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Abstract Autophagy-mediated chemoresistance is the core mechanism for therapeutic failure and poor prognosis in breast cancer. Breast cancer chemotherapy resistance is believed to be influenced by tumor-associated macrophages (TAMs), by which C-X-C motif chemokine ligand 1 (CXCL1) is the most abundant cytokine secreted. Yet, its role in mediating autophagy-related chemoresistance is still unknown. This study aimed to explore the molecular mechanisms by which TAMs/CXCL1 induced autophagy-mediated chemoresistance in breast cancer. It was found that TAMs/CXCL1 promoted chemoresistance of breast cancer cells through autophagy activation in vitro, and CXCL1 silence could enhance the chemosensitivity of paclitaxel-resistant breast cancer cells via autophagy inhibition. A high-throughput quantitative PCR chip and subsequent target validation showed that CXCL1 induced autophagy-mediated chemoresistance by inhibiting VHL-mediated IGF1R ubiquitination. The elevated IGF1R then promoted STAT3/HMGB1 signaling to facilitate autophagy. Additionally, TAMs/CXCL1 silence improved paclitaxel chemosensitivity by suppressing autophagy in breast cancer mice xenografts, and clinical studies further linked CXCL1 to IGF1R/HMGB1 signaling, as well as shorter free survival of recurrence. Taken together, these results not only uncover the crucial role of TAMs/CXCL1 signaling in mediating breast cancer chemoresistance through enhancing autophagy, but also shed novel light on the molecular mechanism of IGF1R/STAT3/HMGB1 pathway in regulating autophagy and its impact on cancer prognosis.

Abstract Background Previous studies have shown that the vitrification of metaphase II (MII) oocytes significantly represses their developmental potential. Abnormally increased oxidative stress is the probable factor; however, the underlying mechanism remains unclear. The walnut-derived peptide TW-7 was initially isolated and purified from walnut protein hydrolysate. Accumulating evidences implied that TW-7 was a powerful antioxidant, while its prospective application in oocyte cryopreservation has not been reported. Result Here, we found that parthenogenetic activation (PA) zygotes derived from vitrified MII oocytes showed elevated ROS level and delayed progression of pronucleus formation. Addition of 25 μmol/L TW-7 in warming, recovery, PA, and embryo culture medium could alleviate oxidative stress in PA zygotes from vitrified mouse MII oocytes, furtherly increase proteins related to histone lactylation such as LDHA, LDHB, and EP300 and finally improve histone lactylation in PA zygotes. The elevated histone lactylation facilitated the expression of minor zygotic genome activation (ZGA) genes and preimplantation embryo development. Conclusions Our findings revealed the mechanism of oxidative stress inducing repressed development of PA embryos from vitrified mouse MII oocytes and found a potent and easy-obtained short peptide that could significantly rescue the decreased developmental potential of vitrified oocytes, which would potentially contribute to reproductive medicine, animal protection, and breeding.

Abstract Continental intraplate volcano is an ideal probe to unravel the composition and structure of the deep Earth. The intraplate Changbaishan‐Tianchi volcano was one of the most hazardous eruptions on the Earth's planet. The long‐term activity of this volcano from the Pleistocene to 946 CE has erupted materials with a broad compositional range from basalt to rhyolite, which are expected to be associated with the continuous northeastward subduction of the Pacific plate, but the magma source remains controversial. In this paper, we present a comprehensive data set of in situ zircon Hf and O isotope data, combined with whole‐rock element and Sr‐Nd‐Pb isotope compositions, for selected eruptions of the Changbaishan‐Tianchi volcano, aiming to provide new insights into their magma source and the associated geodynamics. Radiogenic isotopic ratios and incompatible trace element compositions indicate that the erupted volcanic rocks at different stages, although with a varied differentiation degree, were derived from a common magma source characterized by a mixture of DM and EM1 end‐members. Zircon Hf and O isotopes are both relatively homogeneous for different lithologies and eruption stages, with the εHf(t) values varying between −5 and +5, and δ18O values between 3.58‰ and 5.97‰. Modeling of source mixing indicates that high‐temperature altered oceanic crust materials are an important component in the source of Changbaishan‐Tianchi volcano, likely derived from an ancient stagnant slab that has been reactivated by the subduction of the Pacific plate. This study demonstrates that the recycling of deeply subducted oceanic crust is potentially an important source and trigger for continental intraplate volcanism.

BackgroundOverexpression of monopolar spindle 1 (MPS1) and histone deacetylase 8 (HDAC8) is associated with the proliferation of liver cancer cells, so simultaneous inhibition of both MPS1 and HDAC8 could offer a promising therapeutic approach for the treatment of liver cancer. Dual-targeted MPS1/HDAC8 inhibitors have not been reported.MethodsA combined approach of pharmacophore modeling and molecular docking was used to identify potent dual-target inhibitors of MPS1 and HDAC8. Enzyme inhibition assays were performed to evaluate the optimal compound with the strongest inhibitory activity against MPS1 and HDAC8. The selectivity of MPH-5 for MPS1 and HDAC8 was assessed on a panel of 68 kinases and other histone deacetylases. Subsequently, molecular dynamics (MD) simulation verified the binding stability of the optimal compound to MPS1 and HDAC8. Ultimately, in vitro cellular assays and in vivo antitumor assays evaluated the antitumor efficacy of the most promising compound for the treatment of hepatocellular carcinoma.ResultsSix dual-target compounds (MPHs 1–6) of both MPS1 and HDAC8 were identified from the database using a combined virtual screening protocol. Notably, MPH-5 showed nanomolar inhibitory effect on both MPS1 (IC50 = 4.52 ± 0.21 nM) and HDAC8 (IC50 = 6.07 ± 0.37 nM). MD simulation indicated that MPH-5 stably binds to both MPS1 and HDAC8. Importantly, cellular assays revealed that MPH-5 exhibited significant antiproliferative activity against human liver cancer cells, especially HepG2 cells. Moreover, MPH-5 exhibited low toxicity and high efficacy against tumor cells, and it overcomes drug resistance to some extent. In addition, MPH-5 may exert its antitumor effects by downregulating MPS1-driven phosphorylation of histone H3 and upregulating HDAC8-mediated K62 acetylation of PKM2. Furthermore, MPH-5 showed potent inhibition of HepG2 xenograft tumor growth in mice with no apparent toxicity and presented favorable pharmacokinetics.ConclusionThe study suggests that MPH-5 is a potent, selective, high-efficacy, and low-toxicity antitumor candidate for the treatment of hepatocellular carcinoma.

Abstract The response of soil microorganisms and plants in soil ecosystems to biochar is well recognised. However, biochars’ impact on large soil animal, such as ants, is inadequately understood, with only limited studies focusing on the abundance and mortality rates of some specific ant species. In this study, soil physicochemical properties, and ant community diversity and functional characteristics were compared between experimental plots with and without biochar application. No significant differences in soil (soil physicochemical properties) or ants (ant community richness, species abundance, and morphological characteristics) were observed between the two plots before biochar application. However, the biochar-treated plot soil surface temperatures, pH, and soil water content were significantly higher after 48 weeks. Biochar application promoted Cardiocondyla nuda (by 426%) and Formica japonica abundance (by 93%), but decreased Solenopsis invicta invasive ant species richness (by 54%), consistent with the fact that changes in soil properties were more beneficial to the former two species. In addition, in biochar-treated plots, F. japonica and S. invicta generally showed larger body size (18% and 6.7%), larger eyes (2.7% and 4.0%), and longer femurs (6.3% and 7.9%), which enabled them to respond better to potential barriers, such as plants. Our results highlighted that, besides species abundance and community structure, certain ant functional morphological indicators were also informative in evaluating biochar ecological implications. Graphical abstract

Abstract The main objective of this study was to investigate the incidence and characteristics of electrocardiographic abnormalities in patients with microtia, and to explore cardiac maldevelopment associated with microtia. This retrospective study analyzed a large cohort of microtia patients admitted to Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, from September 2017 to August 2022. The routine electrocardiographic reports of these patients were reviewed to assess the incidence and characteristics of abnormalities. The study included a total of 10,151 patients (5598 in the microtia group and 4553 in the control group) who were admitted to the Plastic Surgery Hospital of Peking Union Medical College. The microtia group had a significantly higher incidence of abnormal electrocardiographies compared to the control group (18.3% vs. 13.6%, P

Abstract Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and chemotherapy still serves as the cornerstone treatment functioning by inducing cytotoxic cell death. Notably, emerging evidence suggests that dying cell-released signals may induce cancer progression and metastasis by modulating the surrounding microenvironment. However, the underlying molecular mechanisms and targeting strategies are yet to be explored. Methods Apoptotic TNBC cells induced by paclitaxel or adriamycin treatment were sorted and their released extracellular vesicles (EV-dead) were isolated from the cell supernatants. Chemokine array analysis was conducted to identify the crucial molecules in EV-dead. Zebrafish and mouse xenograft models were used to investigate the effect of EV-dead on TNBC progression in vivo. Results It was demonstrated that EV-dead were phagocytized by macrophages and induced TNBC metastasis by promoting the infiltration of immunosuppressive PD-L1+ TAMs. Chemokine array identified CXCL1 as a crucial component in EV-dead to activate TAM/PD-L1 signaling. CXCL1 knockdown in EV-dead or macrophage depletion significantly inhibited EV-dead-induced TNBC growth and metastasis. Mechanistic investigations revealed that CXCL1EV-dead enhanced TAM/PD-L1 signaling by transcriptionally activating EED-mediated PD-L1 promoter activity. More importantly, TPCA-1 (2-[(aminocarbonyl) amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide) was screened as a promising inhibitor targeting CXCL1 signals in EVs to enhance paclitaxel chemosensitivity and limit TNBC metastasis without noticeable toxicities. Conclusions Our results highlight CXCL1EV-dead as a novel dying cell-released signal and provide TPCA-1 as a targeting candidate to improve TNBC prognosis. Graphical abstract

Abstract Endocrine therapy is standard for hormone receptor–positive (HR+) breast cancer treatment. However, current strategies targeting estrogen signaling pay little attention to estradiol metabolism in the liver and is usually challenged by treatment failure. In a previous study, we demonstrated that the natural compound naringenin (NAR) inhibited HR+ breast cancer growth by activating estrogen sulfotransferase (EST) expression in the liver. Nevertheless, the poor water solubility, low bio-barrier permeability, and non-specific distribution limited its clinical application, particularly for oral administration. Here, a novel nano endocrine drug NAR-cell penetrating peptide-galactose nanoparticles (NCG) is reported. We demonstrated that NCG presented specific liver targeting and increased intestinal barrier permeability in both cell and zebrafish xenotransplantation models. Furthermore, NCG showed liver targeting and enterohepatic circulation in mouse breast cancer xenografts following oral administration. Notably, the cancer inhibition efficacy of NCG was superior to that of both NAR and the positive control tamoxifen, and was accompanied by increased hepatic EST expression and reduced estradiol levels in the liver, blood, and tumor tissue. Moreover, few side effects were observed after NCG treatment. Our findings reveal NCG as a promising candidate for endocrine therapy and highlight hepatic EST targeting as a novel therapeutic strategy for HR+ breast cancer. Graphical Abstract

AbstractContext Coix [Coix lacryma-jobi L. var. mayuen (Roman.) Stapf (Poaceae)], a crop of medicinal and edible significance, contains coixol, which has demonstrated anticancer properties. However, the limited solubility of coixol restricts its potential therapeutic applications.Objective This study prepared a water-soluble coixol-β-cyclodextrin polymer (CDP) inclusion compound and evaluated its anticancer effect.Materials and methods The coixol-CDP compound was synthesized through a solvent-stirring and freeze-drying technique. Its coixol content was quantified using HPLC, and its stability was tested under various conditions. The anticancer effects of the coixol-CDP compound (4.129, 8.259, 16.518, and 33.035 mg/L for 24, 48, and 72 h) on the proliferation of non-small cell lung cancer (NSCLC) A549 cells were evaluated using an MTT assay; cell morphology was examined by Hoechst nuclear staining; apoptosis and cell cycle was detected by flow cytometry; and the expression of apoptosis-related proteins was assessed by Western blots.Results The water-soluble coixol-CDP inclusion compound was successfully prepared with an inclusion ratio of 86.6% and an inclusion yield rate of 84.1%. The coixol content of the compound was 5.63% and the compound remained stable under various conditions. Compared to coixol alone, all 24, 48, and 72 h administrations with the coixol-CDP compound exhibited lower IC50 values (33.93 ± 2.28, 16.80 ± 1.46, and 6.93 ± 0.83 mg/L) in A549 cells; the compound also showed stronger regulatory effects on apoptosis-related proteins.Discussion and conclusions These findings offer a new perspective for the potential clinical application of Coix in NSCLC therapy and its future research.

Purpose Breast cancer, the most common cancer in women globally, highlights the need for patient education. Despite many breast cancer discussions on TikTok, their scientific evaluation is lacking. Our study seeks to assess the content quality and accuracy of popular TikTok videos on breast cancer, to improve the dissemination of health knowledge. Methods On August 22, 2023, we collected the top 100 trending videos from TikTok's Chinese version using “breast cancer/breast nodule” as keywords. We noted their length, TikTok duration, likes, comments, favorites, reposts, uploader types, and topics. Four assessment tools were used: Goobie's six questions, the Patient Educational Material Assessment Tool (PEMAT), the Video Information and Quality Index (VIQI), and the Global Quality Score (GQS). These instruments evaluate videos based on content, informational integrity, and overall quality. Results Among the 100 videos, content quality was low with Goobie's questions mostly scoring 0, except for management at 1.0 (QR 1.0). PEMAT scores were moderate: 54.1 (QR 1.6) for sum, 47.0 (QR 18.8) for PEMAT-A, and 52.3 (QR 11.7) for PEMAT-U. Regarding the quality of information, the VIQI (sum) median was 14.1 (QR 0.2). Additionally, the median GQS score was 3.5 (QR 0.1). Medical professionals’ videos focused on breast cancer stages, while patient videos centered on personal experiences. Patient videos had lower content and overall quality compared to those by medical professionals (PEMAT, GQS: P

Abstract Inflammation may contribute to postoperative cardiac complications and ketorolac, an anti‐inflammatory agent inhibiting cyclooxygenase (COX), shows promise in enhancing cardiac graft patency by suppressing endothelial cell proliferation in animal studies. However, the safety of postoperative ketorolac use remains controversial. This study investigates the association between early ketorolac application and complications following cardiac surgery. Data from the Medical Information Mart for Intensive Care‐IV (MIMIC‐IV) database fueled this retrospective cohort study. The primary outcome is a composite of mortality, pulmonary insufficiency, severe acute kidney injury (AKI), hemorrhage or hematoma, infection, cardiogenic shock, and cerebrovascular infarction postcardiac surgery. Propensity score matching (PSM; 1:1 match, caliper 0.2), multivariate logistic regression, interaction stratification analysis, pairwise algorithmic, and overlap weight model analyses were employed. Following inclusion and exclusion criteria, 7143 patients who underwent valvular surgery or coronary artery bypass grafting (CABG) were included. PSM created a balanced cohort of 3270 individuals (1635 in the ketorolac group). The matched cohort exhibited an 8.1% overall rate of postoperative complications, with a lower composite outcome rate in patients receiving ketorolac within 48 h of surgery compared with those without (PSM, OR 0.70 [95% CI, 0.54–0.90]). Consistent associations were observed in total cohort analyses, sensitivity, and subgroup analyses. Early ketorolac use within 48 h post‐CABG or valvular procedures in adults is independently associated with a lower incidence of composite postoperative adverse events. Prospective trials are warranted to assess causality.

Background: STIL is an important cell cycle-regulating protein specifically recruited to the mitotic centrosome to promote the replication of centrioles in dividing cells. However, the potential role of STIL in the regulation of the biological functions of triple-negative breast cancer remains still unclear. Methods: We screened for differentially expressed STIL in the Cancer Genome Atlas database. The expression of STIL protein in 10 pairs of breast cancer tissues and adjacent normal tissues was further assessed by western blotting. Functionally, the knockdown and overexpression of STIL have been used to explore the effects of STIL on breast cancer cell proliferation, migration, and invasion. Mechanistically, RNA-seq, dual-luciferase reporter assay, chromatin immunoprecipitation assay, mass spectrometry, immunoprecipitation assay, and DNA pull-down assay were performed. Results: Breast cancer tissues and cells have higher STIL expression than normal tissues and cells. STIL knockdown impairs breast cancer cell growth, migration, and invasion, whereas STIL overexpression accelerates these processes. STIL promotes breast cancer progression by regulating FANCD2 expression, and exploration of its molecular mechanism demonstrated that STIL interacts with KLF16 to regulate the expression of FANCD2. Conclusions: Collectively, our findings identified STIL as a critical promoter of breast cancer progression that interacts with KLF16 to regulate Fanconi anemia pathway protein FANCD2. In summary, STIL is a potential novel biomarker and therapeutic target for breast cancer.

Abstract Triple‐negative breast cancer (TNBC) is the most aggressive breast cancer subtype and chemotherapy is the cornerstone treatment for TNBC. Regrettably, emerging findings suggest that chemotherapy facilitates pro‐metastatic changes in the tumour microenvironment. Extracellular vesicles (EVs) have been highly implicated in cancer drug resistance and metastasis. However, the effects of the EVs released from dying cancer cells on TNBC prognosis and corresponding therapeutic strategies have been poorly investigated. This study demonstrated that paclitaxel chemotherapy elicited CXCL1‐enriched EVs from apoptotic TNBC cells (EV‐Apo). EV‐Apo promoted the chemoresistance and invasion of co‐cultured TNBC cells by polarizing M2 macrophages through activating PD‐L1 signalling. However, baohuoside I (BHS) remarkably sensitized the co‐cultured TNBC cells to paclitaxel chemotherapy via modulating EV‐Apo signalling. Mechanistically, BHS remarkably decreased C‐X‐C motif chemokine ligand 1 (CXCL1) cargo within EV‐Apo and therefore attenuated macrophage M2 polarization by suppressing PD‐L1 activation. Additionally, BHS decreased EV‐Apo release by diminishing the biogenesis of intraluminal vesicles (ILVs) within multivesicular bodies (MVBs) of TNBC cells. Furthermore, BHS bound to the LEU104 residue of flotillin 2 (FLOT2) and interrupted its interaction with RAS oncogene family member 31 (RAB31), leading to the blockage of RAB31‐FLOT2 complex‐driven ILV biogenesis. Importantly, BHS remarkably chemosensitised paclitaxel to inhibit TNBC metastasis in vivo by suppressing EV‐ApoCXCL1‐induced PD‐L1 activation and M2 polarization of tumour‐associated macrophages (TAMs). This pioneering study sheds light on EV‐ApoCXCL1 as a novel therapeutic target to chemosensitise TNBC, and presents BHS as a promising chemotherapy adjuvant to improve TNBC chemosensitivity and prognosis by disturbing EV‐ApoCXCL1 biogenesis.

Background: Brain metastasis (BM) is a prevalent form of metastasis in lung adenocarcinoma (LUAD), necessitating investigations into the underlying mechanisms. Interleukin 34 (IL-34) and its receptors, macrophage colony-stimulating factor-1 receptor (CSF-IR), Syndecan-1 (SDC-1), and protein-tyrosine phosphatase zeta receptor (PTPRZ1), are known to play pivotal roles in the metastasis of malignant tumors, thereby holding promise as potential biomarkers for studying BM in LUAD. Methods: We performed immunohistochemistry to analyze the expression of IL-34, CSF-1R, SDC-1, and PTPRZ1 in 10 pairs of LUAD primary tissues and BMs, along with 96 unpaired primary tissues and 68 unpaired BMs. Subsequently, we evaluated the association between protein expression and the occurrence of BM. Furthermore, Kaplan-Meier survival curve analysis was conducted on both network and clinical data to explore the association between protein expression and patient prognosis and survival. Results: At the protein level, the expression of IL-34 and its receptors showed significant variation between paired primary tumors and BMs in 10 LUAD patients. The levels of IL-34, CSF-1R, and SDC-1 expression are typically elevated in brain metastatic lesions of LUAD compared to primary LUAD tumors. Furthermore, patients with high CSF-1R expression in primary LUAD are at a greater risk of developing brain metastases. High expression of IL-34 and CSF-1R in primary LUAD lesions indicated poor disease-free survival (DFS) and overall survival (OS), while high expression of SDC-1 indicated poor OS. Cox multivariate analysis further revealed that CSF-1R and IL-34+CSF-1R positivity independently affected LUAD OS. These findings were further substantiated in unpaired samples. Conclusions: Our results indicate significant alterations in the expression of IL-34 and its receptors, CSF-1R and SDC-1, between LUAD primary lesions and BMs, with increased expression observed in BMs. LUAD patients with positive CSF-1R expression in primary lesions exhibited a higher likelihood of developing BM, and high expression of IL-34, CSF-1R, and SDC-1 correlated with poor prognosis. These findings contribute novel insights towards identifying potential treatment or diagnostic targets for metastatic LUAD.

BackgroundCervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) are among the most prevalent gynecologic malignancies globally. The prognosis is abysmal once cervical cancer progresses to lymphatic metastasis. Anoikis, a specialized form of apoptosis induced by loss of cell adhesion to the extracellular matrix, plays a critical role. The prediction model based on anoikis-related genes (ARGs) expression and clinical data could greatly aid clinical decision-making. However, the relationship between ARGs and CESC remains unclear.MethodsARGs curated from the GeneCards and Harmonizome portals were instrumental in delineating CESC subtypes and in developing a prognostic framework for patients afflicted with this condition. We further delved into the intricacies of the immune microenvironment and pathway enrichment across the identified subtypes. Finally, our efforts culminated in the creation of an innovative nomogram that integrates ARGs. The utility of this prognostic tool was underscored by Decision Curve Analysis (DCA), which illuminate its prospective benefits in guiding clinical interventions.ResultsIn our study, We discerned a set of 17 survival-pertinent, anoikis-related differentially expressed genes (DEGs) in CESC, from which nine were meticulously selected for the construction of prognostic models. The derived prognostic risk score was subsequently validated as an autonomous prognostic determinant. Through comprehensive functional analyses, we observed distinct immune profiles and drug response patterns among divergent prognostic stratifications. Further, we integrated the risk scores with the clinicopathological characteristics of CESC to develop a robust nomogram. DCA corroborated the utility of our model, demonstrating its potential to enhance patient outcomes through tailored clinical treatment strategies.ConclusionThe predictive signature, encompassing nine pivotal genes, alongside the meticulously constructed nomogram developed in this research, furnishes clinicians with a sophisticated tool for tailoring treatment strategies to individual patients diagnosed with CESC.

Abstract Incomplete biomass burning produces considerable amounts of pyrogenic carbonaceous materials (PCMs), which are widely distributed in environmental matrices. Those PCMs undergo different environmental processes and consequently have non-negligible impacts on the global carbon cycle, ecological functions and environmental security. This review provided a comprehensive review of qualitative and quantitative methods, carbon sequestration capabilities and other ecosystem functions of PCMs. In addition, the generation mechanism and environmental health risks of emerging contaminants, especially persistent free radicals (EPFRs) and polycyclic aromatic hydrocarbons (PAHs) associated with PCMs were discussed. The results showed that the coexisting kerogen and coal may interfere with PCMs quantification, and that estimates of PCMs pools vary significantly due to methodological differences, natural variability and limited spatial coverage. The input of PCMs into soils increased soil carbon sequestration through direct carbon contribution and indirect negative priming effect on native SOC. In addition, PCMs can improve soil structure and properties and immobilize/degrade pollutants, which is conducive to the restoration of soil ecology. However, various contaminants associated with PCMs may threaten ecological safety, and thus their formation mechanisms and toxicological pathway to living organisms need to be further investigated. The development of standards for PCMs identification and quantification, application protocols of PCMs in pilot scale, and assessing the effects of PCMs on soil health deserve extended studies.

Abstract Plant lateral organs are often elaborated through repetitive formation of developmental units, which progress robustly in predetermined patterns along their axes. Leaflets in compound leaves provide an example of such units that are generated sequentially along the longitudinal axis, in species-specific patterns. In this context, we explored the molecular mechanisms underlying an acropetal mode of leaflet initiation in chickpea pinnate compound leaf patterning. By analyzing naturally occurring mutants multi-pinnate leaf1 (mpl1) that develop higher-ordered pinnate leaves with more than forty leaflets, we show that MPL1 encoding a C2H2-zinc finger protein sculpts a morphogenetic gradient along the proximodistal axis of the early leaf primordium, thereby conferring the acropetal leaflet formation. This is achieved by defining the spatiotemporal expression pattern of CaLEAFY, a key regulator of leaflet initiation, and also perhaps by modulating the auxin signaling pathway. Our work provides novel molecular insights into the sequential progression of leaflet formation.

Summary: Lunar-based equipment plays a vital role in the exploration of the moon because it undertakes the tasks of moving, transporting, digging, and so on. In order to control the gait of lunar-based equipment more precisely and guarantee mobile stability, the contact mechanism between its foot and lunar soil is worthy of in-depth study. In this paper, a contact model is proposed to predict the stress, strain, and displacement both on the contact surface and in the lunar soil when the foot is under vertical load. The axial stress in the proposed contact model is verified through the experiment and its accuracy in the lunar equipment is verified through simulation. The error is in a reasonable range and the influence depth of load conforms to the experiment results. This paper provides a relatively accurate model to describe the contact force between the lunar-based equipment’s foot and the lunar soil and will promote the research of lunar exploration.

Abstract Genetic defects have been increasingly found in cardiomyopathies, which are often present with mutations in cardiac contractile proteins. These congenital defects involve numerous intracellular pathways and share several critical clinical features, such as systolic or diastolic dysfunction fostering the various cardiomyopathic phenotypes. Hypertrophic cardiomyopathy and restrictive cardiomyopathy (RCM) share a common pathological feature, that is, diastolic dysfunction. Studies have shown that mutations of contractile proteins, especially myosin heavy chain and troponin, are tightly associated with diastolic dysfunction in patients with Cardiomyopathies (CMs), including pediatric patients with CM. Therapeutics, including green tea extract (epigallocatechin gallate) and mavacamten, interact directly with these contractile proteins and have shown promising results. This article will review recent and contemporary research on diastolic dysfunction in CMs, especially hypertrophic cardiomyopathy and RCM, which include their target proteins, mechanisms, clinical diagnosis, and potential therapies.

Abstract Background Hemifacial macrosomia (HFM, OMIM 164210) is a complex and highly heterogeneous disease. FORKHEAD BOX I3 (FOXI3) is a susceptibility gene for HFM, and mice with loss of function of Foxi3 did exhibit a phenotype similar to craniofacial dysmorphism. However, the specific pathogenesis of HFM caused by FOXI3 deficiency remains unclear till now. Method In this study, we first constructed a Foxi3 deficiency (Foxi3−/−) mouse model to verify the craniofacial phenotype of Foxi3−/− mice, and then used RNAseq data for gene differential expression analysis to screen candidate pathogenic genes, and conducted gene expression verification analysis using quantitative real‐time PCR. Results By observing the phenotype of Foxi3−/− mice, we found that craniofacial dysmorphism was present. The results of comprehensive bioinformatics analysis suggested that the craniofacial dysmorphism caused by Foxi3 deficiency may be involved in the PI3K‐Akt signaling pathway. Quantitative real‐time PCR results showed that the expression of PI3K‐Akt signaling pathway‐related gene Akt2 was significantly increased in Foxi3−/− mice. Conclusion The craniofacial dysmorphism caused by the deficiency of Foxi3 may be related to the expression of Akt2 and PI3K‐Akt signaling pathway. This study laid a foundation for understanding the function of FOXI3 and the pathogenesis and treatment of related craniofacial dysmorphism caused by FOXI3 dysfunction.

Increasing evidences have revealed a close relationship between various environmental exposures and reproductive health. The real-world complex exposure scenario along with intricate interactions effects of these exposures has high demands of exposome-wide association studies for human risk assessment. With the development of exposomic studies, applying hair exposome to link environmental factors and reproductive health outcomes has obvious potential advantages. However, the reliability of utilizing hair to characterize exposome is always of high concern for researchers. In this review, we briefly summarized studies about the effects of environmental exposures on several typical reproductive health outcomes, described state-of-the-art situation of applying hair exposome for reproductive health risk assessment, elucidated the advantages (e.g., containing abundant exposure factors, low expenses for sampling, and tracing exposure history), and proposed the unsolved issues in this area. We also conducted a comprehensive discussion about the reliability of various hair biomarkers and primarily established the biomarker databases. Finally, a standardized framework on using hair exposome for reproductive health study was proposed to provide fundamental approach for future studies. We concluded that it is promising to apply hair exposome to evaluate the effects of the environmental factors on human reproductive health.

A suspension of copper oxide nanoparticles (CuO NPs) is a mixture of dissolved and particulate Cu, the relative proportions of which highly depend on the water chemistry. However, the relationship between different proportions of particulate and dissolved Cu and the overall toxicity of CuO NPs is still unknown. This study investigated the response of Chlorella vulgaris to CuO NPs at varying solution pH and at different tannic acid (TA) additions, with a focus on exploring whether and how dissolved and particulate Cu contribute to the overall toxicity of CuO NPs. The results of the exposure experiments demonstrated the involvement of both dissolved and particulate Cu in inducing toxicity of CuO NPs, and the inhibition of CuO NPs on cell density of Chlorella vulgaris was found to be significantly (p

Abstract Background The 70-gene signature (70-GS, MammaPrint) test has been recommended by the main guidelines to evaluate prognosis and chemotherapy benefit of hormonal receptor positive human epidermal receptor 2 negative (HR + /Her2−) early breast cancer (BC). However, this expensive assay is not always accessible and affordable worldwide. Based on our previous study, we established nomogram models to predict the binary and quartile categorized risk of 70-GS. Methods We retrospectively analyzed a consecutive cohort of 150 female patients with HR + /Her2− BC and eligible 70-GS test. Comparison of 40 parameters including the patients’ medical history risk factors, imaging features and clinicopathological characteristics was performed between patients with high risk (N = 62) and low risk (N = 88) of 70-GS test, whereas risk calculations from established models including Clinical Treatment Score Post-5 years (CTS5), Immunohistochemistry 3 (IHC3) and Nottingham Prognostic Index (NPI) were also compared between high vs low binary risk of 70-GS and among ultra-high (N = 12), high (N = 50), low (N = 65) and ultra-low (N = 23) quartile categorized risk of 70-GS. The data of 150 patients were randomly split by 4:1 ratio with training set of 120 patients and testing set 30 patients. Univariate analyses and multivariate logistic regression were performed to establish the two nomogram models to predict the the binary and quartile categorized risk of 70-GS. Results Compared to 70-GS low-risk patients, the high-risk patients had significantly less cardiovascular co-morbidity (p = 0.034), more grade 3 BC (p = 0.006), lower progesterone receptor (PR) positive percentage (p = 0.007), more Ki67 high BC (≥ 20%, p

Abstract Background Familial exudative vitreoretinopathy (FEVR) is a genetic eye disorder that leads to abnormal development of retinal blood vessels, resulting in vision impairment. This study aims to identify pathogenic variants by targeted exome sequencing in 9 independent pedigrees with FEVR and characterize the novel pathogenic variants by molecular dynamics simulation. Methods Clinical data were collected from 9 families with FEVR. The causative genes were screened by targeted next-generation sequencing (TGS) and verified by Sanger sequencing. In silico analyses (SIFT, Polyphen2, Revel, MutationTaster, and GERP + +) were carried out to evaluate the pathogenicity of the variants. Molecular dynamics was simulated to predict protein conformation and flexibility transformation alterations on pathogenesis. Furthermore, molecular docking techniques were employed to explore the interactions and binding properties between LRP5 and DKK1 proteins relevant to the disease. Results A 44% overall detection rate was achieved with four variants including c.4289delC: p.Pro1431Argfs*8, c.2073G > T: p.Trp691Cys, c.1801G > A: p.Gly601Arg in LRP5 and c.633 T > A: p.Tyr211* in TSPAN12 in 4 unrelated probands. Based on in silico analysis and ACMG standard, two of them, c.4289delC: p.Pro1431Argfs*8 and c.2073G > T: p.Trp691Cys of LRP5 were identified as novel pathogenic variants. Based on computational predictions using molecular dynamics simulations and molecular docking, there are indications that these two variants might lead to alterations in the secondary structure and spatial conformation of the protein, potentially impacting its rigidity and flexibility. Furthermore, these pathogenic variants are speculated to potentially influence hydrogen bonding interactions and could result in an increased binding affinity with the DKK1 protein. Conclusions Two novel genetic variants of the LRP5 gene were identified, expanding the range of mutations associated with FEVR. Through molecular dynamics simulations and molecular docking, the potential impact of these variants on protein structure and their interactions with the DKK1 protein has been explored. These findings provide further support for the involvement of these variants in the pathogenesis of the disease.

Sodium-glucose linked transporter (SGLT-2) inhibitors are the most emerging glucose-lowering agents. Predominantly expressed in kidney, SGLT-2 is mainly distributed in upper part of proximal tubule. Mainly responsible for a reabsorption of filtered glucose, it accounts for over 80%-90% of glucose reabsorption. And SGLT-1 takes up the remainders. SGLT-2 inhibitors act at proximal tubule where they inhibit glucose and sodium reabsorption, thus enhancing urinary sugar excretion and lowering body glucose burden. Several studies have confirmed that SGLT-2 inhibitors might improve the prognoses of renal and cardiovascular disease in diabetics. Also there are significant protective effects on renal system of patients with non-diabetic kidney disease (NDKD). Therefore the induction protection mechanism of SGLT-2 inhibitors on non-diabetic chronic kidney disease (CKD) has attracted growing attention. This review summarized the latest researches of renoprotective mechanism of SGLT-2 inhibitors in NDKD.

Abstract Background Sepsis is an overwhelming reaction to infection that comes with high morbidity and mortality. It requires urgent interventions in order to improve outcomes. Intravenous immunoglobulins (IVIG) are considered as potential therapy in sepsis patients. Results of trials on IVIG as adjunctive therapy for sepsis have been conflicting due to the variability in population characteristics, country geography and drug dosage form in different studies. Methods A systematic article search was performed for eligible studies published up to January, 31, 2023, through the PubMed, Embase, Cochrane Library and Chinese National Knowledge Infrastructure database. The included articles were screened by using rigorous inclusion and exclusion criteria. Subgroup analyses were conducted according to different IVIG types, ages and economic regions. All analyses were conducted using Review Manager 5.4. Quality of studies and risk of bias were evaluated. Results In total, 31 randomized controlled trials were included with a sample size of 6,276 participants. IVIG could reduce the mortality (RR 0.86, 95% CI: 0.77–0.95, p = 0.005), the hospital stay (MD − 4.46, 95% CI: − 6.35 to − 2.57, p = 0.00001), and the APACHE II scores (MD − 1.65, 95% CI: − 2.89 to − 0.63, p = 0.001). Additionally, the results showed that IgM-enriched IVIG was effective in treating sepsis (RR 0.55, 95% CI: 0.40 − 0.76; p = 0.0003), while standard IVIG failed to be effective (RR 0.91, 95% CI: 0.81–1.02, p = 0.10). And the effect of IVIG in reducing neonatal mortality was inconclusive (RR 0.93, 95% CI: 0.81–1.05, p = 0.24), but it played a large role in reducing sepsis mortality in adults (RR 0.70, 95% CI: 0.57–0.86, p = 0.0006). Besides, from the subgroup of different economic regions, it indicated that IVIG was effective for sepsis in high-income (RR 0.89, 95% CI: 0.79–0.99, p = 0.03) and middle-income countries (RR 0.49, 95% CI: 0.28–0.84, p = 0.01), while no benefit was demonstrated in low-income countries (RR 0.56, 95% CI: 0.27–1.14, p = 0.11). Conclusions There is sufficient evidence to support that IVIG reduces sepsis mortality. IgM-enriched IVIG is effective in both adult and neonatal sepsis, while standard IVIG is only effective in adult sepsis. IVIG for sepsis has shown efficacy in high- and middle-income countries, but is still debatable in low-income countries. More RCTs are needed in the future to confirm the true clinical potential of IVIG for sepsis in low-income countries.

This study aimed to investigate the impact of different curing regimes on the strength of magnesium silicate hydrate cement (MSHC). The study employed various microscopic tests, including XRD, TG, SEM, and MIP, to analyze the underlying mechanisms. The research findings demonstrated that the use of short-term high-temperature curing under the two-stage variable temperature curing regime (TTC) significantly enhanced the early strength of MSHC, with a 3d strength exceeding 30 MPa. In contrast, under standard curing (SC), the strength was only around 2 MPa. The samples subjected to TTC did not exhibit the strength retrogression phenomenon observed under high-temperature curing in previous research, and a high-temperature curing duration of 48 h was found to be more beneficial for the strength development of MSHC. However, from a long-term perspective, the late-stage strength of the TTC samples was lower than that of the SC samples. Microscopic tests revealed that increasing the curing temperature substantially improved the early hydration degree of MSHC, reduced its porosity, and resulted in a more compact cement matrix, thereby enhancing the early strength. Under TTC, hydration continued in the later stage, leading to a decrease in porosity and promoting further strength growth. However, in the long-term, the microstructure of the TTC samples became loose, and the interface connection between silica particles and gel weakened. Compared to the SC samples, the TTC samples exhibited higher porosity, resulting in lower long-term strength.

Abstract The goals of this study were to investigate the incidence and characteristics of hematuria in patients with microtia, and to clarify that more attention should be paid to renal dysfunction in patients with microtia. We conducted a retrospective cohort study of a total 9447 children diagnosed with microtia (selected as study group, 7037 children) or pigmented nevus (selected as control group, 2410 children) at the Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College from January 2009 to June 2021. All of the routine urinalysis report of these children were reviewed to assess the incidence and characteristics of hematuria in each group. No statistically significant differences were observed when analyzing the overall incidence of hematuria between the study and control groups (P > 0.05). However, after grouping by sex, the incidence of hematuria in female children with microtia was significantly higher than that in femalecontrol group and no similar results were observed in the male patients. In addition, after further grouping by age in case group, the incidence of hematuria in girls of all ages with microtia was significantly higher than that in males with microtia (age 0–10:males: Girls = 1.89%:4.14%; age 0–5: males: Girls = 1.22%:3.73%; age 6–10: males:Girls = 1.97%:4.14%,P 0.05). Higher incidence of hematuria was observed in female children with microtia.

Abstract Whether the alternated microbiota in the gut contribute to the risk of allograft rejection (AR) and pulmonary infection (PI) in the setting of lung transplant recipients (LTRs) remains unexplored. A prospective multicenter cohort of LTRs was identified in the four lung transplant centers. Paired fecal and serum specimens were collected and divided into AR, PI, and event-free (EF) groups according to the diagnosis at sampling. Fecal samples were determined by metagenomic sequencing. And metabolites and cytokines were detected in the paired serum to analyze the potential effect of the altered microbiota community. In total, we analyzed 146 paired samples (AR = 25, PI = 43, and EF = 78). Notably, we found that the gut microbiome of AR followed a major depletion pattern with decreased 487 species and compositional diversity. Further multi-omics analysis showed depleted serum metabolites and increased inflammatory cytokines in AR and PI. Bacteroides uniformis, which declined in AR (2.4% vs 0.6%) and was negatively associated with serum IL-1β and IL-12, was identified as a driven specie in the network of gut microbiome of EF. Functionally, the EF specimens were abundant in probiotics related to mannose and cationic antimicrobial peptide metabolism. Furthermore, a support-vector machine classifier based on microbiome, metabolome, and clinical parameters highly predicted AR (AUPRC = 0.801) and PI (AUPRC = 0.855), whereby the microbiome dataset showed a particularly high diagnostic power. In conclusion, a disruptive gut microbiota showed a significant association with allograft rejection and infection and with systemic cytokines and metabolites in LTRs.

Chrysanthemum morifolium ‘11-C-2’ is a variety of chrysanthemums with high ornamental and tea value, experiencing significant market demand. However, as cultivation areas expand, issues such as viral infection, germplasm degradation, low proliferation coefficient, and slow proliferation rate arise, necessitating the establishment of an efficient in vitro regeneration system. This study, based on the principles of orthogonal experimental design, explored the regeneration system of Chrysanthemum cultivar ‘11-C-2’ using sterile seedlings. The research focused on three key stages: adventitious bud differentiation, rooting culture, and acclimatization–transplantation, employing shoot-bearing stem segments and leaves as explants. The findings indicate that the optimal explant for the Chrysanthemum ‘11-C-2’ sterile seedlings is the shoot-bearing stem segment. The best medium for adventitious bud differentiation was determined to be MS supplemented with 1.5 mg/L 6-BA and 0.5 mg/L NAA. Bud differentiation began on day 17 with a 100% differentiation rate, completing around day 48. The maximum differentiation coefficient reached 87, with an average of 26.67. The adventitious buds were then cultured for rooting in the optimal medium of 1/2 MS supplemented with 0.1 mg/L NAA. Rooting was initiated on day 4 and was completed by day 14, achieving a rooting rate of 97.62%. After a 5-day acclimatization under natural light, the rooted seedlings were transplanted into a growth substrate with a peat-to-vermiculite ratio of 1:2. The plants exhibited optimal growth, with a transplantation survival rate of 100%. The findings provide data support for the efficient large-scale propagation of ‘11-C-2’ and lay the foundation for germplasm preservation and genetic transformation research of tea chrysanthemums.

Abstract The structure and properties of phytoglycogen and glycogen subjected to acid hydrolysis was investigated using amylopectin as a reference. The degradation took place in two stages and the degree of hydrolysis was in the following order: amylopectin > phytoglycogen > glycogen. Upon acid hydrolysis, the molar mass distribution of phytoglycogen or glycogen gradually shifted to the smaller and broadening distribution region, whereas the distribution of amyopectin changed from bimodal to monomodal shape. The kinetic rate constant for depolymerization of phytoglycogen, amylopectin, and glycogen were 3.45 × 10−5/s, 6.13 × 10−5/s, and 0.96 × 10−5/s, respectively. The acid-treated sample had the smaller particle radius, lower percentage of α-1,6 linkage as well as higher rapidly digestible starch fractions. The depolymerization models were built to interpret the structural differences of glucose polymer during acid treatment, which would provide guideline to improve the structure understanding and precise application of branched glucan with desired properties.

Abstract Left ventricle ejection fraction (LVEF) is still not well acknowledged in classification of pediatric heart failure (PHF). We categorized PHF according to LVEF and aimed to determine the role of LVEF in PHF classification. Patients who were diagnosed with HF were divided into three groups according to their LVEF values: HF with reduced ejection fraction (HFrEF), HF with mildly reduced ejection fraction (HFmrEF), and HF with preserved ejection fraction (HFpEF). The clinical information of PHF patients was compared among those three groups. Factors associated with HF with improved EF (HFimpEF) and risk factors for in‐hospital death in PHF patients were analyzed. A total number of 1228 cases were collected. The proportion of HF patients with preserved LVEF (66.3%) was significantly higher than those with mildly reduced LVEF (21.7%) and reduced LVEF (12%). Clinical features such as age, B‐type natriuretic peptide (BNP) level, Ross classification, and E/A abnormal proportion in HF children with different LVEF value were statistically different. HF patients with younger age, lower BNP levels, minor cardiac dysfunction and less E/A abnormality could be found with higher LVEF value. The proportion of primary disease in PHF was largely different in HFpEF, HFmrEF and HFrEF groups. Medication treatment was more aggressive in patients with lower LVEF, except for vasoactive drugs. Children with congenital heart disease in HFrEF group were more prone to develop into HFimpEF. Sepsis, renal insufficiency, and an abnormal E/A ratio are risk factors for in‐hospital death of HF children. Clinical features of PHF could be well classified by LVEF, which is an essential and helpful indicator for PHF classification and management.

ABSTRACTHuman papillomavirus (HPV) has a great impact on world health. Vaccination is among the most important methods of preventing HPV infection. This study investigated Chinese male college students’ knowledge of, attitude toward, and acceptance of the 9vHPV vaccine and the independent predictors. An online cross-sectional study was conducted among male college students at Chinese colleges and universities from March 12 to March 23, 2022. Based on a literature review of similar studies, a self-questionnaire was designed to investigate the students’ knowledge of, attitude toward, and acceptance of the 9vHPV vaccine. Multivariate logistic regression analysis was performed to identify factors influencing their willingness to be vaccinated. In addition, the structural equation model was constructed. A total of 1,547 male college students completed the survey. Of all the students, 54.95% were unwilling to receive a 9vHPV vaccination, while only 45.05% expressed willingness. Multivariate logistic regression analysis revealed that the male college students willing to receive the vaccine included medical students, those in a romantic relationship, those whose relatives and friends had cervical cancer, those whose relatives and friends had received the 9vHPV vaccine, those supportive of promoting the vaccine for men, and those who would recommend the vaccine to their relatives and friends. Male college students exhibited high hesitancy toward the 9vHPV vaccine. Acceptance of the 9vHPV vaccine by male college students can be improved by deepening their accurate understanding of the vaccine and enhancing their positive attitude toward it.

Vortex pumps are usually designed based on its inner flow model. Currently, the flow models of vortex pump just consider flow rate at the design condition, which results in low efficiency under off-design flow rates in practical engineering. Therefore, the main objective of this article is to build a flow model that takes into account the impact of flow rates. To reveal the flow mechanism of vortex pump, we provide refined flow field simulations for a vortex pump. Performance experiments were conducted to validate the numerical simulation method. The study found that the vortex structure in the non-blade cavity can be regarded as a Rankine-like vortex. The inflow range is limited to the hub diameter (45 mm), smaller than the volute inlet diameter (85 mm). The action radius of the forced vortex gradually decreases from the impeller side to the inlet side. The maximum radius of the forced vortex on the impeller side is determined by the impeller diameter. As the flow rate increases, the action radius of the forced vortex on the inlet side gradually increases, while the axial length of the vortex in the inlet pipe gradually decreases. Based on the study of internal flow, a new flow model is proposed. HIGHLIGHTS The vortex structure in the non-blade cavity could be regarded as a kind of Rankine-like vortex.; The relationship between flow structure and physical parameters was established.; A more accurate and comprehensive flow model of the vortex pump was established.;

Introduction: Chronic psychological stress is a well-established risk factor for breast cancer development. Si-Ni-San (SNS) is a classical traditional Chinese medicine formula prescribed to psychological disorder patients. However, its action effects, molecular mechanisms, and bioactive phytochemicals against breast cancer are not yet clear. Objectives: This study aimed to explore the modulatory mechanism and bioactive compound of SNS in regulating estrogen metabolism during breast cancer development induced by chronic psychological stress. Methods: Mouse breast cancer xenograft was used to determine the effect of SNS on breast cancer growth and metastasis. Metabolomics analysis was conducted to discover the impact of SNS on metabolic profile changes in vivo. Multiple molecular biology experiments and breast cancer xenografts were applied to verify the anti-metastatic potentials of the screened bioactive compound. Results: SNS remarkably inhibited chronic psychological stress-induced breast cancer growth and metastasis in the mouse breast cancer xenograft. Meanwhile, chronic psychological stress increased the level of cholic acid, accompanied by the elevation of estradiol. Mechanistic investigation demonstrated that cholic acid activated farnesoid X receptor (FXR) expression, which inhibited hepatocyte nuclear factor 4α (HNF4α)-mediated estrogen sulfotransferase (EST) transcription in hepatocytes, and finally resulting in estradiol elevation. Notably, SNS inhibited breast cancer growth by suppressing estradiol level via modulating FXR/EST signaling. Furthermore, luciferase-reporting gene assay screened naringenin as the most bioactive compound in SNS for triggering EST activity in hepatocytes. Interestingly, pharmacokinetic study revealed that naringenin had the highest absorption in the liver tissue. Following in vivo and in vitro studies demonstrated that naringenin inhibited stress-induced breast cancer growth and metastasis by promoting estradiol metabolism via FXR/EST signaling. Conclusion: This study not only highlights FXR/EST signaling as a crucial target in mediating stress-induced breast cancer development, but also provides naringenin as a potential candidate for breast cancer endocrine therapy via promoting estradiol metabolism.

Abstract Polycystic ovarian syndrome (PCOS) is a complex multi-factorial syndrome associated with androgen excess and anovulatory infertility. In the current study, we investigated the role of dihydrotestosterone-induced exosomal miR-379-5p release in determining the destiny of the developing follicles. Our hypothesis was that androgen regulates granulosa cell miR-379-5p content by facilitating its exosomal release in a follicular-stage dependent manner, a process which determines granulosa cell fate. Compared to human non-PCOS subjects, individuals with PCOS exhibit higher follicular fluid free testosterone levels, lower exosomal miR-379-5p content and granulosa cell proliferation. Androgenized rats exhibited lower granulosa cell miR-379-5p but higher phosphoinositide-dependent kinase-1 (PDK1; a miR-379-5p target) content and proliferation. Androgen reduced granulosa cell miR-379-5p content by increasing its exosomal release in preantral follicles, but not in antral follicles in vitro. Studies with an exosomal release inhibitor confirmed that androgen-induced exosomal miR-379-5p release decreased granulosa cell miR-379-5p content and proliferation. Ovarian overexpression of miR-379-5p suppressed granulosa cell proliferation, and basal and androgen-induced preantral follicle growth in vivo. These findings suggest that increased exosomal miR-379-5p release in granulosa cells is a proliferative response to androgenic stimulation specific for the preantral stage of follicle development and that dysregulation of this response at the antral stage is associated with follicular growth arrest, as observed in human PCOS.

Abstract Objective The Coronavirus Disease 2019 (COVID-19) has brought severe damage to global health and socioeconomics. In China, traditional Chinese medicine (TCM) is the most important complementary and alternative medicine (CAM) and it has shown a beneficial role in the prevention and treatment of COVID-19. However, it is unknown whether patients are willing to accept TCM treatment. The objective of our study is to investigate the acceptance, attitude, and independent predictors of TCM among asymptomatic COVID-19 patients admitted to Shanghai fangcang hospital during the outbreak of the COVID-19 pandemic in Shanghai in 2022. Methods A cross-sectional study was conducted on asymptomatic COVID-19 patients in the largest fangcang hospital in Shanghai, China, from April 22, 2022, to May 25, 2022. Based on the literature review of previous similar studies, a self-report questionnaire was developed to assess the patients’ attitude and acceptance of TCM, and a multivariate logistic regression analysis was conducted to determine the independent predictors of TCM acceptance. Results A total of 1,121 patients completed the survey, of whom 91.35% were willing to accept CAM treatment whereas 8.65% of participants showed no willingness. Multivariate logistic regression analysis revealed that the patients who have received two doses of COVID-19 vaccine (OR = 2.069, 95%CI: 1.029–4.162, P = 0.041 vs. not received), understood the culture of TCM (OR = 2.293, 95%CI: 1.029–4.162, P = 0.014 vs. not understood), thought the TCM treatment is safe (OR = 2.856, 95%CI: 1.334–6.112, P = 0.007 vs. not thought), thought the TCM treatment is effective (OR = 2.724, 95%CI: 1.249–5.940, P = 0.012 vs. not thought), and those who informed their attending physician if using TCM for treatment (OR = 3.455, 95%CI:1.867–6.392, P

The non-destructive measurement of fish is an important link in intelligent aquaculture, and realizing the accurate estimation of fish mass is the key to the stable operation of this link. Taking tilapia as the object, this study proposes an underwater tilapia mass estimation method, which can accurately estimate the mass of free-swimming tilapia under non-contact conditions. First, image enhancement is performed on the original image, and the depth image is obtained by correcting and stereo matching the enhanced image using binocular stereo vision technology. And the fish body is segmented by an SAM model. Then, the segmented fish body is labeled with key points, thus realizing the 3D reconstruction of tilapia. Five mass estimation models are established based on the relationship between the body length and the mass of tilapia, so as to realize the mass estimation of tilapia. The results showed that the average relative errors of the method models were 5.34%~7.25%. The coefficient of determination of the final tilapia mass estimation with manual measurement was 0.99, and the average relative error was 5.90%. The improvement over existing deep learning methods is about 1.54%. This study will provide key technical support for the non-destructive measurement of tilapia, which is of great significance to the information management of aquaculture, the assessment of fish growth condition, and baiting control.

Background: Banxia Xiexin decoction (BXD) is a classic traditional Chinese medicine (TCM) formula clinically used to treat chronic gastritis, gastric ulcers, gastric cancer, and many other gastrointestinal diseases. Long noncoding RNAs (lncRNAs) have been shown to play an important role in maintaining the malignant phenotype of tumors. However, no relevant studies have shown whether Banxia Xiexin decoction regulates and controls lncRNA TUC338, and the effect of TUC338 on the regulation of gastric cancer invasion and metastasis remains unclear. Purpose: To investigate the ability of the traditional Chinese medicine (TCM) Banxia Xiexin decoction (BXD) to inhibit the migration and invasion of human gastric cancer AGS cells by regulating the long noncoding RNA (lncRNA) TUC338. Methods: UHPLC‒MS/MS was used to analyze the chemical components of BXD. MTT was performed to determine the effects of BXD on the proliferation of AGS cells. qRT‒PCR was used to determine the expression of lncRNA TUC338 in gastric cancer tissues, paracarcinoma tissues, AGS human gastric cancer cells and GES-1 normal gastric mucosa cells and to evaluate the effects of BXD on the expression of lncRNA TUC338 in AGS cells. Lentiviral transfection was used to establish human gastric cancer AGS cells with knocked down lncRNA TUC338 expression. The effects of lncRNA TUC338 knockdown on the migration and invasion of AGS cells were observed by a scratch assay and Transwell migration assay, respectively. Western blotting was performed to analyze the effects of lncRNA TUC338 knockdown on epithelial-to-mesenchymal transition (EMT) in AGS cells. We performed quality control on three batches of BXD. We used UHPLC‒MS/MS to control the quality of three random batches of BXD used throughout the study. Results: Ninety-five chemical components were identified from the water extract of BXD, some of which have anticancer effects. The expression of TUC.338 in gastric cancer tissues was higher than that in para-carcinoma tissues. BXD inhibited the invasion and migration of gastric cancer cells by inhibiting the expression of lncRNA TUC338, which reduced EMT. After knockdown of lncRNA TUC338, the migration and invasion of AGS cells were reduced; the expression of the EMT-related protein E-cadherin was increased, and the expression of N-cadherin and vimentin was reduced. Conclusions: The present results suggest that BXD has potential as an effective treatment for gastric cancer through the inhibition of lncRNA TUC338 expression.

Mammalian apurinic/apyrimidinic endonuclease 1 (APE1, APEX1) is a multifunctional enzyme that maintains cellular homeostasis. It is involved in the base excision repair (BER) pathway and plays a key role in radiation-induced DNA damage response. However, the relationship between APE1-driven radiation resistance and pyroptosis in lung adenocarcinoma (LUAD) cells and the underlying molecular mechanisms remain unclear. We found that APE1 was significantly upregulated in LUAD tissues compared to para-carcinoma tissues and promoted the proliferation and invasion of LUAD cells in vitro and in vivo. Mechanistically, APE1 inhibited pyroptosis by inactivating the interferon gene stimulator (STING) pathway via direct interaction with AIM2 and DDX41, as detected by RNA-seq and co-immunoprecipitation. APE1 protects LUAD cells against radiation-induced damage and induces radio-resistance by targeting the STING pathway. It can induce pyroptosis and is negatively regulated by interactions with AIM2 and DDX41. Therefore, APE1 inhibitors should be considered to enhance the radiosensitivity of LUAD cells and improve patient prognosis and therapeutic outcomes. Thus, APE1 play a role in the tumor immune microenvironment and in tumor immunotherapy.

Chrysanthemums are one of the top ten most well-known traditional famous flowers in China and one of the top four cut flowers worldwide, holding a significant position in landscape gardening. The cold temperatures of winter restrict the cultivation, introduction, and application of chrysanthemum, resulting in high costs for year-round production. This severely impacts the ornamental and economic value of chrysanthemum. Therefore, research on cold tolerance is of vital importance for guiding chrysanthemum production and application. With the development of genomics, transcriptomics, metabolomics, and other omics approaches, along with high-throughput molecular marker technologies, research on chrysanthemum cold tolerance has been continuously advancing. This article provides a comprehensive overview of the progress in cold tolerance research from various aspects, including chrysanthemum phenotype, physiological mechanisms, the forward genetics, molecular mechanisms, and breeding. The aim is to offer insights into the mechanisms of cold tolerance in chrysanthemum and provide reference for in-depth research and the development of new cold tolerance chrysanthemum varieties.

Schizophrenia is a group of severe neurodevelopmental disorders. Identification of peripheral diagnostic biomarkers is an effective approach to improving diagnosis of schizophrenia. In this study, four datasets of schizophrenia patients’ blood or serum samples were downloaded from the GEO database and merged and de-batched for the analyses of differentially expressed genes (DEGs) and weighted gene co-expression network analysis (WCGNA). The WGCNA analysis showed that the cyan module, among 9 modules, was significantly related to schizophrenia, which subsequently yielded 317 schizophrenia-related key genes by comparing with the DEGs. The enrichment analyses on these key genes indicated a strong correlation with immune-related processes. The CIBERSORT algorithm was adopted to analyze immune cell infiltration, which revealed differences in eosinophils, M0 macrophages, resting mast cells, and gamma delta T cells. Furthermore, by comparing with the immune genes obtained from online databases, 95 immune-related key genes for schizophrenia were screened out. Moreover, machine learning algorithms including Random Forest, LASSO, and SVM-RFE were used to further screen immune-related hub genes of schizophrenia. Finally, CLIC3 was found as an immune-related hub gene of schizophrenia by the three machine learning algorithms. A schizophrenia rat model was established to validate CLIC3 expression and found that CLIC3 levels were reduced in the model rat plasma and brains in a brain-regional dependent manner, but can be reversed by an antipsychotic drug risperidone. In conclusion, using various bioinformatic and biological methods, this study found an immune-related hub gene of schizophrenia – CLIC3 that might be a potential diagnostic biomarker and therapeutic target for schizophrenia.

Microtia is a congenital deformity of the ear with an incidence of about 0.8–4.2 per 10,000 births. Total auricular reconstruction is the preferred treatment of microtia at present, and one of the core technologies is the preparation of cartilage scaffolds. Autologous costal cartilage is recognized as the best material source for constructing scaffold platforms. However, costal cartilage harvest can lead to donor-site injuries such as pneumothorax, postoperative pain, chest wall scar and deformity. Therefore, with the need of alternative to autologous cartilage, in vitro and in vivo studies of biomaterial scaffolds and cartilage tissue engineering have gradually become novel research hot points in auricular reconstruction research. Tissue-engineered cartilage possesses obvious advantages including non-rejection, minimally invasive or non-invasive, the potential of large-scale production to ensure sufficient donors and controllable morphology. Exploration and advancements of tissue-engineered cartilaginous framework are also emerging in aspects including three-dimensional biomaterial scaffolds, acquisition of seed cells and chondrocytes, 3D printing techniques, inducing factors for chondrogenesis and so on, which has greatly promoted the research process of biomaterial substitute. This review discussed the development, current application and research progress of cartilage tissue engineering in auricular reconstruction, particularly the usage and creation of biomaterial scaffolds. The development and selection of various types of seed cells and inducing factors to stimulate chondrogenic differentiation in auricular cartilage were also highlighted. There are still confronted challenges before the clinical application becomes widely available for patients, and its long-term effect remains to be evaluated. We hope to provide guidance for future research directions of biomaterials as an alternative to autologous cartilage in ear reconstruction, and finally benefit the transformation and clinical application of cartilage tissue engineering and biomaterials in microtia treatment.

BackgroundDepression increases the risk of breast cancer recurrence and metastasis. However, there lacks potential biomarkers for predicting prognosis in breast cancer. 5-hydroxytryptamine (5-HT) plays a key role in the pathogenesis and treatment of depression. In this study, we developed a prognostic signature based on 5-HT receptors (5-HTRs) and elucidated its potential immune regulatory mechanisms for breast cancer prognosis.MethodsOncomine, GEPIA, UALCAN, cBioPortal, Kaplan-Meier plotter, and TIMER were used to analyze differential expression, prognostic value, genetic alteration, and immune cell infiltration of HTRs in breast cancer patients. The model training and validation assays were based on the analyses of GSE1456 and GSE86166. A risk signature was established by univariate and multivariate Cox regression analyses. The transwell assay was utilized to verify the effect of the 5-HTRs expression on breast cancer invasion. Effects of HTR2A/2B inhibitor on CD8+ T cell proliferation and infiltration as well as apoptosis of 4T1 cells in the tumor microenvironment were detected by flow cytometry and TUNEL assay. Zebrafish and mouse breast cancer xenografts were used to determine the effect of HTR2A/2B inhibitor on breast cancer metastasis.ResultsThe expression levels of HTR1A, HTR1B, HTR2A, HTR2B, HTR2C, HTR4, and HTR7 were significantly downregulated in highly malignant breast cancer types. 5-HTRs were significantly associated with recurrence-free survival (RFS) in breast cancer patients. The genetic alteration of HTR1D, HTR3A, HTR3B, and HTR6 in breast cancer patients was significantly associated with shorter overall survival (OS). Finally, HTR2A and HTR2B were determined to construct the risk signature. The expression of HTR2A/2B was positively correlated with the infiltration of immune cells such as CD8+ T cells and macrophages. Furthermore, inhibition of HTR2A expression could suppress CD8+ T cell proliferation and enhance invasion and metastasis of breast cancer cells in both zebrafish and mice model.ConclusionsThe HTR2A/2B risk signature not only highlights the significance of HTRs in breast cancer prognosis by modulating cancer immune microenvironment, but also provides a novel gene-testing tool for early prevention of depression in breast cancer patients and lead to an improved prognosis and quality of life.

As an effective soil amendment, biochars require a comprehensive ecological evaluation before they can be widely used in agriculture because endogenous contaminants, such as environmentally persistent free radicals (EPFRs), certainly pose an ecological risk to soil invertebrates. In this study, Caenorhabditis elegans (C. elegans) was used as a model organism to investigate the neurotoxicity of two rice straw biochars pyrolyzed at 500 and 700 °C. After 24 h exposure to unwashed biochar, washed biochar, and leaching fluids (supernatants), the neurobehavioral parameters of C. elegans were determined in a liquid toxicity test. The results showed that the washed 700 °C biochar particles significantly impaired locomotion and prolonged the defecation interval at a biochar concentration of 4 g·well−1, while the unwashed biochar and supernatants caused no apparent impairment. Supporting this, electron paramagnetic resonance (EPR) results showed that the intensity of EPFRs in unwashed 700 °C biochar was stronger than that of the corresponding washed particles. This indicates that, in the liquid test, the EPR signal alone is not indicative of particle toxicity. The accessibility and activity of the EPFRs should be considered. Dissolved organic matter (DOM) was observed in the leaching fluids. The neurotoxic activity of the washed biochar was alleviated after the re-addition of leaching fluids to the washed biochar, suggesting that the dissolved organic materials modulate the reactivity of the EPFRs in the liquid phase. This study suggests that the leaching process may increase the risk of biochar when used in the field environment.

Abstract Double-sided lapping is an precision machining method capable of obtaining high-precision surface. However, during the lapping process of thin pure copper substrate, the workpiece will be warped due to the influence of residual stress, including the machining stress and initial residual stress, which will deteriorate the flatness of the workpiece and ultimately affect the performance of components. In this study, finite element method (FEM) was adopted to study the effect of residual stress-related on the deformation of pure copper substrate during double-sided lapping. Considering the initial residual stress of the workpiece, the stress caused by the lapping and their distribution characteristics, a prediction model was proposed for simulating workpiece machining deformation in lapping process by measuring the material removal rate of the upper and lower surfaces of the workpiece under the corresponding parameters. The results showed that the primary cause of the warping deformation of the workpiece in the double-sided lapping is the redistribution of initial residual stress caused by uneven material removal on the both surfaces. The finite element simulation results were in good agreement with the experimental results.

Background: Taxane-induced peripheral neuropathy (TIPN) is a debilitating adverse effect of cancer treatments with taxanes which may require a reduction or discontinuation chemotherapy and affect clinical and survival outcomes. A number of factors have contributed to the increasing prevalence of TIPN. Nonetheless, limited knowledge exists of potential prechemotherapy blood-based biochemical factors associated with TIPN development. Methods: We recruited breast cancer patients at seven cancer institutions in China. Participants aged 18 years or older with stage I to III breast cancer who scheduled to undergo primary neoadjuvant and adjuvant chemotherapy with taxanes were eligible. Eligible patients underwent patient-reported neuropathy assessments using the EORTC-CIPN20 questionnaire. Patients completed the questionnaire before commencing treatment and after every cycle. For every patient, we selected the highest TIPN toxicity score for analysis since the first cycle. The posttreatment TIPN severity was compared with blood-based biochemical factors within 30 days before commencing treatment. Independent samples t tests, Mann-Whitney U tests and linear regression were used to identify blood-based and clinical associations with TIPN development. Results: The study included 873 breast cancer participants who received paclitaxel, docetaxel or nanoparticle albumin-bound (nab)-paclitaxel. In the whole cohort, factors associated with higher TIPN toxicity scores were higher cumulative chemotherapy dose (β = 0.005; 95% CI, 0.004 to 0.006; P

Abstract Zircon double dating (ZDD) of comendite lava reveals an eruption age of 7.0 ± 0.9 ka for the Qixiangzhan eruption (QXZ), Changbaishan-Tianchi volcano, China/DPRK. This age is supported by new 40Ar/39Ar sanidine experiments and a previous age control from charcoal at the base of the QXZ. The revised age supports correlations with distal ash in Eastern China and Central Japan and establishes a significant (estimated at Volcanic Explosivity Index 5+) eruption that may provide a useful Holocene stratigraphic marker in East Asia. The new age indicates that the QXZ lava does not record a ca. 17 ka Hilina Pali/Tianchi geomagnetic field excursion but rather a heretofore unrecognized younger Holocene excursion at ca. 7–8 ka. Comparison between U–Th zircon crystallization and ZDD as well as 40Ar/39Ar sanidine ages indicates a protracted period of accumulation of the QXZ magma that extends from ca. 18 ka to the eruption age. This connotes an eruption that mixed remobilized early formed crystals (antecrysts) from prior stages of magma accumulation with crystals formed near the time of eruption. Based on these results, a recurrence rate of ca. 7–8 ka for the Changbaishan-Tianchi magma system is found over the last two major eruption cycles.

Abstract Background Blood derivatives therapy is a conventional clinical treatment, while the treatment for Alzheimer’s disease (AD) is relatively novel. To provide clinical references for treating AD, this meta-analysis was performed to evaluate the efficacy and safety of blood derivatives therapy on the patients with AD. Methods A systematic articles search was performed for eligible studies published up to December 6, 2021 through the PubMed, Embase, Cochrane library, ClinicalTrials.gov , Chinese National Knowledge Infrastructure database, and Wanfang databases. The included articles were screened by using rigorous inclusion and exclusion criteria. Study selection and data-extraction were performed by two authors independently. Random effects model or fixed effects model was used. Quality of studies and risk of bias were evaluated according to the Cochrane risk of bias tool. All analyses were conducted using Review Manager 5.4. The study was designed and conducted according to the Preferring Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Results A total of three plasma administrations (two plasma exchange and one young plasma infusion) and five intravenous immunoglobulin (IVIG) randomized controlled trials with a sample size of 1148 subjects diagnosed with AD were included. There was no significant difference in cognitive improvement and all-cause discontinuation between intervention and placebo groups (RR 1.10, 95% CI 0.79–1.54). And Intervention groups showed not a statistically significant improvement in cognition of included subjects measured by the ADAS-Cog (MD 0.36, 95% CI 0.87–1.59), ADCS-ADL (MD −1.34, 95% CI − 5.01–2.32) and NPI (MD 2.20, 95% CI 0.07–4.32) score compared to the control groups. IVIG is well tolerated for AD patients even under the maximum dose (0.4 g/kg), but it is inferior to placebo in Neuropsychiatric Inventory scale in AD patients (MD 2.19, 95% CI 0.02–4.37). Conclusions The benefits of blood derivatives therapy for AD are limited. It is necessary to perform well-designed randomized controlled trials with large sample sizes focusing on the appropriate blood derivatives for the specific AD sub-populations in the future. Systematic review registration PROSPERO CRD42021233886

In the past studies, it is shown that cardiac troponin I (cTnI, encoded by TNNI3), as a cytoplasmic protein, is an inhibitory subunit in troponin complex, and involves in cardiomyocyte diastolic regulation. Here, we assessed a novel role of cTnI as a nucleoprotein. Firstly, the nuclear translocation of cTnI was found in mouse, human fetuses and rat heart tissues. In addition, there were differences in percentage of intranuclear cTnI in different conditions. Based on weighted gene co-expression network analyses (WGCNA) and verification in cell experiments, a strong expression correlation was found between TNNI3 and Atp2a2, which encodes sarco-endoplasmic reticulum Ca2+ ATPase isoform 2a (SERCA2a), and involves in ATP hydrolysis and Ca2+ transient. TNNI3 gain and loss caused Atpa2a2 increase/decrease in a dose-dependent manner both in mRNA and protein levels, in vivo and in vitro. By using ChIP-sequence we demonstrated specific binding DNA sequences of cTnI were enriched in ATP2a2 promoter −239∼–889 region and the specific binding sequence motif of cTnI was analyzed by software as ''CCAT'', which has been reported to be required for YY1 binding to the promoter region of YY1-related genes. Moreover, it was further verified that pcDNA3.1 (−)-TNNI3 could express cTnI proteins and increase the promoter activity of Atp2a2 through luciferase report assay. In the end, we evaluated beat frequencies, total ATP contents, Ca2+ transients in TNNI3-siRNA myocardial cells. These findings indicated, for the first time, cTnI may regulate Atp2a2 in cardiomyocytes as a co-regulatory factor and participate in the regulation of intracellular Ca ions.