Nanoscale Optical Conductivity Imaging of Double-Moiré Twisted Bilayer Graphene.

A central paradigm of moiré materials relies on the formation of superlattices that yield enlarged effective crystal unit cells. While a critical consequence of this phenomenon is the celebrated flat electronic bands that foster strong interaction effects, the presence of superlattices has further implications. Here we explore the advantages of moiré superlattices in twisted bilayer graphene (TBG) aligned with hexagonal boron nitride (hBN) for passively enhancing optical conductivity in the low-energy regime. To probe the local optical response of TBG/hBN double-moiré lattices, we use infrared (IR) nano-imaging in conjunction with nanocurrent imaging to examine local optical conductivity over a wide range of TBG twist angles. We show that interband transitions associated with the multiple moiré flat and dispersive bands produce tunable transparent IR responses even at finite carrier densities, which is in stark contrast to the previously limited metallic near transparency observed only in undoped pristine graphene.

crVDAC3 alleviates ferroptosis by impeding HSPB1 ubiquitination and confers trastuzumab deruxtecan resistance in HER2-low breast cancer.

AIMS: With the wide application of trastuzumab deruxtecan (T-DXd), the survival of HER2-low breast cancer patients is dramatically improved. However, resistance to T-DXd still exists in a subset of patients, and the molecular mechanism remains unclear. METHODS: An in vivo shRNA lentiviral library functional screening was performed to identify potential circular RNA (crRNA) that mediates T-DXd resistance. RNA pull-down, mass spectrometry, RNA immunoprecipitation, and co-immunoprecipitation assays were conducted to investigate the molecular mechanism. Ferroptosis was detected using C11-BODIPY, Liperfluo, FerroOrange staining, glutathione quantification, malondialdehyde quantification, and transmission electron microscopy. Molecular docking, virtual screening, and patient-derived xenograft (PDX) models were used to validate therapeutic agents. RESULTS: VDAC3-derived crRNA (crVDAC3) ranked first in functional shRNA library screening. Knockdown of crVDAC3 increased the sensitivity of HER2-low breast cancer cells to T-DXd treatment. Further mechanistic research revealed that crVDAC3 specifically binds to HSPB1 protein and inhibits its ubiquitination degradation, leading to intracellular accumulation and increased levels of HSPB1 protein. Notably, suppression of crVDAC3 dramatically increases excessive ROS levels and labile iron pool accumulation. Inhibition of crVDAC3 induces ferroptosis in breast cancer cells by reducing HSPB1 expression, thereby mediating T-DXd resistance. Through virtual screening and experimental validation, we identified that paritaprevir could effectively bind to crVDAC3 and prevent its interaction with HSPB1 protein, thereby increasing ubiquitination degradation of HSPB1 protein to overcome T-DXd resistance. Finally, we validated the enhanced therapeutic efficacy of T-DXd by paritaprevir in a HER2-low PDX model. CONCLUSION: This finding reveals the molecular mechanisms underlying T-DXd resistance in HER2-low breast cancer. Our study provides a new strategy to overcome T-DXd resistance by inhibiting the interaction between crVDAC3 and HSPB1 protein.

Accelerated proton dissociation in an excited state induces superacidic microenvironments around graphene quantum dots.

Investigating proton transport at the interface in an excited state facilitates the mechanistic investigation and utilization of nanomaterials. However, there is a lack of suitable tools for in-situ and interfacial analysis. Here we addresses this gap by in-situ observing the proton transport of graphene quantum dots (GQDs) in an excited state through reduction of magnetic resonance relaxation time. Experimental results, utilizing 0.1 mT ultra-low-field nuclear magnetic resonance relaxometry compatible with a light source, reveal the light-induced proton dissociation and acidity of GQDs' microenvironment in the excited state (Hammett acidity function: -13.40). Theoretical calculations demonstrate significant acidity enhancement in -OH functionalized GQDs with light induction ( p K a * = -4.62, stronger than that of H2SO4). Simulations highlight the contributions of edge and phenolic -OH groups to proton dissociation. The light-induced superacidic microenvironment of GQDs benefits functionalization and improves the catalytic performances of GQDs. Importantly, this work advances the understanding of interfacial properties of light-induced sp2-sp3 carbon nanostructure and provides a valuable tool for exploring catalyst interfaces in photocatalysis.

Causal relationship between gut microbiota and thyroid nodules: a bidirectional two-sample Mendelian randomization study.

Objective: Emerging evidence suggests alterations in gut microbiota (GM) composition following thyroid nodules (TNs) development, yet the causal relationship remains unclear. Utilizing Mendelian Randomization (MR), this study aims to elucidate the causal dynamics between GM and TNs. Methods: Employing summary statistics from the MiBioGen consortium (n=18,340) and FinnGen consortium (1,634 TNs cases, 263,704 controls), we conducted univariable and multivariable MR analyses to explore the GM-TNs association. Techniques including inverse variance weighted, MR-Egger regression, weighted median, and MR-PRESSO were utilized for causal inference. Instrumental variable heterogeneity was assessed through Cochran's Q statistic and leave-one-out analysis. Reverse MR was applied for taxa showing significant forward MR associations, with multivariate adjustments for confounders. Results: Our findings suggest that certain microbiota, identified as Ruminococcaceae_NK4A214_group (OR, 1.89; 95%CI, 0.47-7.64; p = 0.040), Senegalimassilia (OR, 1.72; 95%CI, 1.03-2.87; p =0.037), Lachnospiraceae (OR,0.64; 95%CI,0.41-0.99; p =0.045), exhibit a protective influence against TNs' development, indicated by negative causal associations. In contrast, microbiota categorized as Desulfovibrionales (OR, 0.63; 95%CI, 0.41-0.95; p =0.028), Prevotella_7 (OR, 0.79; 95%CI, 0.63-1.00; p =0.049), Faecalibacterium (OR, 0.66; 95%CI, 0.44-1.00; p =0.050), Desulfovibrionaceae (OR, 0.55; 95%CI, 0.35-0.86; p =0.008), Deltaproteobacteria (OR, 0.65; 95%CI, 0.43-0.97; p =0.036) are have a positive correlation with with TNs, suggesting they may serve as risk factors. Reverse MR analyses did not establish significant causal links. After comprehensive adjustment for confounders, taxa Desulfovibrionales (Order), Desulfovibrionaceae (Family), Deltaproteobacteria (Class) remain implicated as potential contributors to TNs' risk. Discussion: This study substantiates a significant causal link between GM composition and TNs development, underscoring the thyroid-gut axis's relevance. The findings advocate for the integration of GM profiles in TNs' prevention and management, offering a foundation for future research in this domain.

Autophagy Deficiency Induced by SAT1 Potentiates Tumor Progression in Triple-Negative Breast Cancer.

Aggressive triple-negative breast cancer (TNBC) still lacks approved targeted therapies, requiring more exploration of its underlying mechanisms. Previous studies have suggested a potential role of SAT1 (Spermidine/Spermine N1-acetyltransferase 1) in cancer, which needs to be further elucidated in breast cancer. In this study, highly expressed SAT1 in TNBC signified worse patient prognoses. And SAT1 knockdown effectively inhibited the proliferation and migration abilities of TNBC cells in vitro and in vivo. In terms of mechanism, the transcription factor JUN enhanced SAT1 transcriptional activity by binding to its promoter region. Then, SAT1 protein in the cytoplasm engaged in directly binding with YBX1 for sustaining YBX1 protein stability via deubiquitylation mediated by the E3 ligase HERC5. Further, SAT1 was found to suppress autophagy remarkably via stabilization of mTOR mRNA with the accumulation of YBX1-mediated methyl-5-cytosine (m5C) modification. These findings proved that SAT1 drives TNBC progression through the SAT1/YBX1/mTOR axis, which may provide a potential candidate for targeted therapy in advanced TNBC.

A solvent-free processed low-temperature tolerant adhesive.

Ultra-low temperature resistant adhesive is highly desired yet scarce for material adhesion for the potential usage in Arctic/Antarctic or outer space exploration. Here we develop a solvent-free processed low-temperature tolerant adhesive with excellent adhesion strength and organic solvent stability, wide tolerable temperature range (i.e. -196 to 55 °C), long-lasting adhesion effect ( > 60 days, -196 °C) that exceeds the classic commercial hot melt adhesives. Furthermore, combine experimental results with theoretical calculations, the strong interaction energy between polyoxometalate and polymer is the main factor for the low-temperature tolerant adhesive, possessing enhanced cohesion strength, suppressed polymer crystallization and volumetric contraction. Notably, manufacturing at scale can be easily achieved by the facile scale-up solvent-free processing, showing much potential towards practical application in Arctic/Antarctic or planetary exploration.

Gut microbiota reshapes cancer immunotherapy efficacy: Mechanisms and therapeutic strategies.

Gut microbiota is essential for maintaining local and systemic immune homeostasis in the presence of bacterial challenges. It has been demonstrated that microbiota play contrasting roles in cancer development as well as anticancer immunity. Cancer immunotherapy, a novel anticancer therapy that relies on the stimulation of host immunity, has suffered from a low responding rate and incidence of severe immune-related adverse events (irAEs). Previous studies have demonstrated that the diversity and composition of gut microbiota were associated with the heterogeneity of therapeutic effects. Therefore, alteration in microbiota taxa can lead to improved clinical outcomes in immunotherapy. In this review, we determine whether microbiota composition or microbiota-derived metabolites are linked to responses to immunotherapy and irAEs. Moreover, we discuss various approaches to improve immunotherapy efficacy or reduce toxicities by modulating microbiota composition.

The Application of "Table Tennis Racquet" Random Skin Flap in the Treatment of Facial Skin Carcinoma.

BACKGROUND: The repair of facial skin and soft tissue defects remains a clinical challenge. The author introduced a novel "table tennis racquet" random skin flap for wound repair after facial skin cancer excision and discussed its survival mechanisms. METHODS: A lateral mandibular neck skin flap shaped like a table tennis racquet with no well-known blood vessels at the narrow pedicle was designed in 31 cases to repair tissue defects. Among them, there were 8 cases of skin carcinoma in the frontotemporal area and 23 cases of skin carcinoma in the cheek. The flap area was 8.0 × 7.0 cm at maximum and 3.0 × 2.5 cm at minimum, with a pedicle width of 1.0-2.0 cm and a pedicle length of 2.0-6.0 cm. RESULTS: All 31 "table tennis racquet" random skin flaps survived, although there were 3 cases with delayed healing of distal flap bruising. All of them had an ideal local shape after repair with a concealed donor area and inconspicuous scars. CONCLUSIONS: This flap has a "table tennis racquet" shape with a pedicle without well-known blood vessels and has a length-to-width ratio that exceeds that of conventional random flaps, making it unconventional. Because of its long and narrow pedicle, it not only has a large rotation and coverage area but also can be designed away from the defect area, avoiding the defect of no donor tissue being localized near the defect. Overall, this approach is an ideal option for repairing tissue defects after enlarged excision of facial skin carcinoma.

Accurate diagnosis of severe coronary stenosis based on resting magnetocardiography: a prospective, single-center, cross-sectional analysis.

OBJECTIVE: To evaluate the role of resting magnetocardiography in identifying severe coronary artery stenosis in patients with suspected coronary artery disease. METHODS: A total of 513 patients with angina symptoms were included and divided into two groups based on the extent of coronary artery disease determined by angiography: the non-severe coronary stenosis group (< 70% stenosis) and the severe coronary stenosis group (≥ 70% stenosis). The diagnostic model was constructed using magnetic field map (MFM) parameters, either individually or in combination with clinical indicators. The performance of the models was evaluated using receiver operating characteristic curves, accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). Calibration plots and decision curve analysis were performed to investigate the clinical utility and performance of the models, respectively. RESULTS: In the severe coronary stenosis group, QR_MCTDd, S_MDp, and TT_MAC50 were significantly higher than those in the non-severe coronary stenosis group (10.46 ± 10.66 vs. 5.11 ± 6.07, P < 0.001; 7.2 ± 8.64 vs. 4.68 ± 6.95, P = 0.003; 0.32 ± 57.29 vs. 0.26 ± 57.29, P < 0.001). While, QR_MVamp, R_MA, and T_MA in the severe coronary stenosis group were lower (0.23 ± 0.16 vs. 0.28 ± 0.16, P < 0.001; 55.06 ± 48.68 vs. 59.24 ± 53.01, P < 0.001; 51.67 ± 39.32 vs. 60.45 ± 51.33, P < 0.001). Seven MFM parameters were integrated into the model, resulting in an area under the curve of 0.810 (95% CI: 0.765-0.855). The sensitivity, specificity, PPV, NPV, and accuracy were 71.7%, 80.4%, 93.3%, 42.8%, and 73.5%; respectively. The combined model exhibited an area under the curve of 0.845 (95% CI: 0.798-0.892). The sensitivity, specificity, PPV, NPV, and accuracy were 84.3%, 73.8%, 92.6%, 54.6%, and 82.1%; respectively. Calibration curves demonstrated excellent agreement between the nomogram prediction and actual observation. The decision curve analysis showed that the combined model provided greater net benefit compared to the magnetocardiography model. CONCLUSIONS: The novel quantitative MFM parameters, whether used individually or in combination with clinical indicators, have been shown to effectively predict the risk of severe coronary stenosis in patients presenting with angina-like symptoms. Magnetocardiography, an emerging non-invasive diagnostic tool, warrants further exploration for its potential in diagnosing coronary heart disease.

Methylation of GPRC5A promotes liver metastasis and docetaxel resistance through activating mTOR signaling pathway in triple negative breast cancer.

AIMS: This study aims to explore the function and mechanism of G Protein-coupled receptor class C group 5 member A (GPRC5A) in docetaxel-resistance and liver metastasis of breast cancer. METHODS: Single-cell RNA transcriptomic analysis and bioinformatic analysis are used to screen relevant genes in breast cancer metastatic hepatic specimens. MeRIP, dual-luciferase analysis and bioinformation were used to detect m6A modulation. Mass spectrometry (MS), co-inmunoprecipitation (co-IP) and immunofluorescence colocalization were executed to explore the mechanism of GPRC5A in breast cancer cells. RESULT: GPRC5A was upregulated in triple-negative breast cancer (TNBC) and was associated with a poor prognosis. In vitro and in vivo experiments demonstrated that knockdown of GPRC5A alleviated metastasis and resistance to docetaxel in TNBC. Overexpression of GPRC5A had the opposite effects. The m6A methylation of GPRC5A mRNA was modulated by METTL3 and YTHDF1, which facilitates its translation. GPRC5A inhibited the ubiquitination-dependent degradation of LAMTOR1, resulting in the recruitment of mTORC1 to lysosomes and activating the mTORC1/p70s6k signaling pathway. CONCLUSION: METTL3/YTHDF1 axis up-regulates GPRC5A expression by m6A methylation. GPRC5A activates mTORC1/p70s6k signaling pathway by recruiting mTORC1 to lysosomes, consequently promotes docetaxel-resistance and liver metastasis.

Multi-omics analysis of disulfidptosis regulators and therapeutic potential reveals glycogen synthase 1 as a disulfidptosis triggering target for triple-negative breast cancer.

Disruption of disulfide homeostasis during biological processes can have fatal consequences. Excess disulfides induce cell death in a novel manner, termed as "disulfidptosis." However, the specific mechanism of disulfidptosis has not yet been elucidated. To determine the cancer types sensitive to disulfidptosis and outline the corresponding treatment strategies, we firstly investigated the crucial functions of disulfidptosis regulators pan-cancer at multi-omics levels. We found that different tumor types expressed dysregulated levels of disulfidptosis regulators, most of which had an impact on tumor prognosis. Moreover, we calculated the disulfidptosis activity score in tumors and validated it using multiple independent datasets. Additionally, we found that disulfidptosis activity was correlated with classic biological processes and pathways in various cancers. Disulfidptosis activity was also associated with tumor immune characteristics and could predict immunotherapy outcomes. Notably, the disulfidptosis regulator, glycogen synthase 1 (GYS1), was identified as a promising target for triple-negative breast cancer and validated via in vitro and in vivo experiments. In conclusion, our study elucidated the complex molecular phenotypes and clinicopathological correlations of disulfidptosis regulators in tumors, laying a solid foundation for the development of disulfidptosis-targeting strategies for cancer treatment.

Analysis of cellular response to drugs with a microfluidic single-cell platform based on hyperspectral imaging.

BACKGROUND: Cellular response to pharmacological action of drugs is significant for drug development. Traditional detection method for cellular response to drugs normally rely on cell proliferation assay and metabolomics examination. In principle, these analytical methods often required cell labeling, invasion analysis, and hours of co-culture with drugs, which are relatively complex and time-consuming. Moreover, these methods can only indicate the drug effectiveness on cell colony rather than single cells. Thus, to meet the requirements of personal precision medicine, the development of drug response analysis on the high resolution of single cell is demanded. RESULTS: To provide precise result for drug response on single-cell level, a microfluidic platform coupled with the label-free hyperspectral imaging was developed. With the help of horizontal single-cell trapping sieves, hundreds of single cells were trapped independently in microfluidic channels for the purposes of real-time drug delivery and single-cell hyperspectral image recording. To significantly identify the cellular hyperspectral change after drug stimulation, the differenced single-cell spectrum was proposed. Compared with the deep learning classification method based on hyperspectral images, an optimal performance can be achieved by the classification strategy based on differenced spectra. And the cellular response to different reagents, for example, K+, Epidermal Growth Factor (EGF), and Gefitinib at different concentrations can be accurately characterized by the differenced single-cell spectra analysis. SIGNIFICANCE AND NOVELTY: The high-throughput, rapid analysis of cellular response to drugs at the single-cell level can be accurately performed by our platform. After systematically analyzing the materials and the structures of the single-cell microfluidic chip, the optimal single-cell trapping method was proposed to contribute to the further application of hyperspectral imaging on microfluidic single-cell analysis. And the hyperspectral characterization of single-cell with cancer drug stimulation proved the application potential of our method in personal cancer medication.

Autophagy inhibition mediated by trillin promotes apoptosis in hepatocellular carcinoma cells via activation of mTOR/STAT3 signaling.

Apoptosis and autophagy have been shown to act cooperatively and antagonistically in self-elimination process. On the one side, apoptosis and autophagy can act as partners to induce cell death in a coordinated or cooperative manner; on the flip side, autophagy acts as an antagonist to block apoptotic cell death by promoting cell survival. Our previous research indicated that trillin could induce apoptosis of PLC/PRF/5 cells, but the effects of trillin on autophagy as well as its functional relationship to apoptosis have not been elucidated. Here, the running study aims to investigate the function and molecular mechanism of trillin on autophagy with hepatocellular carcinoma (HCC) cells. The objective of this study is to investigate the molecular mechanism of trillin on autophagy in HCC cells. Protein levels of autophagy markers beclin1, LC3B, and p62 were detected by western blotting. 6-Hydroxyflavone and stattic were used to test the role of trillin regulation of autophagy via serine threonine kinase (AKT)/extracellular-regulated protein kinases (ERK) 1/2/mammalian target of rapamycin (mTOR)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Flow cytometry was used to detect caspase 3 activity and apoptosis in PLC/PRF/5 cells treated with trillin for 24 h with or without rapamycin, stattic, and 6-hydroxyflavone. The protein level of autophagy marker beclin1 was decreased, whilst the protein level of p62 was significantly increased by trillin treatment, indicating trillin treatment led to inhibition of autophagy in HCC cells. Trillin treatment could reduce the protein levels of p-AKT and p-ERK1/2, but enhance the protein levels of mTOR and p-mTOR, suggesting that trillin could inhibit AKT/ERK rather than mTOR. The AKT/ERK activator 6-hydroxyflavone could reverse the loss of AKT and ERK1/2 phosphorylation induced by trillin, implying that trillin impairs autophagy through activated mTOR rather than AKT/ERK. STAT3 and p-STAT3 were significantly upregulated by the trillin treatment with an increase in dose from 0 to 50 µM, suggesting that autophagy inhibition is mediated by trillin via activation of STAT3 signaling. The STAT3 inhibitor stattic significantly reversed the increased STAT3 phosphorylation at tyrosine 705 induced by trillin. The mTOR signaling inhibitor rapamycin reversed the trillin-induced mTOR phosphorylation enhancement but exerted no effects on total mTOR levels, suggesting trillin treatment led to inhibition of autophagy in HCC cells through activating mTOR/STAT3 pathway. Furthermore, caspase 3 activities and the total rate of apoptosis were increased by trillin treatment, which was reversed by rapamycin, stattic, and 6-hydroxyflavone, proving that trillin promotes apoptosis via activation of mTOR/STAT3 signaling. Trillin induced autophagy inhibition and promoted apoptosis in PLC/PRF/5 cells via the activation of mTOR/STAT3 signaling. Trillin has the potential to be a viable therapeutic option for HCC treatment.

A novel axis of circKIF4A-miR-637-STAT3 promotes brain metastasis in triple-negative breast cancer.

Among patients with triple-negative breast cancer (TNBC), distant metastasis is the leading cause of death. Our previous studies have shown that TNBC progression is greatly facilitated by circKIF4A, but uncertainty remains regarding its role in TNBC brain metastasis and the molecular mechanism. In this study, we found notable upregulation of circKIF4A in TNBC cell lines and brain metastases. Inhibition of circKIF4A impaired the ability of TNBC to proliferate, migrate, and cause brain metastasis. Luciferase reporter assays confirmed that circKIF4A competed for binding to miR-637 with STAT3 3' UTR. Western blot analysis revealed that inhibition of circKIF4A decreased STAT3 and p62 expression, while increased the LC3B-II/LC3B-I ratio and the expression of Beclin, indicating that downregulation of circKIF4A induced autophagy by competing with STAT3 for binding to miR-637. By employing a competitive endogenous RNA (ceRNA) mechanism, the circKIF4A-miR-637-STAT3 axis coordinates brain metastasis in TNBC. circKIF4A can therefore be used as a prognostic biomarker for brain metastasis in TNBC and as a therapeutic target.

AURKAIP1 actuates tumor progression through stabilizing DDX5 in triple negative breast cancer.

Aurora-A kinase interacting protein 1 (AURKAIP1) has been proved to take an intermediary role in cancer by functioning as a negative regulator of Aurora-A kinase. However, it remains unclear whether and how AURKAIP1 itself would directly engage in regulating malignancies. The expression levels of AURKAIP1 were detected in triple negative breast cancer (TNBC) by immunohistochemistry and western blots. The CCK8, colony formation assays and nude mouse model were conducted to determine cell proliferation whereas transwell and wound healing assays were performed to observe cell migration. The interaction of AURKAIP1 and DEAD-box helicase 5 (DDX5) were verified through co-immunoprecipitation and successively western blots. From the results, we found that AURKAIP1 was explicitly upregulated in TNBC, which was positively associated with tumor size, lymph node metastases, pathological stage and unfavorable prognosis. AURKAIP1 silencing markedly inhibited TNBC cell proliferation and migration in vitro and in vivo. AURKAIP1 directly interacted with and stabilized DDX5 protein by preventing ubiquitination and degradation, and DDX5 overexpression successfully reversed proliferation inhibition induced by knockdown of AURKAIP1. Consequently, AURKAIP1 silencing suppressed the activity of Wnt/ß-catenin signaling in a DDX5-dependent manner. Our study may primarily disclose the molecular mechanism by which AURKAIP1/DDX5/ß-catenin axis modulated TNBC progression, indicating that AURKAIP1 might serve as a therapeutic target as well as a TNBC-specific biomarker for prognosis.

Single-cell histone chaperones patterns guide intercellular communication of tumor microenvironment that contribute to breast cancer metastases.

BACKGROUND: Histone chaperones (HCs) are crucial for governing genome stability and gene expression in multiple cancers. However, the functioning of HCs in the tumor microenvironment (TME) is still not clearly understood. METHODS: Self-tested single-cell RNA-seq data derived from 6 breast cancer (BC) patients with brain and liver metastases were reanalyzed by nonnegative matrix factorization (NMF) algorithm for 36 HCs. TME subclusters were observed with BC and immunotherapy public cohorts to assess their prognosis and immune response. The biological effect of HSPA8, one of the HCs, was verified by transwell assay and wound-healing assays. RESULTS: Cells including fibroblasts, macrophages, B cells, and T cells, were classified into various subclusters based on marker genes. Additionally, it showed that HCs might be strongly associated with biological and clinical features of BC metastases, along with the pseudotime trajectory of each TME cell type. Besides, the results of bulk-seq analysis revealed that TME cell subclusters mediated by HCs distinguished significant prognostic value for BC patients and were relevant to patients' immunotherapy responses, especially for B cells and macrophages. In particular, CellChat analysis exhibited that HCs-related TME cell subclusters revealed extensive and diverse interactions with malignant cells. Finally, transwell and wound-healing assays exhibited that HSPA8 deficiency inhibited BC cell migration and invasion. CONCLUSIONS: Collectively, our study first dissected HCs-guided intercellular communication of TME that contribute to BC metastases.

Dissection of FOXO1-Induced LYPLAL1-DT Impeding Triple-Negative Breast Cancer Progression via Mediating hnRNPK/ß-Catenin Complex.

Triple-negative breast cancer (TNBC) is considered as the most hazardous subtype of breast cancer owing to its accelerated progression, enormous metastatic potential, and refractoriness to standard treatments. Long noncoding RNAs (lncRNAs) are extremely intricate in tumorigenesis and cancerous metastasis. Nonetheless, their roles in the initiation and augmentation of TNBC remain elusive. Here, in silico analysis and validation experiments were utilized to analyze the expression pattern of clinically effective lncRNAs in TNBC, among which a protective lncRNA LYPLAL1-DT was essentially curbed in TNBC samples and indicated a favorable prognosis. Gain- and loss-of-function assays elucidated that LYPLAL1-DT considerably attenuated the proliferative and metastatic properties along with epithelial-mesenchymal transition of TNBC cells. Moreover, forkhead box O1 (FOXO1) was validated to modulate the transcription of LYPLAL1-DT. Mechanistically, LYPLAL1-DT impinged on the malignancy of TNBC mainly by restraining the aberrant reactivation of the Wnt/ß-catenin signaling pathway, explicitly destabilizing and diminishing ß-catenin protein by interacting with heterogeneous nuclear ribonucleoprotein K (hnRNPK) and constricting the formation of the hnRNPK/ß-catenin complex. Conclusively, our present research revealed the anti-oncogenic effects of LYPLAL1-DT in TNBC, unraveling the molecular mechanisms of the FOXO1/LYPLAL1-DT/hnRNPK/ß-catenin signaling axis, which shed innovative light on the potential curative medicine of TNBC.

Hypoxia-induced endothelial cell-derived exosome stimulates vascular smooth muscle cell proliferation and migration.

This study mainly used human VSMCs and ECs cultured in vitro to investigate whether exosomes (Exos) are involved in the communication between ECs and VSMCs under hypoxia, and to explore the role and mechanism of ECs-derived exosomes in the abnormal proliferation of VSMCs. VSMCs proliferation and migration were assessed by a series of cell function assays after culturing VSMCs alone or co-culturing ECs under hypoxia or normoxia. Next, exosomes were extracted from ECs under hypoxia or normoxia and characterized. We then introduced ECs-Exos to observe their effects on VSMCs proliferation and migration, and further evaluated the expression of transforming growth factor-beta receptor 1 (TGFBR1) pathway-related proteins. Finally, the effect of ECs-Exos on VSMCs function was evaluated after knocking down TGFBR1 in ECs. VSMCs treated with ECs-Exos exhibited increased proliferation and migration ability in hypoxic environment, and the expression of TGFBR1 pathway-related proteins was upregulated. Administration of ECs-Exos with TGFß1 knockdown conspicuously reversed the promoting effects of ECs-Exos on cell proliferation and migration under hypoxia. In summary, hypoxia affected the secretion of extracellular vesicles by endothelial cells, which can be internalized by VSMCs and accelerate the abnormal proliferation and migration of VSMCs by delivering TGFBR1.

Microfluidic magnetic detection system combined with a DNA framework-mediated immune-sandwich assay for rapid and sensitive detection of tumor-derived exosomes.

Tumor-derived circulating exosomes (TDEs) are being pursued as informative and noninvasive biomarkers. However, quantitatively detecting TDEs is still challenging. Herein, we constructed a DNA tetrahedral-structured probe (TSP)-mediated microfluidic magnetic detection system (µFMS) to provide a rapid and sensitive platform for analyzing TDEs. CD63 aptamer-modified Fe3O4 magnetic nanoparticles (MNPs) were constructed to form magnetic nano-report probes (MNRs). The microfluidic chips were fabricated from glass functionalized with DNA TSP-modified aldehyde groups and a PDMS layer designed with serpentine microchannels. An induction coil-based magnetic detector was used to measure the magnetic signal. The linear dynamic range of the µFMS system for TDE assays was 1.98 × 103-1.98 × 107 particles/mL with a limit of detection of 1.98 × 103 particles/mL in PBS. There was no significant difference in TDE detection between the simulated serum and PBS, which indicated the feasibility of the constructed µFMS system for TDE analysis in complex biological systems. In terms of cost, reaction time and operation procedure, this µFMS has the potential to be developed as a clinical point-of-care testing tool for cancer diagnosis and therapeutics.

TaACTIN7-D regulates plant height and grain shape in bread wheat.

Exploitation of new gene resources and genetic networks contributing to the control of crop yield-related traits, such as plant height, grain size, and shape, may enable us to breed modern high-yielding wheat varieties through molecular methods. In this study, via ethylmethanesulfonate mutagenesis, we identify a wheat mutant plant, mu-597, that shows semi-dwarf plant architecture and round grain shape. Through bulked segregant RNA-seq and map-based cloning, the causal gene for the semi-dwarf phenotype of mu-597 is located. We find that a single-base mutation in the coding region of TaACTIN7-D (TaACT7-D), leading to a Gly-to-Ser (G65S) amino acid mutation at the 65th residue of the deduced TaACT7-D protein, can explain the semi-dwarfism and round grain shape of mu-597. Further evidence shows that the G65S mutation in TaACT7-D hinders the polymerization of actin from monomeric (G-actin) to filamentous (F-actin) status while attenuates wheat responses to multiple phytohormones, including brassinosteroids, auxin, and gibberellin. Together, these findings not only define a new semi-dwarfing gene resource that can be potentially used to design plant height and grain shape of bread wheat but also establish a direct link between actin structure modulation and phytohormone signal transduction.