Application of slow-controlled release fertilizer coordinates the carbon flow in carbon-nitrogen metabolism to effect rice quality.

Slow-controlled release fertilizers are experiencing a popularity in rice cultivation due to their effectiveness in yield and quality with low environmental costs. However, the underlying mechanism by which these fertilizers regulate grain quality remains inadequately understood. This study investigated the effects of five fertilizer management practices on rice yield and quality in a two-year field experiment: CK, conventional fertilization, and four applications of slow-controlled release fertilizer (UF, urea formaldehyde; SCU, sulfur-coated urea; PCU, polymer-coated urea; BBF, controlled-release bulk blending fertilizer). In 2020 and 2021, the yields of UF and SCU groups showed significant decreases when compared to conventional fertilization, accompanied by a decline in nutritional quality. Additionally, PCU group exhibited poorer cooking and eating qualities. However, BBF group achieved increases in both yield (10.8 t hm-2 and 11.0 t hm-2) and grain quality reaching the level of CK group. The adequate nitrogen supply in PCU group during the grain-filling stage led to a greater capacity for the accumulation of proteins and amino acids in the PCU group compared to starch accumulation. Intriguingly, BBF group showed better carbon-nitrogen metabolism than that of PCU group. The optimal nitrogen supply present in BBF group suitable boosted the synthesis of amino acids involved in the glycolysis/ tricarboxylic acid cycle, thereby effectively coordinating carbon-nitrogen metabolism. The application of the new slow-controlled release fertilizer, BBF, is advantageous in regulating the carbon flow in the carbon-nitrogen metabolism to enhance rice quality.

Integrated analysis of bulk and single-cell RNA sequencing reveals the impact of nicotinamide and tryptophan metabolism on glioma prognosis and immunotherapy sensitivity.

BACKGROUND: Nicotinamide and tryptophan metabolism play important roles in regulating tumor synthesis metabolism and signal transduction functions. However, their comprehensive impact on the prognosis and the tumor immune microenvironment of glioma is still unclear. The purpose of this study was to investigate the association of nicotinamide and tryptophan metabolism with prognosis and immune status of gliomas and to develop relevant models for predicting prognosis and sensitivity to immunotherapy in gliomas. METHODS: Bulk and single-cell transcriptome data from TCGA, CGGA and GSE159416 were obtained for this study. Gliomas were classified based on nicotinamide and tryptophan metabolism, and PPI network associated with differentially expressed genes was established. The core genes were identified and the risk model was established by machine learning techniques, including univariate Cox regression and LASSO regression. Then the risk model was validated with data from the CGGA. Finally, the effects of genes in the risk model on the biological behavior of gliomas were verified by in vitro experiments. RESULTS: The high nicotinamide and tryptophan metabolism is associated with poor prognosis and high levels of immune cell infiltration in glioma. Seven of the core genes related to nicotinamide and tryptophan metabolism were used to construct a risk model, and the model has good predictive ability for prognosis, immune microenvironment, and response to immune checkpoint therapy of glioma. We also confirmed that high expression of TGFBI can lead to an increased level of migration, invasion, and EMT of glioma cells, and the aforementioned effect of TGFBI can be reduced by FAK inhibitor PF-573,228. CONCLUSIONS: Our study evaluated the effects of nicotinamide and tryptophan metabolism on the prognosis and tumor immune microenvironment of glioma, which can help predict the prognosis and sensitivity to immunotherapy of glioma.

Associations of Ambient Particulate Matter with Maternal Thyroid Autoimmunity and Thyroid Function in Early Pregnancy.

This prospective birth cohort study evaluated the association of exposure to PM2.5 (diameter ≤2.5 µm), PM1-2.5 (1-2.5 µm), and PM1 (≤1 µm) with maternal thyroid autoimmunity and function during early pregnancy. A total of 15,664 pregnant women were included at 6 to 13+6 gestation weeks in China from 2018 to 2020. Single-pollutant models using generalized linear models (GLMs) showed that each 10 µg/m3 increase in PM2.5 and PM1-2.5 was related with 6% (odds ratio [OR] = 1.06, 95% confidence interval [CI]: 1.01, 1.12) and 15% (OR = 1.15, 95% CI: 1.08, 1.22) increases in the risk of thyroid autoimmunity, respectively. The odds of thyroid autoimmunity significantly increased with each interquartile range increase in PM2.5 and PM1-2.5 exposure (P for trend <0.001). PM1 exposure was not significantly associated with thyroid autoimmunity. GLM with natural cubic splines demonstrated that increases in PM2.5 and PM1-2.5 exposure were associated with lower maternal FT4 levels, while a negative association between PM1 and FT4 levels was found when exposure exceeded 32.13 µg/m3. Only PM2.5 exposure was positively associated with thyrotropin (TSH) levels. Our findings suggest that high PM exposure is associated with maternal thyroid disruption during the early pregnancy.

Elevated serum uric acid to creatinine ratio is associated with adverse pregnancy outcomes: a prospective birth cohort study.

Purpose: This study evaluated the association between maternal serum uric acid-to-creatinine ratio (SUA/SCr) in the first trimester and adverse maternal and neonatal outcomes. Methods: A prospective birth cohort study was conducted between 2018 and 2021. Logistic regression models and restricted cubic splines were utilized to estimate the associations between the SUA/SCr ratio and feto-maternal pregnancy outcomes. Women were stratified according to maternal age and pre-pregnancy body mass index. Results: This study included 33,030 pregnant women with live singleton pregnancies. The overall prevalence of gestational diabetes mellitus (GDM), pregnancy-induced hypertension (PIH), cesarean delivery, preterm birth, large-for-gestational age (LGA), small-for-gestational age, and low Apgar scores were 15.18%, 7.96%, 37.62%, 4.93%, 9.39%, 4.79% and 0.28%, respectively. The highest quartile of SUA/SCr was associated with the highest risk of GDM (odds ratio [OR] 2.14, 95% CI 1.93-2.36), PIH (OR 1.79, 95% CI 1.58-2.04), cesarean delivery (OR 1.24, 95% CI 1.16-1.33), and preterm birth (OR 1.30, 95% CI 1.12-1.51). The associations between SUA/SCr with adverse pregnancy outcomes showed linear relationships except for GDM (P < 0.001 for all, P < 0.001 for non-linearity). Subgroup analyses revealed that the associations between the SUA/SCr ratio and the risks of PIH and LGA were significantly stronger in younger pregnant women (P = 0.033 and 0.035, respectively). Conclusion: Maternal SUA/SCr levels were associated positively with the risk of adverse pregnancy outcomes. Timely monitoring of SUA and SCr levels during early pregnancy may help reduce the risk of adverse pregnancy outcomes and provide a basis for interventions.

MiR26a reverses enzalutamide resistance in a bone-tumor targeted system with an enhanced effect on bone metastatic CRPC.

Resistance to androgen receptor (AR) inhibitors, including enzalutamide (Enz), as well as bone metastasis, are major challenges for castration-resistant prostate cancer (CRPC) treatment. In this study, we identified that miR26a can restore Enz sensitivity and inhibit bone metastatic CRPC. To achieve the highest combination effect of miR26a and Enz, we developed a cancer-targeted nano-system (Bm@PT/Enz-miR26a) using bone marrow mesenchymal stem cell (BMSC) membrane and T140 peptide to co-deliver Enz and miR26a. The in vitro/in vivo results demonstrated that miR26a can reverse Enz resistance and synergistically shrink tumor growth, invasion, and metastasis (especially secondary metastasis) in both subcutaneous and bone metastatic CRPC mouse models. We also found that the EZH2/SFRP1/WNT5A axis may be involved in this role. These findings open new avenues for treating bone metastatic and Enz-resistant CRPC.

Associations of remnant cholesterol in early pregnancy with gestational diabetes mellitus risk: a prospective birth cohort study.

BACKGROUND: Remnant cholesterol (RC) reportedly contributes to the development of diabetes mellitus. However, evidence on the relationship between maternal RC and the risk of developing gestational diabetes mellitus (GDM) during pregnancy is limited. This study aimed to assess the relationship between maternal RC and GDM risk during early pregnancy, and explore the potential pathways involved in the relationship between RC levels and GDM risk. METHODS: From 2018 to 2021, a prospective birth cohort study was designed and carried out in China. The associations of maternal RC and other lipid parameters with GDM risk were estimated using logistic regression models and restricted cubic splines. Subgroup analyses were performed stratified by prepregnancy body mass index (pre-BMI), maternal age and gravidity. Mediation analyses were conducted to explore the mediating effect of some related factors on the relationship between RC levels and the risk of GDM. RESULTS: A total of 33,018 pregnant women were included. The median RC level was 0.47 ± 0.20 mmol/L. The prevalence of GDM was 15.19%. As RC quartiles increased, the incidence of GDM increased substantially, reaching 19.24% for the highest quartile of RC (P < 0.001). Maternal RC in the first trimester was positively correlated with GDM risk (OR: 2.254, 95% CI: 1.943-2.615). Compared to the lowest RC quartile, higher RC quartiles were correlated with an increased risk of GDM, and the ORs (95% CIs) for Q3 and Q4 were 1.208 (1.101-1.325) and 1.489 (1.364-1.626), respectively. Moreover, a linear dose-response relationship was found for this association (P for all < 0.001, P for nonlinearity > 0.05) and was consistent across subgroups with different pre-BMIs, maternal ages and gravidities (all P values for interactions > 0.05). Furthermore, the correlation between RC level and GDM risk was partially mediated by pre-BMI (9.20%) and blood glucose level (-11.1%). CONCLUSIONS: Higher maternal RC levels in the early stage of pregnancy was positively associated with an increased risk of developing GDM. This association was partially mediated by pre- BMI and blood glucose levels.

The association between dyslipidaemia in the first trimester and adverse pregnancy outcomes in pregnant women with subclinical hypothyroidism: a cohort study.

BACKGROUND: Subclinical hypothyroidism (SCH) is linked to dyslipidaemia and adverse pregnancy outcomes. However, the impact of dyslipidaemia on the outcome of pregnancy in SCH is unclear. METHODS: We enrolled 36,256 pregnant women and evaluated their pregnancy outcomes. The following data was gathered during the first trimester (≤ 13+ 6 weeks of gestation): total cholesterol (TC), low-density lipoprotein (LDL-C), triglyceride (TG), high-density lipoprotein (HDL-C), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) concentrations. The reference ranges for lipids were estimated to range from the 5th to the 95th percentile. Logistic regression assessed the relationships between dyslipidaemia and adverse pregnancy outcomes, including abortion, preeclampsia/eclampsia, low birth weight, foetal growth restriction, premature rupture of foetal membranes, gestational hypertension, preterm birth, macrosomia and gestational diabetes mellitus (GDM). Additionally, the best thresholds for predicting adverse pregnancy outcomes based on TSH, FT4, and lipid levels were determined using receiver operating characteristic curves. RESULTS: In the first trimester, LDL-C > 3.24 mmol/L, TG > 1.92 mmol/L, HDL-C < 1.06 mmol/L, and TC > 5.39 mmol/L were used to define dyslipidaemia. In this cohort, 952 (3.56%) patients were diagnosed with SCH, and those who had dyslipidaemia in the first trimester had higher incidences of gestational hypertension (6.59% vs. 3.25%), preeclampsia/eclampsia (7.14% vs. 3.12%), GDM (22.53% vs. 13.77%), and low birth weight (4.95% vs. 2.08%) than did those without dyslipidaemia. However, after adjusting for prepregnancy body mass index (pre-BMI), dyslipidaemia was no longer related to these risks. Furthermore, elevated TG dyslipidaemia in SCH patients was connected to an enhanced potential of gestational hypertension (odds ratio [OR]: 2.687, 95% confidence interval [CI]: 1.074 ~ 6.722), and elevated LDL-C dyslipidaemia correlated with increased preeclampsia/eclampsia risk (OR: 3.172, 95% CI: 1.204 ~ 8.355) after accounting for age, smoking status, alcohol use, pre-BMI, and levothyroxine use. Additionally, the combination of TC, TG, LDL-C, pre-BMI, and TSH exhibited enhanced predictive capabilities for gestational hypertension, preeclampsia/eclampsia, and GDM. Values of 0.767, 0.704, and 0.706 were obtained from the area under the curve. CONCLUSIONS: Among pregnant women with SCH, dyslipidaemia in early pregnancy was related to elevated risks of adverse pregnancy consequences. The combined consideration of age, pre-BMI, TSH, and lipid levels in the first trimester could be beneficial for monitoring patients and implementing interventions to reduce adverse pregnancy outcomes.

Synergistic Photoredox/Palladium Catalyzed Enantioconvergent Carboxylation of Racemic Heterobiaryl (Pseudo)Halides with CO2.

Herein, we report a synergistic photoredox/palladium catalytic system for the efficient enantioconvergent synthesis of axially chiral esters from racemic heterobiaryl (pseudo)halides (bromides/triflates) with CO2 and alkyl bromides under mild conditions. A wide range of axially chiral esters were obtained in good to high yields with excellent enantioselectivities. Detailed mechanistic studies unveiled that the ratio of photocatalyst and palladium catalyst exhibited significant impact on the chemo- and enantioselectivities of the reaction. Kinetic studies and control experiments supported the proposed mechanism involving cascade asymmetric carboxylation followed by SN2 substitution. The achievement of high enantioselectivity relies not only on the choice of synergistic metallaphotoredox catalysts but also on the utilization of alkyl bromides, which trap the generated chiral carboxylic anions in situ, thus preventing their immediate racemization.

High-Selectivity Tandem Photocatalytic Methanation of CO2 by Lacunary Polyoxometalates-Stabilized *CO Intermediate.

Stabilizing specific intermediates to produce CH4 remains a main challenge in solar-driven CO2 reduction. Herein, g-C3N4 is modified with saturated and lacunary phosphotungstates (PWx, x = 12, 11, 9) to tailor the CO2 reduction pathway to yield CH4 in high selectivity. Increased lacuna of phosphotungstates leads to higher CH4 yield and selectivity, with a superior CH4 selectivity of 80% and 40.8 µmol·g-1·h-1 evolution rate for PW9/g-C3N4. Conversely, g-C3N4 and PWx alone show negligible CH4 production. The conversion of CO2 to CH4 follows a tandem catalytic process. CO2 is initially activated on g-C3N4 to form *CO intermediates, meanwhile photogenerated electrons derived from g-C3N4 transfer to PWx. Then the reduced PWx captures *CO, which is subsquently hydrogenated to CH4. With the injection of two photogenerated electrons, PW9 is capable of adsorbing and activating *CO. However, the reduced PW12 and PW11 are incapable of adsorbing *CO due to the small energy of occupied molecular orbitals, which is the reason for the poorer activity of PWx/g-C3N4 (x = 12, 11) compared with that of PW9/g-C3N4. This work provides new insights to regulate highly selective CO2 photoreduction to CH4 by utilizing lacuna of polyoxometalates to enhance the interaction of metals in polyoxometalates with key intermediates.

Self-Propelled Janus Nanocatalytic Robots Guided by Magnetic Resonance Imaging for Enhanced Tumor Penetration and Therapy.

Biomedical micro/nanorobots as active delivery systems with the features of self-propulsion and controllable navigation have made tremendous progress in disease therapy and diagnosis, detection, and biodetoxification. However, existing micro/nanorobots are still suffering from complex drug loading, physiological drug stability, and uncontrollable drug release. To solve these problems, micro/nanorobots and nanocatalytic medicine as two independent research fields were integrated in this study to achieve self-propulsion-induced deeper tumor penetration and catalytic reaction-initiated tumor therapy in vivo. We presented self-propelled Janus nanocatalytic robots (JNCRs) guided by magnetic resonance imaging (MRI) for in vivo enhanced tumor therapy. These JNCRs exhibited active movement in H2O2 solution, and their migration in the tumor tissue could be tracked by non-invasive MRI in real time. Both increased temperature and reactive oxygen species production were induced by near-infrared light irradiation and iron-mediated Fenton reaction, showing great potential for tumor photothermal and chemodynamic therapy. In comparison with passive nanoparticles, these self-propelled JNCRs enabled deeper tumor penetration and enhanced tumor therapy after intratumoral injection. Importantly, these robots with biocompatible components and byproducts exhibited biosecurity in the mouse model. It is expected that our work could promote the combination of micro/nanorobots and nanocatalytic medicine, resulting in improved tumor therapy and potential clinical transformations.

Predicting Breast Cancer Subtypes Using Magnetic Resonance Imaging Based Radiomics With Automatic Segmentation.

OBJECTIVE: The aim of the study is to demonstrate whether radiomics based on an automatic segmentation method is feasible for predicting molecular subtypes. METHODS: This retrospective study included 516 patients with confirmed breast cancer. An automatic segmentation-3-dimensional UNet-based Convolutional Neural Networks, trained on our in-house data set-was applied to segment the regions of interest. A set of 1316 radiomics features per region of interest was extracted. Eighteen cross-combination radiomics methods-with 6 feature selection methods and 3 classifiers-were used for model selection. Model classification performance was assessed using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity. RESULTS: The average dice similarity coefficient value of the automatic segmentation was 0.89. The radiomics models were predictive of 4 molecular subtypes with the best average: AUC = 0.8623, accuracy = 0.6596, sensitivity = 0.6383, and specificity = 0.8775. For luminal versus nonluminal subtypes, AUC = 0.8788 (95% confidence interval [CI], 0.8505-0.9071), accuracy = 0.7756, sensitivity = 0.7973, and specificity = 0.7466. For human epidermal growth factor receptor 2 (HER2)-enriched versus non-HER2-enriched subtypes, AUC = 0.8676 (95% CI, 0.8370-0.8982), accuracy = 0.7737, sensitivity = 0.8859, and specificity = 0.7283. For triple-negative breast cancer versus non-triple-negative breast cancer subtypes, AUC = 0.9335 (95% CI, 0.9027-0.9643), accuracy = 0.9110, sensitivity = 0.4444, and specificity = 0.9865. CONCLUSIONS: Radiomics based on automatic segmentation of magnetic resonance imaging can predict breast cancer of 4 molecular subtypes noninvasively and is potentially applicable in large samples.

Biomimetic liposomal nanozymes improve breast cancer chemotherapy with enhanced penetration and alleviated hypoxia.

BACKGROUND: Doxorubicin (Dox) has been recommended in clinical guidelines for the standard-of-care treatment of breast cancer. However, Dox therapy faces challenges such as hypoxia, acidosis, H2O2-rich conditions and condensed extracellular matrix in TME as well as low targeted ability. METHODS: We developed a nanosystem H-MnO2-Dox-Col NPs based on mesoporous manganese dioxide (H-MnO2) in which Dox was loaded in the core and collagenase (Col) was wrapped in the surface. Further the H-MnO2-Dox-Col NPs were covered by a fusion membrane (MP) of inflammation-targeted RAW264.7 cell membrane and pH-sensitive liposomes to form biomimetic MP@H-MnO2-Dox-Col for in vitro and in vivo study. RESULTS: Our results shows that MP@H-MnO2-Dox-Col can increase the Dox effect with low cardiotoxicity based on multi-functions of effective penetration in tumor tissue, alleviating hypoxia in TME, pH sensitive drug release as well as targeted delivery of Dox. CONCLUSIONS: This multifunctional biomimetic nanodelivery system exhibited antitumor efficacy in vivo and in vitro, thus having potential for the treatment of breast cancer.

Serum uric acid and the risk of gestational diabetes mellitus: a systematic review and meta-analysis.

AIMS: Serum uric acid (SUA) is considered as a risk factor for gestational diabetes mellitus (GDM). However, current studies showed inconsistent results. This study aimed to explore the relationship between SUA levels and GDM risk. METHODS: Eligible studies were retrieved from PubMed, Web of Science, Embase, China National Knowledge Infrastructure, and Wanfang databases up to November 1, 2022. The pooled standardized mean difference (SMD) and 95% confidence interval (CI) were used to represent the difference in SUA levels between GDM women and controls. The combined odds ratios (OR) and 95% CI were applied to assess association between SUA levels and GDM risk. Subgroup analyses were conducted on study continents, design, and quality, detection time of SUA, and GDM diagnostic criteria. RESULTS: Totally 11 studies including five case-control and six cohort studies, in which 80,387 pregnant women with 9815 GDM were included. The overall meta-analysis showed that the mean SUA level in GDM group was significantly higher than in controls (SMD = 0.423, 95%CI = 0.019-0.826, p = .040, I2 = 93%). Notably, pregnant women with elevated levels of SUA had a significantly increased risk of GDM (OR = 1.670, 95%CI = 1.184-2.356, p = .0035, I2 = 95%). Furthermore, subgroup analysis performed on the detection time of SUA showed a significant difference in the association between SUA and GDM risk within different trimesters (1st trimester: OR = 3.978, 95%CI = 2.177-7.268; 1st to 2nd trimester: OR = 1.340, 95%CI = 1.078-1.667; p between subgroups <.01). CONCLUSIONS: Elevated SUA was positively associated with GDM risk, particularly in the 1st trimester of pregnancy. Further studies with high quality are required to validate the findings of this study.

Vasoprotective Effects of Hyperoside against Cerebral Ischemia/Reperfusion Injury in Rats: Activation of Large-Conductance Ca2+-Activated K+ Channels.

Hyperoside (Hyp), a kind of Chinese herbal medicine, exerts multiple therapeutic effects on many diseases. However, the role and mechanisms of Hyp in vascular pathophysiology in ischemic stroke need to be further established. The study aimed to investigate the role of (large-conductance Ca2+-activated K+) BK channels on the vasoprotection of Hyp against cerebral ischemia and reperfusion (I/R) injury in rats. The concentration gradient of Hyp was pretreated in both the middle cerebral artery occlusion and reperfusion model and oxygen-glucose deprivation/reoxygenation (OGD/R) model of primary vascular smooth muscle cells (VSMCs) in rats. A series of indicators were detected, including neurological deficit score, infarct volume, malondialdehyde (MDA), superoxide dismutase (SOD), cerebral blood flow (CBF), cell viability, membrane potential, and BK channels α- and ß1-subunits expression. The results showed that Hyp significantly reduced infarct volume and ameliorated neurological dysfunction in I/R-injured rats. Besides, the effects of I/R-induced reduction of BK channels α- and ß1-subunits expression were significantly reversed by Hyp in endothelial-denudated cerebral basilar arteries. Furthermore, the protective effect against I/R-induced increases of MDA and reduction of SOD as well as CBF induced by Hyp was significantly reversed by iberiotoxin (IbTX). In OGD/R-injured VSMCs, downregulated cellular viability and BK channels ß1-subunits expression were remarkably reversed by Hyp. However, neither OGD/R nor Hyp affected BK channels α-subunits expression, and Hyp failed to induced hyperpolarization of VSMCs. Moreover, the protective effect against OGD/R-induced reduction of cell viability and SOD level and increases of MDA production induced by Hyp was significantly reversed by IbTX in VSMCs. The study indicates that Hyp has the therapeutic potential to improve vascular outcomes, and the mechanism is associated with suppressing oxidative stress and improving CBF through upregulating BK channels.

Coronavirus Disease 2019 Pandemic-Related Long-Term Chronic Impacts on Psychological Health of Perinatal Women in China.

OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic has caused far-reaching changes in all areas of society. However, limited data have focused on the long-term impacts on perinatal psychological health. This study aims to evaluate long-term impacts of COVID-19 pandemic crisis on psychological health among perinatal women and investigate associated factors. STUDY DESIGN: A multicenter, cross-sectional study, the psychological subproject of China Birth Cohort Study (CBCS), was conducted in 2021. Demographic and obstetric characteristics, pregnancy outcomes, psychological status, and COVID-19-pandemic-related factors were obtained. The symptoms of depression, anxiety, and insomnia of participants were assessed by Patient Health Questionnaire, Edinburgh Postpartum Depression Scale, Generalized Anxiety Disorder Scale, and Insomnia Severity Index, respectively. Multivariate logistic regression was used to identify associated factors of adverse psychological symptoms. RESULTS: Totally, 1,246 perinatal women were enrolled, with the overall prevalence of depression, anxiety, and insomnia symptoms being 63.16, 41.89, and 44.38%, respectively. Perinatal women who needed psychological counseling and were very worried about the COVID-19 pandemic were 1.8 to 7.2 times more likely to report symptoms of depression, anxiety, and insomnia. Unemployment, flu-like symptoms, younger maternal age, and previous diseases before pregnancy were risk factors for depression, anxiety, or insomnia. CONCLUSION: Our study revealed that the prevalence of perinatal depression, anxiety, and insomnia symptoms was at a high level even 1 year after the pandemic outbreak, implying pandemic-associated long-term psychological impacts on perinatal women existed. Government should not only pay attention to the acute effects of psychological health but also to long-term psychological impacts on perinatal women after major social events. KEY POINTS: · The prevalence of perinatal psychological symptoms was at a high level after the COVID-19 outbreak.. · Perinatal women who were very worried about COVID-19 were more often to have psychological symptoms.. · Perinatal women with demands of mental counseling were more likely to report psychological symptoms..

Research and Application of Kupffer Cell Thresholds for BSA Nanoparticles.

Over the past decade, the dose of nanoparticles given to solid tumors has remained at a median of 0.7% of the injected dose. Most nanoparticles are trapped in a mononuclear phagocyte system (MPS), of which 85% are Kupffer cells. In our study, threshold doses of bovine serum albumin (BSA) nanoparticles were investigated for the uptake of Kupffer cells in vitro and in vivo. The antitumor effect and safety of albumin-bound paclitaxel (ABP) were improved by using threshold doses of BSA nanoparticles. We found a threshold dose of 20,000 nanoparticles per macrophage uptake in vitro and a saturation dose of 0.3 trillion nanoparticles in tumor-bearing mice. In vivo efficacy and safety evaluations demonstrated that the threshold doses of blank BSA nanoparticles could significantly improve the efficacy and safety of ABP against tumors compared with ABP alone. In this study, the delivery efficiency of ABP was improved by using blank nanoparticles to saturate Kupffer cells, which provided a new approach to studying the Kupffer cell saturation threshold and thus a new scheme for improving the curative effect of ABP.

Biodegradable Ferrous Sulfide-Based Nanocomposites for Tumor Theranostics through Specific Intratumoral Acidosis-Induced Metabolic Symbiosis Disruption.

Abnormal metabolic symbiosis is a typical characteristic that differentiates the tumor regions from healthy tissues and meanwhile maintains tumor survival. It is of great potential to disrupt intratumoral metabolic symbiosis in tumor therapy. Herein, we report a specific tumor therapy strategy through inducing acidosis to disrupt intratumoral metabolic symbiosis for tumor elimination, which is based on carbonic anhydrase inhibitor (CAI)-modified ferrous sulfide nanoparticles (FeS-PEG-CAI NPs). The FeS-PEG-CAI NPs show the acid-responsive degradation capacity to release functional components, including CAI, Fe2+, and H2S, while remaining quite stable under normal physiological conditions. The generated CAI and H2S gas can not only disrupt the intracellular metabolic symbiosis to induce acidosis but also provide suitable circumstances for Fe2+-mediated Fenton reaction, producing abundant toxic hydroxyl radicals. Meanwhile, these NPs also show the dual-mode imaging capacity with photoacoustic and magnetic resonance imaging, which can dynamically monitor tumor location in the process of synergistic chemodynamic/photothermal/gas therapy. Overall, the developed FeS-PEG-CAI NPs exert their role of disrupting intratumoral metabolic symbiosis and other synergistic effects, which further enrich tumor treatment strategies.

Phase I clinical trial of HC-1119 soft capsule in Chinese healthy adult male subjects: Pharmacokinetics and safety of single-dose proportionality and effects of food.

BACKGROUND: Preclinical studies showed that HC-1119, a deuterated version of enzalutamide, could competitively inhibit androgen binding to androgen receptor by blocking the transmission of androgen receptor signaling pathway as enzalutamide, inducing apoptosis of prostate cancer cells and reducing the proliferation of prostate cancer cells. Animal pharmacokinetic studies also show that deuterization of enzalutamide as HC-1119 could retain the basic properties of mother drug, increases the stability of compounds to metabolic enzymes and the drug exposure in vivo, prolong the half-life and reduce the production of metabolites, which may lead to a better efficacy and safety of HC-1119 compared with enzalutamide. METHODS: To evaluate the pharmacokinetics and safety of HC-1119 and the effects of food on pharmacokinetics in healthy adult Chinese men after single-dose administration of HC-1119. A total of 47 Chinese healthy adult male subjects received HC-1119 soft capsule at a single oral dose of 40, 80, or 160 mg followed on fasting or 160 mg after high-fat meal respectively. HC-1119 prototype and its metabolites M1 and M2 in plasma were collected individually in a total 23 time points. Pharmacokinetics were determined by sensitive LC/MS/MS for dose-proportionality study. RESULTS: In subjects taking HC-1119 soft capsules on fasting, Cmax of HC-1119 prototype increased dose-dependently. Either Cmax and AUC0-∞ of M1 or Cmax of M2 showed statistically significant difference. Dose-proportionality evaluation showed linear pharmacokinetic characteristics in Cmax of HC-1119 prototype, Cmax and AUC0-∞ of M2 in dose range of 40-160 mg. Cmax of HC-1119 was significantly different between the two groups as 160 mg HC-1119 on fasting or after a high-fat diet respectively, while the other parameter were not. HC-1119 and its metabolites M1 and M2 showed a linear dynamic trend. CONCLUSIONS: HC-1119 is expected to have lower clinical dose than the similar drug enzalutamide. The absorption of HC-1119 and the main pharmacokinetic parameters of HC-1119 and its metabolites M1 and M2 were not affected by high-fat diet. The clinical application of HC-1119 soft capsule in the later stage can be recommended for both fasting and postprandial. The safety and tolerance were good in this population.

Profiles of transcriptome and metabolic pathways after hypobaric hypoxia exposure.

BACKGROUND: Hypoxia is a risk factor for non-alcoholic fatty liver diseases, leading to permanent imbalance of liver lipid homeostasis and steatohepatitis. However, a detailed understanding of the metabolic genes and pathways involved remains elusive. METHODS: In vivo experiments were designed to analyze body weight and lipid metabolism changes of rats under hypoxia. After this, we combined microarray analysis and gene overexpression experiments to validate the core mechanisms involved in the response to hypoxia. RESULTS: The hypobaric hypoxia treated rats exhibited significantly increased serum triglycerides (TG) (p < 0.05), despite no significant changes in serum alanine aminotransferase (ALT) and blood glucose (BG) were observed. In addition, serum high-density lipoprotein cholesterol (HDL-C) greatly increased after 3 days and then returned to normal level at 30 days. Interestingly, serum low-density lipoprotein cholesterol (LDL-C) showed an opposite pattern. Transcriptome analysis, qRT-PCR, ICC revealed that the genes PPARA, ANGPTL4, CPT-I, ACC and LPL play a crucial role in response to hypobaric hypoxia. IPA pathway analysis further confirmed that PPARA-mediated regulation of ANGPTL4 participated in TG clearance and lipoprotein metabolism. Finally, the PPARA-ANGPTL4 pathway was validated in rats and HL 7702 cells treated with Fenofibrate, a PPARA specific agonist. CONCLUSIONS: Our study showed this pathway plays an important role on lipid metabolism caused by hypobaric hypoxia and the potential target genes associated with oxygen-dependent lipid homeostasis in the liver.

Identification of LAT/ZAP70 characterized immune subtypes of prostate cancer.

BACKGROUND: While immunotherapy has shown potent efficacy in clinical practices, patient selection to receive checkpoint blockade is still challenging in prostate cancer (PCa). LAT and ZAP70 functions in lymphocyte activation and plays a critical role in T cell receptor (TCR) signal transduction. However, PCa genomic and clinical data regarding the role of LAT and ZAP70 are limited. We aim to identify and characterize LAT/ZAP70 defined subtypes of PCa. METHODS: We elaborated the TCGA PCa data and metastatic castration-resistant prostate cancer (mCRPC) RNA-seq data bioinformatic analysis and systematically elucidated the role of intra-tumoral expressed LAT and ZAP70 in the progression-free survival and immunotherapeutic-related signals. LAT/ZAP70-associated immune infiltration was evaluated using bioinformatic tools. Immunohistochemical staining of serial sections was used to confirm the expression and distribution of LAT, ZAP70 and androgen receptor (AR) in PCa tissues. RESULTS: Specifically, LAT and ZAP70 revealed increased expressions in PCa when compared to normal tissues and positively associated with intra-tumoral immune cells infiltration. LAT/ZAP70 defined immune-high early-stage PCa revealed higher TP53 mutation frequency and poor prognosis. Transcriptome analysis indicated immune-related signals and CTLA4 expression were highly enhanced in immune-high PCa parallel with higher protein level of MYC and lower AR expression. In mCRPC, LAT/ZAP70 defined immune-high patients also revealed upregulated immune related signals, higher CTLA4 expression and DNA repair deficiency. CONCLUSION: LAT/ZAP70 defined immune-high PCa linked to immune infiltration and predicts poor prognosis. Immune-high PCa may receive effective response from immune checkpoint inhibitor parallel with systemic treatment.