95% CI 0.28–0.70) and CVD-specific (HR 0.67, 95% CI 0.47–0.96) mortality risks; isorhamnetin intake was associated with all-cause (HR 0.72, 95% CI 0.60–0.86), and cancer-specific (HR 0.62, 95% CI 0.46–0.83) mortality risks; kaempferol intake was associated with all-cause (HR 0.74, 95% CI 0.63–0.86), and cancer-specific (HR 0.62, 95% CI 0.40–0.97) mortality risks; myricetin intake was associated with all-cause (HR 0.77, 95% CI 0.67–0.88), AD-specific (HR 0.34, 95% CI 0.14–0.85), and CVD-specific (HR 0.61, 95% CI 0.47–0.80) mortality risks; quercetin intake was associated with all-cause (HR 0.66, 95% CI 0.54–0.81), cancer-specific (HR 0.54, 95% CI 0.35–0.84), and CVD-specific (HR 0.61, 95% CI 0.40–0.93) mortality risks; there was no correlation observed between dietary flavonol intake and DM-specific mortality. According to the current study, all-cause, AD, cancer, and CVD mortality risks declined with increased dietary flavonoid intake in the U.S. adults. This finding may be related to the anti-tumor, anti-inflammatory, and anti-oxidative stress properties of flavonol.

Abstract Background Astragaloside IV (As-IV) and Tanshinone IIA (Ta-IIA) are the main ingredients of traditional Chinese medicinal Astragalus membranaceus (Fisch.) Bunge and Salvia miltiorrhiza Bunge, respectively, both of which have been employed in the treatment of cardiovascular diseases. Nevertheless, the efficacy of the combination (Co) of Ta-IIA and As-IV for cardiovascular diseases remain unclear and warrant further investigation. This study aimed to investigate the efficacy and the underlying molecular mechanism of Co in treating myocardial ischemia–reperfusion injury (MIRI). Methods In order to assess the efficacy of Co, an in vivo MIRI mouse model was created by temporarily blocking the coronary arteries for 30 min and then releasing the blockage. Parameters such as blood myocardial enzymes, infarct size, and ventricular function were measured. Additionally, in vitro experiments were conducted using HL1 cells in both hypoxia-reoxygenation model and oxidative stress models. The apoptosis rate, expression levels of apoptosis-related proteins, oxidative stress indexes, and release of inflammatory factors were detected. Furthermore, molecular docking was applied to examine the binding properties of Ta-IIA and As-IV to STING, and western blotting was performed to analyze protein expression of the STING pathway. Additionally, the protective effect of Ta-IIA, As-IV and Co via inhibiting STING was further confirmed in models of knockdown STING by siRNA and adding STING agonist. Results Both in vitro and in vivo data demonstrated that, compared to Ta-IIA or As-IV alone, the Co exhibited superior efficacy in reducing the area of myocardial infarction, lowering myocardial enzyme levels, and promoting the recovery of myocardial contractility. Furthermore, the Co showed more potent anti-apoptosis, antioxidant, and anti-inflammation effects. Additionally, the Co enhanced the inhibitory effects of Ta-IIA and As-IV on STING phosphorylation and the activation of STING signaling pathway. However, the administration of a STING agonist attenuated the protective effects of the Co, Ta-IIA, and As-IV by compromising their anti-apoptotic, antioxidant, and anti-inflammatory effects in MIRI. Conclusion Compared to the individual administration of Ta-IIA or As-IV, the combined treatment demonstrated more potent ability in inhibiting apoptosis, oxidative stress, inflammation, and the STING signaling pathway in the context of MIRI, indicating a more powerful protective effect against MIRI. Graphical Abstract

Abstract With the large scale mining of coal and the increase of abandoned goafs under weakly cemented aquifer strata in Western China, it is urgent to study the time dependent mechanical properties of water sensitive aquifer strata. In this paper, creep behavior of dry and saturated medium-grain sandstone, which represent two limit states affected by water, were studied and compared. The results showed that water greatly weakens the compressive strength of medium-grained sandstone, but the difference in axial strain between dry and saturated rock samples decreases with the increase of confining pressure. The creep compression volume of rocks decreases with the increase of deviatoric stress, and only under low confining pressure does the creep volume of rocks exhibit expansion. There is an order of magnitude difference in creep strain between medium grained sandstone and other common rocks. The instantaneous elastic modulus has a negative exponential relationship with deviating stress. The creep rate has a positive exponential relationship with deviating stress. Based on Burges model with exponential damage variables, the law of the influence of confining pressure on creep model parameters has been discussed. The linear relationship between elastic modulus of medium-grained sandstone and parameters of Burgers model with damage was found. The research results are conducive to the convenient prediction of creep behavior of medium grained sandstone engineering and the long-term stability control of the surrounding rock.

To address the slow response time of existing detection modules to Internet of things (IoT) distributed denial of service (DDoS) attacks, their low feature differentiation, and poor detection performance, a single flow detection enabled method based on traffic feature reconstruction and mapping (SFDTFRM) was proposed.Firstly, SFDTFRM employed a queue to store previously arrived flow based on the first in, first out rule.Secondly, to address the issue of similarity between normal communication traffic of IoT devices and DDoS attack traffic, a multidimensional reconstruction neural network model more lightweight compared to the baseline model and a function mapping method were proposed.The modified model loss function was utilized to reconstruct the quantitative feature matrix of the queue according to the corresponding index, and transformed into a mapping feature matrix through the function mapping method, enhancing the differences between different types of traffic, including normal communication traffic of IoT devices and DDoS attack traffic.Finally, the frequency information was extracted using a text convolutional network and information entropy calculation and the machine learning classifier was employed for DDoS attack traffic detection.The experimental results on two benchmark datasets show that SFDTFRM can effectively detect different DDoS attacks, and the average metrics value of SFDTFRM is a maximum of 12.01% higher than other existing methods.

Background & Aims: Apolipoprotein A-1 (ApoA-1), the main apolipoprotein of high-density lipoprotein, has been well studied in the area of lipid metabolism and cardiovascular diseases. In this project, we clarify the function and mechanism of ApoA-1 in liver regeneration. Methods: Seventy percent of partial hepatectomy was applied in male ApoA-1 knockout mice and wild-type mice to investigate the effects of ApoA-1 on liver regeneration. D-4F (ApoA-1 mimetic peptide), autophagy activator, and AMPK activator were used to explore the mechanism of ApoA-1 on liver regeneration. Results: We demonstrated that ApoA-1 levels were highly expressed during the early stage of liver regeneration. ApoA-1 deficiency greatly impaired liver regeneration after hepatectomy. Meanwhile, we found that ApoA-1 deficiency inhibited autophagy during liver regeneration. The activation of autophagy protected against ApoA-1 deficiency in inhibiting liver regeneration. Furthermore, ApoA-1 deficiency impaired autophagy through AMPK-ULK1 pathway, and AMPK activation significantly improved liver regeneration. The administration of D-4F could accelerated liver regeneration after hepatectomy. Conclusions: These findings suggested that ApoA-1 played an essential role in liver regeneration through promoting autophagy in hepatocytes via AMPK-ULK1 pathway. Our findings enrich the understanding of the underlying mechanism of liver regeneration and provide a potential therapeutic strategy for liver injury.

Abstract. Inflammation is a major underlying mechanism in the progression of numerous cardiovascular diseases (CVDs). Regulatory T cells (Tregs) are typical immune regulatory cells with recognized immunosuppressive properties. Despite the immunosuppressive properties, researchers have acknowledged the significance of Tregs in maintaining tissue homeostasis and facilitating repair/regeneration. Previous studies unveiled the heterogeneity of Tregs in the heart and aorta, which expanded in CVDs with unique transcriptional phenotypes and reparative/regenerative function. This review briefly summarizes the functional principles of Tregs, also including the synergistic effect of Tregs and other immune cells in CVDs. We discriminate the roles and therapeutic potential of Tregs in CVDs such as atherosclerosis, hypertension, abdominal arterial aneurysm, pulmonary arterial hypertension, Kawasaki disease, myocarditis, myocardial infarction, and heart failure. Tregs not only exert anti-inflammatory effects but also actively promote myocardial regeneration and vascular repair, maintaining the stability of the local microenvironment. Given that the specific mechanism of Tregs functioning in CVDs remains unclear, we reviewed previous clinical and basic studies and the latest findings on the function and mechanism of Tregs in CVDs.

Abstract Photodynamic therapy (PDT) is a minimally invasive and controllable local cancer treatment for cholangiocarcinoma (CCA). However, the efficacy of PDT is hindered by intratumoral hypoxia and the presence of an antioxidant microenvironment. To address these limitations, combining PDT with gas therapy may be a promising strategy to enhance tumor oxygenation. Moreover, the augmentation of oxidative damage induced by PDT and gas therapy can be achieved by inhibiting NRF2, a core regulatory molecule involved in the antioxidant response. In this study, an integrated nanotherapeutic platform called CMArg@Lip, incorporating PDT and gas therapies using ROS‐responsive liposomes encapsulating the photosensitizer Ce6, the NO gas‐generating agent L‐arginine, and the NRF2 inhibitor ML385, is successfully developed. The utilization of CMArg@Lip effectively deals with challenges posed by tumor hypoxia and antioxidant microenvironment, resulting in elevated levels of oxidative damage and subsequent induction of ferroptosis in CCA. Additionally, these findings suggest that CMArg@Lip exhibits notable immunomodulatory effects, including the promotion of immunogenic cell death and facilitation of dendritic cell maturation. Furthermore, it contributes to the anti‐tumor function of cytotoxic T lymphocytes through the downregulation of PD‐L1 expression in tumor cells and the activation of the STING signaling pathway in myeloid‐derived suppressor cells, thereby reprogramming the immunosuppressive microenvironment via various mechanisms.

Background: Neuroinflammation is responsible for neuropsychiatric dysfunction following acute brain injury and neurodegenerative diseases. This study describes how a hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitor FG-4592 prevents the lipopolysaccharide (LPS)-induced acute neuroinflammation in microglia. Methods: The distribution of FG-4592 in mouse brain tissues was determined by collision-induced dissociation tandem mass spectrometry. Microglial activation in the hippocampus was analyzed by immunofluorescence. Moreover, we determined the activation of HIF-1 and nuclear factor-κB (NF-κB) signaling pathways, proinflammatory responses using molecular biological techniques. Transcriptome sequencing and BNIP3 silencing were conducted to explore signaling pathway and molecular mechanisms underlying FG-4592 anti-inflammatory activity. Results: FG-4592 was transported into the brain tissues and LPS increased its transportation. FG-4592 promoted the expression of HIF-1α and induced the downstream gene transcription in the hippocampus. Administration with FG-4592 significantly inhibited microglial hyperactivation and decreased proinflammatory cytokine levels following LPS treatment in the hippocampus. The LPS-induced inflammatory responses and the NF-κB signaling pathway were also downregulated by FG-4592 pretreatment in microglial cells. Mechanistically, Venn diagram analysis of transcriptomic changes of BV2 cells identified that BNIP3 was a shared and common differentially expressed gene among different treatment groups. FG-4592 markedly upregulated the protein levels of BNIP3 in microglia. Importantly, BNIP3 knockdown aggravated the LPS-stimulated inflammatory responses and partially reversed the protection of FG-4592 against microglial inflammatory signaling and microglial activation in the mouse hippocampus. Conclusions: FG-4592 alleviates neuroinflammation through facilitating microglial HIF-1/BNIP3 signaling pathway in mice. Targeting HIF-PHD/HIF-1/BNIP3 axis is a promising strategy for the development of anti-neuroinflammation drugs.

Time-reversibility, which is inherent in many physical systems, is crucial in tailoring temporal waveforms for optimum light–matter interactions. Among the time-reversible atomic systems, narrowband biphoton sources are essential for efficient quantum storage. In this work, we demonstrate time-reversed and fully time-resolved ultra-narrowband single-sided biphoton frequency combs with an average free-spectral range (FSR) of 42.66 MHz and an average linewidth of 4.60 MHz in the telecommunication band. We experimentally observe the fully time-resolved and reversible temporal oscillations by second-order cross correlation and joint temporal intensity measurements. The potential benefits of the time-reversed and fully time-resolved temporal oscillations from our source include enhancing the efficiency of quantum storage in atomic memories and maximizing the utilization of temporal information in multimode biphoton frequency combs. We further verify the heralded single-photon state generation from the multimode biphoton frequency combs by using Hanbury Brown and Twiss interference measurements. To the best of our knowledge, this 42.66 MHz FSR of our photon-pair source represents the narrowest among all of the different configurated biphoton sources reported to date. This ultra-narrow FSR and its 4.60 MHz linewidth provide the highest frequency mode number of 5786 and the longest coherence time among all the singly configurated biphoton sources so far. Our time-reversed and fully time-resolved massive-mode biphoton source could be useful for high-dimensional quantum information processing and efficient time–frequency multiplexed quantum storage toward long-distance and large-scale quantum networks.

A mechanical model of full-length anchoring bolt is established to study the stability of mechanical bearing structure of surrounding rock in high stress soft rock roadway after full-length anchoring bolt. The model considers the dilatancy characteristics of soft rock post-peak strength softening and the stress boundary conditions of full-length bolt, and the analytical formula of bolt stress is derived. Furthermore, the mechanical model of full-length anchored surrounding rock is established by equivalent the anchoring force to the form of volume force. From shallow to deep, it is divided into anchorage residual zone, anchorage plastic softening zone, non-anchorage plastic softening zone and elastic zone, and the stress expression of each zone is deduced. Combined with engineering examples, the influence of space effect, expansion coefficient, bolt length and tray reaction force on surrounding rock stress and bolt stress is analyzed. The results show that under the influence of spatial effect, the deformation and failure of roadway presents progressive development. The concept of ' anchorage control zone ' is proposed, that is, in the process of full-length bolt support, the virtual support force and anchoring force of surrounding rock are in a state of reciprocal growth and decline, thus inhibiting the transfer of surrounding rock stress to the deep and effectively reducing the plastic zone. The earlier the anchor bolt is installed, the greater the deformation of the surrounding rock acting on the rod body, and the easier it is to form a common bearing body with the surrounding rock. The axial force of the anchor bolt is proportional to the expansion coefficient. With the increase of the expansion coefficient, the growth rate of the anchoring force is significantly accelerated, which ensures the recovery effect of the anchor bolt on the radial stress of the surrounding rock. The axial force distribution and peak value of the rod body will increase with the increase of the length of the bolt and the bonding range of the surrounding rock/anchoring agent interface, and then the peak area of the tangential stress of the surrounding rock will shift to the direction of the tunnel wall. The effect of the reaction force of the full-length bolt tray is mainly reflected in improving the stress of the bolt, giving full play to the anchoring effect of the bolt and the ability to protect the surface, and having little effect on the boundary of the residual zone and the plastic zone.

Abstract Estuaries play an important role in the global nitrous oxide budget. However, considerable uncertainties exist in estimating their nitrous oxide emissions, largely due to anthropogenic impacts, particularly wastewater discharge. Here we investigate nitrous oxide emission dynamics in the Pearl River Estuary through advanced high-resolution, real-time measurements. Results suggest that Pearl River Estuary is a strong nitrous oxide emission source (1.05 Gg yr−1; range: 0.92–1.23 Gg yr−1) with pronounced spatial heterogeneity. Wastewater discharge substantially impacts emissions by introducing abundant nutrients, altering carbon-to-nitrogen stoichiometry, and stimulating biochemical processes. A meta-analysis further reveals the widespread enhancement of nitrous oxide emission induced by wastewater nitrogen input in global estuaries, with nitrous oxide emission factors considerably lower than that suggested by the IPCC owing to progressive biological saturation. Consequently, refining emission factor estimates through comprehensive bottom-up studies is imperative to improve the understanding of estuarine contributions to the global nitrous oxide budget.

Abstract High-dimensional quantum entanglement is a cornerstone for advanced technology enabling large-scale noise-tolerant quantum systems, fault-tolerant quantum computing, and distributed quantum networks. The recently developed biphoton frequency comb (BFC) provides a powerful platform for high-dimensional quantum information processing in its spectral and temporal quantum modes. Here we propose and generate a singly-filtered high-dimensional BFC via spontaneous parametric down-conversion by spectrally shaping only the signal photons with a Fabry-Pérot cavity. High-dimensional energy-time entanglement is verified through Franson-interference recurrences and temporal correlation with low-jitter detectors. Frequency- and temporal- entanglement of our singly-filtered BFC is then quantified by Schmidt mode decomposition. Subsequently, we distribute the high-dimensional singly-filtered BFC state over a 10 km fiber link with a post-distribution time-bin dimension lower bounded to be at least 168. Our demonstrations of high-dimensional entanglement and entanglement distribution show the singly-filtered quantum frequency comb’s capability for high-efficiency quantum information processing and high-capacity quantum networks.

Curcumin, a naturally occurring poorly water-soluble polyphenol with a broad spectrum, is a typical BCS IV drug. The objective of this study was to develop curcumin nanocrystals liposomes with the aim of improving bioavailability. In this study, we prepared cationic curcumin nanocrystals with a particle size of only 29.42 nm; such a phenomenal range of particle sizes is very rare. Moreover, we summarized and evaluated the parameters of the nanocrystal preparation process, including methods, formulations, etc., and the rules we concluded can be generalized to other nanocrystal preparation processes. To counteract the instability of the nanocrystals in the digestive tract, cationic curcumin nanocrystals were loaded into negatively charged liposomes through gravitational force between different charges. Unexpectedly, chitosan oligosaccharide was found to promote the self-assembly process of curcumin nanocrystal liposomes. In vitro and in vivo experiments demonstrated that chitosan-modified curcumin nanocrystal liposomes exhibited enhanced resistance to enzyme barriers, mucus barriers, and cellular barriers, resulting in a 5.4-fold increase in bioavailability compared to crude powder formulations. It can be concluded that cationic nanocrystals liposomes represent an appropriate novel strategy for improving the dissolution rate and bioavailability of poorly soluble natural products such as curcumin.

This paper depicts the distribution of the Wushenqi paleo-uplift in the Ordos Basin by using the latest drilling and seismic data, and analyzes the tectonic evolution of the paleo-uplift with the support of Bischke curve and balanced section. The compressional Wushenqi paleo-uplift which developed in the Early Caledonian orogeny (Huaiyuan orogeny) is approximately a ellipse extending in S-N direction. Its long axis is about 194 km and short axis is about 55–94 km in nearly W-E direction. The denudation thickness and area of the Cambrian in the core are 170–196 m and 11 298 kmbrespectively. It was mainly formed during the Huaiyuan orogeny according to the chronostratigraphic framework. It was in the embryonic stage in the Middle–Late Cambrian, denuded after developed obviously at the end of Late Cambrian. The paleo-uplift of the 3rd member of the Ordovician Majiagou Formation was reactivated and reduced in area. In the sedimentary period of the Ma4 Member–pre-Carboniferous, the paleo-uplift experienced non-uniform uplift and denudation. It entered the stable period of burial and preservation in the Carboniferous and later period. The Wushenqi paleo-uplift was formed on the weak area of the basement and tectonic belts, into an compressional structure with irregular morphology, under the control of the non-coaxial compression in the south and north and the stress transmitted by the uplift in the basin. The Wushenqi paleo-uplift has a controlling effect on the sedimentary reservoirs and hydrocarbon accumulation.

Abstract Dietary methionine interventions are beneficial to apoptosis-inducing chemotherapy and radiotherapy for cancer, while their effects on ferroptosis-targeting therapy and immunotherapy are unknown. Here we show the length of time methionine deprivation affects tumoral ferroptosis differently. Prolonged methionine deprivation prevents glutathione (GSH) depletion from exceeding the death threshold by blocking cation transport regulator homolog 1 (CHAC1) protein synthesis. Whereas, short-term methionine starvation accelerates ferroptosis by stimulating CHAC1 transcription. In vivo, dietary methionine with intermittent but not sustained deprivation augments tumoral ferroptosis. Intermittent methionine deprivation also sensitizes tumor cells against CD8+ T cell-mediated cytotoxicity and synergize checkpoint blockade therapy by CHAC1 upregulation. Clinically, tumor CHAC1 correlates with clinical benefits and improved survival in cancer patients treated with checkpoint blockades. Lastly, the triple combination of methionine intermittent deprivation, system xc - inhibitor and PD-1 blockade shows superior antitumor efficacy. Thus, intermittent methionine deprivation is a promising regimen to target ferroptosis and augment cancer immunotherapy.

To carry out the system design and technology development for emergency communications, and greatly improve our ability of risk prevention and emergency disposal, the research on multi-unmanned aerial vehicle (multi-UAV) cooperative channel model for emergency communications was carried out.First, the channel dataset of multi-UAV cooperative emergency communications in two typical emergency environments, i.e., the urban earthquake and suburban blizzard, was established.The channel parameters and statistical properties of multi-UAV cooperative emergency communications were analyzed.Second, a more general geometry-based stochastic channel model (GBSM) was proposed for multi-UAV cooperative emergency communications.The channel impulse response (CIR) and the cooperative non-station arity of multi-UAV cooperative channels in the space and time domains in multi-UAV cooperative emergency communications were calculated and captured.Finally, the channel characteristics of multi-UAV cooperative emergency communication in urban earthquake and suburban blizzard scenarios were analyzed, which could support the practical implementation of multi-UAV cooperative emergency communications.Meanwhile, the statistical characteristic of the proposed model can fit well with that of ray-tracing-based channel data, verifying the utility of the proposed model.

Abstract Cardiac myxoma (CM) is the most common benign cardiac tumor, and most CMs are left atrial myxomas (LAMs). Six variations of KIF1C, c.899 A > T, c.772 T > G, c.352 A > T, c.2895 C > T, c.3049 G > A, and c.*442_*443dup in left atrial myxoma tissues are identified by whole-exome sequencing (WES) and Sanger sequencing. RNA-seq and function experiments show the reduction of the expression of KIF1C and PRKAR1A caused by rare variations of KIF1C. KIF1C is observed to be located in the nucleus, bind to the promoter region of PRKAR1A, and regulate its transcription. Reduction of KIF1C decreases PRKAR1A expression and activates the PKA, which causes an increase in ERK1/2 phosphorylation and SRC-mediated STAT3 activation, a reduction of CDH1, TP53, CDKN1A, and BAX, and eventually promotes tumor formation both in vitro and in vivo. The results suggest that inhibition of KIF1C promotes the pathogenesis of LAM through positive feedback formed by the crosstalk between KIF1C and PRKAR1A.

Hydrogel products for chronic diabetic wounds, a serious and prevalent complication of diabetes, show limited effects on disability and remain nonspecific. Thus, improvements in the usage of pharmaceutical molecule in the hydrogels are highly desirable to increase the therapeutic effect of hydrogels. In this study, thioctic acid (a common medicine molecule in diabetes treatment) is used for preparing regenerative antibacterial hydrogels (RAH) which contains in situ synthesized silver nanoparticles (AgNPs). The RAH shows regenerative, self-healing and injectable ability, because of the reversible hydrogen and coordination bonds. With good regenerative capacity, RAH can be stored as powder to avoid the water loss and facilitate storage availability. Owing to the antioxidant properties of thioctic acid, the RAH can decrease the oxidative damage and retain cell proliferation efficiency. Due to the in situ synthesized AgNPs, the RAH also exhibits extraordinary antimicrobial capacities against MDR bacteria. All of these superiorities enable RAH to be a promising therapy for chronic diabetic wounds.

Along with urbanization and industrialization, carbon emissions have been increasing significantly, resulting in global warming. Green space has been widely accepted as a natural element in cities to directly increase carbon sinks and indirectly reduce carbon emissions. The quantification of carbon benefits generated by green space is an important topic. This paper aims to provide a comprehensive review of the methods for measuring carbon sinks of green spaces. The results indicate that existing assessment methods can accurately estimate the carbon sinks in green spaces at large scales. However, existing methods are not fully applicable to studies of urban green spaces, due to the low precision of research results. The assimilation method is the most suitable method to study the carbon sequestration efficiency of plants and can project the carbon sinks of urban green spaces at large scales through macroscopic means. Even though, the results of assimilation experiments are unstable under different weather conditions. To address existing research challenges, this paper proposes a photosynthetic rate estimation method based on the light-response curve which is an efficient method to describe the relationship between light intensity and net photosynthetic rate in studying plant physiological characteristics. The newly proposed method, through integrating net photosynthesis-light response curves and urban light intensity associated with meteorological data, has advantages of short measurement time and ensuring standardized experimental environment for result comparability. Overall, this study is important to combine meteorology and plant physiology to propose a photosynthetic rate estimation method for optimizing carbon sink measurement in urban green spaces. The method is more convenient for application for its simple experimental process and result comparability. In practice, this study provides guidance for low-carbon urban green space planning and design, and helps to promote energy conservation and emission reduction through nature-based solutions.

BackgroundEmpirical evidence has shown that light therapy (LT) can reduce depression symptoms by stimulating circadian rhythms. However, there is skepticism and inconclusive results, along with confusion regarding dosing. The purpose of this study is to quantify light as a stimulus for the circadian system and create a dose-response relationship that can help reduce maladies among adolescents and young adults (AYAs). This will provide a reference for light exposure and neural response, which are crucial in the neuropsychological mechanism of light intervention. The study also aims to provide guidance for clinical application.MethodsThe latest quantitative model of CLA (circadian light) and CSt,f (circadian stimulus) was adopted to quantify light dose for circadian phototransduction in youth depression-related light therapy. Articles published up to 2023 through Web of Science, Cochrane Library, Medline (OVID), CINAHL, APA PsycINFO, Embase, and Scholars were retrieved. A meta-analysis of 31 articles (1,031 subjects) was performed using Stata17.0, CMA3.0 (comprehensive meta-analysis version 3.0) software, and Python 3.9 platform for light therapy efficacy comparison and dose-response quantification.ResultsUnder various circadian stimulus conditions (0.1 < CSt,f < 0.7) of light therapy (LT), malady reductions among AYAs were observed (pooled SMD = −1.59, 95%CI = −1.86 to −1.32; z = −11.654, p = 0.000; I2 = 92.8%), with temporal pattern (p = 0.044) and co-medication (p = 0.000) suggested as main heterogeneity sources. For the efficacy advantage of LT with a higher circadian stimulus that is assumed to be influenced by visualization, co-medication, disease severity, and time pattern, sets of meta-analysis among random-controlled trials (RCTs) found evidence for significant efficacy of circadian-active bright light therapy (BLT) over circadian-inactive dim red light (SMD = −0.65, 95% CI = −0.96 to −0.34; z = −4.101, p = 0.000; I2 = 84.9%) or circadian-active dimmer white light (SMD = −0.37, 95% CI = −0.68 to −0.06; z = −2.318, p = 0.02; I2 = 33.8%), whereas green-blue, circadian-active BLT showed no significant superiority over circadian-inactive red/amber light controls (SMD = −0.21, 95% CI = −0.45 to 0.04; z = −2.318, p = 0.099; I2 = 0%). Overall, circadian-active BLT showed a greater likelihood of clinical response than dim light controls, with increased superiority observed with co-medication. For pre-to-post-treatment amelioration and corresponding dose-response relationship, cumulative duration was found more influential than other categorical (co-medication, severity, study design) or continuous (CSt,f) variables. Dose-response fitting indicated that the therapeutic effect would reach saturation among co-medicated patients at 32–42 days (900–1,000 min) and 58–59 days (1,100–1,500 min) among non-medicated AYAs. When exerting high circadian stimulus of light therapy (0.6 < CSt,f < 0.7), there was a significantly greater effect size in 1,000–1,500 min of accumulative duration than 1,500 min of duration, indicating a threshold for practical guidance.LimitationsThe results have been based on limited samples and influenced by a small sample effect. The placebo effect could not be ignored.ConclusionsAlthough the superiority of LT with higher circadian stimulus over dimmer light controls remains unproven, greater response potentials of circadian-active BLT have been noticed among AYAs, taking co-medication, disease severity, time pattern, and visual characteristics into consideration. The dose-response relationship with quantified circadian stimulus and temporal pattern had been elaborated under various conditions to support clinical depression treatment and LT device application in the post-pandemic era.

Genike, the imatinib (IM)-alpha form is widely used in the treatment of gastrointestinal stromal tumor (GIST) patients in China. We wanted to investigate whether there are differences in IM plasma concentrations, adverse events, health-related quality of life (QOL) and outcomes between patients treated with Genike and Glivec. Thirty included GIST patients receiving IM treatment were matched to either Genike or Glivec according to gastrectomy, body weight, body surface area and sex. There was no statistically significant difference in IM trough plasma levels between the two groups. There were no significant differences in very common adverse events of IM between the Genike and Glivec groups. IM was well tolerated, although it was associated with a significant change in cognitive function (P < 0.001), fatigue (P = 0.015), pain (P = 0.015), nausea/vomiting (P = 0.029), insomnia (P = 0.019), diarrhea (P = 0.003) and financial difficulties (P < 0.001). Physical functioning, financial burden and insomnia were significantly different between the two groups (P = 0.026). Until Aug. 2022, there was no significant difference in time to imatinib treatment failure (TTF) between the two groups. In conclusion, there was no difference in IM plasma concentration and adverse events between Genike and Glivec. Both Genike and Glivec could partially decrease the QOL of GIST patients. Physical functioning was worse in Genike group than in Glivec group, while the economic burden and symptoms of insomnia in Glivec patients were worse. There was no significant difference in TTF between the two groups.

Carbon trading mechanisms and the development of integrated energy systems are important ways to realize the “carbon peaking and carbon neutrality” goal, and the problem of benefit distribution is of paramount importance to achieving the goal. The article innovatively takes the supply side of the provincial integrated energy system as the entry point, considers the economic value of carbon, and focuses on the rational allocation of each subject obtained by comparing different methods. The paper mainly uses the Shapley value of the cooperative game and the kernel method to establish the initial allocation to the main actors, and subsequently, it considers the introduction of the risk level, resource input, environmental pollution, technological innovation, and profit of the main actors to modify the result of the benefit allocation. This paper takes the power generation data of the Xinjiang region as an example, and the results show that 1) thermal power still has the most weight among all power generation modes and obtains 522.83, 503.48, and 406.30 billion yuan under the initial, nucleolus, and modified allocation methods, respectively, and receives the most revenue. 2) Considering that the multi-factor allocation method pays more attention to the allocation of fairness, compared with the initial allocation, thermal power gains decreased by 22.29%, while wind and solar power gains were improved by 17.87% and 60.90%, respectively. The result could be a stronger push for the development and transformation of power energy. 3) The feasibility of this game as a convex game should be verified, the improvement method should be demonstrated through examples, and the results should be compared with reality. Finally, policy recommendations are proposed, which will be useful for realizing the “carbon peaking and carbon neutrality” goal and the synergistic development of integrated energy systems.

ABSTRACTObjective This study aims to evaluate the consistency of heterogeneity degree of erythrocyte volume parameters between the blood automated analyzer Sysmex-XN9000 and the advanced red blood cell software CellaVisionDI-60.Method 500 blood samples of volunteers were analyzed by Sysmex-XN9000 and CellaVision-DI60. The sensitivity, specificity, positive predictive value, negative predictive value, false positive rate, and false negative rate were evaluated. The consistency of all parameters was tested.Result Taking the standard RBC group as the control group, the RBC parameters of the macrocytic and the microcytic group were compared. There was a statistical difference between the groups. ROC curve analysis showed that the best cutoff value of microcytic and of macrocytic affecting MCV were 4.1% and 5.7%, respectively. The best cutoff value of anisocytosis was 15.0%. The correlation coefficient between anisocytosis and red blood cell distribution width (RDW-CV) was 0.756. The sensitivity, specificity, positive predictive value and coincidence rate of anisocytosis were high. The false negative rate was 10.0%, and the false positive rate was 7.4%.Conclusion All parameters of the degree of heterogeneity have good accuracy and consistency in the two instruments. Anisocytosis is with higher coincidence rate and positive predictive value. MIC and MAC have a good prediction on the increase or decrease of MCV. Although advanced RBC software's false negative and false positive rates are high, the red blood cell image system is more intuitive and time-saving in observing cells. Consequently, CellaVision-DI60 is suggested to combine with XN-9000 for judging the anisocytosis in daily work comprehensively.

Falling film evaporation technology is widely used in the treatment of salt-containing wastewater in coal chemical industry. However, there is still a lack of research on the inlet method of vertical falling film evaporation tubes. In this paper, the heat and mass transfer processes of saline wastewater under vertical and tangential inlets were investigated using numerical simulations. On this basis, the differences in flow and heat transfer processes between saline wastewater and pure water under tangential inlet were investigated. The results showed that the flow velocity of saline wastewater with a falling film evaporation tube in a tangential inlet mode was larger. Meanwhile, the turbulence in this way was more intense and the fluid temperature in the vertical tube was higher. Saline wastewater has higher temperature and smaller liquid volume fraction than pure water liquid membrane in the range of 193–1,000 mm from the inlet. The use of tangential inlet method to treat salt-containing wastewater has higher evaporation efficiency and is a very effective way to guide the improvement of heat transfer efficiency. HIGHLIGHTS Study on the heat transfer of a falling film evaporator tube with different inlets.; The liquid film velocity at the tangential inlet is faster than that at the vertical inlet.; Salty wastewater is thinner than pure water, which is more conducive to evaporation.;

Abstract Background In current percutaneous coronary intervention (PCI) practice, the balloon used in the procedure should be deflated a short time after balloon dilation to avoid having prolonged balloon dilation in the coronary artery, which would block the coronary artery and cause myocardial ischemia. It is very rare for a dilated stent balloon to fail to deflate. Case summary A 44-year-old male was admitted to the hospital due to chest pain after exercise. Coronary angiography showed severe proximal stenosis of the right coronary artery (RCA) consistent with a diagnosis of coronary artery disease, and coronary stent implantation was required. After the last stent balloon was dilated, the stent balloon could not be deflated and continued to expand, resulting in blockage of the RCA blood flow. The patient then suffered decreased blood pressure and heart rate. Finally, the stent balloon in its expanded state was forcefully and directly withdrawn from the RCA and successfully removed from the body. Conclusion Deflation failure of a stent balloon is an extremely rare complication of PCI. Various treatment strategies can be considered based on hemodynamic status. In the case described herein, the balloon was pulled out of the RCA directly to restore blood flow, which kept the patient safe.

Abstract Background Both the crystalline and soluble forms of cholesterol increase macrophage secretion of interleukin 1β (IL-1β), aggravating the inflammatory response in atherosclerosis (AS). However, the link between cholesterol and regulatory T cells (Tregs) remains unclear. This study aimed to investigate the effect of cholesterol treatment on Tregs. Methods Differentiation of induced Tregs (iTregs) was analyzed using flow cytometry. The expression of hypoxia-inducible factor-1a (HIF-1a) and its target genes was measured by western blotting and/or RT-qPCR. Two reporter jurkat cell lines were constructed by lentiviral transfection. Mitochondrial function and the structure of natural Tregs (nTregs) were determined by tetramethylrhodamine (TMRM) and mitoSOX staining, Seahorse assay, and electron microscopy. The immunoregulatory function of nTregs was determined by nTreg-macrophage co-culture assay and ELISA. Results Cholesterol treatment suppressed iTreg differentiation and impaired nTreg function. Mechanistically, cholesterol induced the production of mitochondrial reactive oxygen species (mtROS) in naïve T cells, inhibiting the degradation of HIF-1α and unleashing its inhibitory effects on iTreg differentiation. Furthermore, cholesterol-induced mitochondrial oxidative damage impaired the immunosuppressive function of nTregs. Mixed lymphocyte reaction and nTreg-macrophage co-culture assays revealed that cholesterol treatment compromised the ability of nTregs to inhibit pro-inflammatory conventional T cell proliferation and promote the anti-inflammatory functions of macrophages. Finally, mitoTEMPO (MT), a specific mtROS scavenger, restored iTreg differentiation and protected nTreg from further deterioration. Conclusion Our findings suggest that cholesterol may aggravate inflammation within AS plaques by acting on both iTregs and nTregs, and that MT may be a promising anti-atherogenic drug.

Investigation of unloading rock failure under different σ2 facilitates the control mechanism of excavation surrounding rock. This study focused on single-sided unloading tests of granite specimens under true triaxial conditions. The strength and failure characteristics were studied with micro-camera and acoustic emission (AE) monitoring. Furthermore, the choice of test path and the effect of σ2 on fracture of unloading rock were discussed. Results show that the increased σ2 can strengthen the stability of single-sided unloading rock. After unloading, the rock's free surface underwent five phases, namely, inoculation, particle ejection, buckling rupture, stable failure, and unstable rockburst phases. Moreover, at σ2≤30 MPa, the b value shows the following variation tendency: rising, dropping, significant fluctuation, and dropping, with dispersed damages signal. At σ2≥40 MPa, the tendency shows: a rise, a decrease, a slight fluctuation, and final drop, with concentrated damages signal. After unloading, AE energy is mainly concentrated in the micro-energy range. With the increased σ2, the micro-energy ratio rises. In contrast, low, medium and large energy ratios drop gradually. The increased tensile fractures and decreased shear fractures indicate that the failure mode of the unloading rock gradually changes from tensile-shear mode to tensile-split one. The fractional dimension of the rock fragments first increases and then decreases with an inflection point at 20 MPa. The distribution of SIF on the planes changes as σ2 increases, resulting in strengthening and then weakening of the rock bearing capacity.

Human interventions mobilize massive nitrogen (N) emissions to freshwater and result in serious eutrophication impacts. Life cycle impact assessment (LCIA) provides a reliable quantitative tool to address the challenges of potential ecological impact induced by increasing nutrient inputs. However, characterization procedures that relate N emissions to ecological damage in freshwater ecosystems in LCIA methodology are still lacking. This study aims to propose a spatially explicit characterization model (1 km × 1 km) for N-induced freshwater eutrophication. A complete cause-effect chains linking the N emission with species loss endpoint impact was constructed, in which the site-specific fate factor modelling contained transfer and removal processes in terrestrial and freshwater compartments, and the mechanistic modelling of ecosystem exposure and damage effect were quantified with species loss. The eutrophication characterization was conducted with a case study in Guangzhou, China, and 1 km × 1 km spatial differentiation of eutrophication susceptibility was intuitively demonstrated, with higher values in the Pearl River Estuary area. Method comparisons and further improvements were discussed in support of model generalization and further application.

Given the problem that the existing source code loophole detection methods did not explicitly maintain the semantic information related to the loophole in the source code, which led to the difficulty of feature extraction of loo-phole statements and the high false positive rate of loophole detection, a source code loophole detection method based on feature dependency graph was proposed.First, extracted the candidate loophole statements in the function slice, and gen-erated the feature dependency graph by analyzing the control dependency chain and data dependency chain of the candi-date loophole statements.Secondly, the word vector model was used to generate the initial node representation vector of the feature dependency graph.Finally, a loophole detection neural network oriented to feature dependence graph was constructed, in which the graph learning network learned the heterogeneous neighbor node information of the feature de-pendency graph and the detection network extracted global features and performed loophole detection.The experimental results show that the recall rate and F1 score of the proposed method are improved by 1.50%～22.32% and 1.86%～16.69% respectively, which is superior to the existing method.

Stochastic parallel gradient descent (SPGD) is the most frequently used optimization algorithm for correcting wavefront distortion in the wavefront sensorless adaptive optics(WFS-Less AO)system. However, the convergence speed of the SPGD algorithm becomes slow rapidly as increasing of distortion, and the probability of falling into local optimum is rising owing to the fixed gain coefficient. It cannot meet the requirement of real-time wavefront distortion correction. Therefore, a novel algorithm is proposed in this paper, called as adaptive gain stochastic parallel gradient descent (AGSPGD) based on the AMSGrad optimizer in the deep learning, to improve the convergence speed of the algorithm and to reduce the probability of falling into local optimum. The AGSPGD algorithm adopts the first-order moment and the second-order moment of the performance index, which are combined to dynamically adjust the gain. The numerical simulations are completed in this article. The results of ${\bm{D}}/\ {{\bm{r}}}_0 = \ 2.5$ conditions demonstrate that the AGSPGD can reduce the number of iterations by 25%, and the probability of the algorithm falling into local optimum is reduced from 16% to 4%. In addition, the AGSPGD still outperforms the SPGD as ${\bm{D}}/{{\bm{r}}}_0$ increasing.

Abstract While the terrestrial base stations (TBSs) in the fifth‐generation (5G) network provide high throughput for the conventional terrestrial users (TUs), it is still challenging for the network to support massive TUs and unmanned aerial vehicles (UAVs) simultaneously due to the complicated air–ground channel and severe interference. In this paper, the deployment of a high‐altitude platform (HAP) as a supplement for the terrestrial networks, in which the HAP and TBSs serve TUs and UAVs simultaneously in a joint manner, is studied. The novel network has two challenges. First, the deployment of the HAP, which is a new degree of freedom, should be optimized considering the terrestrial network. Second, the channel of the joint HAP and TBS network that serves multiple TUs and UAVs concurrently is complicated, and the resource allocation of the network should be designed. To tackle the above two challenges, a joint resource allocation and HAP deployment problem are formulated, and a gradient‐and‐matching‐based algorithm is proposed to solve it efficiently. Simulation results show that the HAP and the proposed algorithm enhance the sum‐rate of the network by over 30%, and the average data rate of both the TUs and the UAVs can be effectively improved.