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Abstract Background Peritoneal metastases frequently occur in epithelial ovarian cancer (EOC), resulting in poor prognosis and survival rates. Tumor-associated-macrophages (TAMs) massively infiltrate into ascites spheroids and are multi-polarized as protumoral M2-like phenotype, orchestrating the immunosuppression and promoting tumor progression. However, the impact of omental conditioned medium/ascites (OCM/AS) on TAM polarization and its function in tumor progression remains elusive. Methods The distribution and polarization of TAMs in primary and omental metastatic EOC patients’ tumors and ascites were examined by m-IHC, FACS analysis, and immunofluorescence. QPCR, immunofluorescence, FACS analysis, lipid staining assay, ROS assay, and Seahorse real-time cell metabolic assay characterized TAMs as being polarized in the ascites microenvironment. The oncogenic role of TAMs in tumor cells was demonstrated by co-cultured migration/invasion, proliferation, and spheroid formation assays. Mechanistic studies of the regulations of TAM polarization were performed by using RNA-Seq, GTPase pull-down, G-LISA activation assays, and other biochemical assays. A Yap1 macrophages (MФs) conditional knockout (cKO) mouse model demonstrated the roles of YAP1 in TAM polarization status and its pro-metastatic function. Finally, the anti-metastatic potential of targeting TAMs through restoring YAP1 by pharmacological agonist XMU MP1 was demonstrated in vitro and in vivo. Results Abundant polyunsaturated fatty acids (PUFAs) in OCM/AS suppressed RhoA-GTPase activities, which, in turn, downregulated nuclear YAP1 in MФs, leading to increased protumoral TAM polarization accompanied by elevated OXPHOS metabolism. Abolishment of YAP1 in MФs further confirmed that a higher M2/M1 ratio of TAM polarization could alleviate CD8+ T cell infiltration and cytotoxicity in vivo. Consistently, the loss of YAP1 has been observed in EOC metastatic tissues, suggesting its clinical relevance. On the contrary, restoration of YAP1 expression by pharmaceutical inhibition of MST1/2 induced conversion of M2-to-M1-like polarized MФs, elevating the infiltration of CD8+ T cells and attenuating tumor growth. Conclusion This study revealed that PUFAs-enriched OCM/AS of EOC promotes M2-like TAM polarization through RhoA-YAP1 inhibition, where YAP1 downregulation is required for accelerating protumoral M2-like TAM polarization, thereby causing immunosuppression and enhancing tumor progression. Conversion of M2-to-M1-like polarized MФs through Yap1 activation inhibits tumor progression and contributes to developing potential TAMs-targeted immunotherapies in combating EOC peritoneal metastases.

Abstract Background N6-methyladenosine (m6A) regulates the progression of breast cancer (BC). We aimed to investigate the action and mechanism involved of methyltransferase-like protein 16 (METTL16) in BC growth and metastasis. Methods RT-qPCR, immunoblotting, and IHC were performed to test the levels of gene expression. CCK-8, clone formation, wound healing, and transwell assays were applied to measure the cell proliferation, migration, and invasion. m6A RNA methylation and MeRIP assay were utilized to confirm the m6A level of total RNA and FBXO5 mRNA. RIP was utilized to ascertain the interaction between METTL16 and FBXO5 mRNA. The in vivo murine subcutaneous tumor and metastasis model were constructed to further confirm the action of METTL16. Results METTL16 was overexpression in BC cells and tissues. Inhibition of METTL16 restrained the growth and metastasis of BC. Furthermore, the METTL16 level and FBXO5 level was positively correlated in BC tissues, and METTL16 aggrandized the stability of FBXO5 mRNA depending on the m6A modification. Overexpression of FBXO5 antagonized the restrained function of METTL16 knockdown on BC cells’ proliferation, migration, invasion, and EMT. Conclusion METTL16 boosts the mRNA stability of FBXO5 via m6A modification to facilitate the malignant action of BC in vitro and in vivo, offering new latent targets for cure of BC.

Abstract Targeting ferroptosis-related pathway is a potential strategy for treatment of lung cancer (LC). Consequently, exploration of ferroptosis-related markers is important for treating LC. We collected LC clinical data and mRNA expression profiles from TCGA and GEO database. Ferroptosis-related genes (FRGs) were obtained through FerrDB database. Expression analysis was performed to obtain differentially expressed FRGs. Diagnostic and prognostic models were constructed based on FRGs by LASSO regression, univariate, and multivariate Cox regression analysis, respectively. External verification cohorts GSE72094 and GSE157011 were used for validation. The interrelationship between prognostic risk scores based on FRGs and the tumor immune microenvironment was analyzed. Immunocytochemistry, Western blotting, and RT-qPCR detected the FRGs level. Eighteen FRGs were used for diagnostic models, 8 FRGs were used for prognostic models. The diagnostic model distinguished well between LC and normal samples in training and validation cohorts of TCGA. The prognostic models for TCGA, GSE72094, and GSE157011 cohorts significantly confirmed lower overall survival (OS) in high-risk group, which demonstrated excellent predictive properties of the survival model. Multivariate Cox regression analysis further confirmed risk score was an independent risk factor related with OS. Immunoassays revealed that in high-risk group, a significantly higher proportion of Macrophages_M0, Neutrophils, resting Natural killer cells and activated Mast cells and the level of B7H3, CD112, CD155, B7H5, and ICOSL were increased. In conclusion, diagnostic and prognostic models provided superior diagnostic and predictive power for LC and revealed a potential link between ferroptosis and TIME.

Abstract Seamounts are globally distributed across the oceans and form one of the major oceanic biomes. Here, we utilized combined analyses of bulk metagenome and virome to study viral communities in seamount sediments in the western Pacific Ocean. Phylogenetic analyses and the protein-sharing network demonstrate extensive diversity and previously unknown viral clades. Inference of virus-host linkages uncovers extensive interactions between viruses and dominant prokaryote lineages, and suggests that viruses play significant roles in carbon, sulfur, and nitrogen cycling by compensating or augmenting host metabolisms. Moreover, temperate viruses are predicted to be prevalent in seamount sediments, which tend to carry auxiliary metabolic genes for host survivability. Intriguingly, the geographical features of seamounts likely compromise the connectivity of viral communities and thus contribute to the high divergence of viral genetic spaces and populations across seamounts. Altogether, these findings provides knowledge essential for understanding the biogeography and ecological roles of viruses in globally widespread seamounts.

Background: The Chinese herbal compound Lian-Gui-Ning-Xin-Tang (LGNXT), composed of 9 herbs, has a significant antiarrhythmic effect. Previous studies have confirmed that preventing intracellular Ca2+ overload and maintaining intracellular Ca2+ homeostasis may be the important antiarrhythmic mechanisms of LGNXT. Recent studies are focused on elucidating the mechanisms and pharmacodynamic substances of LGNXT. Purpose: 1) To investigate the antiarrhythmic mechanisms of LGNXT; 2) to explore the association of pharmacodynamics (PD) and pharmacokinetics (PK) of the potential pharmacodynamic substances in LGNXT to further verify the mechanisms of action. Methods: First, pharmacodynamic studies were conducted to determine the effect of LGNXT in arrhythmia at the electrophysiological, molecular, and tissue levels, and the “effect–time” relationship of LGNXT was further proposed. Next, an HPLC-MS/MS method was established to identify the “dose–time” relationship of the 9 potential compounds. Combining the “effect–time” and “dose–time” curves, the active ingredients closely related to the inhibition of inflammation, oxidative stress, and energy metabolism were identified to further verify the mechanisms and pharmacodynamic substances of LGNXT. Results: Pretreatment with LGNXT could delay the occurrence of arrhythmias and reduce their duration and severity. LGNXT exerted antiarrhythmic effects by inhibiting MDA, LPO, IL-6, and cAMP; restoring Cx43 coupling function; and upregulating SOD, Ca2+-ATPase, and Na+-K+-ATPase levels. PK-PD association showed that nobiletin, methylophiopogonanone A, trigonelline, cinnamic acid, liquiritin, dehydropolisic acid, berberine, and puerarin were the main pharmacodynamic substances responsible for inhibiting the inflammatory response in arrhythmia. Methylophiopogonanone A, dehydropalingic acid, nobiletin, trigonelline, berberine, and puerarin in LGNXT exerted antiarrhythmic effects by inhibiting oxidative stress. Dehydropalingic acid, berberine, cinnamic acid, liquiritin, puerarin, trigonelline, methylophiopogonanone A, nobiletin, and tetrahydropalmatine exerted antiarrhythmic effects by inhibiting the energy-metabolism process. Conclusions: LGNXT had a positive intervention effect on arrhythmias, especially ventricular tachyarrhythmias, which could inhibit inflammation, oxidative stress, and energy metabolism; positively stabilize the structure, and remodify the function of myocardial cell membranes. Additionally, the PD–PK association study revealed that methylophiopogonanone A, berberine, trigonelline, liquiritin, puerarin, tetrahydropalmatine, nobiletin, dehydropachymic acid, and cinnamic acid directly targeted inflammation, oxidative stress, and energy metabolism, which could be considered the pharmacodynamic substances of LGNXT. Thus, the antiarrhythmic mechanisms of LGNXT were further elucidated.

Using FY–2G satellite data, Aircraft Meteorological Data Relay (AMDAR) downlink data, and the fifth generation European Centre for Medium–Range Weather Forecasts (ECMWF) atmospheric reanalysis of the global climate (ERA5) dataset, we analyzed the circulation, thermal, and dynamic characteristics of the convective aircraft turbulence over Australia in the Southern Hemisphere. The results show that the near-convective clouds turbulence (NCCT) in the Southern Hemisphere mostly occurred in front of deep warm high–pressure ridges in mid–latitude regions and on the left side of the axis of the subtropical westerly jet stream. The isotherms in this area were relatively dense (i.e., large gradients), and the wind speed was high, with strong horizontal and/or vertical cyclonic wind shear. In addition, the NCCT usually occurred near the zero–divergence or zero–vorticity line and in areas with large vertical wind speed gradients. There were also strong vertical and horizontal wind shears in this area, which could easily trigger severe turbulence. Furthermore, the NCCT in the Southern Hemisphere mostly occurred at the intersection of cold and warm temperature advections (i.e., near the zero–temperature advection line), and the turbulence point was located near the high–altitude frontal zone where there was a strong gradient of cold and warm advections. There was temperature inversion with pseudo–equivalent potential temperatures in the middle and lower troposphere on the warmer side of the turbulence point. The unstable stratification of cold air at the top and warm air at the bottom was conducive to triggering convection from the ground, forming strong convective clouds, and causing severe turbulence.

The aim of this study was to identify Artemis as a predictive biomarker for guiding preoperative chemoradiotherapy in locally advanced rectal cancer. The resection specimens were collected from 50 patients with rectal cancer who underwent preoperative chemoradiotherapy. Artemis expression in biopsy tissues was evaluated using immunohistochemical staining according to the percentage of positively stained cells combined with staining intensity. Among the 50 patients, 36 (72%) had a weakly positive Artemis protein expression, 10 (20%) had a moderately positive expression, and 4 (8%) showed a strongly positive expression. The criteria of magnetic resonance imaging tumor regression grade (mrTRG) and pathological rectal cancer regression grade (RCRG) were used to assess the tumor response to chemoradiotherapy. Correlation analysis shows that there is a significant negative correlation between high Artemis immunoscore and treatment response (r = −0.532, p < 0.001). The results imply that high Artemis expression was associated with poor treatment response. Our study suggested a potential role of Artemis as a predictive biomarker of the tumor response to preoperative chemoradiotherapy in patients with locally advanced rectal cancer.

Abstract Background ASXL1 mutation is an independent prognostic factor in adult acute myeloid leukemia (AML), but its effect on the prognosis of pediatric AML is poorly understood. Aims This study aimed to investigate the clinical characteristics and prognostic factors of ASXL1‐mutant pediatric AML from a large Chinese multicenter cohort. Methods A total of 584 pediatric patients with newly diagnosed AML from 10 centers in South China were enrolled. The exon 13 of ASXL1 was amplified by polymerase chain reaction (PCR), and then analyzed the mutation status of the locus. (n = 59 for ASXL1‐mut group, n = 487 for ASXL1‐wt group). Results ASXL1 mutations were found in 10.81% of all patients with AML. A complex karyotype was significantly less common in the ASXL1‐mut AML group than in the ASXL1‐wt group (1.7% vs. 11.9%, p = 0.013). Furthermore, TET2 or TP53 mutations were predominantly found in the ASXL1+ group (p = 0.003 and 0.023, respectively). The 5‐year overall survival (OS) and event‐free survival (EFS) of the total cohort were 76.9% and 69.9%. In ASXL1‐mut AML patients, a white blood cell (WBC) count ≥50 × 109/L had significantly poorer 5‐year OS and EFS than a WBC count

Abstract Background Thrombosis is a serious condition in children and neonates. However, the risk factors for thrombosis have not been conclusively determined. This study aimed to identify the risk factors for thrombosis in children and neonates in Intensive Care Unit (ICU) through a meta-analysis to better guide clinical treatment. Methods A systematic search of electronic databases (PubMed, Embase, Cochrane Library, WOS, CNKI, Wanfang, VIP) was conducted to retrieve studies from creation on 23 May 2022. Data on the year of publication, study design, country of origin, number of patients/controls, ethnicity, and type of thrombus were extracted. The publication bias and heterogeneity between studies were assessed, and pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed or random effects models. Results A total of 18 studies met the inclusion criteria. The incidence of thrombosis in children was 2% per year (95% CI 1%-2%, P

Abstract Background Vestimentifera (Polychaeta, Siboglinidae) is a taxon of deep-sea worm-like animals living in deep-sea hydrothermal vents, cold seeps, and organic falls. The morphology and lifespan of Ridgeia piscesae, which is the only vestimentiferan tubeworm species found in the hydrothermal vents on the Juan de Fuca Ridge, vary greatly according to endemic environment. Recent analyses have revealed the genomic basis of adaptation in three vent- and seep-dwelling vestimentiferan tubeworms. However, the evolutionary history and mechanism of adaptation in R. piscesae, a unique species in the family Siboglinidae, remain to be investigated. Result We assembled a draft genome of R. piscesae collected at the Cathedral vent of the Juan de Fuca Ridge. Comparative genomic analysis showed that vent-dwelling tubeworms with a higher growth rate had smaller genome sizes than seep-dwelling tubeworms that grew much slower. A strong positive correlation between repeat content and genome size but not intron size and the number of protein-coding genes was identified in these deep-sea tubeworm species. Evolutionary analysis revealed that Ridgeia pachyptila and R. piscesae, the two tubeworm species that are endemic to hydrothermal vents of the eastern Pacific, started to diverge between 28.5 and 35 million years ago. Four genes involved in cell proliferation were found to be subject to positive selection in the genome of R. piscesae. Conclusion Ridgeia pachyptila and R. piscesae started to diverge after the formation of the Gorda/Juan de Fuca/Explorer ridge systems and the East Pacific Rise. The high growth rates of vent-dwelling tubeworms might be derived from their small genome sizes. Cell proliferation is important for regulating the growth rate in R. piscesae.

Purpose: MXene is two-dimensional (2D) nanomaterials that comprise transition metal carbides, nitrides, and carbonitrides. Their unique nanostructure attributes it a special role in medical applications. However, bibliometric studies have not been conducted in this field. Therefore, the aim of the present study was to conduct a bibliometric analysis to evaluate the global scientific output of MXene in biomedical research, explore the current situation of this field in the past years and predicte its research hotpots.Methods: We utilized visual analysis softwares Citespace and Bibliometrix to analyze all relevant documents published in the period of 2011–2022. The bibliometric records were obtained from the Web of Science Core Collection.Results: A total of 1,489 publications were analyzed in this study. We observed that China is the country with the largest number of publications, with Sichuan University being the institution with the highest number of publications in this field. The most publications on MXene medicine research in the past year were found primarily in journals about Chemistry/Materials/Physics. Moreover, ACS Applied Materials and Interfaces was found to be the most productive journal in this field. Co-cited references and keyword cluster analysis revealed that #antibacterial# and #photothermal therapy# are the research focus keyword and burst detection suggested that driven wearable electronics were newly-emergent research hot spots.Conclusion: Our bibliometric analysis indicates that research on MXene medical application remains an active field of study. At present, the research focus is on the application of MXene in the field of antibacterial taking advantage of its photothermal properties. In the future, wearable electronics is the research direction of MXene medical application.

Seafloor geodetic network (SGN) is the foundation for building an underwater positioning, navigation and timing (PNT) system. Traditional network deployment mainly focuses on the deployment of underwater sensor network nodes. However, for SGN, there is no surface buoy node and submarine buoy node, and the number of anchors is limited because it is quite expensive to fully cover large scale areas. To achieve wide coverage and good positioning service of each set of underwater base stations, we focus on the network design of a single set of reference stations in this paper. We propose several deployment plans for a local SGN and then analyze their service quality indicators by considering the stratification effect caused by non-uniformly distributed sound speed. To evaluate the performance of each topology of SGN, we compare their coverage range, horizontal dilution precision (HDOP) and accuracy performance of positioning tests. Based on the overall performance in our simulation, we believe that the star five-node topology is a good topology design under sufficient economic conditions.

Treated dentin matrix (TDM) is an ideal scaffold material containing multiple extracellular matrix factors. The canonical Wnt signaling pathway is necessary for tooth regeneration. Thus, this study investigated whether the TDM can promote the odontogenic differentiation of human dental pulp stem cells (hDPSCs) and determined the potential role of Wnt/β-catenin signaling in this process. Different concentrations of TDM promoted the dental differentiation of the hDPSCs and meanwhile, the expression of GSK3β was decreased. Of note, the expression of the Wnt/β-catenin pathway-related genes changed significantly in the context of TDM induction, as per RNA sequencing (RNA seq) data. In addition, the experiment showed that new dentin was visible in rat mandible cultured with TDM, and the thickness was significantly thicker than that of the control group. In addition, immunohistochemical staining showed lower GSK3β expression in new dentin. Consistently, the GSK3β knockdown hDPSCs performed enhanced odotogenesis compared with the control groups. However, GSK3β overexpressing could decrease odotogenesis of TDM-induced hDPSCs. These results were confirmed in immunodeficient mice and Wistar rats. These suggest that TDM promotes odontogenic differentiation of hDPSCs by directly targeting GSK3β and activating the canonical Wnt/β-catenin signaling pathway and provide a theoretical basis for tooth regeneration engineering.

Using FY-2G satellite data, Aircraft Meteorological Data Relay (AMDAR) downlink data, and the fifth generation European Centre for Medium-Range Weather Forecasts (ECMWF) atmospheric reanalysis of the global climate (ERA5) dataset, we analyzed the circulation, thermal, and dynamic characteristics of the convective aircraft turbulence over Australia in the Southern Hemisphere. The results show that the near-convective clouds turbulence (NCCT) in the Southern Hemisphere mostly occurred in front of deep warm high-pressure ridges in mid-latitude regions and on the left side of the axis of the subtropical westerly jet stream. The isotherms in this area were relatively dense (i.e., large gradients), and the wind speed was high, with strong horizontal and/or vertical cyclonic wind shear. In addition, the NCCT usually occurred near the zero-divergence or zero-vorticity line and in areas with large vertical wind speed gradients. There were also strong vertical and horizontal wind shears in this area, which could easily trigger severe turbulence. Furthermore, the NCCT in the Southern Hemisphere mostly occurred at the intersection of cold and warm temperature advections (i.e., near the zero-temperature advection line), and the turbulence point was located near the high-altitude frontal zone where there was a strong gradient of cold and warm advections. There was temperature inversion with pseudo-equivalent potential temperatures in the middle and lower troposphere on the warmer side of the turbulence point. The unstable stratification of cold air at the top and warm air at the bottom was conducive to triggering convection from the ground, forming strong convective clouds, and causing severe turbulence. [ABSTRACT FROM AUTHOR]

As the most abundant biological entities, viruses are the major players in marine ecosystems. However, our knowledge on virus diversity and virus–host interactions in the deep sea remains very limited. In this study, vB_BteM-A9Y, a novel bacteriophage infecting Bacillus tequilensis, was isolated from deep-sea sediments in the South China Sea. vB_BteM-A9Y has a hexametric head and a long, complex contractile tail, which are typical features of myophages. vB_BteM-A9Y initiated host lysis at 60 min post infection with a burst size of 75 PFU/cell. The phage genome comprises 38,634 base pairs and encodes 54 predicted open reading frames (ORFs), of which 27 ORFs can be functionally annotated by homology analysis. Interestingly, abundant ORFs involved in DNA damage repair were identified in the phage genome, suggesting that vB_BteM-A9Y encodes multiple pathways for DNA damage repair, which may help to maintain the stability of the host/phage genome. A BLASTn search of the whole genome sequence of vB_BteM-A9Y against the GenBank revealed no existing homolog. Consistently, a phylogenomic tree and proteome-based phylogenetic tree analysis showed that vB_BteM-A9Y formed a unique branch. Further comparative analysis of genomic nucleotide similarity and ORF homology of vB_BteM-A9Y with its mostly related phages showed that the intergenomic similarity between vB_BteM-A9Y and these phages was 0–33.2%. Collectively, based on the comprehensive morphological, phylogenetic, and comparative genomic analysis, we propose that vB_BteM-A9Y belongs to a novel genus under Caudoviricetes. Therefore, our study will increase our knowledge on deep-sea virus diversity and virus–host interactions, as well as expanding our knowledge on phage taxonomy.

Objective: Hydroxypropyl-β-cyclodextrin (HP-β-CD)/menthyl acetate (MA) microcapsules were developed to overcome the volatile and unstable defects of MA and improve the ease of use and storage. Methods: MA microcapsules were prepared via spray drying using HP-β-CD as the wall material. The embedding rate of MA microcapsules was determined through gas chromatography. The embedding characteristics were studied using phase solubility and nuclear magnetic resonance (NMR). The stability was characterized via differential scanning calorimetry (DSC) and the release and retention rates of MA microcapsules at different temperatures. Results: The embedding rate of HP-β-CD /MA microcapsules was 96.3%. The Gibbs free energy change, enthalpy change and entropy change of the embedding reaction between HP-β-CD and MA were all less than zero, indicating that the embedding process was a spontaneous exothermic reaction. NMR spectra showed that MA entered the cavity of HP-β-CD through the large opening end and interacted with the inner wall of the small opening end. DSC and the release and retention rates of MA microcapsules at different temperatures showed that the stability of MA was significantly enhanced after being embedded in HP-β-CD. Conclusion: The HP-β-CD/MA microcapsules are able to significantly improve the stability of MA and reduce the volatilization of MA.

This study aimed to examine the effects of loading different concentrations of metformin onto an α-hemihydrate calcium sulfate/nano-hydroxyapatite (α-CSH/nHA) composite. The material characteristics, biocompatibility, and bone formation were compared as functions of the metformin concentration. X-ray diffraction results indicated that the metformin loading had little influence on the phase composition of the composite. The hemolytic potential of the composite was found to be low, and a CCK-8 assay revealed only weak cytotoxicity. However, the metformin-loaded composite was found to enhance the osteogenic ability of MC3T3-E1 cells, as revealed by alkaline phosphate and alizarin red staining, real-time PCR, and western blotting, and the optimal amount was 500 µM. RNA sequencing results also showed that the composite material increased the expression of osteogenic-related genes. Cranial bone lacks muscle tissue, and the low blood supply leads to poor bone regeneration. As most mammalian cranial and maxillofacial bones are membranous and of similar embryonic origin, the rat cranial defect model has become an ideal animal model for in vivo experiments in bone tissue engineering. Thus, we introduced a rat cranial defect with a diameter of 5 mm as an experimental defect model. Micro-computed tomography, hematoxylin and eosin staining, Masson staining, and immunohistochemical staining were used to determine the effectiveness of the composite as a scaffold in a rat skull defect model. The composite material loaded with 500 µM of metformin had the strongest osteoinduction ability under these conditions. These results are promising for the development of new methods for repairing craniofacial bone defects.