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Abstract The structural basis for the allosteric interactions within G protein-coupled receptors (GPCRs) heterodimers remains largely unknown. The metabotropic glutamate (mGlu) receptors are complex dimeric GPCRs important for the fine tuning of many synapses. Heterodimeric mGlu receptors with specific allosteric properties have been identified in the brain. Here we report four cryo-electron microscopy structures of mGlu2-4 heterodimer in different states: an inactive state bound to antagonists, two intermediate states bound to either mGlu2 or mGlu4 agonist only and an active state bound to both glutamate and a mGlu4 positive allosteric modulator (PAM) in complex with Gi protein. In addition to revealing a unique PAM binding pocket among mGlu receptors, our data bring important information for the asymmetric activation of mGlu heterodimers. First, we show that agonist binding to a single subunit in the extracellular domain is not sufficient to stabilize an active dimer conformation. Single-molecule FRET data show that the monoliganded mGlu2-4 can be found in both intermediate states and an active one. Second, we provide a detailed view of the asymmetric interface in seven-transmembrane (7TM) domains and identified key residues within the mGlu2 7TM that limits its activation leaving mGlu4 as the only subunit activating G proteins.

Abstract Purpose The characteristic of RENT3B in cancer remains ambiguous. We aimed to study the relationship between RENT3B and immune infiltration in liver hepatocellular carcinoma (LIHC) and lung squamous cell carcinoma (LUSC). Patients and methods We investigated the expression levels of RENT3B using ONCOMINE and TIMER databases, and assessed the interrelationship between RENT3B expression and survival using PrognoScan, GEPIA, and Kaplan–Meier plotter. Additionally, we examined the association between RENT3B and immune cells in the tumor microenvironment (TME), as well as markers of immune cells, using TIMER. Subsequently, we performed prognostic analysis based on the expression level of RENT3B within specific immune cell subgroups. Furthermore, we evaluated the promoter methylation profile of RENT3B between tumor and normal tissues in LIHC and LUSC using the DNMIVD database. Results RENT3B exhibited increased levels in both in LIHC and LUSC. High RENT3B expression was associated with unfavorable prognosis in LIHC, whereas it indicated a beneficial prognosis in LUSC. In LIHC, the expression of RENT3B positively correlated with immune infiltration levels of B cells, CD4 + T cells, CD8 + T cells, neutrophils, macrophages, and dendritic cells. However, in LUSC, the expression of RENT3B showed a negative correlation with immune infiltration levels of B cells, CD8 + T cells, neutrophils, macrophages, and dendritic cells. RENT3B exhibited positive correlations with 42 immune markers in LIHC, while it displayed negative associations with 10 immune markers in LUSC. Despite variations in immune cell enrichment and reduction subgroups, high RENT3B expression consistently indicated poor prognosis in LIHC, whereas it remained favorable in LUSC. Additionally, there were no significant differences observed in RENT3B promoter methylation between tumor and normal tissues in both LIHC and LUSC. Conclusion RENT3B can affect the overall tumor prognosis and is associated with immune infiltration, especially in LIHC and LUSC. Consequently, RENT3B can become a prognostic biomarker for LIHC and LUSC.

Toxoplasma gondii, a neurotropic protozoan parasite, affects the central nervous system and causes various neurological disorders. Previous studies have demonstrated that Arctigenin (AG) exhibits anti-T. gondii activity and reduces depression-like behaviors induced by T. gondii infection. This study aimed to enhance AG's brain-targeting and therapeutic efficacy by developing lactoferrin-modified nanoemulsions loaded with AG (Lf-AG-NEs). Lf-modified nanoemulsions were prepared and assessed using in vivo and in vitro infection models with the T. gondii RH strain, and a co-culture system of BV2 microglia and primary neuron cells. The effects of Lf-AG-NEs on T. gondii-induced neuronal injury were examined, and potential molecular mechanisms were elucidated through real-time quantitative PCR, western blotting, immunofluorescence, flow cytometry, immunohistochemistry, and Nissl staining. In vitro assessments showed significant increases in cellular uptake and blood-brain barrier penetration by Lf-AG-NEs. These nanoemulsions notably inhibited T. gondii proliferation in brain tissue and BV2 cells, surpassing the effects of free AG or AG-NEs alone. Additionally, Lf-AG-NEs substantially alleviated neuropathological changes and reduced microglial activation and neuroinflammation by downregulating the TLR4/NF-κB and TNFR1/NF-κB signaling pathways. Co-culturing BV2 cells with primary cortical neurons indicated that Lf-AG-NEs, similarly to CLI-095 and R7050, attenuated T. gondii-induced microglial activation and subsequent neuronal injury. In conclusion, the successfully prepared Lf-AG-NEs not only enhanced the anti-T. gondii effect but also strengthened the protective impact against neuronal injury induced by T. gondii, through the modulation of microglial signaling pathways.

PurposeRefractive errors, particularly myopia, constitute a significant global public health concern, contributing to morbidity and disability. A more comprehensive understanding of the determinants of refractive errors and the differences between urban and rural areas is essential to develop effective preventive measures for youth. This study aimed to compare the prevalence and risk factors of refractive errors among youth in urban and rural Tianjin, China.MethodsThis school-based cross-sectional study was conducted in 2022. Elementary, middle, and high school students aged 6–18 years from both urban and rural areas of Tianjin were included. All participants underwent visual acuity testing and refractive measurement and completed comprehensive questionnaires.ResultsA total of 346,146 participants (176,628 boys) were included in this investigation (50.36% for urban and 49.64% for rural, respectively). Myopia, hyperopia, astigmatism, and anisometropia were present in 56.8, 9.7, 56.64, and 21.3% of urban students, respectively. Similarly, rural students had a prevalence of 57.6, 11.5, 56.48, and 22.0% for the respective conditions. Compared to rural students, after adjusting for age, sex, and other significant variables, urban students were 1.05 times more likely to have myopia (95% CI: 1.03–1.07, p

Abstract The use of trastuzumab emtansine (T‐DM1) has revealed significant efficacy in HER2‐positive metastatic breast cancer (MBC). However, optimal therapeutic strategies following T‐DM1 failure remain a subject of debate in clinical practice. In this multicenter, retrospective, real‐world study, we sought to examine the effectiveness and safety of tyrosine kinase inhibitors (TKIs) as a therapeutic strategy in HER2‐positive MBC who developed T‐DM1 resistance. Between September 2018 and December 2022, 66 patients were enrolled. The median progression‐free survival of TKIs‐based therapy was 10.1 months (95% CI, 4.7–15.6). Objective response rate and clinical benefit rate were 18.2 and 66.7%, respectively. TKIs‐based therapy demonstrated better effectiveness in patients who had previously derived benefit from T‐DM1 and featured acquired resistance to trastuzumab. The most common adverse events were diarrhea (36, 54.5%), hand‐foot syndrome (31, 47.0%), and leucopenia (30, 45.5%). In conclusion, TKIs‐based therapy showed promising effectiveness and safety in HER2‐positive MBC patients after T‐DM1 failure.

Background: Human epidermal growth factor receptor 2 (HER2)-targeted agents have significantly improved the outcomes of patients with HER2-positive breast cancer; however, a large proportion of patients still develop resistance to trastuzumab. In this study, we investigated the efficacy and safety of inetetamab, another anti-HER2 antibody, combined with pyrotinib and oral vinorelbine in patients with HER2-positive advanced breast cancer so as to provide new ideas for the treatment. Methods: In this prospective, single-arm, phase 2 trial, patients with HER2-positive advanced breast cancer with disease progression after trastuzumab were recruited. Patients received a combination of inetetamab (loading dose of 8 mg/kg and subsequent doses of 6 mg/kg intravenously once every 3 weeks), pyrotinib (400 mg orally once daily), and vinorelbine (60 mg/m2 orally once weekly) until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), overall survival (OS), disease control rate (DCR), and safety. Results: Between February 13, 2022 and December 25, 2022, 30 patients were screened and enrolled in this study. The median age of the patients at enrollment was 54 years, 12 patients (40.0 %) had hormone-receptor-positive disease and 23 patients (76.7 %) had visceral metastasis. The median PFS was 8.63 months (95 % confidence interval [CI] 4.15–13.12 months). The median OS was not reached. The ORR was 53.3 % (16/30) and the DCR was 96.7 % (29/30). The most common Grade III/IV adverse events were leukopenia (n = 5, 16.7 %), neutropenia (n = 4, 13.3 %), and diarrhea (n = 3, 10 %). No treatment-related serious adverse events or deaths occurred. Conclusions: The combination regimen of inetetamab, pyrotinib, and oral vinorelbine showed encouraging efficacy and favorable safety in patients with HER2-positive advanced breast cancer and could be considered as an alternative treatment option for the patients. Trial registration: No.NCT05823623; https://www.clinicaltrials.gov/.

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The contents of selenomethionine (SeMet) and selenomethylcysteine (SeMC) in Selenium-Enriched black garlic extract (Se-BGE), a popular functional food in Asian countries, were 2.9 ± 0.6 μg/g and 12.2 ± 2.3 μg/g by PITC pre-column derivatization UPLC-MS method. Improved histological injury, significant extension of the median survival time, and attenuated serum levels of alanine aminotransferase, total bilirubin and SOD activity were observed in the acute liver failure (ALF) rats treated with Se-BGE (1.0 g/mL). 1HNMR-based metabonomics revealed that serum levels of lactate, pyruvate, betaine, choline, taurine, and glycine were restored, and 16S rDNA sequencing analysis showed that the composition and number of the intestinal flora were regressed to healthy levels in ALF rats treated by Se-BGE. Serum choline and betaine showed significant correlations with g_Lactobacillus and g_Escherichia. Our findings demonstrated that Se-BGE protects against LPS/D-GalN-induced ALF in rats, possibly due to antioxidation, metabolism, and intestinal flora regulations of Se-BGE.

IntroductionClonal fragmentation helps to assess clonal plants' growth resilience to human and environmental disturbance. Although clonal integration in epiphytes in tropical rubber plantations is important to understand their role in enhancing biodiversity and ecosystem services, research on this subject is limited. These plantations are typically monospecific economic forests that face increased anthropogenic disturbances.MethodsIn this study, we selected the clonal fern Pyrrosia nuda to study its survival status, biomass, maximum quantum yield of photosystem II (Fv/Fm), and frond length in response to the level of clonal fragmentation in a tropical rubber plantation.Results and discussionThe results showed that (1) clonal fragmentation significantly negatively affected the survival rate, biomass, and frond length of clonal plants, but with minimal effects on Fv/Fm at different growth stages; (2) the performance of a ramet (e.g., biomass or frond length) increased with ramet developmental ages and decreased with the number of ramets in a clonal fragment. The age-dependent impacts of clonal fragmentation provide insights into the biodiversity conservation of epiphytes and forest management in man-made plantations. Therefore, to better conserve the biodiversity in tropical forests, especially in environment-friendly rubber plantations, there is a need to reduce anthropogenic disturbances and alleviate the level of fragmentation.

Epigenetic therapies that cause genome-wide epigenetic alterations, could trigger local interplay between different histone marks, leading to a switch of transcriptional outcome and therapeutic responses of epigenetic treatment. However, in human cancers with diverse oncogenic activation, how oncogenic pathways cooperate with epigenetic modifiers to regulate the histone mark interplay is poorly understood. We herein discover that the hedgehog (Hh) pathway reprograms the histone methylation landscape in breast cancer, especially in triple-negative breast cancer (TNBC). This facilitates the histone acetylation caused by histone deacetylase (HDAC) inhibitors and gives rise to new therapeutic vulnerability of combination therapies. Specifically, overexpression of zinc finger protein of the cerebellum 1 (ZIC1) in breast cancer promotes Hh activation, facilitating the switch of H3K27 methylation (H3K27me) to acetylation (H3K27ac). The mutually exclusive relationship of H3K27me and H3K27ac allows their functional interplay at oncogenic gene locus and switches therapeutic outcomes. Using multiple in vivo breast cancer models including patient-derived TNBC xenograft, we show that Hh signaling-orchestrated H3K27me and H3K27ac interplay tailors combination epigenetic drugs in treating breast cancer. Together, this study reveals the new role of Hh signaling-regulated histone modifications interplay in responding to HDAC inhibitors and suggests new epigenetically-targeted therapeutic solutions for treating TNBC.

To analyze the potential mechanisms of growth differences in spotted seabass (Lateolabrax maculatus) fed a low-phosphorus diet, a total of 150 spotted seabass with an initial body weight of 4.49 ± 0.01 g were used (50 fish per tank) and fed a low-phosphorus diet for eight weeks. At the end of the experiment, five of the heaviest and five of the lightest fish were selected from each tank as fast-growing spotted seabass (FG) and slow-growing spotted seabass (SG), respectively, and their livers were analyzed by metabolomics and transcriptomics. The hepatic antioxidant capacity of the FG fed a low-phosphorus diet was significantly higher than that of the SG. A total of 431 differentially expressed genes (DEGs) were determined in the two groups, and most of the DEGs were involved in metabolism-related pathways such as steroid biosynthesis, glycolysis/gluconeogenesis, and protein digestion and absorption. Substance transport-related regulators and transporters were predominantly up-regulated. Furthermore, a large number of metabolites in the liver of FG were significantly up-regulated, especially amino acids, decanoyl-L-carnitine and dehydroepiandrosterone. The integration analysis of differential metabolites and genes further revealed that the interaction between protein digestion and absorption, as well as phenylalanine metabolism pathways were significantly increased in the liver of FG compared to those of the SG. In general, FG fed a low-phosphorus diet induced an enhancement in hepatic immune response, substance transport, and amino acid metabolism. This study provides new information on genetic mechanisms and regulatory pathways underlying differential growth rate and provides a basis for the foundation of efficient utilization of low-phosphorus diets and selective breeding programs for spotted seabass.

IntroductionCanopy species need to shift their ecological adaptation to improve light and water resources utilization, and the study of intraspecific variations in plant leaf functional traits based at individual scale is of great significance for evaluating plant adaptability to climate change.MethodsIn this study, we evaluate how leaf functional traits of giant trees relate to spatial niche specialization along a vertical gradient. We sampled the tropical flagship species of Parashorea chinensis around 60 meters tall and divided their crowns into three vertical layers. Fourteen key leaf functional traits including leaf morphology, photosynthetic, hydraulic and chemical physiology were measured at each canopy layer to investigate the intraspecific variation of leaf traits and the interrelationships between different functional traits. Additionally, due to the potential impact of different measurement methods (in-situ and ex-situ branch) on photosynthetic physiological parameters, we also compared the effects of these two gas exchange measurements.Results and discussionIn-situ measurements revealed that most leaf functional traits of individual-to-individual P. chinensis varied significantly at different canopy heights. Leaf hydraulic traits such as midday leaf water potential (MWP) and leaf osmotic potential (OP) were insignificantly correlated with leaf photosynthetic physiological traits such as maximal net assimilation rate per mass (Amass). In addition, great discrepancies were found between in-situ and ex-situ measurements of photosynthetic parameters. The ex-situ measurements caused a decrease by 53.63%, 27.86%, and 38.05% in Amass, and a decrease of 50.00%, 19.21%, and 27.90% in light saturation point compared to the in-situ measurements. These findings provided insights into our understanding of the response mechanisms of P. chinensis to micro-habitat in Xishuangbanna tropical seasonal rainforests and the fine scale adaption of different resultant of decoupled traits, which have implications for understanding ecological adaption strategies of P. chinensis under environmental changes.

ObjectiveThis study aimed to understand the health of workers exposed to occupational noise and explore the influencing factors related to workers' health, especially the impact of noise on workers' hearing. This work can provide a basis for formulating relevant measures for occupational noise prevention and control in the future.MethodsOn the basis of the key occupational disease monitoring project in Chongqing, China, in 2021, the data of 1125 workers exposed to occupational noise were analyzed. Data included demographic information, occupational history, clinical physical examination information, and noise detection information of the working environment. Chi-square test and multifactorial logistic regression were used for statistical analysis.ResultsThe prevalence rates of abnormal electrocardiogram (ECG), blood pressure (BP), and pure tone audiometry (PTA) were 21.9% (246/1125), 27.8% (313/1125), and 18.0% (202/1125), respectively. Male workers accounted for 78.8%. Compared with male workers, female workers had a lower prevalence of abnormal PTA (OR = 0.28, 95% CI = 0.16-0.50). Workers working in medium enterprises had a lower prevalence of abnormal BP than workers in micro enterprises (OR = 0.36, 95% CI = 0.19-0.66). The prevalence of abnormal BP and PTA of workers increased with age. After adjusting for age, sex, and body mass index, the prevalence of abnormal ECG of mining workers was higher than that of manufacturing workers (OR = 1.54, 95% CI = 1.07-2.24), and the prevalence of abnormal PTA had a rising trend with the increase in noise exposure value.ConclusionNoise-exposed workers have a high prevalence of abnormal ECG, BP, and PTA, and factors such as age, enterprise size, and workplace noise exposure are correlated with the aberrant health of workers. Governments, enterprises, and individuals need to attach great importance to the possible adverse effects of noise. They must also actively adopt various effective measures to protect the occupational safety and health of workers.

In this study, classic thin-layer drying models such as the Page model, Verma model, and Two-term model were used to fit the thin-layer drying data of feed. Based on this, a novel thin-layer drying model for pelleted feed (modified Verma model) was proposed. The results indicate that the new model is the optimal choice for describing the drying kinetics of pelleted feed for growing pig and calf. The drying rate of pelleted feed is linearly correlated with the feed moisture content. The effective water diffusion coefficient for pelleted feed of growing pig and calf ranges from 1.86 × 10−10 to 2.75 × 10−9 m2/s and 3.32 × 10−10 to 3.87 × 10−9 m2/s, respectively. The activation energy (Ea) for moisture diffusion in both types of feed is 26.42 kJ/mol and 25.86 kJ/mol, respectively. By establishing predictive models for model parameters based on air temperature and air velocity variables, the new model demonstrates extrapolation capability, wide applicability, and practical value. This work lays the foundation for developing a similarly characterized deep-bed cooling drying model for pelleted feed.

We study the CP-odd and CP-even observables of the B mesons decaying into a baryon and antibaryon. We estimate these observables through the P03 model and chiral selection rule. The decay branching ratio of B+→pΛ‾ is calculated to be (2.31±0.69)×10−7, which is consistent with the current experiments. The effects of the B−B‾ oscillations are considered, which largely suppress the direct CP asymmetries in the Bs0 decays. We suggest the experiments to visit Bs0→Λ(→pπ−)Λ‾(→p‾π+), where the time-averaged CP-odd observables are estimated to be large. The direct CP asymmetries of B+→pΛ‾ and B0→pp‾ are found to be (26.2±7.9)% and (−3.1±0.9)% for a positive strong phase and (−36.9±11.1)% and (4.2±1.3)% for a negative strong phase, respectively.

Abstract Background Although the use of regorafenib plus nivolumab demonstrates promising outcomes in patients with refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC), this effect has not been substantiated in other studies. Moreover, a comparison between the outcomes of regorafenib and programmed cell death protein 1 (PD‐1) antibody combination therapy and regorafenib monotherapy remains unexplored. In this study, we aimed to assess whether regorafenib and PD‐1 antibody combination therapy is superior to regorafenib monotherapy as a third‐line treatment for MSS mCRC. Methods Patients with MSS mCRC who received regorafenib and PD‐1 antibody or regorafenib monotherapy as third‐line treatment were eligible for inclusion. Results In total, 179 patients were enrolled, of which 84 were administered regorafenib combined with a PD‐1 antibody and 95 were administered regorafenib monotherapy. Patients administered regorafenib combined with a PD‐1 antibody had similar progression‐free survival (PFS) as those on regorafenib monotherapy (median PFS was 2.4 months and 1.9 months, respectively, p = 0.086). The administration of regorafenib combined with a PD‐1 antibody resulted in significantly longer PFS than that seen with regorafenib monotherapy in both male (5.2 months vs. 2.4 months, p = 0.001) and female (3.9 months vs. 1.8 months, p = 0.037) patients without liver metastasis. Female patients with liver metastasis who were administered regorafenib combined with a PD‐1 antibody had shorter PFS than those administered regorafenib monotherapy (1.8 months vs. 2.0 months, p = 0.030). Conclusion Liver metastasis and sex are predictors of survival benefit following the addition of a PD‐1 antibody to regorafenib in patients with MSS mCRC.

Abstract Background Pulmonary arterial hypertension is a common complication in patients with congenital heart disease. In the absence of early diagnosis and treatment, pediatric patients with PAH has a poor survival rate. Here, we explore serum biomarkers for distinguishing children with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) from CHD. Methods Samples were analyzed by nuclear magnetic resonance spectroscopy-based metabolomics and 22 metabolites were further quantified by ultra-high-performance liquid chromatography–tandem mass spectroscopy. Results Serum levels of betaine, choline, S-Adenosyl methionine (SAM), acetylcholine, xanthosine, guanosine, inosine and guanine were significantly altered between CHD and PAH-CHD. Logistic regression analysis showed that combination of serum SAM, guanine and N-terminal pro-brain natriuretic peptide (NT-proBNP), yielded the predictive accuracy of 157 cases was 92.70% with area under the curve of the receiver operating characteristic curve value of 0.9455. Conclusion We demonstrated that a panel of serum SAM, guanine and NT-proBNP is potential serum biomarkers for screening PAH-CHD from CHD.

In the finite control set model predictive control (FCS-MPC) strategy of the grid-tied inverter, the current ripple (CR) affects the selection of optimal voltage vectors, which leads to the increase of output current ripples. In order to solve this problem, this paper proposes a CR reduction method based on reference current compensation (RCC) for the FCS-MPC strategy of grid-tied inverters. Firstly, the influence of the CR on optimal voltage vector selection is analyzed. The conventional CR prediction method is improved, which uses inverter output voltage and grid voltage to calculate current ripples based on the space state equation. It makes up for the shortcomings that the conventional CR prediction method cannot predict in some switching states. The improved CR method is more suitable for the FCS-MPC strategy. In addition, the differences between the two cost functions are compared through visual analysis. It is found that the sensitivity of the square cost function to small errors is better than that of the absolute value function. Finally, the predicted CR is used to compensate the reference current. The compensated reference current is substituted into the square cost function to reduce the CR. The experimental results show that the proposed method reduces the CR by 47.3%. The total harmonic distortion (THD) of output current is reduced from 3.86% to 2.96%.

Abstract Background Nutritional status influences the growth and development of the eyes. However, there are few studies on the association between diet, especially whole grains (WG) consumption, and myopia. The study aimed to evaluate the association between WG intake and myopia prevalence among primary school-age children in China. Methods This cross-sectional epidemiological study conducted between November 2019 and December 2019 included 586 children, aged 6–12 years, attending primary school in Binhai district, Tianjin, China. Ophthalmologic examinations and optometric cycloplegic refraction measurements were conducted. Information was collected on known risks and protective factors for myopia and the consumption of WGs, vegetables, and fruits. This association between the probability of myopia and the proportion of WG consumption (WG proportion was calculated as the mean intake from WG sources divided by total grain intake), adjusted for protective and risk factors, was analysed using crude and multivariable logistic regression. Results Among the study participants, 226/586 (38.57%) children had myopia in at least one eye. WG intake was inversely correlated with the prevalence of myopia. Furthermore, in the multivariate analysis, WG intake of > 50% was identified as a protective factor against myopia after subsequent adjustment for children’s age, sex, parental myopia, near-work activity, screen time, reading and writing habits, visual fatigue, outdoor time, and classroom light environment (all P 50%) was an independent protective factor against myopia. Modifying the form of grains consumed (whole versus refined) could be one of the targets of future public health measures.

Objectives: To study the effect of TET on the reversal of drug resistance in the bone marrow microenvironment, and to further promote the research on drug reversal.Methods: We established a co-culture system of bone marrow mesenchymal stem cells (BM-MSC) and K562 cell lines, and compared the cell inhibition rate of K562 cells between the co-culture group and K562 singleculture group by daunorubicin (DNR) single-drug intervention with CCK-8 and also compared K562 proliferation in the co-culture group and K562 single-culture group after combined intervention with DNR and TET, then used Western blot and RT-qPCR to verify the expression of P-gp of K562 cells at protein and mRNA levels, confirmed the concentration of DNR in K562 of different experimental groups by HPLC-MS.Results: According to the results of CCK-8, after co-culture with bone marrow mesenchymal stem cells (BM-MSCs), the inhibition rate of DNR on K562 decreased significantly. When TET (1μmol/L) combined with daunorubicin (DNR) treated on the co-culture group, the inhibition rate increased significantly. Then, the results of RT-qPCR and western blot showed a remarkable difference of the expression of P-glycoprotein (P-gp). After co-culture with BM-MSCs, the protein expression of P-gp showed a significant upward trend. After adding TET intervention, the expression of P-gp decreased both in mRNA and protein levels. Also, the DNR concentration in K562 also performed the correspondent trend.Conclusion: The bone marrow microenvironment can promote the MDR of acute leukemia. TET can reverse the MDR mediated by the bone marrow microenvironment by inhibiting the expression of P-glycoprotein.

The Virtual Synchronous Generator (VSG) emulates the characteristics of a synchronous generator to provide inertia and damping for renewable energy systems. In the case of using the NPC three-level converter structure, traditional control methods require complex dual-loop control and internal PI parameter tuning. Furthermore, although fixed-parameter VSG control can provide inertia and damping when a significant power load is switched in an islanded microgrid, it cannot guarantee frequency regulation performance. To address these issues, this paper proposes an NPC three-level VSG parameter adaptive finite control set model predictive control strategy. This method eliminates the need for dual-loop control and PI parameter tuning. By incorporating angular velocity deviation and its rate of change into adaptive adjustment, a Tracking-Differentiator (TD) is designed to calculate the rate of change of angular velocity. This approach avoids frequent fluctuation of adaptive parameters during load power switching and improves the frequency stability of the microgrid. The effectiveness of the proposed strategy is validated through simulation and experimental verification.

In this paper, A high-order response surface method is proposed for finite element model updating of continuous beam bridges. Firstly, based on visual inspection and environmental vibration testing, the peak picking (PP) method and random subspace identification (SSI) method are used to identify the dynamic characteristic parameters of the structure. Then, the finite element model of the continuous beam bridge is updated based on the third-order response surface method. It can be concluded that the results of the updated finite element model are in good agreement with the test results, and the maximum error between the calculated and measured frequency is less than 3%, with MAC values greater than 85%. Moreover, the updated finite element model can reflect the current situation of real bridges and serve as the basis for bridge health monitoring, damage detection, and safety assessment.

As an essential reference to bridge dynamic characteristics, the identification of bridge frequencies has far-reaching consequences for the health monitoring and damage evaluation of bridges. This study proposes a uniform scheme to identify bridge frequencies with two different subspace-based methodologies, i.e., an improved Short-Time Stochastic Subspace Identification (ST-SSI) method and an improved Multivariable Output Error State Space (MOESP) method, by simply adjusting the signal inputs. One of the key features of the proposed scheme is the dimensionless description of the vehicle–bridge interaction system and the employment of the dimensionless response of a two-axle vehicle as the state input, which enhances the robustness of the vehicle properties and speed. Additionally, it establishes the equation of the vehicle biaxial response difference considering the time shift between the front and the rear wheels, theoretically eliminating the road roughness information in the state equation and output signal effectively. The numerical examples discuss the effects of vehicle speeds, road roughness conditions, and ongoing traffic on the bridge identification. According to the dimensionless speed parameter Sv1 of the vehicle, the ST-SSI (Sv1 < 0.1) or MOESP (Sv1 ≥ 0.1) algorithm is applied to extract the frequencies of a simply supported bridge from the dimensionless response of a two-axle vehicle on a single passage. In addition, the proposed methodology is applied to two types of long-span complex bridges. The results show that the proposed approaches exhibit good performance in identifying multi-order frequencies of the bridges, even considering high vehicle speeds, high levels of road surface roughness, and random traffic flows.

Traditional attention-based recommendation algorithms only use position embeddings to model user behavior sequences, however, ignore specific timestamp information, resulting in poor recommendation performance and overfitting of model training.The multi-task matrix factorization recommendation model based on time attention was proposed, which used the attention mechanism to extract the neighborhood information for the user and item embedding, and used the Ebbinghaus forgetting curve to describe the changing characteristics of user interests over time.The model training process introduced a reinforcement learning strategy of experience replay to simulate the human memory review process.Experimental results on real datasets show that the proposed model has better recommendation performance than existing recommendation models.

AIM: To investigate the influencing factors of disequilibrium refractive development in children aged 6-12 years old.METHODS: A total of 607 children with a mean age of 8.2±1.8 years old from two primary schools in Binhai New Area of Tianjin in December 2019 were selected by cluster sampling for optical biometry measurement(axial length and equivalent corneal power), cycloplegia refractive examination and questionnaire survey.RESULTS: The childrens'spherical equivalent was -0.11±1.63D, binocular spherical equivalent difference was -0.08±0.64D and absolute value of spherical equivalent difference was 0.41±0.49D. There were 56 children with anisometropia and 551 children without anisometropia. There was no difference in the absolute value of binocular corneal power difference between anisometropia and non-anisometropia group(0.30±0.34D vs 0.27±0.24D, P=0.430). But the absolute value of axial difference was significantly different(0.67±0.39mm vs 0.13±0.13mm, P=0.005). Multivariate linear regression analysis showed that weekly usage time of phones/computers, weekly close work hours, weekly visual fatigue times and habitual reading distance were the influencing factors of refractive imbalance development(the absolute value of binocular spherical equivalent difference). Habitual reading distance and handedness in writing are the influencing factors of the developmental bias of refractive imbalance(binocular spherical equivalent difference).CONCLUSION: Children aged 6-12 years old who spend more time on phones/computers, and have prolonged close work, more times of visual fatigue and close habitual reading distance may increase the degree of refractive imbalance. Children with right-handed handwriting and severe left or right head deviation have a deeper degree of myopia in the right eye than in the left eye.

In obesity, adipose tissue is chronically inflamed, leading to insulin resistance, and adipose tissue macrophages (ATMs) are a major source of cytokines that aggravate adipocyte dysfunction. Here, the authors show that selective deletion of the epidermal growth factor receptor in ATMs decreased obesity and development of insulin resistance.

Objective: The aim of this study was to compare the pharmacokinetics and steady-state serum concentrations of lenvatinib in adult and juvenile rats.Experimental study: An ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) method was developed to quantify lenvatinib in the serum and liver of rats. Six juvenile and six adult rats in each group were orally administered with a single dose of 7.0 mg/kg lenvatinib suspension for pharmacokinetics. Another 12 juvenile and adult rats were subjected to oral gavage with 7.0 mg/kg lenvatinib once daily for 5 days. Biofluild samples were pre-treated by protein precipitation and sorafenib was used as the internal standard for UPLC-MS analysis. The pharmacokinetic parameters were estimated by compartment and statistical model. The mRNA expression of CYP3A2 and SLC22A1 in liver of adult and juvenile rats was measured by real-time fluorescence quantitative PCR (RT-qPCR).Results: The UPLC-MS method met the requirements for quantitative analysis of lenvatinib in serum and liver. The pharmacokinetic results showed that the mean retention time (MRT(0-∞)) was 19.64 ± 7.64 h and 126.38 ± 130.18 h, with AUC(0-∞) values of 3.97 ± 0.73 μg‧mL-1 h and 5.95 ± 2.27 μg mL-1 h in adult and juvenile rats, respectively. When comparing adult rats (0.35 ± 0.15 μg/mL) to juvenile rats, no significant differences were observed in steady-state serum lenvatinib (0.32 ± 0.11 μg/mL), but a noteworthy decrease to one-third of steady-state liver lenvatinib was observed after multiple oral doses of lenvatinib in juvenile rats. Additional findings revealed that the mRNA expression of CYP3A2 and SLC22A1 was notably increased by 6.86 and 14.67 times, respectively, in juvenile rats compared to adult rats.Conclusion: Juvenile rats exhibit lower levels of lenvatinib in the liver’s steady-state, potentially due to the disparity in CYP3A2 mRNA expression. These results imply that the dosage of lenvatinib for pediatric patients may need to be augmented in order to attain the desired clinical outcome.

The application of high-strength and high-toughness titanium alloy in armour protection is increasing with its excellent properties. However, there is little research on titanium alloy in explosion protection, especially the dynamic response process under localised explosion load and finite element simulation of the explosion resistance process of titanium alloy sheet. In this paper, the deformation and fracture failure features of the 1.6 mm thick Ti6Al4V titanium alloy sheet during the blast loading process were studied by combining LS-DYNA finite element simulation and air explosion experiments. The error of the overpressure peak value of explosion shock wave between the value obtained by improved theoretical empirical formula calculation of cylindrical charge and the value obtained by numerical simulation is only 0.2%. By studying the influence of explosive shape and air domain mesh size on the overpressure value in the process of detonation wave propagation, the Structured Arbitrary Lagrangian-Eulerian (S-ALE) algorithm was selected for finite element simulation. When the air domain mesh size is 1 mm, the tensile failure criterion was introduced into the finite element simulation process. The results show that the numerical simulation results of the full-scale model and the test results were consistent. The destruction morphology of the target showed severe asymmetry. Under 50 g TNT blast load, the 1.6 mm thick Ti6Al4V titanium alloy target was damaged seriously, and the central area of the target was completely torn. The failure features were mainly petal-shaped warping tearing cracks and localised plastic deformation. The tensile stress is the main stress mode of the target failure. Therefore, dynamic tensile strength should be used as one of the selection criteria for explosion-resistant titanium alloy sheets. The target failure mode is dominated by adiabatic shear fracture.

Abstract Background We aim to investigate the prognostic value of weight loss during radiotherapy (RT) among patients with nasopharyngeal carcinoma (NPC). Methods A total of 1149 NPC patients who received radical RT were retrospectively analyzed. Patients’ weight were measured at initiation of RT (WPre-RT) and every week during RT (WRT1,2,3,4,5,6,7). Percentage of weight loss (PWL) at 1st, 2nd, 3rd, 4th, 5th, 6th, and 7th week of RT (RT-PWL1,2,3,4,5,6,7) were calculated using the following equation: (WPre-RT –WRT1,2,3,4,5,6,7)/WPre-RT × 100%. The optimal threshold of RT-PWL7 was determined by recursive partitioning analyses (RPAs). Our endpoints included disease-free survival (DFS), overall survival (OS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRRFS). Results The median RT-PWLs were 0, 0, 1.5, 2.9, 4.1, 5.5, 6.6% at 1st, 2nd, 3rd, 4th, 5th, 6th, and 7th week of RT, respectively. RT-PWL7 optimal threshold with respect to DFS was 5.3% based on RPAs. Therefore, a consistent threshold of 5% ( ≥5%) was selected to classify NPC patients into low RT-PWL7 and high RT-PWL7 groups for survival analysis. Compared to high RT-PWL7 (≥5%), patients with low RT-PWL7 (

Abstract Background The increase in the prevalence of myopia has become a matter of serious public health concern, and few studies to date have examined the ocular biometric parameters of myopia in young Chinese adults. This study aimed to investigate the longitudinal ocular biometric and refractive development of first-year university students and the influence of near work. Methods This study included 526 first-year university students from Tianjin Medical University (mean age, 18.34 years; 313 females and 213 males). From 2016 to 2018, participants underwent ocular biometry measurements and subjective refraction annually. Near-work activities such as the use of electronic devices, online games, reading, and writing as well as demographic data were recorded by questionnaires. Results The prevalence of myopia in this population from 2016 to 2018 was 92.40%, 92.59%, and 92.97%, respectively. Importantly, the prevalence of high myopia increased significantly from 20.91% to 28.33% (P

The neutral point clamped (NPC) three-level grid-tied converter is the key equipment connecting renewable energy and power grids. The current sensor fault caused by harsh environment may lead to the split of renewable energy. The existing sensor fault-tolerant methods will reduce the modulation ratio index of the converter system. To ensure continuous operation of the converter system and improve the modulation index, a model predictive control method based on reconstructed current is proposed in this paper. According to the relationship between fault phase current and a voltage vector, the original voltage vector is combined and classified. To maintain the stable operation of the converter and improve the utilization rate of DC voltage, two kinds of fault phase current are reconstructed with DC current, normal phase current and predicted current, respectively. Based on reconstructed three-phase current, a current predictive control model is designed, and a model predictive control method is proposed. The proposed method selects the optimal voltage vector with the cost function and reduces time delay with the current reconstruction sector. The simulation and experimental results showthat the proposed strategy can keep the NPC converter running stably with one AC sensor, and the modulation index is increased from 57.7% to 100%.

Single‐atom nanozymes (SAzymes) can maximize atomic utilization efficiency and construct highly active catalytic sites for biomedical applications. Herein, atomically dispersed iron (Fe) and cobalt (Co) dual sites anchored N‐doped graphene carbon (FeCoCN) catalyst is rationally constructed to achieve photothermally augmented catalytic oxidation for effective biocatalytic tumor nanotherapy. Compared with Fe SAzyme, FeCoCN SAzyme can significantly accelerate the charge transfer and improve the activity of catalytic reactions. Co‐doping optimizes coordination structure and charge redistribution by facilitating the ratio of Fe2+ and regulating charge transfer between different metal sites and nearby coordination atoms. Bimetallic FeCoCN SAzyme possessed an ultra‐high affinity for substrate H2O2, and the catalytic kinetic Km value (0.589 mm) is superior to natural catalase and most reported nanozymes. The boosted catalytic activity in producing •OH is identified by density functional theory (DFT) studies. In vivo, investigation demonstrates that atomically dispersed Fe and Co dual sites anchored FeCoCN SAzyme significantly suppresses tumor proliferation under NIR laser irradiation by photothermally enhanced catalytic oxidation. Additionally, Fe‐ and Co‐doping in FeCoCN make it suitable as a tracer for T2 magnetic resonance imaging. This work provides a paradigm to rationally design bimetallic SAzymes with enhanced biocatalytic performance for tumor treatment. [ABSTRACT FROM AUTHOR]

The design of high-aspect-ratio wings enhances the flight efficiency of UAVs but also introduces significant aeroelasticity challenges. The efficient optimization of wing structures in complex environments has become critical. To address the current challenges in balancing wing strength with lightweight structural designs, this study proposed an intelligent solution method for optimizing wing dimensions and structural layout. Driven by mechanical simulation data, the method established a mapping relationship between the structural layout and dimensions of the wing and its bending stiffness. This approach was further enhanced by the mind evolution algorithm (MEA) to optimize the solution performance of the surrogate model. The wing structure optimization model was established using the multi-objective grey wolf optimizer (MOGWO) based on the surrogate model for search and optimization. This study focused on the composite material wing of a long-endurance unmanned aerial vehicle (UAV). The established MEA-BP surrogate model demonstrated high computational efficiency, with the prediction error standard deviation (STD) of wing deflection not exceeding 0.495 mm. The optimization model required 175 s to calculate the Pareto front solutions. The optimized structure resulted in a 28.32% increase in wing equivalent stiffness, and weight only increased by 6.67% compared to the original structure. These results showcased the effectiveness of the proposed method and validated the feasibility of integrating intelligent optimization algorithms and machine learning in the field of aircraft design. [ABSTRACT FROM AUTHOR]

Abstract In order to solve the coordinated optimization problem of distributed generation (DG), on‐load tap changer (OLTC) and capacitor banks, a dynamic reactive power optimization (DRPO) method based on fuzzy time clustering is proposed. In the method, fuzzy time clustering algorithm is used to cluster the static optimal switching sequence of OLTC and capacitor banks. The time decoupling of control variables is realized and it meets the constraints of the maximum switching times. Next, the influencing factors of DG reactive power limit are analysed. Considering the control ability of OLTC, capacitor banks and DG in voltage and reactive power optimization, a coordinated optimization method is proposed. Since the adjustment of OLTC tap position directly affects the voltage and reactive power distribution of the whole line, the switching time and tap position of OLTC are determined based on the static optimization results of each time and fuzzy time clustering algorithm. Then, the switching time of capacitor banks is determined by fuzzy time clustering algorithm. At last, the switching capacity of capacitor banks and DG reactive power are jointly optimized to get the final control scheme. The proposed method demonstrated good performance in the modified IEEE33 node system and two actual power grid examples.

Abstract Background Budding yeast, Saccharomyces cerevisiae, has been extensively favored as a model organism in aging and age-related studies, thanks to versatile microfluidic chips for cell dynamics assay and replicative lifespan (RLS) determination at single-cell resolution. However, previous microfluidic structures aiming to immobilize haploid yeast may impose excessive spatial constraint and mechanical stress on cells, especially for larger diploid cells that sprout in a bipolar pattern. Results We developed a high-throughput microfluidic chip for diploid yeast long-term culturing (DYLC), optical inspection and cell-aging analysis. The DYLC chip features 1100 “leaky bowl”-shaped traps formatted in an array to dock single cells under laminar-perfused medium and effectively remove daughter cells by hydraulic shear forces. The delicate microstructures of cell traps enable hydrodynamic rotation of newborn buds, so as to ensure bud reorientation towards downstream and concerted daughter dissection thereafter. The traps provide sufficient space for cell-volume enlargement during aging, and thus properly alleviate structural compression and external stress on budding yeast. Trapping efficiency and long-term maintenance of single cells were optimized according to computational fluid dynamics simulations and experimental characterization in terms of critical parameters of the trap and array geometries. Owing to the self-filling of daughter cells dissected from traps upstream, an initial trapping efficiency of about 70% can rapidly reach a high value of over 92% after 4-hour cell culturing. During yeast proliferation and aging, cellular processes of growth, budding and daughter dissection were continuously tracked for over 60 h by time-lapse imaging. Yeast RLS and budding time interval (BTI) were directly calculated by the sequential two-digit codes indicating the budding status in images. With the employed diploid yeast strain, we obtained an RLS of 24.29 ± 3.65 generations, and verified the extension of BTI in the first couple of generations after birth and the last several generations approaching death, as well as cell de-synchronization along diploid yeast aging. Conclusions The DYLC chip offers a promising platform for reliable capture and culturing of diploid yeast cells and for life-long tracking of cell dynamics and replicative aging processes so that grasping comprehensive insights of aging mechanism in complex eukaryotic cells. Graphical Abstract

Abstract Background We aimed to determine the time interval between alfentanil and rocuronium administration, at a 50% probability of preventing pain-induced withdrawal movement from rocuronium injection (TimeAR50). Methods A total of 64 patients scheduled for general anesthesia were enrolled in this study (33 men and 31 women). Anesthesia was induced with target-controlled infusion of propofol, at an effect-site target concentration of 3 μg/mL. Then, alfentanil 15 μg/kg was injected for 30 s. After 60 s, rocuronium 0.6 mg/kg was administered to the first patient. The Dixon’s up-and-down method was used to determine the time interval for each subsequent patient (interval of 5 s). Mean arterial pressure (MAP) and heart rate (HR) were recorded at three time points: T0, pre-induction; T1, before rocuronium injection; and T2, 1 min after rocuronium injection. Results The TimeAR50 ± standard deviation (SD) was 5.6 ± 3.7 s and 21.9 ± 5.6 s in the male and female patients, respectively. Based on the probit regression, the TimeAR50 was 4.7 s (95% confidence interval [CI], 1.2–7.6 s) and 20.3 s (95% CI, 7.7–26.1 s) in the male and female patients, respectively. The TimeAR95 was 10.6 s (95% CI, 7.7–25.3 s) and 35.0 s (95% CI, 28.1–95.5 s) in the male and female patients, respectively, with significantly higher values in females than in males (P