Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Oral AL01211 in Healthy Chinese Volunteers.

BACKGROUND AND OBJECTIVE: Aberrant accumulation of glycosphingolipids (GSLs) in the lysosome leads to GSL storage diseases. Glucosylceramide synthase inhibitors (GCSi) have the potential to treat several GSL storage diseases by reducing the synthesis of the disease-causing GSLs. AL01211 is a potent oral GCSi under investigation for Type 1 Gaucher disease and Fabry disease. Here, we evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of AL01211 in healthy Chinese volunteers. METHODS: AL01211 was tested in a Phase 1, single-center, randomized, double-blind, placebo-controlled study with single-dose (15 and 60 mg) and multiple-dose (30 mg) arms. RESULTS: Results of AL01211 demonstrated dose-dependent pharmacokinetics, rapid absorption (median time to maximum plasma concentration [tmax] 2.5-4 hours), relatively slow clearance rate (mean apparent total clearance from plasma [CL/F] 88.3-200 L/h) and the mean terminal half-life above 30 hours. Repeated once-daily oral administration of AL01211 for 14 days had an approximately 2-fold accumulation, reaching steady-state levels between 7 and 10 days, and led to a 73% reduction in plasma glucosylceramide (GL1) on Day 14. AL01211 was safe and well tolerated, with no identified serious adverse events. CONCLUSION: AL01211 showed a favorable pharmacokinetic, pharmacodynamics, safety, and tolerability profile in healthy Chinese volunteers. These data support the further clinical development of AL01211 as a therapy for GSL storage diseases. CLINICAL TRIAL REGISTRY: Clinical Trial Registry no. CTR20221202 ( http://www.chinadrugtrials.org.cn ) registered on 6 June 2022 and ChiCTR2200061431 ( http://www.chictr.org.cn ) registered on 24 June 2022.

Subacute exposure to DEHP leads to impairing decidualization process and exacerbating the risk of early pregnancy miscar-riage in mice. / 孕早期增塑剂DEHPäºšæ€¥æ€§æš´éœ²å½±å“èœ•è†œååº”å¹¶å¢žåŠ æµäº§é£Žé™©.

OBJECTIVES: To investigate the effect of subacute exposure of Di (2-ethylhexyl) phthalate (DEHP) on endometrial decidualization in mice. METHODS: CD1 mice were orally administrated with 300 mg·kg－1·d－1 (low-dose group), 1000 mg·kg－1·d－1 (medium-dose group), or 3000 mg·kg－1·d－1 DEHP (1/10 LD50, high-dose group) for 28 days, respectively. The early natural pregnancy model and artificially induced decidualization model were established, and the uterine tissues were collected on D7 of natural pregnancy and D8 of artificially induced decidualization, respectively. The effects of subacute exposure to DEHP on the decidualization of mice were detected by HE staining, Masson staining, TUNEL staining, and Western blotting, respectively. A model of spontaneous abortion was constructed in mice after subacute exposure to 300 mg·kg-1·d-1 DEHP, and the effect of impaired decidualization on pregnancy was investigated by observing the pregnancy outcome on the 10th day of gestation. RESULTS: Compared with the control group, the conception rate was significantly lower in the high-dose DEHP subacute exposure group. HE staining showed that, compared with the control group, the decidual stromal cells in the low- and medium-dose exposure groups were disorganized, the nuclei of the cells were irregular, the cytoplasmic staining was uneven, and the number of polymorphonuclear cells was significantly reduced. Masson staining showed that compared with the control group, the collagen fibers in the decidua region of the DEHP low-dose group and the medium-dose group were more distributed, more abundant and more disorderly. TUNEL staining showed increased apoptosis in the decidua area compared to the control group. Western blotting showed that the expression of BMP2, a marker molecule for endometrial decidualization, was significantly reduced. The abortion rate and embryo resorption rate were significantly higher, and the number of embryos, uterine wet weight, uterine area and placenta wet weight were significantly lower in mice exposed to 300 mg·kg－1·d－1 DEHP than in control mice stimulated by mifepristone abortifacient drug. CONCLUSIONS: Subacute exposure to DEHP leads to impaired endometrial decidualization during early pregnancy and exacerbates the risk of adverse pregnant outcomes in mice.

Prognostic impact of age in advanced non-small cell lung cancer patients undergoing first-line checkpoint inhibitor immunotherapy and chemotherapy treatment.

BACKGROUND: Research on the association between age and clinical outcome in patients with non-small cell lung cancer (NSCLC) treated with immunotherapy combined with chemotherapy as first-line setting is limited. The aim of study is to determine the influence of age on the progress-free survival (PFS) and overall survival (OS) in those patients after adjusting for potential confounders. METHODS: A total of 207 advanced NSCLC patients treated with immunotherapy combined with chemotherapy in the first-line treatment in Guangxi Medical University Cancer Hospital from March 10, 2019, to December 31, 2022, was retrospectively analyzed. χ2 (categorical variables) was used to analyze the differences among the different age groups. Cox regression and Kaplan-Meier analyses were used to assess the association between age and clinical outcomes. P values < 0.05 (two-sided) were considered statistically significant. RESULTS: The mean age of the cohort was 58.8 ± 10.3 years. The percentages of patients < 65, 65-69, 70-74, and ≥ 75 years were 66.7 %, 19.3 %, 9.2 % and 4.8 %, respectively. Compared to the aged < 65 years group, the HR for the risk of disease progression for each group are 0.67 (95 %CI = 0.40-1.12, P = 0.125), 0.66 (95 %CI = 0.31, 1.43, P = 0.298), and 2.27 (95 %CI = 0.80, 6.45, P = 0.124), respectively, with no significant differences in the results. And the HR for risk of death for the 65-69 years and 70-74 years groups was 1.16 (95 %CI = 0.64-2.08, P = 0.628) and 0.93 (95 %CI = 0.39-2.23, P = 0.879), respectively. The difference has no statistical significance. Whereas in patients aged ≥ 75, there is an increased risk of death after adjusted confounders with HR = 4.83 (95 %CI = 2.06-11.35). The difference was statistically significant (P < 0.001). Trend test indicates that with advancing age, the patient's risk of death increases (HR = 1.33, 95 % CI = 1.02-1.75, P = 0.034). CONCLUSION: Age may not be the primary factor influencing the efficacy of immunotherapy combined with chemotherapy, but particular attention should be given to the elderly population.

FoxO1 promotes ovarian cancer by increasing transcription and METTL14-mediated m6A modification of SMC4.

The transcription factor forkhead box protein O1 (FoxO1) is closely related to the occurrence and development of ovarian cancer (OC), however its role and molecular mechanisms remain unclear. Herein, we found that FoxO1 was highly expressed in clinical samples of OC patients and was significantly correlated with poor prognosis. FoxO1 knockdown inhibited the proliferation of OC cells in vitro and in vivo. ChIP-seq combined with GEPIA2 and Kaplan-Meier database analysis showed that structural maintenance of chromosome 4 (SMC4) is a downstream target of FoxO1, and FoxO1 promotes SMC4 transcription by binding to its -1400/-1390 bp promoter. The high expression of SMC4 significantly blocked the tumor inhibition effect of FoxO1 knockdown. Furtherly, FoxO1 increased SMC4 mRNA abundance by transcriptionally activating methyltransferase-like 14 (METTL14) and increasing SMC4 m6A methylation on its coding sequence region. The Cancer Genome Atlas dataset analysis confirmed a significant positive correlation between FoxO1, SMC4, and METTL14 expression in OC. In summary, this study revealed the molecular mechanisms of FoxO1 regulating SMC4 and established a clinical link between the expression of FoxO1/METTL14/SMC4 in the occurrence of OC, thus providing a potential diagnostic target and therapeutic strategy.

Pharmacology of bioactive compounds from plant extracts for improving non-alcoholic fatty liver disease through endoplasmic reticulum stress modulation: A comprehensive review.

Background: Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver condition with significant clinical implications. Emerging research indicates endoplasmic reticulum (ER) stress as a critical pathogenic factor governing inflammatory responses, lipid metabolism and insulin signal transduction in patients with NAFLD. ER stress-associated activation of multiple signal transduction pathways, including the unfolded protein response, disrupts lipid homeostasis and substantially contributes to NAFLD development and progression. Targeting ER stress for liver function enhancement presents an innovative therapeutic strategy. Notably, the natural bioactive compounds of plant extracts have shown potential for treating NAFLD by reducing the level of ER stress marker proteins and mitigating inflammation, stress responses, and de novo lipogenesis. However, owing to limited comprehensive reviews, the effectiveness and pharmacology of these bioactive compounds remain uncertain. Objectives: To address the abovementioned challenges, the current review categorizes the bioactive compounds of plant extracts by chemical structures and properties into flavonoids, phenols, terpenoids, glycosides, lipids and quinones and examines their ameliorative potential for NAFLD under ER stress. Methods: This review systematically analyses the literature on the interactions of bioactive compounds from plant extracts with molecular targets under ER stress, providing a holistic view of NAFLD therapy. Results: Bioactive compounds from plant extracts may improve NAFLD by alleviating ER stress; reducing lipid synthesis, inflammation, oxidative stress and apoptosis and enhancing fatty acid metabolism. This provides a multifaceted approach for treating NAFLD. Conclusion: This review underscores the role of ER stress in NAFLD and the potential of plant bioactive compounds in treating this condition. The molecular mechanisms by which plant bioactive compounds interact with their ER stress targets provide a basis for further exploration in NAFLD management.

Incidence of and Risk Factors for Third-Generation Cephalosporin-Resistant Escherichia coli Bloodstream Infections in Children.

Objective: Third-generation cephalosporin-resistant (3GC-R) bloodstream infection (BSI) is associated with poor prognosis. We investigated the incidence of and risk factors for 3GC-R Escherichia coli (E. coli) BSI in children. Methods: Patients with E. coli BSIs who were hospitalized at the Children's Hospital of Chongqing Medical University were retrospectively enrolled. Univariate and multivariate logistic regression analyses were used to identify the independent risk factors for 3GC-R BSI. Results: Two hundred fifty-two children with E. coli BSIs were enrolled. The mortality rate was 11.51% (29/252). The infection rate of 3GC-R E. coli was 48.81% (123/252), and the incidence of E. coli BSI during hospitalization was 18.58 per 1000 person-days. Approximately half (47.22%, 119/252) of the children were infected with extended-spectrum beta-lactamases (ESBLs) produced by E. coli. More than one-third (37.30%, 94/252) of the children were unnecessarily administrated carbapenems. According to our logistic regression analysis, a history of carbapenem administration, an elevated Pediatric Sequential Organ Failure Assessment (pSOFA) score ≥2, and antimicrobial agent administration before blood culture were independently associated with 3GC-R BSI (odds ratio [OR] 2.05, 95% confidence interval [CI] 1.08-3.94, P=0.029; OR 2.00, 95% CI 1.10-3.71, P=0.025, OR 1.86, 95% CI 1.02-3.42, P=0.044, respectively). Conclusion: In this study, the incidence of 3GC-R E. coli BSI among children was retrospectively evaluated. Patients with a history of carbapenem administration, an elevated pSOFA score ≥2 and who were administrated antimicrobial agents before blood culture had an increased risk of 3GC-R E. coli BSI.

Metabolomic analysis of hydroxycinnamic acid inhibition on Saccharomyces cerevisiae.

Ferulic acid (FA) and p-coumaric acid (p-CA) are hydroxycinnamic acid inhibitors that are mainly produced during the pretreatment of lignocellulose. To date, the inhibitory mechanism of hydroxycinnamic acid compounds on Saccharomyces cerevisiae has not been fully elucidated. In this study, liquid chromatography-mass spectrometry (LC-MS) and scanning electron microscopy (SEM) were used to investigate the changes in S. cerevisiae cells treated with FA and p-CA. In this experiment, the control group was denoted as group CK, the FA-treated group was denoted as group F, and the p-CA-treated group was denoted as group P. One hundred different metabolites in group F and group CK and 92 different metabolites in group P and group CK were selected and introduced to metaboanalyst, respectively. A total of 38 metabolic pathways were enriched in S. cerevisiae under FA stress, and 27 metabolic pathways were enriched in S. cerevisiae under p-CA stress as identified through Kyoto Encyclopaedia of Genes and Genomes (KEGG) analysis. The differential metabolites involved included S-adenosine methionine, L-arginine, and cysteine, which were significantly downregulated, and acetyl-CoA, L-glutamic acid, and L-threonine, which were significantly upregulated. Analysis of differential metabolic pathways showed that the differentially expressed metabolites were mainly related to amino acid metabolism, nucleotide metabolism, fatty acid degradation, and the tricarboxylic acid cycle (TCA). Under the stress of FA and p-CA, the metabolism of some amino acids was blocked, which disturbed the redox balance in the cells and destroyed the synthesis of most proteins, which was the main reason for the inhibition of yeast cell growth. This study provided a strong scientific reference to improve the durability of S. cerevisiae against hydroxycinnamic acid inhibitors. KEY POINTS: • Morphological changes of S. cerevisiae cells under inhibitors stress were observed. • Changes of the metabolites in S. cerevisiae cells were explored by metabolomics. • One of the inhibitory effects on yeast is due to changes in the metabolic network.

A novel chaotic and neighborhood search-based artificial bee colony algorithm for solving optimization problems.

With the development of artificial intelligence, numerous researchers are attracted to study new heuristic algorithms and improve traditional algorithms. Artificial bee colony (ABC) algorithm is a swarm intelligence optimization algorithm inspired by the foraging behavior of honeybees, which is one of the most widely applied methods to solve optimization problems. However, the traditional ABC has some shortcomings such as under-exploitation and slow convergence, etc. In this study, a novel variant of ABC named chaotic and neighborhood search-based ABC algorithm (CNSABC) is proposed. The CNSABC contains three improved mechanisms, including Bernoulli chaotic mapping with mutual exclusion mechanism, neighborhood search mechanism with compression factor, and sustained bees. In detail, Bernoulli chaotic mapping with mutual exclusion mechanism is introduced to enhance the diversity and the exploration ability. To enhance the convergence efficiency and exploitation capability of the algorithm, the neighborhood search mechanism with compression factor and sustained bees are presented. Subsequently, a series of experiments are conducted to verify the effectiveness of the three presented mechanisms and the superiority of the proposed CNSABC, the results demonstrate that the proposed CNSABC has better convergence efficiency and search ability. Finally, the CNSABC is applied to solve two engineering optimization problems, experimental results show that CNSABC can produce satisfactory solutions.

Nucleated red blood cells as a novel biomarker in the diagnosis and prediction of sepsis severity in children.

Introduction: Sepsis is a vitally serious disease leading to high mortality. Nucleated red blood cells (NRBCs) are present in some noninfectious diseases, but the relationship between NRBCs and sepsis in children remains unknown. The purpose of this study was to compare the clinical characteristics and outcomes of sepsis with positive NRBCs and negative NRBCs in children, and to further explore whether the count of NRBCs has a relationship with the severity of sepsis. Methods: We enrolled children with sepsis who were admitted to the Children's Hospital of Chongqing Medical University between January 2020 and December 2022. The children's clinical data, laboratory data and outcomes were recorded and analyzed. Results: One hundred and fifteen children met the inclusion criteria in our study. Compared to negative NRBCs patients, the C-reactive protein, alanine transaminase, urea nitrogen values, mortality rate and length of hospitalization were found to be significantly increased, while platelet counts, and hemoglobin were significantly decreased in sepsis patients with positive NRBC (P < 0.05). Receiver operating characteristic (ROC) curves analysis showed that the optimal cutoff value of the NRBC count in the diagnosis of severe sepsis was 3, with a sensitivity of 87.5% and specificity of 94.9%. The area under the ROC curve was 0.877 (95% CI: 0.798-0.957). Discussion: These findings demonstrated that NRBC count has the potential to be a biomarker for the diagnosis of sepsis in children, especially an NRBC count greater than 3, which may predict the severity and poor prognosis in children suffering from sepsis.

Prognostic Significance of Pretreatment Plasma D-dimer Levels in EGFR-Positive Advanced Non-Small Cell Lung Cancer Patients Receiving Osimertinib: A Multicentre Retrospective Study.

Purpose: This study examined the association between plasma D-dimer levels and overall survival (OS) in advanced non-small cell lung cancer (NSCLC) patients treated with osimertinib. Methods: In this multicenter study, 88 patients with advanced non-small cell lung cancer (NSCLC) carrying epidermal growth factor receptor (EGFR) mutations and receiving osimertinib were enrolled. The target independent and dependent variables were the D-dimer levels before osimertinib treatment and OS time, respectively. The t-test or chi-square test was utilized to analyze the variances among various groups. The predictive significance of D-dimer for overall survival (OS) was assessed using Kaplan-Meier survival analysis and the Cox proportional hazard regression model. Results: The selected patients had an average age of 58.01±10.72 years, with females comprising 54.55%. Based on their D-dimer levels, the patients were categorized into three groups: low-level (< 0.6 mg/L), middle-level (0.6 ~ 2 mg/L), and high-level (≥ 2 mg/L). After accounting for possible confounding variables, the Cox proportional hazard model showed that increased D-dimer levels were linked to a greater likelihood of death (HR 2.28, 95% CI = 1.09 ~ 4.76, p = 0.029). Importantly, there was a significant trend indicating that as D-dimer levels rose, the risk of mortality also increased (p for trend, HR 1.15, 95% CI = 1.03 ~ 1.28, p = 0.012). Consistently comparable outcomes were noted in the majority of subcategories. Patients with low-middle and high D dimer levels had a median OS of 28.6 and 17 months, respectively (p =0.014). Conclusion: In conclusion, elevated levels of D-dimer in the bloodstream were found to have a significant negative correlation with the overall survival (OS) of patients with EGFR-positive non-small cell lung cancer (NSCLC) who underwent treatment with osimertinib.

Comparative analysis of transvaginal natural orifice transluminal endoscopic surgery versus laparoendoscopic single-site sacrocolpopexy for pelvic organ prolapse: A propensity score matching study.

Purpose: To compare the safety, feasibility, and effectiveness of transvaginal natural orifice transluminal endoscopic sacrocolpopexy (vNOTES-SC) and laparoendoscopic single-site sacrocolpopexy (LESS-SC) for pelvic organ prolapse (POP). Method: Ninety-four patients with POP who underwent vNOTES-SC or LESS-SC from October 2016 to November 2018 were included. The propensity score matching method was used for 1:1 matching between the two surgery groups. After matching, the general perioperative indicators, surgical complications, and the subjective and objective therapeutic effects of the two groups 3 years post-surgery were analyzed. Results: After matching, 36 patients in each group were included, exhibiting balanced and comparable baseline data and an average follow-up of 48.6 ± 7.44 months. The operation time and postoperative hospitalization days were significantly reduced in the vNOTES-SC group (P < 0.05). However, perioperative complication incidence was not significantly different between the two groups (P > 0.05). Additionally, no significant differences were detected in de novo stress urinary incontinence (16.7% vs. 13.9%), de novo overactive bladder (de novo OAB, 8.3% vs. 0.0%), urination disorder (2.8% vs. 0.0%), defecation disorder (0.0% vs. 2.8%), lumbosacral pain (0.0% vs. 2.8%), or mesh complication (2.8% vs. 5.6%) incidences between the vNOTES-SC and LESS-SC groups (P > 0.05). Prolapse recurrence was not reported in either group. The quantitative description of pelvic organ position (POP-Q), Pelvic Floor Impact Questionnaire-7 (PFIQ-7), and Patient Global Impression of Improvement scale (PGI-I) scores showed improvement after the operation, but no significant differences were observed between the two groups (P > 0.05). Conclusion: The 3-year follow-up revealed that vNOTES-SC and LESS-SC had similar complications and efficacy rates. Compared with LESS-SC, vNOTES-SC resulted in shorter operation time and fewer postoperative hospitalization days (corresponding to the enhanced recovery after surgery [ERAS] concept), along with better cosmetic results without a scar. Therefore, our study findings suggest that clinicians should choose the surgery method based on the specific situation, and we recommend choosing vNOTES-SC when both surgeries are suitable.

Novel CSF biomarkers for diagnosis and integrated analysis of neuropsychiatric systemic lupus erythematosus: based on antibody profiling.

BACKGROUND: Neuropsychiatric systemic lupus erythematosus (NPSLE), with various morbidities and multiple manifestations in the central nervous system, remains a limited standard for diagnosis. Our study was to discover novel biomarkers for improving the diagnostic efficiency for NPSLE. METHODS: We performed a quantitative planar protein antibody microarray to screen 1000 proteins in cerebrospinal fluid from controls, systemic lupus erythematosus (SLE, non-NPSLE) patients, and NPSLE patients. Differentially expressed proteins (DEPs) as candidate biomarkers were developed into a custom multiplexed protein antibody array for further validation in an independent larger cohort. Subsequently, we used least absolute shrinkage and selection operator regression (LASSO) analysis and multivariable logistic regression analysis for optimizing feature selection and constructing a diagnostic model. A receiver operating characteristic curve (ROC) was generated to assess the effectiveness of the models. RESULTS: The expression of 29 proteins in CSF was significantly altered in the comparison of the three groups. We selected 17 proteins as candidate biomarkers in accordance with protein interaction analysis. In the larger cohort, we identified 5 DEPs as biomarkers for NPSLE, including TCN2, CST6, KLK5, L-selectin, and Trappin-2. The diagnostic model included 3 hub proteins (CST6, TCN2, KLK5) and was best at discriminating NPSLE from SLE patients. These CSF biomarkers were also highly associated with disease activity. In addition, there were 6 molecules with remarkable changes in NPSLE CSF and hippocampus, which indicated the consistency of the environment in the brain and the promising molecular targets in the pathogenesis of NPSLE. CONCLUSIONS: The dual-chips screening strategy demonstrated KLK5, L-selectin, Trappin-2, TCN2, and CST6 as CSF biomarkers for diagnosing NPSLE.

Plasticizer DEHP exposure in early pregnancy affects the endometrial decidualization in mice through reducing lncRNA RP24-315D19.10 expression. / 孕早期增塑剂DEHPæš´éœ²é™ä½Žé•¿é“¾éžç¼–ç RNA RP24-315D19.10è¡¨è¾¾å½±å“å­å®«å† è†œèœ•è†œååº”.

OBJECTIVES: To explore the effect of exposure to di (2-ethyl) hexyl phthalate (DEHP) in early pregnancy on endometrial decidualization in mice and its relation with lncRNA RP24-315D19.10. METHODS: Early pregnancy mice were exposed to DEHP (1000 mg·kg－1·d－1) to construct the model. The uterus was collected on day 6 of pregnancy to detect its effect on decidualization by HE staining and immunofluorescence. A decidualization induction model of mouse endometrial stromal cells exposed to DEHP (0.1, 0.5, 2.5, 12.5, 62.5 µmol/L) was constructed. The changes of cell morphology were observed by light microscopy and phalloidin staining, and the expression of decidual reaction related molecular markers were detected by immunofluorescence, realtime RT-PCR and Western blotting. The expression of RP24-315D19.10 in decidua tissue and cells was detected by realtime RT-PCR. Cellular localization of RP24-315D19.10 was determined by lncLocator database and RNA FISH. AnnoLnc2 database was used to predict miRNAs bound to RP24-315D19.10. RESULTS: The number of embryo implantation sites, uterine weight and uterine area were significantly lower in the DEHP exposed group than those in the control group, and the expression of the decidual reaction related molecular markers matrix metalloprotein 9 and homeobox A10 in the DEHP exposure group were also significantly lower than those in the control group (all P<0.05). With the increase of DEHP concentration, the expression of dtprp in decidua cells was gradually decreased. 2.5 µmol/L DEHP exposed stromal cells failed to be fully decidualized in vitro, andphalloidin staining showed abnormal cytoskeleton morphology. The expression levels of homeobox A10, bone morphogenetic protein 2 and proliferating cell nuclear antigen in the DEHP exposure group were significantly lower than those in the control group (all P<0.05). The expression of RP24-315D19.10 in DEHP exposed decidua tissue and cells was significantly reduced (both P<0.05). RP24-315D19.10 is mainly localized in the cytoplasm and RP24-315D19.10 might bind to 45 miRNAs, among them, miR-138-5p, miR-155-5p, miR-183-5p and miR-223-3p were associated with endometrial decidualization. CONCLUSIONS: DEHP exposure in early pregnancy may impair endometrial decidualization, and the damage may be associated with the down-regulation of RP24-315D19.10.

lincRNA RP24-315D19.10 promotes endometrial decidualization via upregulation of hnRNPA2B1.

Decidualization is a critical process for successful pregnancy. Disorders in this process are tightly associated with adverse pregnancy outcomes including spontaneous abortion. However, the potential molecular mechanisms of lncRNAs underlying this process are yet to be fully elucidated. In this study, we utilized RNA sequencing (RNA-seq) to identify differentially expressed lncRNAs during endometrial decidualization with a pregnant mouse model. Based on RNA-seq analysis, weighted gene co-expression network analysis (WGCNA) was performed to construct the lncRNA-mRNA co-expression network and to identify decidualization-associated hub lncRNAs. Through comprehensive screening and validation, we identified a novel lncRNA, RP24-315D19.10 and studied its function in primary mouse endometrial stromal cells (mESCs). lncRNA RP24-315D19.10 was highly expressed during decidualization. Knockdown of RP24-315D19.10 significantly inhibited mESCs decidualization in vitro. Mechanistically, RNA pull-down and RNA immunoprecipitation assays indicated that cytoplasmic RP24-315D19.10 could bind to hnRNPA2B1, thereby upregulating hnRNPA2B1 expression. Site-directed mutagenesis followed by biolayer interferometry analysis additionally illustrated that hnRNPA2B1 protein specifically bound to the ~-142ccccc~-167 region of the RP24-315D19.10 sequence. hnRPA2B1 deficiency impairs mESCs decidualization in vitro and we found that the inhibition in decidualization caused by RP24-315D19.10 knockdown was rescued by hnRNPA2B1 overexpression. Moreover, the expression of hnRNPA2B1 in spontaneous abortion women with deficient decidualization was significantly lower than that in healthy individuals, suggesting that hnRNPA2B1 may be involved in the development and progression of spontaneous abortion caused by decidualization failure. Collectively, our study indicates RP24-315D19.10 is a critical regulator for endometrial decidualization and RP24-315D19.10-regulated hnRNPA2B1 might be a new mark of decidualization-related spontaneous abortion.

Risk perception in the era of COVID-19 and related factors among nurses: A cross-sectional study.

AIM: Our study aimed at investigating the risk perception of nurses and related factors in the era of COVID-19 period. DESIGN: Cross-sectional study. METHODS: Four hundred and forty-two participants completed an online questionnaire relating to their risk perception on public health emergencies. Data were collected between 25 November 2020 and 1 December 2020. Kruskal-Wallis test, Mann-Whitney U test and Ordinal logistic regression analysis were used to examine factors impacting on risk perception. RESULTS: 65.2% of nurses' risk perception of COVID-19 was the moderate level even below the moderate level in the postperiod of COVID-19. Kruskal-Wallis test results indicated significant differences in gender, age, education status, working years, professional title, postlevel, COVID-19 contact experience, marital status and health status (p < 0.05). Ordinal logistic regression showed that gender, education status, professional title, work department, COVID-19 contact experience, character, health status and nursing work environment are associated with risk perception (p < 0.05). No Patient or Public Contribution.

Phosphorylation of Li-Rich Mn-Based Layered Oxides for Anion Redox and Structural Stability.

Li-rich Mn-based layered oxides are proposed to be candidates for high-energy Li-ion batteries. However, their large-scale production is still hampered by poor rate capability and severe voltage decay. It was mainly attributed to the irreversible oxygen loss, which induces transition metal ion migration, electrolyte consumption, and structural evolution. Herein, we propose an effective strategy of phosphorylation, in which the phosphate ion is induced to remove the surface labile oxygen. It urges the Li2MnO3 component to transform to the spinel-like structure and promotes the anionic redox process, thus facilitating lithium-ion diffusion and improving structural stability. As a result, the Li2MnO3 component is more prone to be activated, with the capacity increased by 18% in comparison with the pristine one. It also exhibits a superior capacity retention of 86.1% after 150 extended cycles and better rate performance delivering a capacity of 148.1 mA h g-1 even at 10 C. The effective phosphorylation opens a new way to tune anion redox chemistry and obtain structurally stable materials.

Effects of Five-Step Nutritional Interventions Conducted by a Multidisciplinary Care Team on Gastroenteric Cancer Patients Undergoing Chemotherapy: A Randomized Clinical Trial.

The present study aims to report a five-step nutritional intervention conducted by a multidisciplinary care team as well as to investigate its effects on the nutritional status and quality of life of gastroenteric cancer patients undergoing chemotherapy. A total of 176 patients with newly diagnosed gastroenteric cancer were enrolled in the observational study. The nutritional status of the patients was assessed using Patient-Generated Subjective Global Assessment (PG-SGA) and Nutritional Risk Screening-2002 (NRS-2002), and anthropometry and biological tests were performed. Patients were randomly divided into intervention group (n = 40) and control group (n = 38). Patients in the intervention group received five-step nutrition intervention, while the control group received routine nutrition management. In the newly diagnosed patients with gastroenteric cancer, 50% presented mild to moderate malnutrition, 29.5% presented severe malnutrition, while only 20.5% of patients were in good nutritional status. Nutritional interventions reduced the progression of malnutrition after 10 weeks. Anthropometric parameters increased as well as function and symptoms improved; therefore, controlled the decline in quality of life. To sum up, five-step nutritional interventions conducted by a multidisciplinary care team improved the nutritional status of patients with gastroenteric cancer undergoing chemotherapy, and showed positive impacts on quality of life.

[A cohort study of developing a death risk prediction model in patients with septic shock based on MIMIC-III database].

OBJECTIVE: To develop and validate a model for predicting death risk in septic shock patients using LASSO-Logistic methods. METHODS: A retrospective cohort study was conducted. Based on the open-source database Medical Information Mart for Intensive Care-III v1.4 (MIMIC-III v1.4), the septic shock patients meeting the Sepsis-3 criteria were included, and the data on demographic characteristics, major signs, laboratory examinations, hospitalization, and outcomes were extracted. Predictive variables were selected by LASSO regression and predictive models were derived using Logistic regression. The calibration of the model was evaluated using the Hosmer-Lemeshow test and discrimination was evaluated using the receiver operator characteristic curve (ROC curve). RESULTS: A total of 693 patients with septic shock were enrolled, in which 445 patients survived and 248 patients dead within 30 days and the mortality was 35.8%. Logistic regression model was constructed according to nine predictive variables and outcome variables screened by LASSO regression method, which showed that advanced age, Elixhauser index, blood lactic acid (Lac), K+ level and mechanical ventilation were associated with increased 30-day mortality [odds ratio (OR) and 95% confidence interval (95%CI) was 1.023 (1.010-1.037), 1.047 (1.022-1.074), 1.213 (1.133-1.305), 2.241 (1.664-3.057), 2.165 (1.433-3.301), respectively, all P < 0.01], and reduced systolic blood pressure (SBP), diastolic blood pressure (DBP), body temperature, and pulse oxygen saturation (SpO2) were also associated with increased 30-day mortality [OR (95%CI) was 0.974 (0.957-0.990), 0.972 (0.950-0.994), 0.693 (0.556-0.857), 0.971 (0.949-0.992), respectively, all P < 0.05]. The calibration curve showed that the predicted risk of septic shock death risk prediction model had good agreement with the real situation. ROC curve analysis showed that the area under the ROC curve (AUC) of the prediction model was 0.839 (95%CI was 0.803-0.876), which could distinguish patients at risk of death from those at risk of survival. CONCLUSIONS: The septic shock death risk prediction model has a good ability to identify the 30-day mortality risk of septic shock patients, including nine hospital readily variables (age, Elixhauser index, mechanical ventilation, Lac, K+, SBP, DBP, body temperature and SpO2). The model could be used by clinicians to calculate the risk of death in septic shock individuals.

PD-1/PD-L1 inhibitors plus anti-angiogenic agents with or without chemotherapy versus PD-1/PD-L1 inhibitors plus chemotherapy as second or later-line treatment for patients with advanced non-small cell lung cancer: A real-world retrospective cohort study.

Background: The aim of this study was to assessment the efficacy and safety of Programmed cell death protein 1 (PD-1)/Programmed cell death-Ligand protein 1 (PD-L1) inhibitors plus anti-angiogenic agents with or without chemotherapy versus PD-1/PD-L1 inhibitors plus chemotherapy as second or later-line treatment for patients with advanced non-small cell lung cancer. Methods: In this study, pre-treatment clinical and laboratory indicators from 73 patients with advanced non-small cell lung cancer were retrieved for retrospective analysis. According to the therapy regimes they received, the patients were separated into groups, PD-1/PD-L1 inhibitors plus chemotherapy group (PC group), PD-1/PD-L1 inhibitors plus anti-angiogenic agents' group (PA group), PD-1/PD-L1 inhibitors plus anti-angiogenic agents plus chemotherapy group (PAC group). Cox's proportional hazards regression model and Kaplan-Meier (KM) curves were used to assess the connection between treatment regimens and progression free survival (PFS) and overall survival (OS). In addition, the association of treatment regimens with the risk of disease progression and death was evaluated by subgroup analysis. Results: The average age of the enrolled patients was 58.2 ± 10.2 years and 75.3% were male. Multivariate analyses showed that patients in PA group (Disease progression: HR 0.4, P=0.005. Death: HR 0.4, P=0.024) and PAC group (Disease progression: HR 0.3, P=0.012. Death: HR 0.3, P=0.045) had a statistically significant lower hazard ratio (HR) for disease progression and death compared to patients in PC group. Kaplan-Meier analysis showed that patients in PA group (mPFS:7.5 vs.3.5, P=0.00052. mOS:33.1 vs.21.8, P=0.093) and PAC group (mPFS:5.1 vs.3.5, P=0.075. mOS:37.3 vs.21.8, P=0.14) had a longer PFS and OS compared to patients in PC group. In all the pre-defined subgroups, patients in PA and PAC groups showed a decreasing trend in the risk of disease progression and death in most subgroups. The patients in PA group (DCR:96.3% vs.58.3%, P=0.001) and PAC group (DCR:100% vs.58.3%, P=0.019) had a better disease control rate (DCR) than patients in PC group. Conclusion: PD-1/PD-L1 inhibitors plus anti-angiogenic agents with or without chemotherapy were superior to PD-1/PD-L1 inhibitors plus chemotherapy as second or later-line treatment in patients with advanced non-small cell lung cancer.

A mechanism for SARS-CoV-2 RNA capping and its inhibition by nucleotide analog inhibitors.

Decoration of cap on viral RNA plays essential roles in SARS-CoV-2 proliferation. Here, we report a mechanism for SARS-CoV-2 RNA capping and document structural details at atomic resolution. The NiRAN domain in polymerase catalyzes the covalent link of RNA 5' end to the first residue of nsp9 (termed as RNAylation), thus being an intermediate to form cap core (GpppA) with GTP catalyzed again by NiRAN. We also reveal that triphosphorylated nucleotide analog inhibitors can be bonded to nsp9 and fit into a previously unknown "Nuc-pocket" in NiRAN, thus inhibiting nsp9 RNAylation and formation of GpppA. S-loop (residues 50-KTN-52) in NiRAN presents a remarkable conformational shift observed in RTC bound with sofosbuvir monophosphate, reasoning an "induce-and-lock" mechanism to design inhibitors. These findings not only improve the understanding of SARS-CoV-2 RNA capping and the mode of action of NAIs but also provide a strategy to design antiviral drugs.