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Abstract Background The aims of the present study were to investigate the incidence of nurses who suffered anxiety during the COVID-19 pandemic and to explore how expressive suppression influences the relationship between family function and anxiety. Methods This study used cross-sectional research and simple random sampling. A total of 300 questionnaires were distributed and 254 questionnaires were qualified after invalid questionnaires were proposed, thus a total of 254 female nurses from a tertiary hospital were included in this study. The measurement included General demographic questionnaires, the Self-Scale Anxiety, Scale (SAS), Emotion Regulation Strategies Questionnaire (ERQ), and Family Function Assessment (FAD). T-test, nonparametric Wilcoxon or Kruskal-Wallis test, χ2 test, Pearson or Spearman correlation analysis, multiple stepwise regression and bootstrap methods was performed to analyze the data. Results In this study, 22.4% of the nurses exhibited anxiety symptoms, with 17.7% eliciting mild anxiety symptoms, 4.3% showing moderate anxiety symptoms and 0.4% with severe anxiety symptoms. Family function and expressive suppression were positively associated with anxiety severity. And family function influenced anxiety among nurses via direct and indirect (Expressive suppression -mediated) pathways. Conclusions Expressive suppression partially mediated the influence of family function on anxiety symptom. To this end, nurse administrators should establish a robust mental health support system encompassing psychological counseling and emotional support groups. Furthermore, nurse administrators should consistently inquire about nurses’ family situations, encourage nurses to articulate their emotions and needs candidly, both within the domestic sphere and the workplace, while refraining from excessive self-repression.

Abstract N-Hydroxyapiosporamide (N-hydap), a marine product derived from a sponge-associated fungus, has shown promising inhibitory effects on small cell lung cancer (SCLC). However, there is limited understanding of its metabolic pathways and characteristics. This study explored the in vitro metabolic profiles of N-hydap in human recombinant cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs), as well as human/rat/mice microsomes, and also the pharmacokinetic properties by HPLC–MS/MS. Additionally, the cocktail probe method was used to investigate the potential to create drug-drug interactions (DDIs). N-Hydap was metabolically unstable in various microsomes after 1 h, with about 50% and 70% of it being eliminated by CYPs and UGTs, respectively. UGT1A3 was the main enzyme involved in glucuronidation (over 80%), making glucuronide the primary metabolite. With a favorable bioavailability of 24.0%, N-hydap exhibited a higher distribution in the lungs (26.26%), accounting for its efficacy against SCLC. Administering N-hydap to mice at normal doses via gavage did not result in significant toxicity. Furthermore, N-hydap was found to affect the catalytic activity of drug metabolic enzymes (DMEs), particularly increasing the activity of UGT1A3, suggesting potential for DDIs. Understanding the metabolic pathways and properties of N-hydap should improve our knowledge of its drug efficacy, toxicity, and potential for DDIs. Graphical Abstract

Abstract Alzheimer's disease (AD), a neurodegenerative disorder, causes short-term memory and cognition declines. It is estimated that one in three elderly people die from AD or other dementias. Chinese herbal medicine as a potential drug for treating AD has gained growing interest from many researchers. Moschus, a rare and valuable traditional Chinese animal medicine, was originally documented in Shennong Ben Cao Jing and recognized for its properties of reviving consciousness/resuscitation. Additionally, Moschus has the efficacy of “regulation of menstruation with blood activation, relief of swelling and pain” and is used for treating unconsciousness, stroke, coma, and cerebrovascular diseases. However, it is uncertain whether Moschus has any protective effect on AD patients. We explored whether Moschus could protect glutamate (Glu)-induced PC12 cells from cellular injury and preliminarily explored their related action mechanisms. The chemical compounds of Moschus were analyzed and identified by GC–MS. The Glu-induced differentiated PC12 cell model was thought to be the common AD cellular model. The study aims to preliminarily investigate the intervention effect of Moschus on Glu-induced PC12 cell damage as well as their related action mechanisms. Cell viability, lactate dehydrogenase (LDH), mitochondrial reactive oxygen species, mitochondrial membrane potential (MMP), cell apoptosis, autophagic vacuoles, autolysosomes or autophagosomes, proteins related to apoptosis, and the proteins related to autophagy were examined and analyzed. Seventeen active compounds of the Moschus sample were identified based on GC–MS analysis. In comparison to the control group, Glu stimulation increased cell viability loss, LDH release, mitochondrial damage, loss of MMP, apoptosis rate, and the number of cells containing autophagic vacuoles, and autolysosomes or autophagosomes, while these results were decreased after the pretreatment with Moschus and 3-methyladenine (3-MA). Furthermore, Glu stimulation significantly increased cleaved caspase-3, Beclin1, and LC3II protein expression, and reduced B-cell lymphoma 2/BAX ratio and p62 protein expression, but these results were reversed after pretreatment of Moschus and 3-MA. Moschus has protective activity in Glu-induced PC12 cell injury, and the potential mechanism might involve the regulation of autophagy and apoptosis. Our study may promote research on Moschus in the field of neurodegenerative diseases, and Moschus may be considered as a potential therapeutic agent for AD.

Four new sesquiterpenoids, talaroterpenes A–D (1–4), were isolated from the mangrove-derived fungus Talaromyces sp. SCSIO 41412. The structures of compounds 1–4 were elucidated through comprehensive NMR and MS spectroscopic analyses. The absolute configurations of 1–4 were assigned based on single-crystal X-ray diffraction and calculated electronic circular dichroism analysis. Talaroterpenes A–D (1–4) were evaluated with their regulatory activities on nuclear receptors in HepG2 cells. Under the concentrations of 200 μM, 1, 3 and 4 exhibited varying degrees of activation on ABCA1 and PPARα, while 4 showed the strongest activities. Furthermore, 4 induced significant alterations in the expression of downstream target genes CLOCK and BMAL1 of RORα, and the in silico molecular docking analysis supported the direct binding interactions of 4 with RORα protein. This study revealed that talaroterpene D (4) was a new potential non-toxic modulator of nuclear receptors.

Abstract Background TSC22D domain family genes, including TSC22D1-4, play a principal role in cancer progression. However, their expression profiles and prognostic significance in adult acute myeloid leukemia (AML) remain unknown. Methods The online databases, including HPA, CCLE, EMBL-EBI, GEPIA2, BloodSpot, GENT2, UCSCXenaShiny, GSCALite, cBioportal, and GenomicScape, utilized the data of TCGA and GEO to investigate gene expression, mutation, copy number variation (CNV), and prognostic significance of the TSC22D domain family in adult AML. Computational analysis of resistance (CARE) was used to explore the effect of TSC22D3 expression on drug response. Functional enrichment analysis of TSC22D3 was performed in the TRRUST Version 2 database. The STRING, Pathway Commons, and AnimalTFDB3.0 databases were used to investigate the protein–protein interaction (PPI) network of TSC22D3. Harmonizome was used to predict target genes and kinases regulated by TSC22D3. The StarBase v2.0 and CancermiRNome databases were used to predict miRNAs regulated by TSC22D3. UCSCXenaShiny was used to investigate the correlation between TSC22D3 expression and immune infiltration. Results Compared with normal adult hematopoietic stem cells (HSCs), the expression of TSC22D3 and TSC22D4 in adult AML tissues was markedly up-regulated, whereas TSC22D1 expression was markedly down-regulated. The expression of TSC22D1 and TSC22D3 was significantly increased in adult AML tissues compared to normal adult tissues. High TSC22D3 expression was significantly associated with poor overall survival (OS) and event-free survival (EFS) in adult AML patients. Univariate and multivariate Cox analysis showed that overexpression of TSC22D3 was independently associated with adverse OS of adult AML patients. High TSC22D3 expression had a adverse impact on OS and EFS of adult AML patients in the chemotherapy group. TSC22D3 expression correlated with drug resistance to BCL2 inhibitors. Functional enrichment analysis indicated that TSC22D3 might promote AML progression. MIR143-3p sponging TSC22D3 might have anti-leukemia effect in adult AML. Conclusions A significant increase in TSC22D3 expression was observed in adult AML tissues compared to normal adult HSCs and tissues. The prognosis of adult AML patients with high TSC22D3 expression was unfavorable, which could severe as a new prognostic biomarker and potential target for adult AML.

ABSTRACTChimeric antigen receptor (CAR)-T cells have not made significant progress in the treatment of acute myeloid leukemia (AML) in earlyclinical studies. This lack of progress could be attributed in part to the immunosuppressive microenvironment of AML, such as monocyte-like myeloid-derived suppressor cells (M-MDSCs) and alternatively activated macrophages (M2 cells), which can inhibit the antitumor activity of CAR-T cells. Furthermore, AML cells are usually heterogeneous, and single-target CAR-T cells may not be able to eliminate all AML cells, leading to disease relapse. CD123 and NKG2D ligands (NKG2DLs) are commonly used targets for CAR-T therapy of AML, and M-MDSCs and M2 cells express both antigens. We developed dual-targeted CAR-T (123NL CAR-T) cells targeting CD123 and NKG2DL by various structural optimization screens. Our study reveals that 123NL CAR-T cells eradicate AML cells and selectively target immunosuppressive cells. A highly compact marker/suicide gene, RQR8, which binds targeting epitopes of CD34 and CD20 antigens, was also incorporated in front of the CAR structure. The binding of Rituximab to RQR8 leads to the elimination of 123NL CAR-T cells and cessation of their cytotoxicity. In conclusion, we successfully developed dual effects of 123NL CAR-T cells against tumor cells and immunosuppressive cells, which can avoid target escape and resist the effects of immunosuppressive microenvironment.

Purpose: Acute myeloid leukemia (AML) is a highly heterogeneous neoplastic disease with a poor prognosis that relapses even after its treatment with chimeric antigen receptor (CAR)-T cells targeting a single antigen. CD123 and CLL1 are expressed in most AML blasts and leukemia stem cells, and their low expression in normal hematopoietic stem cells makes them ideal targets for CAR-T. In this study, we tested the hypothesis that a new bicistronic CAR targeting CD123 and CLL1 can enhance antigenic coverage and prevent antigen escape and subsequent recurrence of AML. Methods: CD123 and CLL1 expressions were evaluated on AML cell lines and blasts. Then, in addition to concentrating on CD123 and CLL1, we introduced the marker/suicide gene RQR8 with a bicistronic CAR. Xenograft models of disseminated AML and in vitro coculture models were used to assess the anti-leukemia efficacy of CAR-T cells. The hematopoietic toxicity of CAR-T cells was evaluated in vitro by colony cell formation assays. It was demonstrated in vitro that the combination of rituximab and NK cells caused RQR8-mediated clearance of 123CL CAR-T cells. Results: We have successfully established bicistronic 123CL CAR-T cells that can target CD123 and CLL1. 123CL CAR-T cells effectively cleared AML cell lines and blasts. They also demonstrated appreciable anti-AML activity in animal transplant models. Moreover, 123CL CAR-T cells can be eliminated in an emergency by a natural safety switch and don't target hematopoietic stem cells. Conclusions: The bicistronic CAR-T cells targeting CD123 and CLL1 may be a useful and secure method for treating AML.

Abstract Relapsed or refractory (R/R) acute myeloid leukemia (AML) has a poor prognosis. In this study, we evaluated chimeric antigen receptor (CAR) T cell therapy targeting CLL-1 in adults with R/R AML patients. Patients received conditioning chemotherapy with cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) for 3 days and an infusion of a dose of 1–2 × 106 CAR-T cells/kg. The incidence of dose-limiting toxicity was the primary endpoint. Ten patients were treated, and all developed cytokine release syndrome (CRS); 4 cases were low-grade, while the remaining 6 were considered high-grade CRS. No patient developed CAR-T cell-related encephalopathy syndrome (CRES). Severe pancytopenia occurred in all patients. Two patients died of severe infection due to chronic agranulocytosis. The complete response (CR)/CR with incomplete hematologic recovery (CRi) rate was 70% (n = 7/10). The median follow-up time was 173 days (15–488), and 6 patients were alive at the end of the last follow-up. CAR-T cells showed peak expansion within 2 weeks. Notably, CLL-1 is also highly expressed in normal granulocytes, so bridging hematopoietic stem cell transplantation (HSCT) may be a viable strategy to rescue long-term agranulocytosis due to off-target toxicity. In conclusion, this study is the first to demonstrate the positive efficacy and tolerable safety of CLL-1 CAR-T cell therapy in adult R/R AML.

Alzheimer's disease (AD) is a common age-related neurodegenerative disease characterized by progressive cognitive decline and irreversible memory impairment. Currently, several studies have failed to fully elucidate AD's cellular and molecular mechanisms. For this purpose, research on related cellular models may propose potential predictive models for the drug development of AD. Therefore, many cells characterized by neuronal properties are widely used to mimic the pathological process of AD, such as PC12, SH-SY5Y, and N2a, especially the PC12 pheochromocytoma cell line. Thus, this review covers the most systematic essay that used PC12 cells to study AD. We depict the cellular source, culture condition, differentiation methods, transfection methods, drugs inducing AD, general approaches (evaluation methods and metrics), and in vitro cellular models used in parallel with PC12 cells.

Abstract Chimeric antigen receptor T cell (CAR-T cell) therapy is a relatively new, effective, and rapidly evolving therapeutic for adoptive immunotherapies. Although it has achieved remarkable effect in hematological malignancies, there are some problems that remain to be resolved. For example, there are high recurrence rates and poor efficacy in solid tumors. In this review, we first briefly describe the metabolic re-editing of T cells and the changes in metabolism during the preparation of CAR-T cells. Furthermore, we summarize the latest developments and newest strategies to improve the metabolic adaptability and antitumor activity of CAR-T cells in vitro and in vivo.

Over the past few decades, immunotherapy has revolutionized the modern medical oncology field. Chimeric antigen receptor (CAR)-T cell therapy has a promising curative effect in the treatment of hematological malignancies. Anti-CD19 CAR-T cells are the most mature CAR-T cells recently studied and in recent years it has achieved a complete remission rate of approximately 90% in the treatment of B-cell acute lymphoblastic leukemia (B-ALL). Although CAR-T cell therapy has greatly alleviated the disease in patients with leukemia or lymphoma, some of them still relapse after treatment. Therefore, in this article, we discuss the factors that may contribute to disease relapse following CAR-T cell therapy and summarize potential strategies to overcome these obstacles, thus providing the possibility of improving standard treatment regimens.

Bevacizumab (Bev) is a humanized vascular endothelial growth factor monoclonal antibody that is used with chemotherapeutic drugs for the treatment of metastatic colorectal cancer (mCRC). Bev-induced hypertension (HT) is the most common adverse reaction during clinical practice. However, at present, appropriate antihypertensive agents for Bev-induced HT are unavailable. In this study, retrospective analysis of clinical data from mCRC patients who received renin-angiotensin system inhibitors (RASIs) showed significant survival benefits of overall survival (OS) and progression-free survival (PFS) over patients who received calcium channel blockers (CCBs) and patients who received no antihypertensive drug (NO: Y2020046 retrospectively registered). An experiment of HCT116 colon cancer cell xenografts in mice confirmed that combined treatment of Bev and lisinopril (Lis), a RASI, synergistically inhibited subcutaneous tumor growth and enhanced the concentration of 5-fluorouracil (5-Fu) in tumor tissues. Our results showed that the addition of Lis did not interfere with the vascular normalization effect promoted by Bev, but also inhibited collagen and hyaluronic acid (HA) deposition and significantly downregulated the expression of TGF-β1 and downstream SMAD signaling components which were enhanced by Bev, ultimately remodeling primary extracellular matrix components. In conclusion, RASIs and Bev have synergistic effect in the treatment of colorectal cancer and RASIs might be an optimal choice for the treatment of Bev-induced HT.

BackgroundLiving arrangement of the elderly is one of the most important components that affect their quality of life in later years. The aging, with the phenomenon of low fertility rate and family structure transformation, has caused changes in the living arrangements of the elderly. This research aimed to find the elderly's living arrangement preferences and influencing factors.MethodsThe data were obtained from The Chinese Longitudinal Healthy Longevity Survey (CLHLS) in the 2018, and the sample was comprised of 9,638 individuals aged ≥ 60 years. Independent variables were divided into social support, health status and so-economic status. Chi-square test and binary logistic regression were used to analyze the relationship between the above variates and living arrangement preferences.ResultsCurrently, in terms of living arrangement preferences, nearly half (45.6%) of the respondents choose not to live with their children. The binary model results showed that elderly who were married (OR = 0.166, 95% CI: 0.147–0.187), experienced more than 6 years of education (OR = 0.600, 95% CI: 0.517–0.695), ability of daily living (ADL) impaired (OR = 0.810, 95% CI: 0.720–0.912), suffering from multiple chronic diseases (OR = 0.803, 95% CI: 0.720–0.912), and obtained community services (OR = 0.884, 95% CI: 0.803–0.972) incline to not live with their children. The elderly who living in rural areas (OR = 1.244, 95% CI: 1.129–1.371), with an income of more than 500,000 yuan per year (OR = 1.557, 95% CI: 1.380–1.757), having children visiting regularly (OR = 1.405, 95% CI: 1.161–1.707) and receiving children's financial support (OR = 1.194, 95% CI: 1.080–1.319) are more likely to choose to live with their children.ConclusionsThis study found that the living arrangement preferences of the elderly were affected by social support and health status, and living with children is no longer the only option for the elderly these days. The elderly care services provided by communities or professional care institutions may become the mainstream of taking care of the elderly citizens in the aging society. Improving the types and forms of community nursing services to increase the accessibility of these services; setting up elderly care institutions reasonably and equipping adequate professional nursing staff should be considered as priority measures.

Eutrophication is a significant factor that damages the water ecosystem’s species balance. The total phosphorus (TP) concentration is a vital water quality indicator in assessing surface water eutrophication. This paper predicts the spatial distribution of TP concentration using remote sensing, measured data, and the partial least squares regression (PLSR) method. Based on the correlation analysis, the models were built and tested using the TP concentration and Sentinel-2 Multispectral Instrument (MSI) and Landsat-8 Operational Land Imager (OLI) image spectra. The results demonstrated that the best technique based on band combinations of the Sentinel-2 and Landsat-8 images achieved good precision. The coefficient of determination (R2), root mean square error of prediction (RMSEP), and residual prediction deviation (RPD) were 0.771, 0.023 mg/L, and 2.086 for Sentinel-2 images and 0.630, 0.032 mg/L, and 1.644 for Landsat-8 images, respectively. The TP concentration maps were interpolated using the inverse distance weighting method, and the inversion results obtained from the images were in good agreement. The western and northwestern regions of Taihu Lake, where significant cyanobacterial blooms occurred, had TP concentrations greater than 0.20 mg/L; nevertheless, the central and eastern regions had amounts ranging from 0.05 to 0.20 mg/L. In order to prove the extensibility of the model, the optimal algorithm was applied to the Sentinel-2 and Landsat-8 images in 2017. The optimal algorithm based on Landsat-8 images has a better verification effect (RMSEP = 0.027 mg/L, and R = 0.879 for one Landsat-8 image), and the optimal algorithm based on Sentinel-2 images has moderate verification effect (RMSEP = 0.054 mg/L and 0.045 mg/L, and R = 0.771 and 0.787 for two Sentinel-2 images). The interpolation and inversion maps are in good agreement, indicating that the model is suitable for the Landsat-8 and Sentinel-2 images, which can be complementary for higher temporal resolutions. Monitoring water quality using multiple remote sensing images can provide the scientific basis for water quality dynamic monitoring and prevention in China.

Fine particulate matter (PM2.5) is a major pollutant in Guanzhong Urban Agglomeration (GUA) during the winter, and GUA is one of China’s regions with the highest concentrations of PM2.5. Daily surface PM2.5 maps with a spatial resolution of 1 km × 1 km can aid in the control of PM2.5 pollution. Thus, the Random Forest and eXtreme Gradient Boosting (RF-XGBoost) model was proposed to fill the missing aerosol optical depth (AOD) at the station scale before accurately estimating ground-level PM2.5 using the recently released MODIS AOD product derived from Multi-Angle Implementation of Atmospheric Correction (MAIAC), high density meteorological and topographic conditions, land-use, population density, and air pollutions. The RF-XGBoost model was evaluated using an out-of-sample test, revealing excellent performance with a coefficient of determination (R2) of 0.93, root-mean-square error (RMSE) of 12.49 μg/m3, and mean absolution error (MAE) of 8.42 μg/m3. The result derived from the RF-XGBoost model indicates that the GUA had the most severe pollution in the winter of 2018 and 2019, owing to the burning of coal for heating and unfavorable meteorological circumstances. Over 90% of the GUA had an annual average PM2.5 concentrations decrease of 3 to 7 μg/m3 in 2019 compared to the previous year. Nevertheless, the air pollution situation remained grim in the winter of 2019, with more than 65% of the study area meeting the mean PM2.5 values higher than 35 μg/m3 and the maximum reaching 95.57 μg/m3. This research would be valuable for policymakers, environmentalists, and epidemiologists, especially in urban areas.

In financial time series analysis, symmetric and asymmetric GARCH models have become essential models for measuring the characteristics of economic volatility. In this article, we propose the consistency and asymptotic normality properties of the self-weighted quasi-maximum likelihood estimation without assuming the existence of the second moment for the moving average model with a class of GARCH error. Numerical simulation shows that the parameter estimation performs well; empirical analysis shows that the self-weighted quasi-maximum likelihood estimation of the moving average model with a class of GARCH error can improve the data fitting effect and prediction ability.

The contamination of farmlands with hazardous metals from mining puts the safety of agricultural commodities at risk. For remediation, it is crucial to map the spatial distribution of contaminated soil. Typical sampling-based procedures are time-consuming and labor-intensive. The use of visible, near-infrared, and short-wave infrared reflectance (VNIR-SWIR) spectroscopy to detect soil heavy metal pollution is an alternative. With the aim of investigating a methodology of detecting the most sensitive bands using VNIR-SWIR spectra to find lead (Pb) anomalies in agriculture soil near mining activities, the area in Xiaoqinling Mountain, downstream from a series of active gold mines, was selected to test the feasibility of utilizing VNIR-SWIR spectroscopy to map soil Pb. A total of 115 soil samples were collected for laboratory Pb analysis and spectral measurement. Partial least squares regression (PLSR) was adopted to estimate the soil Pb content by building the prediction model, and the model was optimized by finding the optimal number of bands involved. The spatial distribution of Pb concentration was mapped using the ordinary kriging (OK) interpolation method. This study found that five spectral bands (522 nm, 1668 nm, 2207 nm, 2296 nm, and 2345 nm) were sensitive to soil Pb content. The optimized prediction model’s coefficient of determination (R2), residual prediction deviation (RPD), and root mean square error (RMSE) were 0.711, 1.860, and 0.711 ln(mg/kg), respectively. Additionally, the result of OK interpolation was convincing and accurate (R2 = 0.775, RMSE = 0.328 ln(mg/kg)), comparing maps from estimated and ground truth data. This study proves that it is feasible to use VNIR-SWIR spectral data for in situ estimation of the soil Pb content.

The emission of nitrogen oxides (NOx) in China decreased by 15% from 2010 to 2015 (without a significant decrease in NH3 emission), resulting in the decline of nitrogen (N) deposition in East Asia. Empirical N critical load exceedance was used to assess the benefit of the NOx emission reduction in China to natural ecosystems in East Asia. Empirical N critical loads for major forest and grassland types in East Asia were assigned based on field manipulation experiments for N effects. The critical load map based on the minimum of the critical load range of each vegetation type showed that empirical critical loads were generally lower in the Tibetan Plateau and some parts of northeastern China (≤5 kgN·ha−1·a−1), and higher in northern and southern China (≥20 kgN·ha−1·a−1). Empirical critical loads were also low in some parts of central and northern Japan (≤5 kgN·ha−1·a−1) and the south Korean Peninsula (5–10 kgN·ha−1·a−1). As a benefit of NOx emission reduction in China, N deposition in East Asia decreased significantly from 2010 to 2015. The total area and total amount of critical load exceedance in East Asia declined 4.6% and 14.3% respectively, suggesting great benefits to natural ecosystems. Keywords: Nitrogen deposition, Air pollution effect, Fertilization experiment, CMAQ model, Emission abatement, Nitrogen saturation