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Abstract Gastric cancer (GC) is a malignant disease worldwide. Angiopoietin-like protein 4 (ANGPTL4) plays a role in pathophysiological processes, including metabolic reprogramming, angiogenesis, proliferation, and metastasis. Current evidence shows conflicting findings regarding the role of ANGPTL4 in the progression of GC. ANGPTL4 in GC was confirmed through bioinformatic analysis and immunofluorescence staining. The impact of ANGPTL4 was subsequently validated in GC cell lines using various assays, including 5-ethynyl-2-deoxyuridine (EdU), 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Flow Cytometry (FCM), wound healing, transwell, tube formation, chorioallantoic membrane model, and nude mouse model assays. RNA-seq analysis, polymerase chain reaction (PCR), western blotting (WB), immunofluorescence (IF) and coimmunoprecipitation (co-IP) were conducted to determine the potential downstream mechanism of ANGPTL4. In SNU5 and MKN7 cells, ANGPTL4 was found to augment proliferation, migration, invasion, evasion of apoptosis, and angiogenesis. Conversely, in the AGS cell line, ANGPTL4 was observed to suppress these processes. Notably, the overexpression of ANGPTL4 in AGS cells led to the upregulation of LGALS7, which has emerged as a pivotal factor contributing to the manifestation of an anticancer phenotype induced by ANGPTL4. LGALS7, which is involved in the regulation of the hedgehog pathway and subsequent promotion of GC progression through various processes, such as proliferation, migration, apoptosis evasion, angiogenesis, and lymphangiogenesis, was found to contribute to the contradictory effects of ANGPTL4.

Abstract This study aimed to elucidate the role and underlying mechanisms of Peroxisome proliferator-activated receptor gamma (PPARγ) and its m6A methylation in renal ischemia-reperfusion (I/R) injury and ferroptosis of tubular epithelial cells (TECs). High-throughput transcriptome sequencing was performed on renal tissue samples from I/R injury models and sham-operated mice, complemented by in vivo and in vitro experiments focusing on the PPARγ activator Rosiglitazone and the manipulation of METTL14 and IGF2BP2 expression. Key evaluations included renal injury assessment, ferroptosis indicator measurement, and m6A methylation analysis of PPARγ. Our findings highlight the critical role of the PPARγ pathway and ferroptosis in renal I/R injury, with Rosiglitazone ameliorating renal damage and TEC ferroptosis. METTL14-mediated m6A methylation of PPARγ, dependent on IGF2BP2, emerged as a pivotal regulator of PPARγ expression, renal injury, and ferroptosis. This study reveals that PPARγ m6A methylation, orchestrated by METTL14 through an IGF2BP2-dependent mechanism, plays a crucial role in mitigating renal I/R injury and TEC ferroptosis. These insights offer promising avenues for therapeutic strategies targeting acute kidney injury.

Abstract Background To investigate the knowledge, attitudes, and practices (KAP) of individuals who underwent small incision lenticule extraction (SMILE) surgery and explore the influencing factors. Methods This cross-sectional study was conducted from June 21, 2023, to August 13, 2023, at Xiangyang Central Hospital. The participants were patients who had undergone SMILE surgery. The self-designed questionnaire had a Cronbach’s α = 0.849. Multivariable analyses were performed to determine the factors influencing the KAP scores. Results Finally, 485 valid questionnaires were analyzed. The median knowledge score was 14 (/17, 82.4%; IQR: 12–15). The median attitude score was 15 (/20, 75.0%; IQR: 14–16). The median practice score was 48 (/60, 80.0%; IQR: 42–54). The knowledge scores correlated to the attitude (r = 0.323, P

Abstract To accurately measure the vaginal mucosa thickness across different age groups using histopathologic techniques and investigate the factors that may influence the thickness changes. This study aims to provide clinicians with objective evidence of variations in vaginal mucosal thickness, facilitating personalized medical decisions for patients. A retrospective analysis was conducted on clinical data from 348 patients who underwent local vaginal wall resection at the West China Second University Hospital, Sichuan University, from January 2021 and May 2022. The thickness of vaginal mucosa, epithelium and lamina propria was measured precisely under the microscope. And the 10th, 25th, 50th, 75th, and 90th percentile values of vaginal mucosa thickness across different age groups were counted and charted a dot-line plot. The percentile values for vaginal mucosa thickness exhibited a decreasing trend with increasing age; vaginal mucosa thickness showed significant correlations with times of delivery (P = 0.031) and age (P

Abstract Background The hypoxic tumor microenvironment is a key factor that promotes metabolic reprogramming and vascular mimicry (VM) in ovarian cancer (OC) patients. ESM1, a secreted protein, plays an important role in promoting proliferation and angiogenesis in OC. However, the role of ESM1 in metabolic reprogramming and VM in the hypoxic microenvironment in OC patients has not been determined. Methods Liquid chromatography coupled with tandem MS was used to analyze CAOV3 and OV90 cells. Interactions between ESM1, PKM2, UBA2, and SUMO1 were detected by GST pull-down, Co-IP, and molecular docking. The effects of the ESM1-PKM2 axis on cell glucose metabolism were analyzed based on an ECAR experiment. The biological effects of the signaling axis on OC cells were detected by tubule formation, transwell assay, RT‒PCR, Western blot, immunofluorescence, and in vivo xenograft tumor experiments. Results Our findings demonstrated that hypoxia induces the upregulation of ESM1 expression through the transcription of HIF-1α. ESM1 serves as a crucial mediator of the interaction between PKM2 and UBA2, facilitating the SUMOylation of PKM2 and the subsequent formation of PKM2 dimers. This process promotes the Warburg effect and facilitates the nuclear translocation of PKM2, ultimately leading to the phosphorylation of STAT3. These molecular events contribute to the promotion of ovarian cancer glycolysis and vasculogenic mimicry. Furthermore, our study revealed that Shikonin effectively inhibits the molecular interaction between ESM1 and PKM2, consequently preventing the formation of PKM2 dimers and thereby inhibiting ovarian cancer glycolysis, fatty acid synthesis and vasculogenic mimicry. Conclusion Our findings demonstrated that hypoxia increases ESM1 expression through the transcriptional regulation of HIF-1α to induce dimerization via PKM2 SUMOylation, which promotes the OC Warburg effect and VM.

BackgroundExcessive inflammation poses significant risks to human physical and mental health. Astilbe grandis, a traditional Miao medicine, is renowned for its anti-inflammatory properties. However, the specific anti-inflammatory effects and mechanisms of many compounds within this plant remain unclear. This study aims to investigate the anti-inflammatory effects and mechanisms of two characteristic oleanane triterpenoids, 3α-acetoxyolean-12-en-27-oic acid (1) and 3β-acetoxyolean-12-en-27-oic acid (2), isolated from Astilbe grandis, using lipopolysaccharide (LPS)-induced Macrophages.MethodsThe anti-inflammatory effects and mechanisms of compounds 1 and 2 were investigated by establishing an LPS-induced inflammation model in RAW 264.7 cells and THP-1 cells. Nitric oxide (NO) levels were assessed using the Griess method. The concentrations of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1beta (IL-1β) were measured via enzyme-linked immunosorbent assay (ELISA). The expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) was determined using western blotting and quantitative real-time PCR (qRT-PCR). Additionally, the phosphorylation level of p65 in nuclear factor-kappa B (NF-κB) was assessed through western blotting. The nuclear translocation of NF-κB p65 was assessed through immunofluorescence staining. Finally, the binding affinity of the compounds to NF-κB p65 target was validated through molecular docking.ResultsCompounds 1 and 2 significantly inhibited the expression of NO, TNF-α, IL-6, IL-1β, COX-2, and iNOS in LPS-induced Macrophages. Mechanistically, they attenuated the activation of the NF-κB signaling pathway by downregulating the phosphorylation level and nuclear translocation of p65.ConclusionThis study elucidates the anti-inflammatory activities and potential mechanism of the characteristic oleanane triterpenoids with C-14 carboxyl group, compounds 1 and 2, in LPS-induced Macrophages by inhibiting the NF-κB signaling pathway for the first time. These findings suggest that these two compounds hold promise as potential candidates for anti-inflammatory interventions in the future.

Abstract Background Ovarian cancer (OC) is a malignant neoplasm that displays increased vascularization. Angiopoietin-like 4 (ANGPTL4) is a secreted glycoprotein that functions as a regulator of cell metabolism and angiogenesis and plays a critical role in tumorigenesis. However, the precise role of ANGPTL4 in the OC microenvironment, particularly its involvement in angiogenesis, has not been fully elucidated. Methods The expression of ANGPTL4 was confirmed by bioinformatics and IHC in OC. The potential molecular mechanism of ANGPTL4 was measured by RNA-sequence. We used a series of molecular biological experiments to measure the ANGPTL4-JAK2-STAT3 and ANGPTL4-ESM1 axis in OC progression, including MTT, EdU, wound healing, transwell, xenograft model, oil red O staining, chick chorioallantoic membrane assay and zebrafish model. Moreover, the molecular mechanisms were confirmed by Western blot, Co-IP and molecular docking. Results Our study demonstrates a significant upregulation of ANGPTL4 in OC specimens and its strong association with unfavorable prognosis. RNA-seq analysis affirms that ANGPTL4 facilitates OC development by driving JAK2-STAT3 signaling pathway activation. The interaction between ANGPTL4 and ESM1 promotes ANGPTL4 binding to lipoprotein lipase (LPL), thereby resulting in reprogrammed lipid metabolism and the promotion of OC cell proliferation, migration, and invasion. In the OC microenvironment, ESM1 may interfere with the binding of ANGPTL4 to integrin and vascular-endothelial cadherin (VE-Cad), which leads to stabilization of vascular integrity and ultimately promotes angiogenesis. Conclusion Our findings underscore that ANGPTL4 promotes OC development via JAK signaling and induces angiogenesis in the tumor microenvironment through its interaction with ESM1.

Abstract The development of suitable electron donors is critical to single-electron-transfer (SET) processes. The use of heteroatom-centered anions as super-electron-donors (SEDs) for direct SET reactions has rarely been studied. Here we show that heteroatom anions can be applied as SEDs to initiate radical reactions for facile synthesis of 3-substituted benzofurans. Phosphines, thiols and anilines bearing different substitution patterns work well in this inter-molecular radical coupling reaction and the 3-functionalized benzofuran products bearing heteroatomic functionalities are given in moderate to excellent yields. The reaction mechanism is elucidated via control experiments and computational methods. The afforded products show promising applications in both organic synthesis and pesticide development.

Abstract Background The aim of this study was to explore the associations of RIPK1 polymorphisms, plasma levels and mRNA expression with susceptibility to epithelial ovarian cancer (EOC) and clinical outcome. Methods Three hundred and nineteen EOC patients included in a 60-month follow-up program and 376 controls were enrolled. Two tag SNPs (rs6907943 and rs9392453) of RIPK1 were genotyped using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method. Plasma levels of RIPK1 and RIPK1 mRNA expression in white blood cells were determined by ELISA and qPCR, respectively. Results For rs9392453, significantly increased EOC risk was found to be associated with C allele (P = 0.002, OR = 1.49, 95%CI 1.15–1.92), and with CT/CC genotypes in the dominant genetic model (P = 0.006, OR = 1.54, 95%CI 1.12–2.08). CC haplotype (rs6907943-rs9392453) was associated with increased EOC susceptibility. CC genotype of rs6907943 and CT/CC genotypes of rs9392453 were associated with early onset (age ≤ 50 years) of EOC (OR = 2.5, 95%CI 1.03–5.88, and OR = 1.64, 95%CI 1.04–2.63, respectively). AC genotype of rs6907943 was associated with better overall survival of EOC patients in the over-dominant genetic model (P = 0.035, HR = 0.41, 95%CI 0.18–0.94). Multivariate survival analysis identified the AC genotype of rs6907943 as an independent protective factor for survival of early onset patients (P = 0.044, HR = 0.12, 95%CI 0.02–0.95). Compared to controls, significantly increased plasma levels of RIPK1 and reduced RIPK1 mRNA expression were observed in patients. Conclusions Our results suggest that tag SNPs of RIPK1, increased plasma levels of RIPK1 protein and reduced RIPK1 mRNA expression in white blood cells, may influence the susceptibility to EOC. SNP rs6907943 may be a useful marker to distinguish EOC patients with high risk of death.

Summary: The anaphase-promoting complex/cyclosome (APC/C) is a critical and tightly regulated E3 ligase that orchestrates the cellular life cycle by controlling the degradation of cell cycle regulators. An intriguing feature of this complex is an autoinhibition mechanism: an intrinsically disordered loop domain, Apc1-300L, blocks Cdc20 coactivator binding, yet phosphorylation of Apc1-300L counteracts this autoinhibition. Many such disordered loops within APC/C remain unexplored. Our systematic analysis of loop-deficient APC/C mutants uncovered a pivotal role for Apc8’s C-terminal loop (Apc8-L) in mitotic activation. Apc8-L directly recruits the CDK adaptor protein, Xe-p9/Cks2, positioning the Xe-p9-CDK-CycB complex near Apc1-300L. This stimulates the phosphorylation and removal of Apc1-300L, prompting the formation of active APC/CCdc20. Strikingly, without both Apc8-L and Apc3-L, the APC/C is rendered inactive during mitosis, highlighting Apc8-L’s synergistic role with other loops and kinases. This study broadens our understanding of the intricate dynamics in APC/C regulation and provides insights on the regulation of macromolecular complexes.

Summary: Cell cycle control relies on a delicate balance of phosphorylation with CDK1 and phosphatases like PP1 and PP2A-B55. Yet, identifying the primary substrate responsible for cell cycle oscillations remains a challenge. We uncover the pivotal role of phospho-regulation in the anaphase-promoting complex/cyclosome (APC/C), particularly through the Apc1-loop300 domain (Apc1-300L), orchestrated by CDK1 and PP2A-B55. Premature activation of PP2A-B55 during mitosis, induced by Greatwall kinase depletion, leads to Apc1-300L dephosphorylation, stalling APC/C activity and delaying Cyclin B degradation. This effect can be counteracted using the B55-specific inhibitor pEnsa or by removing Apc1-300L. We also show Cdc20’s dynamic APC/C interaction across cell cycle stages, but dephosphorylation of Apc1-300L specifically inhibits further Cdc20 recruitment. Our study underscores APC/C’s central role in cell cycle oscillation, identifying it as a primary substrate regulated by the CDK-PP2A partnership.

Summary: Although the small GTPase RAB37 acts as an organizer of autophagosome biogenesis, the upstream regulatory mechanism of autophagy via guanosine diphosphate (GDP)-guanosine triphosphate (GTP) exchange in maintaining retinal function has not been determined. We found that retinitis pigmentosa GTPase regulator (RPGR) is a guanine nucleotide exchange factor that activates RAB37 by accelerating GDP-to-GTP exchange. RPGR directly interacts with RAB37 via the RPGR-RCC1-like domain to promote autophagy through stimulating exchange. Rpgr knockout (KO) in mice leads to photoreceptor degeneration owing to autophagy impairment in the retina. Notably, the retinopathy phenotypes of Rpgr KO retinas are rescued by the adeno-associated virus-mediated transfer of pre-trans-splicing molecules, which produce normal Rpgr mRNAs via trans-splicing in the Rpgr KO retinas. This rescue upregulates autophagy through the re-expression of RPGR in KO retinas to accelerate GDP-to-GTP exchange; thus, retinal homeostasis reverts to normal. Taken together, these findings provide an important missing link for coordinating RAB37 GDP-GTP exchange via the RPGR and retinal homeostasis by autophagy regulation.

Abstract Background Pregnancy complicated with endometrial atypical hyperplasia, which is often observed during early pregnancy, is extremely rare. Case presentation The patient was a 30-year-old woman who had premature delivery at 30+ 1 weeks gestation, and endometrial atypical hyperplasia was discovered by placental examination. Conclusions For patients who undergo fertility-sparing treatment for endometrial atypical hyperplasia, the evaluation of the decidua via the placental pathological examination is particularly important. These examinations make a great clinical contribution to the early detection and diagnosis of endometrial atypical hyperplasia.

Abstract A carbene-catalyzed asymmetric access to chiral β-cyano carboxylic esters is disclosed. The reaction proceeds between β,β-disubstituted enals and aromatic thiols involving enantioselective protonation of enal β-carbon. Two main factors contribute to the success of this reaction. One involves in situ ultrafast addition of the aromatic thiol substrates to the carbon-carbon double bond of the enal substrate. This reaction converts almost all enal substrate to a Thiol-click Intermediate, significantly reducing aromatic thiol substrates concentration and suppressing the homo-coupling reaction of enals. Another factor is an in situ release of enal substrate from the Thiol-click Intermediate for the desired reaction to proceed effectively. The optically enriched β-cyano carboxylic esters from our method can be readily transformed to medicines that include γ-aminobutyric acids derivatives such as Rolipram. In addition to synthetic utilities, our control of reaction outcomes via in situ substrate modulation and release can likely inspire future reaction development.

Abstract Background This network meta-analysis aimed to assess the comparative efficacy and safety of combinations involving three cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and endocrine therapies (ETs) in patients with metastatic or advanced breast cancer (BC) who are hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-). Methods We initially identified relevant studies from previous meta-analyses and then conducted a comprehensive search of PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases to locate additional studies published between February 2020 and September 2021. Essential data were extracted, and a network meta-analysis was performed using R 4.1.1 software with a random-effects model. Furthermore, we assigned rankings to all available treatment combinations by calculating their cumulative probability. Results Data analysis included ten reports from nine studies. Pooled results demonstrated that each treatment combination significantly reduced the hazard risk of progression-free survival (PFS) compared to treatment with an aromatase inhibitor (AI) or fulvestrant alone. However, there were no differences observed in PFS or overall survival (OS) among the different treatment combinations. Additionally, patients receiving palbociclib plus AI and abemaciclib plus AI or fulvestrant experienced more severe adverse events (AEs), with hazard ratios (HRs) of 10.83 (95% confidence interval [CI] = 2.3 to 52.51) and 4.8 (95%CI = 1.41 to 16.21), respectively. The HR for ribociclib plus AI was 9.45 (95%CI = 2.02 to 43.61), and the HR for palbociclib plus fulvestrant was 6.33 (95%CI = 1.03 to 39.86). Based on the ranking probabilities, palbociclib plus fulvestrant had the highest probability of achieving superior PFS (37.65%), followed by abemaciclib plus fulvestrant (28.76%). For OS, ribociclib plus fulvestrant ranked first (34.11%), with abemaciclib plus fulvestrant in second place (25.75%). In terms of safety, palbociclib plus AI (53.98%) or fulvestrant (51.37%) had the highest probabilities of being associated with adverse events. Conclusions Abemaciclib plus fulvestrant or ribociclib plus AI appear to be effective and relatively safe for the treatment of HR+/HER2- metastatic or advanced BC patients. However, given the reliance on limited evidence, our findings require further validation through additional studies.

Many Cordyceps sensu lato species are used as traditional Chinese medicines. However, Cordyceps are entomopathogenic fungi in the family Clavicipitaceae of Ascomycota, and excessive harvesting severely disrupts natural habitat ecosystems. Artificial cultivation of Cordyceps fruiting bodies offers a viable strategy to protect the ecological environment and mitigate the depletion of wild resource. In this study, mononucleate hyphae were selected using DAPI fluorescence staining, the MAT1-1 and MAT1-2 strains of O. xuefengensis were successfully distinguished using loop-mediated isothermal amplification (LAMP). The chemical composition and bioactive components of fruiting bodies produced by these strains were compared. Results showed that the levels of adenosine, thymidine, adenine, guanosine, uridine, total amino acids, and total essential amino acids in the fruiting bodies of MAT1-1 strains were 1.31 mg/g, 0.15 mg/g, 0.26 mg/g, 2.40 mg/g, 2.34 mg/g, 270.3 mg/g, and 102.5 mg/g, respectively, which were significantly higher than those in the MAT1-2 sample. Contrastingly, the fruiting bodies of MAT1-2 strains contained higher levels of mannose and polysaccharides, at 11.7% and 12.2%, respectively. The levels of toxic elements such as Al, Pb, As, and Hg in the MAT1-1 fruiting bodies were 1.862 mg/kg, 0.0848 mg/kg, 0.534 mg/kg, and 0.0054 mg/kg, respectively, which were markedly lower than those in the MAT1-2 fruiting bodies.

Gastrodia elata, commonly known as Tian Ma, is a perennial mycoheterotrophic orchid. Qianyang Tian Ma (QTM), a geographical indication agricultural product from Hongjiang City, Hunan Province, China, is primarily characterized by the red variety, G. elata f. elata. A severe outbreak of tuber brown rot disease was documented in QTM during the harvesting season in Hunan. The fungal pathogen associated with the disease was isolated on potato saccharose agar (PSA) and identified through morphological and phylogenetic analyses. Pathogenicity tests were performed on healthy tubers of G. elata f. elata. The results showed that the representative isolate, named TMB, produced white hyphal colonies with a ring structure, broom-like phialides, partially curved ellipsoidal conidia, and orange–yellow spherical ascocarps on PSA. Phylogenetic analysis of the ITS, LSU, rpb2 and tub2 sequences using Bayesian and maximum-likelihood methods identified the isolate TMB as Clonostachys rosea, based on morphological and phylogenetic data. Pathogenicity tests revealed typical disease symptoms on healthy G. elata tubers 15 days post-inoculation with the isolate TMB. C. rosea is known to cause diseases in economically important crops, but there are no reports of its occurrence on G. elata f. elata in China. This study provides valuable insights into the occurrence, prevention, and control of brown rot disease in G. elata f. elata.

Breast cancer is the most frequent form of cancer in women and the primary cause of cancer-related deaths globally. DNA methylation and demethylation are important processes in human tumorigenesis. Ten-eleven translocation 3 (TET3) is a DNA demethylase. Prior research has demonstrated that TET3 is highly expressed in various human malignant tumors. However, the exact function and mechanism of TET3 in breast cancer remain unclear. In this study, we investigated TET3 expression in breast cancer and its correlation with clinicopathological characteristics of breast cancer patients. The results presented that TET3 expression was significantly increased in breast cancer and associated with the PAM50 subtype. Subsequently, we performed receiver operating characteristic, survival, and Cox hazard regression analyses. These results suggest that TET3 expression is associated with a poor prognosis and may be an indirect independent prognostic indicator in breast cancer. We also established a protein-protein interaction (PPI) network of TET3 and executed enrichment analyses of TET3 co-expressed genes, revealing their primary association with the cell cycle. Moreover, we identified noncoding RNAs (ncRNAs) contributing to TET3 overexpression using expression, correlation, and survival analyses. We identified the LINC01521/hsa-miR-29a-3p axis as the primary TET3 upstream ncRNA-related pathway in breast cancer. Furthermore, TET3 expression was positively associated with immune cell infiltration, immune cell biomarkers, and eight immune checkpoint gene expressions in breast cancer. TET3 expression also correlated with patient responses to immunotherapy. Finally, we conducted subcellular localization and immunohistochemical staining analysis of TET3 in breast cancer. We found that TET3 localized to the nucleoplasm, vesicles, and cytosol in the MCF-7 cell line, and TET3 expression was significantly upregulated in breast cancer tissues compared to para-tumor tissues. Our findings indicate that ncRNA-mediated overexpression of TET3 predicts an unfavorable prognosis and correlates with immunotherapy efficacy in breast cancer.

Lymphangiogenesis, an integral contributor to lymphatic metastasis, is a significant reason for the poor prognosis of cancer patients. Anti-lymphangiogenesis treatment is a promising novel therapeutic direction, especially for tumors resistant to conventional therapies. We confirmed the ectopic expression of lymphangiogenesis-related genes (LRGs) in lung adenocarcinoma (LUAD) cohorts based on the TCGA database. We constructed a prediction signature with 15 LRG prognostic signatures (F2RL1, LOXL2, MKI67, PTPRM, GPI, POSTN, INHA, LDHA, LINC00857, ITGA2, PECAM1, SOD3, GDF15, SIX1, and FGD5), and the overall survival (OS) was significantly different between the high- and low-risk groups (TCGA-training: p

Abstract Background DNA replication alteration is a hallmark of patients with lung adenocarcinoma (LUAD) and is frequently observed in LUAD progression. Origin recognition complex (ORC) 1, ORC2, ORC3, ORC4, ORC5, and ORC6 form a replication–initiator complex to mediate DNA replication, which plays a key role in carcinogenesis, while their roles in LUAD remain poorly understood. Methods The mRNA and protein expression of ORCs was confirmed by the GEPIA, HPA, CPTAC, and TCGA databases. The protein–protein interaction network was analyzed by the GeneMANIA database. Functional enrichment was confirmed by the Metascape database. The effects of ORCs on immune infiltration were validated by the TIMER database. The prognostic significance of ORCs in LUAD was confirmed by the KM‐plot and GENT2 databases. DNA alteration and protein structure were determined in the cBioProtal and PDB databases. Moreover, the protein expression and prognostic value of ORCs were confirmed in our LUAD data sets by immunohistochemistry (IHC) staining. Results ORC mRNA and protein were significantly increased in patients with LUAD compared with corresponding normal tissue samples. The results of IHC staining analysis were similar result to those of the above bioinformatics analysis. Furthermore, ORC1 and ORC6 had significant prognostic values for LUAD patients. Furthermore, the ORC cooperatively promoted LUAD development by driving DNA replication, cellular senescence, and metabolic processes. Conclusion The ORC, especially ORC1/6, has important prognostic and expression significance for LUAD patients.

Deploying pigeon age detection model on edge equipment can solve the problem of video transmission delay and reduce the pressure of network transmission. Based on the deployment of edge devices, we made some improvements to You Only Look Once version 5 (YOLOv5) to form a new, lightweight, high-performance detector named LN-STEP-YOLO. In order to reduce the size of the model, we halved the number of channels in the YOLOv5s model. However, the decrease in the number of channels brings some problems, such as low global information acquisition, retention of image redundancy information, attention deficit, etc. To solve these problems, we did the following work. First, we proposed a new convolution structure with the effect of a large convolution kernel, StepConv. Second, a $2\times 2$ convolution with step size 2 was used at the input to split each image into individual patches. Third, External Attention (EA) was introduced in the bottleneck structure. Fourth, a modified extremely separated convolutional block (XsepConv) was used for downsampling. Finally, we replaced the batch normalization (BN) of all non-downsampled layers with layer normalization (LN). The results showed that the improved algorithm outperformed generic lightweight networks such as Mixnet, Mobilenetv3, and Ghostnet to distinguish small-sized, overlapping pigeons, achieving 92.8% mean average precision (mAP) at about 17% of YOLOv5s parameters, 0.1% lower than that achieved by use of YOLOv5s. In addition, the improved method had 3.7G floating point operations (FLOPs) and 1.25G parameters, which allowed the detection of the growth stages of pigeons in real environments and provided a reference to guide placement of feeders in automated pigeon farming.

Purpose This study aims to determine the optimal cut-off value of Ki-67 to better predict the recurrence of early low-risk endometrial cancer (EC). Methods Seven hundred and forty-eight patients diagnosed with low-risk EC from West China Second Hospital of Sichuan University and the First Affiliated Hospital of Chongqing Medical University were retrospectively analyzed. The receiver operating characteristic curve (ROC) and Youden index were used to calculate the optimal cut-off value of Ki-67 expression. The clinicopathological indexes between two groups divided by cut-off value of Ki-67 were compared. The univariate and multivariate regression analyses were performed to investigate risk factors connected to the recurrence of early low-risk EC. The survival analysis was shown in Kaplan–Meier curve. Result Thirty-three patients were detected with tumor recurrence after primary surgery (4.4%); 33% was the optimal cut-off value of the Ki-67 index. A high Ki-67 was significantly associated with age ( P = .002), myometrial invasion ( P < .001), and the expression of P53 ( P = .007). The multivariate regression analysis verified that Ki67 ≥ 33% was an independent prognostic factor for predicting recurrence. The recurrence-free survival (RFS) and the overall survival (OS) in high Ki-67 group was significantly lower than that in low Ki-67 group ( P < .001 and P = .029, respectively). The prognostic values of ER, PR, and P53 in combination with Ki-67 were superior to each single predictor. Conclusions The optimal cut-off value of Ki-67 for predicting recurrence is 33%, which quantitatively defines the specific value of Ki-67 that causes high-risk recurrence in early low-risk EC.

Abstract Background Clinical studies show that microorganisms are closely related to human health, and the discovery of potential associations between microbes and drugs will facilitate drug research and development. However, at present, few computational methods for predicting microbe–drug associations have been proposed. Results In this work, we proposed a novel computational model named GSAMDA based on the graph attention network and sparse autoencoder to infer latent microbe–drug associations. In GSAMDA, we first built a heterogeneous network through integrating known microbe–drug associations, microbe similarities and drug similarities. And then, we adopted a GAT-based autoencoder and a sparse autoencoder module respectively to learn topological representations and attribute representations for nodes in the newly constructed heterogeneous network. Finally, based on these two kinds of node representations, we constructed two kinds of feature matrices for microbes and drugs separately, and then, utilized them to calculate possible association scores for microbe–drug pairs. Conclusion A novel computational model is proposed for predicting potential microbe–drug associations based on graph attention network and sparse autoencoder. Compared with other five state-of-the-art competitive methods, the experimental results illustrated that our model can achieve better performance. Moreover, case studies on two categories of representative drugs and microbes further demonstrated the effectiveness of our model as well.

Abstract Isodon amethystoides (Lamiaceae) is a popular plant in folk medicine in the southern provinces of China. Our phytochemical investigation of the twigs and leaves of this plant led to the discovery of five new diterpenoids with isopimarane and 3,4-seco isopimarane scaffolds [isoamethinols A–E (1–5)], along with the known compound 3,4-seco isopimara-4(18),7,15-triene-3-oic acid methylester (6). The chemical structures of these compounds, including the absolute configurations of the new diterpenoids, were determined by comprehensive spectroscopic analyses and single crystal X-ray diffraction measurements. These compounds were evaluated for their biological activities against a panel of human cancer cell lines, gram-positive bacterial strains and HIV. Notably, the 3,4-seco-isopimarane isoamethinol D (4) showed toxicity to the cervical Hela cancer (Hela) cells with an IC50 value of 27.21 μM and the lung (A549) cancer cells with an IC50 value of 21.47 μM. Compound 4 also exhibited mild antimicrobial activity against the oral bacterial strain Streptococcus mutans. These findings suggested that the diterpenoids with a 3,4-seco-isopimarane diterpenoids isolated from I. amethystoides could provide a novel structure scaffold for the discovery of anticancer and antimicrobial compounds. Graphical Abstract

IntroductionPlacenta accreta spectrum (PAS) may cause enormous and potentially life-threatening hemorrhage in the intrapartum and postpartum periods in emergency cesarean section. How to reduce the occurrence of emergency cesarean section in patients with severe PAS is the key to reducing the adverse outcomes of them. This study aimed to investigate the impact of emergency cesarean section on the perioperative outcomes of pregnant women with PAS and neonates, and also aimed to explore the risk factors of emergency cesarean section in pregnant women with PAS.Materials and methodsA retrospective investigation was conducted among 163 pregnant women with severe PAS. Of these, 72 were subjected to emergency cesarean sections. Data on the perioperative characteristics of the mothers and neonates were collected. Multivariable linear regression analysis was used to detect associations between maternal and perioperative characteristics and volume of intraoperative bleeding. Binary logical regression was used to analyze the association between maternal preoperative characteristics and emergency cesarean section. Linear regression analysis is used to analyze the relationship between gestational age and emergency cesarean section.ResultsThe risks of emergency cesarean section increase 98, 112, 124, and 62% when the pregnant women with PAS accompanied by GHD, ICP, more prior cesarean deliveries and more severe PAS type, respectively. Noteworthy, the risk of emergency cesarean section decreases 5% when pre-pregnancy BMI increases 1 kg/m2 (OR: 0.95; CI: 0.82, 0.98; p = 0.038). Moreover, there is no significant linear correlation between emergency cesarean section and gestational age.ConclusionGHD, ICP, multiple prior cesarean deliveries and severe PAS type may all increase the risk of emergency cesarean section for pregnant women with PAS, while high pre-pregnancy BMI may be a protective factor due to less activity level. For pregnant women with severe PAS accompanied by these high risk factors, more adequate maternal and fetal monitoring should be carried out in the third trimester to reduce the risk of emergency cesarean section.

Abstract Background Accumulating evidence suggests a strong association between polycystic ovary syndrome (PCOS) and ovarian cancer (OC), but the potential molecular mechanism remains unclear. In this study, we identified previously unrecognized genes that are significantly correlated with PCOS and OC via bioinformatics. Materials and methods Multiple bioinformatic analyses, such as differential expression analysis, univariate Cox analysis, functional and pathway enrichment analysis, protein–protein interaction (PPI) network construction, survival analysis, and immune infiltration analysis, were utilized. We further evaluated the effect of OGN on FSHR expression via immunofluorescence. Results TCGA-OC, GSE140082 (for OC) and GSE34526 (for PCOS) datasets were downloaded. Twelve genes, including RNF144B, LPAR3, CRISPLD2, JCHAIN, OR7E14P, IL27RA, PTPRD, STAT1, NR4A1, OGN, GALNT6 and CXCL11, were identified as signature genes. Drug sensitivity analysis showed that OGN might represent a hub gene in the progression of PCOS and OC. Experimental analysis found that OGN could increase FSHR expression, indicating that OGN could regulate the hormonal response in PCOS and OC. Furthermore, correlation analysis indicated that OGN function might be closely related to m6A and ferroptosis. Conclusions Our study identified a 12-gene signature that might be involved in the prognostic significance of OC. Furthermore, the hub gene OGN represent a significant gene involved in OC and PCOS progression by regulating the hormonal response.

IntroductionBuckwheat (Fagopyrum tataricum), an important food crop, also has medicinal uses. It is widely planted in Southwest China, overlapping with planting areas remarkably polluted by cadmium (Cd). Therefore, it is of great significance to study the response mechanism of buckwheat under Cd stress and further develop varieties with excellent Cd tolerance.MethodsIn this study, two critical periods of Cd stress treatment (days 7 and 14 after Cd treatment) of cultivated buckwheat (Pinku-1, named K33) and perennial species (F. tatari-cymosum Q.F. Chen) (duoku, named DK19) were analyzed using transcriptome and metabolomics.ResultsThe results showed that Cd stress led to changes in reactive oxygen species (ROS) and the chlorophyll system. Moreover, Cd-response genes related to stress response, amino acid metabolism, and ROS scavenging were enriched or activated in DK19. Transcriptome and metabolomic analyses highlighted the important role of galactose, lipid (glycerophosphatide metabolism and glycerophosphatide metabolism), and glutathione metabolism in response to Cd stress in buckwheat, which are significantly enriched at the gene and metabolic levels in DK19.DiscussionThe results of the present study provide valuable information for a better understanding of the molecular mechanisms underlying Cd tolerance in buckwheat and useful clues for the genetic improvement of drought tolerance in buckwheat.

There are great differences in oil and gas enrichment at different locations in petroliferous basins, and faults are an important factor affecting the differential enrichment of oil and gas. In this paper, taking the No. 2 structure in the Nanpu Sag, Bohai Bay Basin, East China, as an example, based on the analysis of fault geometry and kinematics characteristics, the determination of oil source faults, the analysis of fault trap origin and effectiveness, and the analysis of fault caprock combinations are carried out to study the differences and mechanisms of oil and gas enrichment east and west of the Nanpu No. 2 structure. The results show that the fault-source contact relationship affects the direction of oil and gas migration. The No. 2 structure in the Nanpu Sag has a dual-source hydrocarbon supply. The western structure supplies hydrocarbons from the north and east, with oil and gas migrating along the direction parallel and perpendicular to the fault strike. The east structure supplies hydrocarbons from the south and north, with oil and gas migrating along the direction perpendicular to the fault strike. The effectiveness of fault traps affects the scale of oil and gas accumulation. Most of the traps of the Nanpu No. 2 structure formed before hydrocarbon expulsion, which are all effective traps and are conducive to oil and gas accumulation. The relationship between fault and caprock determines the vertical accumulation layers of oil and gas: The faulted thickness of the east structure is large, the fault is vertically closed, and oil and gas are enriched mainly in the deep layer. The faulted thickness of the west structure is small, and oil and gas are enriched in both deep and shallow layers.

Aqueous zinc (Zn)‐ion batteries (ZIBs) have been considered as the most promising candidate for large‐scale energy storage system. However, the severe and uncontrollable dendrite growth of Zn anodes hinders the practical application. Herein, an ultraconformal horizontal Zn deposition is achieved, which is profiting from the epitaxial interface (InGaZn6O9) formed via spontaneously alloying between liquid Ga–In alloy (EGaIn) and Zn. The exposed (0016) plane of InGaZn6O9 matches well with (002) plane of Zn, inducing horizontal and dense Zn deposition. The resultant anode endows with prolonged cycling stability, and the full battery paired with MnO2 exhibits a stable lifespan over 4400 cycles at 5 A g−1. Meanwhile, the self‐formed ultraconformal interface realizes 360° no dead angle protection of anode, which is promising in flexible electronics. And there is no obvious capacity recession of the pouch cell even after bending 180°, demonstrating impressive flexibility. More importantly, the interface can be simply fabricated over a large area, displaying the large‐scale viability. The tailored approach delivers a constructive guideline for dendrite‐free Zn anode, showing great potential in the industrial production.

Seed germination is an important stage of growth and reproduction and plays an important role in the life cycle of spermatophyte. It is co-determined by both genetic and environmental factors, and plant hormone regulation may be a highly conservative mechanism. Coix lachryrma-jobi (coix) is a grain with balanced nutrition for medicine and food and has substantial production value. It is an important part of agricultural production, and the efficiency of seed germination after sowing is a key link. In this study, coix species “small white shell Xingren” was used as the experimental material, and changes in gene expression levels and metabolite enrichment in seeds were identified by transcriptome and metabonomic analysis before and after seed germination. A total of 599 metabolites, including those from amino acid metabolism, sugar metabolism, and fatty acid metabolism, were significantly increased in germinating coix. Simultaneously, 10,929 differentially expressed genes (DEGs) were identified, and functional clusters of genes were also significantly clustered in hormone-signaling and glucose and fatty acid metabolism. In addition, this study found that a considerable number of hormone-signaling genes were significantly up-regulated during seed germination, activating multiple metabolic processes. The results of our conjoint analysis of multi omics showed that glucose and fatty acid metabolism played an important role in seed germination under hormone regulation.

The roots of Astilbe grandis, known as “Ma sang gou bang”, are used as a Miao traditional medicine with anti-inflammatory and analgesic properties. However, the active components and mechanism of action of this plant remain mostly uncharacterized. The aim of this study was to identify its active components and verify their pharmacological activity. The extract of A. grandis root was separated using various chromatographic methods. As a result, we obtained one novel triterpenoid, named astigranlactone (1), which has an unusual lactone moiety formed between C-7 and C-27. Additionally, a known coumarin compound, 11-O-galloyl bergenin (2) was isolated from this plant. The structures of these two compounds were elucidated by extensive NMR experiments in conjunction with HR-ESI-MS data. To the best of our knowledge, both compounds were isolated from this species for the first time. Moreover, we tested the anti-inflammation effect of the two compounds by establishing a cellular inflammation model induced by LPS in RAW264.7 cells. The effect of different concentrations of these compounds on the activity of RAW264.7 cells was assessed using a CCK8 assay. The levels of nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) in the supernatant of each group were evaluated using the Griess method and an enzyme-linked immunosorbent assay (ELISA). Western blot and quantitative real-time PCR (qRT-RCR) were used to measure the levels of cyclooxygenase 2 (COX-2) and nitric oxide synthase (iNOS) gene expression. Our findings revealed that these two compounds inhibited the high levels of NO, TNF-α, IL-6, IL-1β, COX-2, and iNOS (induced by LPS). Mechanistic studies demonstrated that these two compounds reduced the activation of the nuclear transcription factor-B (NF-κB) signaling pathway by inhibiting the phosphorylation of p65. Therefore, our study indicates that compounds 1 and 2 can exert a definite anti-inflammatory effect by inhibiting the NF-κB signaling pathway.

BackgroundOvarian cancer (OC) is one of the most common types of gynecologic tumor over the world. The Glutathione S-transferase Mu (GSTM) has five members, including GSTM1-5. These GSTMs is involved in cell metabolism and detoxification, but their role in OC remains unknown.MethodsData from multiple public databases associated with OC and GSTMs were collected. Expression, prognosis, function enrichment, immune infiltration, stemness index, and drug sensitivity analysis was utilized to identify the roles of GSTMs in OC progression. RT-qPCR analysis confirmed the effect of AICAR, AT-7519, PHA-793887 and PI-103 on the mRNA levels of GSTM3/4.ResultsGSTM1-5 were decreased in OC samples compared to normal ovary samples. GSTM1/5 were positively correlated with OC prognosis, but GSTM3 was negatively correlated with OC prognosis. Function enrichment analysis indicated GSTMs were involved in glutathione metabolism, drug metabolism, and drug resistance. Immune infiltration analysis indicated GSTM2/3/4 promoted immune escape in OC. GSTM5 was significantly correlated with OC stemness index. GSTM3/4 were remarkedly associated with OC chemoresistance, especially in AICAR, AT-7519, PHA-793887 and PI-103.ConclusionGSTM3 was negatively correlated with OC prognosis, and associated with OC chemoresistance and immune escape. This gene may serve as potential prognostic biomarkers and therapeutic target for OC patients.

Background and ObjectivePrevious studies determined the therapeutic effects of capecitabine-based chemotherapy regimens on early-stage triple-negative breast cancer (TNBC). However, the optimal strategy of capecitabine-based chemotherapy remains uncertain. We conducted this network meta-analysis to address this issue.MethodsWe systematically searched PubMed, Embase, and the Cochrane Registry of Controlled Trials (CENTRAL) to retrieve eligible studies published before September 2021. Two independent reviewers extracted information from eligible studies using a pre-designed data extraction sheet. The primary outcome included disease-free survival, and the second outcome showed overall survival and adverse events. Direct meta-analysis was performed using RevMan 5.4, and Bayesian network analysis was performed using R version 3.6.1 with the “gemtc” and “rjags” packages.ResultsNine studies involving 3661 TNBC patients met the selection criteria. The network meta-analysis suggested that the addition of capecitabine to adjuvant chemotherapy achieved a significantly longer disease-free (HR = 0.66, 95% CrI = 0.49 to 0.86) and overall survival time (HR = 0.60, 95% CrI = 0.43 to 0.83) than standard chemotherapy. All comparisons did not achieve statistical significance. The addition of capecitabine to adjuvant chemotherapy was the most effective treatment for improving disease-free (81.24%) and overall survival (78.46%) times, and the replacement of capecitabine to adjuvant chemotherapy was the safest regime.ConclusionsBased on available evidence, capecitabine-based chemotherapy benefits TNBC patients, and the addition of capecitabine with adjuvant chemotherapy was the most effective regime. In contrast, the replacement of capecitabine to adjuvant chemotherapy was the safest regime. More studies of high quality and large scale are needed to confirm our findings.

Recently, the androgen receptor has been found as a potential prognostic index and therapeutic target for breast cancer. To reveal the current research status and hotspots in this area, we analyzed the characteristics of related publications from 2011 to 2020. All related publications from 2011 to 2020 were retrieved from the Web of Science. Biblioshiny, VOSviewer, and CiteSpace V were applied to obtain the information on annual publications and citations, the highest yielding countries and authors, influential journals and articles, as well as hot keywords. In total, 2,118 documents, including 1,584 original articles and 534 reviews, were retrieved. Annual publication output was rich from 2014 to 2018, reaching the top in 2017. A systematic review written by Lehman et al. in 2011 was the most-cited document and reference. The United States was the leading country with the maximum number of publications, citations, and link strengths with other countries. The journal publishing the most was Oncotarget. Lehmann was the author who had the highest link strengths with other authors. The most highlighted keywords were “androgen receptor” (n = 1,209), “breast cancer” (n = 690), “expression” (n = 545), “breast cancer” (n = 410), “prostate cancer” (n = 290), and so on, revealing the trend from molecular mechanism level to therapeutic use level. The androgen receptor plays a significant role in the development of breast cancers, whereas its therapeutic value seems to be controversial and needs further study. With the help of a scientometric analysis in this field, researchers can clarify the current research status and hotspots worth fully exploring.

In the field of many-objective evolutionary optimization algorithms (MaOEAs), how to maintain the balance between convergence and diversity has been a significant research problem. With the increase of the number of objectives, the number of mutually nondominated solutions increases rapidly, and multi-objective evolutionary optimization algorithms, based on Pareto-dominated relations, become invalid because of the loss of selection pressure in environmental selection. In order to solve this problem, indicator-based many-objective evolutionary algorithms have been proposed; however, they are not good enough at maintaining diversity. Decomposition-based methods have achieved promising performance in keeping diversity. In this paper, we propose a MaOEA based on indicator and decomposition (IDEA) to keep the convergence and diversity simultaneously. Moreover, decomposition-based algorithms do not work well on irregular PFs. To tackle this problem, this paper develops a reference-points adjustment method based on the learning population. Experimental studies of several well-known benchmark problems show that IDEA is very effective compared to ten state-of-the-art many-objective algorithms.

Thyroid cancer (THCA) is a common endocrine malignancy. With increasing incidence and low mortality, balancing the therapeutic approach is an inevitable issue. This study aimed to confirm the role of miR-222-3p and its target genes in THCA survival and immune infiltration. From different expression analyses based on the GEO and TCGA databases, we predicted and subsequently identified the key target genes of miR-222-3p. We then explored the expression, enrichment, pairwise correlation, protein expression, survival analysis, principal component analysis, and immune significance of the critical genes using bioinformatics analysis. The present study demonstrated that NEGR1, NTNG1, XPNPEP2, NTNG2, CD109, OPCML, and PRND are critical genes. The miR-222-3p was highly expressed, probably leading to low NEGR1 and high PRND expression in THCA tissues. Low NEGR1 expression indicated favorable prognosis in THCA patients, and high PRND expression indicated poor prognosis. Seven critical genes were significantly related to gender, age, race, tumor stage, and lymph node metastasis. In addition, the seven-gene biomarker exhibited a certain diagnostic value. Finally, CD109 expression was closely correlated with immune cells, especially B cells and CD4+ T cells. The miR-222-3p and its critical target genes could be promising biomarkers for the prognosis of THCA and may emerge as key regulators of immune infiltration in THCA.

Lamin A is critical for nuclear architecture but its structure and assembly are not fully understood. Here, the authors use quantitative cross-linking mass spectrometry to map intra- and intermolecular interactions within lamin homomers, providing insights into the molecular basis for lamin’s mechanical properties.

Lately, deep learning technology has been extensively investigated for accelerating dynamic magnetic resonance (MR) imaging, with encouraging progresses achieved. However, without fully sampled reference data for training, the current approaches may have limited abilities in recovering fine details or structures. To address this challenge, this paper proposes a self-supervised collaborative learning framework (SelfCoLearn) for accurate dynamic MR image reconstruction from undersampled k-space data directly. The proposed SelfCoLearn is equipped with three important components, namely, dual-network collaborative learning, reunderampling data augmentation and a special-designed co-training loss. The framework is flexible and can be integrated into various model-based iterative un-rolled networks. The proposed method has been evaluated on an in vivo dataset and was compared to four state-of-the-art methods. The results show that the proposed method possesses strong capabilities in capturing essential and inherent representations for direct reconstructions from the undersampled k-space data and thus enables high-quality and fast dynamic MR imaging.

It has become a tendency to use a combination of autoencoders and graph neural networks for attribute graph clustering to solve the community detection problem. However, the existing methods do not consider the influence differences between node neighborhood information and high-order neighborhood information, and the fusion of structural and attribute features is insufficient. In order to make better use of structural information and attribute information, we propose a model named community detection fusing graph attention network (CDFG). Specifically, we firstly use an autoencoder to learn attribute features. Then the graph attention network not only calculates the influence weight of the neighborhood node on the target node but also adds the high-order neighborhood information to learn the structural features. After that, the two features are initially fused by the balance parameter. The feature fusion module extracts the hidden layer representation of the graph attention layer to calculate the self-correlation matrix, which is multiplied by the node representation obtained by the preliminary fusion to achieve secondary fusion. Finally, the self-supervision mechanism makes it face the community detection task. Experiments are conducted on six real datasets. Using four evaluation metrics, the CDFG model performs better on most datasets, especially for the networks with longer average paths and diameters and smaller clustering coefficients.

When solving complex constrained problems, how to efficiently utilize promising infeasible solutions is an essential issue because these promising infeasible solutions can significantly improve the diversity of algorithms. However, most existing constrained multi-objective evolutionary algorithms (CMOEAs) do not fully exploit these promising infeasible solutions. In order to solve this problem, a constrained multi-objective optimization evolutionary algorithm based on the dynamic constraint boundary method is proposed (CDCBM). The proposed algorithm continuously searches for promising infeasible solutions between UPF (the unconstrained Pareto front) and CPF (the constrained Pareto front) during the evolution process by the dynamically changing auxiliary population of the constraint boundary, which continuously provides supplementary evolutionary directions to the main population and improves the convergence and diversity of the main population. Extensive experiments on three well-known test suites and three real-world constrained multi-objective optimization problems demonstrate that CDCBM is more competitive than seven state-of-the-art CMOEAs.

Microliposome maintenance (MCM) 2, MCM3, MCM4, MCM5, MCM6, and MCM7 are DNA replication regulators and are involved in the progression of multiple cancer types, but their role in ovarian cancer is still unclear. The purpose of this study is to clarify the biological function and prognostic value of the MCM complex in ovarian cancer (OS) progression. We analyzed DNA alterations, mRNA and protein levels, protein structure, PPI network, functional enrichment, and prognostic value in OC based on the Oncomine, cBioPortal, TCGA, CPTAC, PDB, GeneMANIA, DAVID, KEGG, and GSCALite databases. The results indicated that the protein levels of these DNA replication regulators were increased significantly. Moreover, survival analysis showed a prognostic signature based on the MCM complex, which performed moderately well in terms of OS prognostic prediction. Additionally, protein structure, functional enrichment, and PPI network analyses indicated that the MCM complex synergistically promoted OC progression by accelerating DNA replication and the cell cycle. In conclusion, our study suggested that the MCM complex might be a potential target and prognostic marker for OC patients.

BackgroundThe burden of breast cancer has been increasing globally. The epidemiology burden and trends need to be updated. This study aimed to update the burden and trends of breast cancer incidences, deaths, and disability-adjusted life-years (DALYs) from 1990 to 2019, using the Global Burden of Disease 2019 study.MethodsThe data of incidences, deaths, DALYs, and age-standardized rates were extracted. Estimated annual percentage changes were used to quantify the trends of age-standardized rates. Besides, the population attributable fractions of the risk factors of breast cancer were also estimated.ResultsGlobally, the incidences of breast cancer increased to 2,002,354 in 2019. High social-development index (SDI) quintiles had the highest incidence cases with a declining trend in age-standardized incidence rate. In 2019, the global deaths and DALYs of breast cancer increased to 700,660 and 20,625,313, respectively. From 1990 to 2019, the age-standardized mortality rates and age-standardized DALY rates declined globally, especially in high and high-middle SDI quintiles. Besides, the trends varied from different regions and countries. The proportion of the patients in the 70+ years age group increased globally. Deaths of breast cancer attributable to high fasting plasma glucose and high body mass index increased globally, and high fasting plasma glucose was the greatest contributor to the global breast cancer deaths.ConclusionThe burden of breast cancer in higher SDI quintiles had gone down while the burden was still on the rise in lower SDI quintiles. It is necessary to appeal to the public to decrease the exposure of the risk factors.

Houttuyniae Herba (HH) refers to the dried aerial part of Houttuynia cordata Thunb. (DHC) or the fresh whole grass of Houttuynia cordata Thunb. (FHC), where DHC are harvested in summer and FHC around the year. However, harvest seasons and processing methods (i.e., medicinal parts and drying process) might affect the quality of HH. To compare the essential oils (EOs) of DHC and FHC and their two harvest seasons, GC-MS analysis combined with chemometric analysis was applied. The results showed that the oil yield of FHC (0.076 ± 0.030%) was higher than that of DHC (0.038 ± 0.029%), and oil yield was higher in summer than in autumn (0.044 ± 0.029% for DHC1, 0.036 ± 0.028% for DHC2, 0.084 ± 0.026% for FHC1, and 0.067 ± 0.033% for FHC2, respectively). Moreover, hierarchical cluster analysis (HCA) and principal component analysis (PCA) successfully distinguished the chemical constituents of DHC and FHC oils. Additionally, according to orthogonal partial least squares discriminant analysis (OPLS-DA), eleven components were selected as chemical markers for discriminating DHC and FHC, and two and four chemical markers for discriminating two harvest seasons of DHC and FHC, respectively. Among these markers, the average contents of α-pinene, limonene, β-phellandrene, α-terpineol, 4-tridecanone, and ethyl decanoate were higher in FHC oils. In contrast, the average contents of nonanal, 1-nonanol, β-cyclocitral, n-hexadecanoic acid, and octadecanol were higher in DHC oils. Additionally, the contents of 4-tridecanone and ethyl decanoate were both higher in DHC1 oils than in DHC2 oils. Moreover, the contents of β-myrcene and β-phellandrene were higher in FHC1 oils, while the contents of 2,6-octadien-1-ol, 3,7-dimethyl-, acetate, and (z)-phytol were higher in FHC2 oils. For these reasons, this study provides a scientific basis for quality control and clinical medication.

OBJECTIVE: Intestinal microbiota plays a vital role in the pathogenesis of colorectal cancer (CRC), which is crucial for assessing the risk and prognosis of CRC. Most studies regarding human gut microbiota mainly based on the feces, but the exact composition of microbiota vary significantly due to fecal composition is easily affected by many factors. We aim to evaluate whether intestinal lavage fluid (IVF) is a better substitution mirroring the gut microbiota. METHODS: We performed 16S rRNA gene analysis on fecal and IVF samples from 30 CRC patients and 25 healthy individuals, comparison in luminal (feces) / mucosal (IVF) adherent bacterial community profiles were analyzed. RESULTS: The difference between feces and IVF were observed, including the diversity and abundance of pathogenic bacteria (either in single strain or in co-occurrence pattern). IVF group shared 605 OTUs with the fecal group, but there was 94 OTUs only observed in fecal samples, while 247 OTUs were mainly existing in the IVF group. Among them, 27 vital bacterial species detected in IVF, while 10 critical species detected in fecal samples. The co-occurrence bacteria Fusobacteria Cluster and Proteobacteria Cluster 2 significantly increased in IVF than in control (P

Three isopimarane diterpenes [fladins B (1), C (2), and D (3)] were isolated from the twigs and leaves of Chinese folk medicine, Isodon flavidus. The chemical structures were determined by the analysis of the comprehensive spectroscopic data, and the absolute configuration was confirmed by X-ray crystallographic analysis. The structures of 1–3 were formed from isopimaranes through the rearrangement of ring A by the bond break at C-3 and C-4 to form a new δ-lactone ring system between C-3 and C-9. This structure type represents the first discovery of a natural isopimarane diterpene with an unusual lactone moiety at C-9 and C-10. In the crystal of 1, molecules are linked to each other by intermolecular O-H···O bonds, forming chains along the b axis. Compounds 1–3 were evaluated for their bioactivities against different diseases. None of these compounds displayed cytotoxic activities against HCT116 and A549 cancer cell lines, antifungal activities against Trichophyton rubrum and T. mentagrophytes, or antiviral activities against HIV entry at 20 µg/mL (62.9–66.7) µM. Compounds 1 and 3 did not show antiviral activities against Ebola entry at 20 µg/mL either; only 2 was found to show an 81% inhibitory effect against Ebola entry activity at 20 µg/mL (66.7 µM). The bioactivity evidence suggested that this type of compound could be a valuable antiviral lead for further structure modification to improve the antiviral potential.

Abstract Background The anti-tumor activities of Natural compounds and their derivatives are of great interest to pharmaceutical industries. Fisetin is one of prospective natural compounds in this regard but unfortunately with poor hydrophilicity. Methods The effects of unmodified and modified fisetin in cultured ovarian cancer cells were compared by transmission electronmicroscopy to determine apoptotic bodies, MTT assay to quantitate cell numbers, and fluorescence activated cell sorting analyse of various markers to determine the apoptotic state. In addition, the efficacy of fisetin and fisetin-micelles in vivo was determined by using immunocompromised mice. Apoptosis was measured by established markers using both western blot analysis and immunochemistry. Angiogenesis in a xenograft mouse model carring SKOV3 cells was evaluated by color Doppler ultrasound and immunohistochemistry. Result Multiple lines of evidence indicated that fisetin and fisetin micelles induce apoptosis in ovarian cancer cells in a dose-dependent manner. Histological analysis, terminal deoxynucleotidyltransferase-mediated nick-end labeling assay, western blot, immunohistochemical detection and microvessel density detection demonstrated that fisetin and fisetin micelles induced increased tumor apoptosis, proliferation suppression and antiangiogenesis activities. Conclusion As far as we know, the present study is the first time to demonstrate the potency of both fisetin and fisetin micelles inducing apoptosis in ovarian cancer cells. Further studies will be needed to validate the therapeutic potential of fisetin and fisetin micelles in ovarian cancer treatment.

Growth of large area and defect-free two-dimensional semiconductor layers for high-performance p–n junction applications has been a great challenge. Yang et al. prepare millimeter-scaled WSe2/SnS2 vertical heterojunctions by two-step van der Waals epitaxy, which show excellent optoelectronic properties.

Abstract This study aims to determine whether enzyme activities are correlated with protein amounts and mRNA expression levels of five major human sulfotransferase (SULT) enzymes in 10 matched pericarcinomatous and hepatocellular carcinoma liver samples. The MRM UHPLC-MS/MS method, Western blot and RT-PCR were used along with SULT activity measurement using probe substrates. The LC-MS/MS method was specific for all five tested SULTs, whereas Western blot was specific for only two isoforms. The activities of SULT1A1, SULT1B1, SULT1E1 and SULT2A1 in 9 of 10 samples showed a significant decrease in tumor tissues relative to matched pericarcinomatous tissues, whereas the activities of SULT1A3 in 7 of 10 samples increased. The turnover numbers of SULTs did not change, except for SULT1A1. A generally high degree of correlations was observed between SULT activities and protein amounts (r2 ≥ 0.59 except one), whereas a low degree of correlations was observed between SULT activities and mRNA expression levels (r2 ≤ 0.48 except one). HCC reduced the SULT activities via impaired protein amounts. LC-MS/MS quantification of SULTs is highly reliable measurement of SULT activities, and may be adopted for implementing precision medicine with respect to drugs mainly metabolized by SULTs in healthy and HCC patients.