3-Amide-ß-carbolines block the cell cycle by targeting CDK2 and DNA in tumor cells potentially as anti-mitotic agents.

ß-Carboline alkaloids are natural and synthetic products with outstanding antitumor activity. C3 substituted and dimerized ß-carbolines exert excellent antitumor activity. In the present research, 37 ß-carboline derivatives were synthesized and characterized. Their cytotoxicity, cell cycle, apoptosis, and CDK2- and DNA-binding affinity were evaluated. ß-Carboline monomer M3 and dimer D4 showed selective activity and higher cytotoxicity in tumor cells than in normal cells. Structure-activity relationships (SAR) indicated that the amide group at C3 enhanced the antitumor activity. M3 blocked the A549 (IC50 = 1.44 ± 1.10 µM) cell cycle in the S phase and inhibited A549 cell migration, while D4 blocked the HepG2 (IC50 = 2.84 ± 0.73 µM) cell cycle in the G0/G1 phase, both of which ultimately induced apoptosis. Furthermore, associations of M3 and D4 with CDK2 and DNA were proven by network pharmacology analysis, molecular docking, and western blotting. The expression level of CDK2 was downregulated in M3-treated A549 cells and D4-treated HepG2 cells. Moreover, M3 and D4 interact with DNA and CDK2 at sub-micromolar concentrations in endothermic interactions caused by entropy-driven adsorption processes, which means that the favorable entropy change (ΔS > 0) overcomes the unfavorable enthalpy change (ΔH > 0) and drives the spontaneous reaction (ΔG < 0). Overall, these results clarified the antitumor mechanisms of M3 and D4 through disrupting the cell cycle by binding DNA and CDK2, which demonstrated the potential of M3 and D4 as novel antiproliferative drugs targeting mitosis.

Cooperation of Amphiphilicity and Smectic Order in Regulating the Self-Assembly of Cholesterol-Functionalized Brush-Like Block Copolymers.

Nanoparticle morphology significantly affects the application of nanometer-scale materials. Understanding nanoparticle formation mechanisms and directing morphological control in nanoparticle self-assembly processes have received wide attention. Herein, a series of brush-like amphiphilic liquid crystalline block copolymers, PChEMA m- b-POEGMA n, containing cholesteryl mesogens with different hydrophobic/hydrophilic block ratios were designed and synthesized. The self-assembly behaviors of the resulting PChEMA m- b-POEGMA n block copolymers in different solvents (tetrahydrofuran/H2O, 1,4-dioxane/H2O, and N, N-dimethylformamide) were investigated in detail. Desirable micellar aggregates with well-organized architectures, including short cylindrical micelles, nanofibers, fringed platelets, and ellipsoidal vesicles with smectic micellar cores, were observed in 1,4-dioxane/H2O with an increasing hydrophobic block ratio. Although both amphiphilicity and smectic order governed the self-assembly, these two factors were differently balanced in the different solvents. This unique supramolecular system provides a new strategy for the design of advanced functional nanomaterials with tunable morphologies.

[Effects of airborne fine particulate matters on pulmonary inflammation injury and Th17/Treg balance of sub-chronic exposure mice].

OBJECTIVE: To explore effects of fine particulate matters (PM 2.5) onpulmonary inflammation, and the changes of Th17/Treg balance as well as related cytokines. METHOD: Thirty-two C57BL/6 male mice were randomly divided into 4 groups including 1 saline control group and 3 PM2.5 exposure groups (1.5, 7.5 and 15 mg/kg BW, respectively). Each group received intratracheal instillation twice per week for 3 consecutive months. 24 hours after the last exposure, anaesthetize the mice with chloral hydrate, bronchoalveolar lavage fluid (BALF) was collected for inflammatory cells and cytokines analysis. The Th17- and Treg-related cytokines in BALF was measured by enzyme linked immunosorbent assay (ELISA). The level of the specific transcription factors of Th17 and Treg in lung tissue was determined by real-time PCR. Unlavaged left lung were fixed with 4% paraformaldehyde for histopathological detection. RESULTS: Th17-related cytokine IL-17 increased, but Treg-related cytokine IL-10 decreased significantly in BALF at 7.5 and 15 mg/kg BW PM2.5 exposure groups compared with control group (P < 0.05). Consistently, the relative mRNA expression of ROR-gammat (specific transcription factors of Th17) increased in a dose-response way, the relative mRNA expression of Foxp3 + (specific transcription factors of Treg) decreased in a dose-response way. CONCLUSION: Sub-chronic PM2.5 exposure caused persistent inflammation, immune injury and disordered the Th17/Treg imbalance as well as related cytokines.

Identification of the body fluid donor in mixtures through target mRNA cSNP sequencing.

In forensic practice, mixture stains containing various body fluids are common, presenting challenges for interpretation, particularly in multi-contributor mixtures. Traditional STR profiles face difficulties in such scenarios. Over recent years, RNA has emerged as a promising biomarker for body fluid identification, and mRNA polymorphism has shown excellent performance in identifying body fluid donors in previous studies. In this study, a massively parallel sequencing assay was developed, encompassing 202 coding region SNPs (cSNPs) from 45 body fluid/tissue-specific genes to identify both body fluid/tissue origin and the respective donors, including blood, saliva, semen, vaginal secretion, menstrual blood, and skin. The specificity was evaluated by examining the single-source body fluids/tissue and revealed that the same body fluid exhibited similar expression profiles and the tissue origin could be identified. For laboratory-generated mixtures containing 2-6 different components and mock case mixtures, the donor of each component could be successfully identified, except for the skin donor. The discriminatory power for all body fluids ranged from 0.997176329 (menstrual blood) to 0.99999999827 (blood). The concordance of DNA typing and mRNA typing for the cSNPs in this system was also validated. This cSNP typing system exhibits excellent performance in mixture deconvolution.

Effect of Dexmedetomidine on Postpartum Depression in Women With Prenatal Depression: A Randomized Clinical Trial.

Importance: Postpartum depression (PPD) is emerging as a major public health problem worldwide. Although the particular period and context in which PPD occurs provides an opportunity for preventive interventions, there is still a lack of pharmacologic prevention strategies for PPD. Objective: To assess the efficacy and safety of dexmedetomidine for prevention of PPD among women with prenatal depression undergoing cesarean delivery. Design, Setting, and Participants: This randomized clinical trial enrolled 338 women who screened positive for prenatal depression at 2 hospitals in Hunan, China from March 28, 2022, to April 16, 2023. Women with an Edinburgh Postnatal Depression Scale score of more than 9 who were 18 years of age or older and were scheduled for elective cesarean delivery were eligible. Interventions: Eligible participants were randomly assigned in a 1:1 ratio to either the dexmedetomidine group or the control group via centrally computer-generated group randomization. Dexmedetomidine, 0.5 µg/kg and 0.9% saline were intravenously infused for 10 minutes after delivery in the dexmedetomidine and control groups, respectively. After infusion, sufentanil or dexmedetomidine plus sufentanil was administered via patient-controlled intravenous analgesia for 48 hours in the control group and dexmedetomidine group, respectively. Main Outcomes and Measures: The primary outcome was positive PPD screening results at 7 and 42 days post partum, defined as a postpartum Edinburgh Postnatal Depression Scale score of more than 9. Analysis was on an intention-to-treat basis. Results: All 338 participants were female, with a mean (SD) age of 31.5 (4.1) years. Positive PPD screening incidence at 7 and 42 days post partum in the dexmedetomidine group vs the control group was significantly decreased (day 7, 21 of 167 [12.6%] vs 53 of 165 [32.1%]; risk ratio, 0.39 [95% CI, 0.25-0.62]; P < .001; day 42, 19 of 167 [11.4%] vs 50 of 165 [30.3%]; risk ratio, 0.38 [95% CI, 0.23-0.61]; P < .001). The dexmedetomidine group showed no significant difference in adverse events vs the control group (46 of 169 [27.2%] vs 33 of 169 [19.5%]; P = .10), but the incidence of hypotension increased (31 of 169 [18.3%] vs 16 of 169 [9.5%]; risk ratio, 2.15 [95% CI, 1.13-4.10]; P = .02). Conclusions and Relevance: Dexmedetomidine administration in the early postpartum period significantly reduced the incidence of a positive PPD screening and maintained a favorable safety profile. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2200057213.

Accuracy of intraoral scanning versus conventional impressions for partial edentulous patients with maxillary defects.

This study aimed to evaluate the accuracy of digital dental impressions obtained by intraoral scanning (IOS) for partial edentulous patients with maxillary defects by comparing them with conventional impression techniques. Ten subjects underwent an experimental procedure where three ceramic blocks were affixed to the healthy palate mucosa. Digital dental impressions were captured using IOS and subsequently imported into software. Conventional impressions obtained by silicone rubber were also taken and scanned. Linear distance and best-fit algorithm measurements were performed using conventional impression techniques as the reference. Twenty impressions were analyzed, which included 30 pairs of linear distances and 10 best-fit algorithm measurements. Regarding linear distance, paired two-sample t-test demonstrated no significant differences between IOS and model scanning in groups A and C, whereas significant differences were found in group B (P < 0.05). Additionally, ANOVA revealed significant differences among the groups (P < 0.05). No significant differences were found for the best-fit algorithm measurement of the dentition. IOS can provide accurate impressions for partial edentulous patients with maxillary defects and its accuracy was found to be comparable with conventional impression techniques. A functional impression may be needed to ensure accurate reproduction of soft and hard tissues in defect or flap areas.

Influence of language use on migrant workers' willingness to Urban settlement-based on the CLDS 2016 survey data.

In the framework of China new urbanization construction, migrant workers are of great significance for urban sustainable development. Based on the data of CLDS2016, we used the multi- -ordered Logistics model to effectively explore the influence of migrant workers ' language use on the urban settlement will. The research results showed that the mastery of the urban dialect and the language used after work had a significant impact on the willingness of the migrant workers in the urban settlement, while the language used at work had no significant impact on the migrant workers' willingness to settle in cities. Therefore, policy implications are proposed on improving the social integration of migrant workers, enhancing the sense of belonging, and removing the obstacles and doubts in the process of urban settlement.

Folk arts-inspired twice-coagulated configuration-editable tough aerogels enabled by transformable gel precursors.

Aerogels, as famous lightweight and porous nanomaterials, have attracted considerable attention in various emerging fields in recent decades, however, both low density and weak mechanical performance make their configuration-editing capability challenging. Inspired by folk arts, herein we establish a highly efficient twice-coagulated (TC) strategy to fabricate configuration-editable tough aerogels enabled by transformable gel precursors. As a proof of concept, aramid nanofibers (ANFs) and polyvinyl alcohol (PVA) are selected as the main components of aerogel, among which PVA forms a flexible configuration-editing gel network in the first coagulation process, and ANF forms a configuration-locking gel network in the second coagulation process. TC strategy guarantees the resulting aerogels with both high toughness and feasible configuration editing capability individually or simultaneously. Altogether, the resulting tough aerogels with special configuration through soft to hard modulation provide great opportunities to break through the performance limits of the aerogels and expand application areas of aerogels.

Smoking cessation and relapse-prevention interventions tailored for expectant and new fathers: protocol of a systematic review and network meta-analysis.

INTRODUCTION: Exposure of pregnant women and newborns to secondhand smoke (SHS) can lead to adverse maternal and neonatal health outcomes. Among expectant and new fathers, who are the main source of SHS exposure for pregnant women, new mothers and babies, smoking rates remain high. A partner's pregnancy potentially constitutes a critical period where expectant and new fathers are motivated to quit smoking. However, there is no consensus on the optimal form and delivery of smoking cessation and relapse-prevention interventions. We present a systematic review and network meta-analysis protocol that aims to synthesise and evaluate the effectiveness of smoking cessation and relapse-prevention interventions tailored for this population. METHODS AND ANALYSIS: To identify relevant studies, we will conduct a comprehensive search, in English and Chinese, of 10 electronic databases. The review will include randomised and quasi-randomised controlled trials that compare behavioural interventions (tailored and non-tailored) with/without the addition of pharmacotherapy with usual care, a minimal or placebo control for assisting expectant and new fathers to quit smoking and prevent smoking relapse. The primary outcome of interest is the self-reported and/or biochemically verified smoking abstinence at ≥1-month follow-up. Two reviewers will independently screen, select and extract relevant studies, and perform a quality assessment. Disagreements will be resolved by a consensus or third-party adjudication. The Cochrane Risk of Bias tool V.2 will be used to assess the risk of bias in the included studies. We will obtain the results of the systematic review through pooled quantitative analyses using a network meta-analysis. Sensitivity and subgroup analyses will be performed. ETHICS AND DISSEMINATION: Ethical approval is not required for this systematic review of published data. The findings will be disseminated via peer-reviewed publication. PROSPERO REGISTRATION NUMBER: CRD42022340617.

Predicting efficacy of sub-anesthetic ketamine/esketamine i.v. dose during course of cesarean section for PPD prevention, utilizing traditional logistic regression and machine learning models.

OBJECTIVE: Increasing researches supported that intravenous ketamine/esketamine during the perioperative period of cesarean section could prevent postpartum depression(PPD). With the effective rate ranging from 87.2 % to 95.5 % in PPD, ketamine/esketamine's responsiveness was individualized. To optimize ketamine dose/form based on puerpera prenatal characteristics, reducing adverse events and improving the total efficacy rate, prediction models were developed to predict ketamine/esketamine's efficacy. METHOD: Based on two randomized controlled trials, 12 prenatal features of 507 women administered the ketamine/esketamine intervention were collected. Traditional logistics regression, SVM, random forest, KNN and XGBoost prediction models were established with prenatal features and dosage regimen as predictors. RESULTS: According to the logistic regression model (ain = 0.10, aout = 0.15, area under the receiver operating characteristic curve, AUC = 0.728), prenatal Edinburgh Postnatal Depression Scale (EPDS) score ≥ 10, thoughts of self-injury and bad mood during pregnancy were associated with poorer ketamine efficacy in PPD prevention, whilst a high dose of esketamine (0.25 mg/kg loading dose+2 mg/kg PCIA) was the most effective dosage regimen and esketamine was more recommended rather than ketamine in PPD. The AUCvalidation set of KNN and XGBoost model were 0.815 and 0.651, respectively. CONCLUSION: Logistic regression and machine learning algorithm, especially the KNN model, could predict the effectiveness of ketamine/esketamine iv. during the course of cesarean section for PPD prevention. An individualized preventative strategy could be developed after entering puerpera clinical features into the model, possessing great clinical practice value in reducing PPD incidence.

Azobenzene/Acid Binary Systems for Colorimetric Humidity Sensing with Reversibility, High Sensitivity, and Tunable Colors.

Humidity sensors are important for humidity detection in many storage and manufacturing processes. Issues like sensibility, response rate, controllability, and material and preparation process costs need to be taken into consideration for practical applications. Herein, we report an investigation on a series of azobenzene/acid binary systems using easily accessible compounds, whose thin films display reversible and widely tunable color changes in response to humidity stimulation, with high sensitivity, fast color change, and recovery speed. The interesting properties for colorimetric humidity sensing are showcased with potential applications in dynamic art painting, smart windows, and respiration monitoring.

Is the R&D Expenditure of Listed Companies Green? Evidence from China's A-Share Market.

Whether the company's R&D expenditure has the green attribute is the focus of current environmental economics research. This paper empirically tests the relationship between R&D expenditure and CO2 emission intensity by taking Chinese A-share listed companies, from 2016 to 2020, as samples. The research found that the R&D expenditure of the company has a significant green effect of reducing its carbon dioxide emission intensity. Further research shows that the institutional investors play a mediating role in the relationship between R&D expenditure and CO2 emission intensity. And the "governance effect" of institutional investors is affected by "short-termism", which leads to the "myopic" of enterprises' management and urges them to invest in the short term, thus being detrimental to the company's environmental performance. In addition, the green attribute of R&D expenditure only exists in the company which has a high concentration of institutional investors, indicating that the institutional investors possess the ability to identify the green value of R&D investment. Extended discussion shows that the investment of R&D personnel plays a moderating role in the first half path of the above mediating mechanism, which weakens the negative relationship between institutional investors and R&D investment. This paper provides empirical evidence for the government to improve environmental performance at the enterprise level. The results of this study show that, in order to reduce the CO2 emission intensity of enterprises, the government should improve incentives for enterprise R&D, make rational use of the information identification ability of institutional investors, advocate long-term investment philosophy, and strengthen the training of R&D team leaders and technicians.

Association between geriatric nutrition risk index and bone mineral density in elderly Chinese people.

Malnutrition contributes to the occurrence of osteoporosis. This study showed that participants with higher GNRI values had higher levels of BMD. GNRIs were positively correlated with BMD and independently associated with total hip T-score. GNRIs may be a good indicator for identifying elderly who need further bone health nutritional support. PURPOSE: To evaluate the relationship between geriatric nutrition risk index (GNRI) and bone mineral density (BMD) in elderly Chinese people. METHODS: We recruited 1130 older adults (60-89 years old) between May 2018 and December 2019. Participants underwent clinical, laboratory, and densitometry examinations. Dual-energy x-ray absorptiometry densitometers and corresponding software were used to assess the BMD and T-scores of participants. Differences between study groups were assessed using one-way analysis of variance (ANOVA) for continuous variables and the chi-square test for categorical variables. Pearson's correlation coefficient was used to assess the correlation between two variables. Multivariate linear regressions with or without adjustments were constructed to explore the possible confounding variables. RESULTS: Individuals with higher GNRI values had higher total hip and lumbar spine T-scores (P < 0.001, P = 0.029, respectively). Pearson's correlation demonstrated that GNRIs were positively correlated with BMD at different anatomical sites, in both sexes but especially in women. A multiple regression demonstrated that GNRIs were independently associated with total hip T-score in both sexes (ß = 0.111 for men and 0.174 for women; P = 0.034 and 0.008, respectively). CONCLUSIONS: Elderly people with higher GNRI values had higher total hip and lumbar spine T-scores, which suggested that GNRI is closely related to BMD. This relationship is maintained at the total hip, even after fully adjusting for possible confounding variables, and consequently, it may be a good indicator for identifying older people who need further bone health nutritional support.

Smart supramolecular nanofibers and nanoribbons from uniform amphiphilic azobenzene oligomers.

A series of self-assembled 1D nanostructures, including straight and helix nanofibers, nanoribbons, and nanobelts, were fabricated from uniform amphiphilic azobenzene oligomers with tunable molecular weight and side chain functionality, promoted by multiple and cooperative supramolecular interactions. Additionally, the morphological transformation of the nanofibers was achieved during the photoisomerization process.

Smart azobenzene-containing tubular polymersomes: fabrication and multiple morphological tuning.

A fundamental challenge in nanomaterial science is to facilely fabricate nonspherical polymersomes. Here, several kinds of novel tubular polymersomes were fabricated via self-assembly of amphiphilic azobenzene-containing block copolymers. Besides, their shape could be tuned by multiple approaches including changes in the chemical structure, self-assembly conditions and external stimuli.

Effect of subclinical hyperthyroidism on osteoporosis: A meta-analysis of cohort studies.

OBJECTIVE: The effect of subclinical hyperthyroidism (SH) on bone mineral density (BMD) remains unclear, as do the linking mechanisms. This review aims to investigate the relationship between SH and bone loss in terms of the gender-dependent effects of SH on BMD. METHODS: The PUBMED, EMBASE, OVID, MEDLINE, SINOMED and COCHRANE LIBRARY databases (inception to August 12, 2019) were searched for cohort studies investigating the effects of SH on BMD. Eligible studies were subjected to qualitative and quantitative analysis using a random-effects model meta-analysis with the Cochrane systematic evaluation method. RESULTS: Twelve cohort studies involving 275,086 participants who were followed for 3 months to 13 years were included based on predefined inclusion and exclusion criteria. The results indicated that SH did not affect lumbar spine BMD in females or males. However, a significant reduction in femoral neck BMD was observed in females, but not in males. Further, there was a significant increase in hip fractures events in both females and males with SH. CONCLUSIONS: The present findings indicate that SH is significantly associated with hip fracture risk, and therefore, it is important to assess the risk of fractures in patients with SH. Future studies should focus on methods for accurately determining this risk in patients with SH and providing them with timely and efficient diagnosis and treatment.

RNA binding protein PUM2 promotes the stemness of breast cancer cells via competitively binding to neuropilin-1 (NRP-1) mRNA with miR-376a.

Others and ours studies have established the promoting roles of NRP-1 (neuropilin-1) in breast cancer, however, the underlying mechanisms by which NRP-1 is regulated are still confused. Here, bioinformatics analysis indicated that RNA binding protein PUM2 could bind to NRP-1 mRNA. Clinical samples showed that PUM2 expression was significantly increased in breast cancer tissues, negatively correlated with the overall survival and relapse-free survival of breast cancer patients, and positively correlated with NRP-1 expression. Meanwhile, PUM2 expression was remarkably increased in non-adherent spheroids. in vitro experiments demonstrated that PUM2 knockdown attenuated the stemness of breast cancer cells, evident by the decrease of spheroid formation capacity, ALDH1 activity and stemness marker expression. Mechanistically, RNA immunoprecipitation (RIP) and luciferase reporter analysis indicated that PUM2 competitively bound to NRP 3'UTR with miR-376a, which had been previously confirmed by us to suppress the stemness of breast cancer cells, and increased NRP-1 mRNA stability and expression. Furthermore, ectopic expression of NRP-1 or miR-376a knockdown rescued the inhibitory effects of NRP-1 knockdown on the stemness of breast cancer cells. Thus, our results suggest that PUM2 could facilitate the stemness of breast cancer cells by competitively binding to NRP-1 3'UTR with miR-376a.

Microbial osteoporosis: The interplay between the gut microbiota and bones via host metabolism and immunity.

The complex relationship between intestinal microbiota and host is a novel field in recent years. A large number of studies are being conducted on the relationship between intestinal microbiota and bone metabolism. Bone metabolism consisted of bone absorption and formation exists in the whole process of human growth and development. The nutrient components, inflammatory factors, and hormone environment play important roles in bone metabolism. Recently, intestinal microbiota has been found to influence bone metabolism via influencing the host metabolism, immune function, and hormone secretion. Here, we searched relevant literature on Pubmed and reviewed the effect of intestinal microbiota on bone metabolism through the three aspects, which may provide new ideas and targets for the clinical treatment of osteoporosis.