Formononetin protects against Aspergillus fumigatus Keratitis: Targeting inflammation and fungal load.

PURPOSE: To investigate the potential treatment of formononetin (FMN) on Aspergillus fumigatus (A. fumigatus) keratitis with anti-inflammatory and antifungal activity. METHODS: The effects of FMN on mice with A. fumigatus keratitis were evaluated through keratitis clinical scores, hematoxylin-eosin (HE) staining, and plate counts. The expression of pro-inflammatory factors was measured using RT-PCR, ELISA, or Western blot. The distribution of macrophages and neutrophils was explored by immunofluorescence staining. The antifungal properties of FMN were assessed through minimum inhibitory concentration (MIC), propidium iodide (PI) staining, fungal spore adhesion, and biofilm formation assay. RESULTS: In A. fumigatus keratitis mice, FMN decreased the keratitis clinical scores, macrophages and neutrophils migration, and the expression of TNF-α, IL-6, and IL-1ß. In A. fumigatus-stimulated human corneal epithelial cells (HCECs), FMN reduced the expression of IL-6, TNF-α, IL-1ß, and NLRP3. FMN also decreased the expression of thymic stromal lymphopoietin (TSLP) and thymic stromal lymphopoietin receptor (TSLPR). Moreover, FMN reduced the levels of reactive oxygen species (ROS) induced by A. fumigatus in HCECs. Furthermore, FMN inhibited A. fumigatus growth, prevented spore adhesion and disrupted fungal biofilm formation in vitro. In vivo, FMN treatment reduced the fungal load in mice cornea at 3 days post infection (p.i.). CONCLUSION: FMN demonstrated anti-inflammatory and antifungal properties, and exhibited a protective effect on mouse A. fumigatus keratitis.

Implementation of whole-exome sequencing for pharmacogenomics profiling and exploring its potential clinical utilities.

Whole-exome sequencing (WES) is widely used in clinical settings; however, the exploration of its use in pharmacogenomic analysis remains limited. Our study compared the variant callings for 28 core absorption, distribution, metabolism and elimination genes by WES and array-based technology using clinical trials samples. The results revealed that WES had a positive predictive value of 0.71-0.92 and a sensitivity of single-nucleotide variants between 0.68 and 0.95, compared with array-based technology, for the variants in the commonly targeted regions of the WES and PhamacoScan™ assay. Besides the common variants detected by both assays, WES identified 200-300 exclusive variants per sample, totalling 55 annotated exclusive variants, including important modulators of metabolism such as rs2032582 (ABCB1) and rs72547527 (SULT1A1). This study highlights the potential clinical advantages of using WES to identify a wider range of genetic variations and enabling precision medicine.

A modified diffusion-weighted magnetic resonance imaging-based model from the radiologist's perspective: improved performance in determining the surgical resectability of advanced high-grade serous ovarian cancer.

BACKGROUND: Complete resection of all visible lesions during primary debulking surgery is associated with the most favorable prognosis in patients with advanced high-grade serous ovarian cancer. An accurate preoperative assessment of resectability is pivotal for tailored management. OBJECTIVE: This study aimed to assess the potential value of a modified model that integrates the original 8 radiologic criteria of the Memorial Sloan Kettering Cancer Center model with imaging features of the subcapsular or diaphragm and mesenteric lesions depicted on diffusion-weighted magnetic resonance imaging and growth patterns of all lesions for predicting the resectability of advanced high-grade serous ovarian cancer. STUDY DESIGN: This study included 184 patients with high-grade serous ovarian cancer who underwent preoperative diffusion-weighted magnetic resonance imaging between December 2018 and May 2023 at 2 medical centers. The patient cohort was divided into 3 subsets, namely a study cohort (n=100), an internal validation cohort (n=46), and an external validation cohort (n=38). Preoperative radiologic evaluations were independently conducted by 2 radiologists using both the Memorial Sloan Kettering Cancer Center model and the modified diffusion-weighted magnetic resonance imaging-based model. The morphologic characteristics of the ovarian tumors depicted on magnetic resonance imaging were assessed as either mass-like or infiltrative, and transcriptomic analysis of the primary tumor samples was performed. Univariate and multivariate statistical analyses were performed. RESULTS: In the study cohort, both the scores derived using the Memorial Sloan Kettering Cancer Center (intraclass correlation coefficients of 0.980 and 0.959, respectively; both P<.001) and modified diffusion-weighted magnetic resonance imaging-based models (intraclass correlation coefficients of 0.962 and 0.940, respectively; both P<.001) demonstrated excellent intra- and interobserver agreement. The Memorial Sloan Kettering Cancer Center model (odds ratio, 1.825; 95% confidence interval, 1.390-2.395; P<.001) and the modified diffusion-weighted magnetic resonance imaging-based model (odds ratio, 1.776; 95% confidence interval, 1.410-2.238; P<.001) independently predicted surgical resectability. The modified diffusion-weighted magnetic resonance imaging-based model demonstrated improved predictive performance with an area under the curve of 0.867 in the study cohort and 0.806 and 0.913 in the internal and external validation cohorts, respectively. Using the modified diffusion-weighted magnetic resonance imaging-based model, patients with scores of 0 to 2, 3 to 4, 5 to 6, 7 to 10, and ≥11 achieved complete tumor debulking rates of 90.3%, 66.7%, 53.3%, 11.8%, and 0%, respectively. Most patients with incomplete tumor debulking had infiltrative tumors, and both the Memorial Sloan Kettering Cancer Center and the modified diffusion-weighted magnetic resonance imaging-based models yielded higher scores. The molecular differences between the 2 morphologic subtypes were identified. CONCLUSION: When compared with the Memorial Sloan Kettering Cancer Center model, the modified diffusion-weighted magnetic resonance imaging-based model demonstrated enhanced accuracy in the preoperative prediction of resectability for advanced high-grade serous ovarian cancer. Patients with scores of 0 to 6 were eligible for primary debulking surgery.

Oridonin loaded peptide nanovesicles alleviate nonalcoholic fatty liver disease in mice.

This study was to construct a nanovesicle delivery system to improve the loading efficiency and stability of ORI for the treatment of nonalcoholic fatty liver disease (NAFLD). This nanovesicles (NVs) exerted a narrow size distribution (195.6 ± 11.49 nm) and high entrapment efficiency (84.46 ± 1.34%). In vitro cell studies demonstrated that the NVs treatment enhanced the cellular uptake of ORI and reduced lipid over-accumulation and total cholesterol levels in NAFLD cell model. At the same time, in vivo study proved that, compared with the normal group, the model group mice showed a decrease in body weight, a significant increase in liver index (6.71 ± 0.62, p < 0.01), and symptoms of liver lipid accumulation, lipid vesicles, and liver tissue fibrosis. Compared with the model group, after high-dose ORI NVs intervention, mice gained weight, decreased liver index (4.69 ± 0.55, p < 0.01), reduced hepatic lipid droplet vacuoles, reduced lipid accumulation (reduced oil red area, p < 0.001), and alleviated the degree of liver fibrosis (reduced blue collagen area, p < 0.001). In conclusion, ORI/HP-ß-CD/H9-HePC NVs showed specific liver accumulation and improved therapeutic effects, the nano drug loading system provides a promising strategy for the encapsulation of ORI to effectively alleviate the process of NAFLD.

Real-World Effectiveness of Lung Cancer Screening Using Deep Learning-Based Counterfactual Prediction.

The benefits and harms of lung cancer screening (LCS) for patients in the real-world clinical setting have been argued. Recently, discriminative prediction modeling of lung cancer with stratified risk factors has been developed to investigate the real-world effectiveness of LCS from observational data. However, most of these studies were conducted at the population level that only measured the difference in the average outcome between groups. In this study, we built counterfactual prediction models for lung cancer risk and mortality and examined for individual patients whether LCS as a hypothetical intervention reduces lung cancer risk and subsequent mortality. We investigated traditional and deep learning (DL)-based causal methods that provide individualized treatment effect (ITE) at the patient level and evaluated them with a cohort from the OneFlorida+ Clinical Research Consortium. We further discussed and demonstrated that the ITE estimation model can be used to personalize clinical decision support for a broader population.

Comparative study of the clinical efficacy of subcostal thoracoscopy and median sternotomy in treating thymoma: a propensity score-matching analysis.

OBJECTIVE: This study was performed to evaluate the clinical efficacy of subcostal thoracoscopy and median sternotomy as surgical approaches for thymoma resection and lymph node dissection. The feasibility, safety, and clinical outcomes of subcostal thoracoscopy were compared with those of median sternotomy. METHODS: The clinical data of 335 patients with thymoma were retrospectively analyzed. The patients were divided into the subcostal thoracoscopy group and the median sternotomy group. Propensity score matching was performed to obtain comparable subsets of 50 patients in each group. A comparative analysis was conducted on various parameters. RESULTS: All surgeries were successful, and no conversions to open thoracotomy were required in the subcostal thoracoscopy group. Significant differences in the operative time, intraoperative blood loss, chest tube drainage duration, postoperative hospital stay, patient satisfaction scores, pain assessment, and postoperative complications were observed between the two groups. However, there was no significant difference in the number of lymph nodes or lymph node stations dissected intraoperatively between the two groups. CONCLUSION: Subcostal thoracoscopy is not inferior to median sternotomy as a surgical approach for thymoma resection and lymph node dissection. Our research provides important new comparative data on minimally invasive thymoma resection.

A novel endoscopic nasopharyngectomy by low-temperature plasma radiofrequency ablation in localized recurrent nasopharyngeal carcinoma.

OBJECTIVE: Endoscopic nasopharyngectomy (ENPG) with en bloc resection has been well accepted in resectable localized recurrent nasopharyngeal carcinoma (rNPC), but it is a difficult technique to master for most otorhinolaryngology head and neck surgeons. Ablation surgery is a new and simplified method to remove tumors. We designed a novel method using low-temperature plasma radiofrequency ablation (LPRA) and evaluated the survival benefit. METHODS: A total of 56 localized rNPC patients were explained in detail and retrospectively analyzed. The surgery method was ablated from the resection margin to the center of the tumor. The postmetastatic overall survival (OS), local relapse-free survival (LRFS) rate, progression-free survival (PFS) and distant metastasis-free survival (DMFS) were analyzed using the Kaplan-Meier method and compared by the log-rank test. RESULTS: All surgeries were successfully performed without any severe postoperative complications or deaths. The median operation time of ablation and harvested NSFF respectively were 29 min (range, 15-100 min) and 101 min (range, 30-180 min). The average number of hospital days postoperation was 3 days (range, 2-5 days). All cases (100.0%) had radical ablation with negative resection margins. The nasopharyngeal defects were completely re-epithelialized in 54 (96.4%) patients. As of the data cutoff (September 3, 2023), the median follow-up time was 44.3 months (range, 17.1-52.7 months, 95% CI: 40.4-48.2). The 3-year OS, LRFS, PFS and DMFS of the entire cohort were 92.9% (95% CI: 0.862-0.996), 89.3% (95% CI: 0.813-0.973), 87.5% (95% CI: 0.789-0.961), and 92.9% (95% CI: 0.862-0.996), respectively. Cycles of radiotherapy were independent risk factors for OS (p = 0.003; HR, 32.041; 95% CI: 3.365-305.064), LRFS (p = 0.002; HR, 10.762; 95% CI: 2.440-47.459), PFS (p = 0.004; HR, 7.457; 95% CI: 1.925-28.877), and DMFS (p = 0.002; HR, 34.776; 95% CI: 3.806-317.799). CONCLUSION: Radical endoscopic nasopharyngectomy by using low-temperature plasma radiofrequency ablation is a novel, safe and simplified method to master and disseminate for treating resectable rNPC. However, further data and longer follow-up time are needed to prove its efficacy.

CircGFPT1 regulates the growth and apoptosis of esophageal squamous cell carcinoma through miR-142-5p/HAX1 axis.

BACKGROUND: Currently, multiple circular RNAs (circRNAs) have been verified to act as essential regulators in the progression of esophageal squamous cell carcinoma (ESCC). However, there is no study regarding the role of circGFPT1 in the progression of cancers including ESCC. We aimed to investigate the role of circGFPT1 in ESCC progression. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was utilized to measure the expression of circGFPT1, miR-142-5p and HS1-associated protein X-1 (HAX1). 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and 5-ethynyl-2'-deoxyuridine (EdU) assays were employed to evaluate cell proliferation. Cell migration and invasion were detected by wound-healing and transwell assays. Flow cytometry analysis was conducted to assess cell apoptosis. The protein expression of E-cadherin, N-cadherin, Vimentin, C-caspase3, HAX1 and nuclear proliferation marker (Ki67) was analyzed by western blot or immunohistochemistry assay. RESULTS: CircGFPT1 was up-regulated in ESCC tissues and cells. Silencing of circGFPT1 repressed cell proliferation and induced cell apoptosis in ESCC cells. CircGFPT1 acted as a sponge of miR-142-5p. The effects of circGFPT1 knockdown on ESCC cell proliferation and apoptosis were reversed by miR-142-5p inhibition. HAX1 was confirmed to be a target gene of miR-142-5p. CircGFPT1 knockdown inhibited HAX1 expression by targeting miR-142-5p. Additionally, circGFPT1 knockdown hampered tumorigenesis in vivo. CONCLUSION: CircGFPT1 promoted ESCC cell growth and repressed apoptosis by up-regulating HAX1 through sponging miR-142-5p.

Heterogeneous treatment effects of metformin on risk of dementia in patients with type 2 diabetes: A longitudinal observational study.

INTRODUCTION: Little is known about the heterogeneous treatment effects of metformin on dementia risk in people with type 2 diabetes (T2D). METHODS: Participants (≥ 50 years) with T2D and normal cognition at baseline were identified from the National Alzheimer's Coordinating Center database (2005-2021). We applied a doubly robust learning approach to estimate risk differences (RD) with a 95% confidence interval (CI) for dementia risk between metformin use and no use in the overall population and subgroups identified through a decision tree model. RESULTS: Among 1393 participants, 104 developed dementia over a 4-year median follow-up. Metformin was significantly associated with a lower risk of dementia in the overall population (RD, -3.2%; 95% CI, -6.2% to -0.2%). We identified four subgroups with varied risks for dementia, defined by neuropsychiatric disorders, non-steroidal anti-inflammatory drugs, and antidepressant use. DISCUSSION: Metformin use was significantly associated with a lower risk of dementia in individuals with T2D, with significant variability among subgroups.

Brønsted Acid-Mediated Conversion of Naturally Abundant Lathyrane Diterpenes: Are Rare 10,11-seco-Lathyrane Diterpenes Artifacts?

The question of whether rare 10,11-seco-lathyranes are natural products or artifacts is thoughtfully considered after a Brønsted acid-mediated chemical conversion of naturally abundant 5/11/3 lathyrane type diterpenes into 10,11-seco-lathyranes was developed. Benefiting from this concise route, a series of 10,11-seco-lathyrane products (1-14) were smoothly synthesized. The conversion may involve an acid promoted cyclopropane ring opening accompanied by a double bond shift with final trapping of carbocation. The ease of this chemical conversion under mildly acidic conditions may imply that the 10,11-seco-lathyranes isolated to date are artifacts. This work not only develops a new modular synthetic strategy for efficient constructing rare 10,11-seco-lathyranes, but also provides a promising bioactive diterpene with excellent effect against the NO production on LPS-induced BV-2 cells.

BatmanNet: bi-branch masked graph transformer autoencoder for molecular representation.

Although substantial efforts have been made using graph neural networks (GNNs) for artificial intelligence (AI)-driven drug discovery, effective molecular representation learning remains an open challenge, especially in the case of insufficient labeled molecules. Recent studies suggest that big GNN models pre-trained by self-supervised learning on unlabeled datasets enable better transfer performance in downstream molecular property prediction tasks. However, the approaches in these studies require multiple complex self-supervised tasks and large-scale datasets , which are time-consuming, computationally expensive and difficult to pre-train end-to-end. Here, we design a simple yet effective self-supervised strategy to simultaneously learn local and global information about molecules, and further propose a novel bi-branch masked graph transformer autoencoder (BatmanNet) to learn molecular representations. BatmanNet features two tailored complementary and asymmetric graph autoencoders to reconstruct the missing nodes and edges, respectively, from a masked molecular graph. With this design, BatmanNet can effectively capture the underlying structure and semantic information of molecules, thus improving the performance of molecular representation. BatmanNet achieves state-of-the-art results for multiple drug discovery tasks, including molecular properties prediction, drug-drug interaction and drug-target interaction, on 13 benchmark datasets, demonstrating its great potential and superiority in molecular representation learning.

Activation of Toll-like receptor 3 inhibits HIV infection of human iPSC-derived microglia.

As a key immune cell in the brain, microglia are essential for protecting the central nervous system (CNS) from viral infections, including HIV. Microglia possess functional Toll-like receptor 3 (TLR3), a key viral sensor for activating interferon (IFN) signaling pathway-mediated antiviral immunity. We, therefore, studied the effect of poly (I:C), a synthetic ligand of TLR3, on the activation of the intracellular innate immunity against HIV in human iPSC-derived microglia (iMg). We found that poly (I:C) treatment of iMg effectively inhibits HIV infection/replication at both mRNA and protein levels. Investigations of the mechanisms revealed that TLR3 activation of iMg by poly (I:C) induced the expression of both type I and type III IFNs. Compared with untreated cells, the poly (I:C)-treated iMg expressed significantly higher levels of IFN-stimulated genes (ISGs) with known anti-HIV activities (ISG15, MxB, Viperin, MxA, and OAS-1). In addition, TLR3 activation elicited the expression of the HIV entry coreceptor CCR5 ligands (CC chemokines) in iMg. Furthermore, the transcriptional profile analysis showed that poly (I:C)-treated cells had the upregulated IFN signaling genes (ISG15, ISG20, IFITM1, IFITM2, IFITM3, IFITM10, APOBEC3A, OAS-2, MxA, and MxB) and the increased CC chemokine signaling genes (CCL1, CCL2, CCL3, CCL4, and CCL15). These observations indicate that TLR3 is a potential therapy target for activating the intracellular innate immunity against HIV infection/replication in human microglial cells. Therefore, further studies with animal models and clinical specimens are necessary to determine the role of TLR3 activation-driven antiviral response in the control and elimination of HIV in infected host cells.

Genetic background influences pig responses to porcine reproductive and respiratory syndrome virus.

Porcine reproductive and respiratory syndrome virus (PRRSV) is a highly infectious and economically significant virus that causes respiratory and reproductive diseases in pigs. It results in reduced productivity and increased mortality in pigs, causing substantial economic losses in the industry. Understanding the factors affecting pig responses to PRRSV is crucial to develop effective control strategies. Genetic background has emerged as a significant determinant of susceptibility and resistance to PRRSV in pigs. This review provides an overview of the basic infection process of PRRSV in pigs, associated symptoms, underlying immune mechanisms, and roles of noncoding RNA and alternative splicing in PRRSV infection. Moreover, it emphasized breed-specific variations in these aspects that may have implications for individual treatment options.

Increased TT-TG distance caused by excessive tibiofemoral rotation predicts poor clinical outcomes after tibial tubercle osteotomy in recurrent patellar dislocation.

PURPOSE: To compare clinical outcome between recurrent patellar dislocation (RPD) with or without actual tibial tubercle lateralisation (TTL) after medial patellofemoral ligament reconstruction (MPFL-R) combined with tibial tubercle transfer. METHODS: From 2015 to 2018, a total of 172 knees with RPD and a tibial tubercle-trochlear groove (TT-TG) distance of > 20 mm were treated with MPFL-R combined with tibial tubercle transfer. Patients were divided into the lateralisation group (TT-PCL > 24 mm, n = 74) and the nonlateralisation group (TT-PCL ≤ 24 mm, n = 60) based on the presence or absence of actual TTL (TT-PCL > 24 mm). Clinical outcomes were assessed postoperatively at a minimum of 2 years. Second-look arthroscopic evaluations were available for 84 knees to assess cartilage damage. RESULTS: A total of 134 knees with a median follow-up time of 32 months were included. Tibiofemoral rotation (TFR) was significantly higher in the nonlateralisation group than in the lateralisation group (15.4° vs. 9.4°, P < 0.001). At the final follow-up, the nonlateralisation group had significantly lower Kujala (78.2 vs. 86.4, P = 0.001) and Lysholm (80.3 vs. 88.2, P = 0.003) scores than the lateralisation group. At the time of the second-look arthroscopic assessment, 38.9% of the patients in the nonlateralisation group showed cartilage worsening in the medial patellar facet that was significantly higher than that in the lateralisation group (38.9% vs. 12.5%, P = 0.015). CONCLUSION: Patients with RPD and an increased TT-TG distance of > 20 mm but without actual tibial tubercle lateralisation benefit less from tibial tubercle transfer than patients with actual tibial tubercle lateralisation, which may be related to the significantly higher tibiofemoral rotation angle of the former. LEVEL OF EVIDENCE: III.

Relationship among DDR gene mutations, TMB and PD-L1 in solid tumour genomes identified using clinically actionable biomarker assays.

The DNA damage response (DDR) pathway regulates DNA repair and cell survival, and inactivating mutations in DDR genes can increase tumour mutational burden (TMB), a predictive biomarker of treatment benefit from anti-PD-1/PD-L1 immunotherapies. However, a better understanding of the relationship among specific DDR mutations, TMB and PD-L1 expression is needed to improve translational strategies. Here, we determined genomic alteration frequencies in selected DDR genes that are clinically actionable biomarkers and investigated their association with TMB and PD-L1 in bladder, colorectal, non-small cell lung, ovarian and prostate cancers using the FoundationInsights® web portal. Our results not only confirm known associations, such as mismatch repair and POLE gene mutations with high TMB, but also identify significant associations between mutations in the SWI/SNF chromatin remodelling genes ARID1A and SMARCA4 and high TMB in multiple tumour types. Mutations in the ATR gene were associated with high TMB in colorectal and prostate cancers; however, associations between individual DDR mutations and high PD-L1 expression were uncommon and tumour-type specific. Finally, we found that high TMB and high PD-L1 expression were poorly associated, emphasising their independence as predictive biomarkers for immune checkpoint inhibitor use.

Photo-induced scandium-catalyzed biomimetic skeleton conversion of lathyrane to naturally rare eupholathone Euphorbia diterpenes.

The naturally scarce eupholathone-type euphornin E (1) was efficiently prepared from abundant lathyrane-type Euphorbia factor L1via a visible-light-induced Sc(OTf)3-catalyzed tandem process. Eupholathones 2 and 3 were also smoothly obtained by changing the reaction solvent. This route provides a convenient method for easily constructing scarce eupholathone- from lathyrane-type Euphorbia diterpenes, and confirms the biogenetic relationship between them from a chemical standpoint. Notably, compound 1 exhibited good anti-HIV activity.

PRRSV alters m6A methylation and alternative splicing to regulate immune, extracellular matrix-associated function.

The alternative splicing and N6-methyladenosine (m6A) modifications occurring during porcine reproductive and respiratory syndrome virus (PRRSV) infections remain poorly understood. Transcriptome and MeRIP-seq analyses were performed to identify the gene expression changes, splicing and m6A modifications in the lungs of PRRSV-infected pigs. In total, 1624 differentially expressed genes (DEGs) were observed between PRRSV-infected and uninfected pigs. We observed significant alterations in alternative splicing (54,367 events) and m6A modifications (2265 DASEs) in numerous genes, including LMO7, SLC25A27, ZNF185, and ECM1, during PRRSV infection. LMO7 and ZNF185 exhibited alternative splicing variants and reduced mRNA expression levels following PRRSV infection. Notably, LMO7 inhibited c-JUN, SMAD3, and FAK expression, whereas ZNF185 affected the expression of FAK, CDH1, and GSK3ß downstream. Additionally, ECM1 influenced FAK expression by targeting ITGB3 and AKT2, suggesting its involvement in extracellular matrix accumulation through the ITGB3-AKT2/FAK pathway. These changes may facilitate viral invasion and replication by modulating the expression of genes and proteins participating in crucial cellular processes associated with immunity and the extracellular matrix. We highlight the importance of these genes and their associated pathways in PRRSV infections and suggest that targeting these may be a promising therapeutic approach for treating viral infections.

Failure Analysis for Gold Wire Bonding of Sensor Packaging Based on Experimental and Numerical Methods.

There is an increasing demand for the use of automotive sensors where complex working environments may easily lead to failure. Wire pull and shear test models based on finite-element analysis are established to evaluate their reliability by investigating the failure mode and mechanism of gold wire bonding. The effect of shear force position and pull force position on failure is also analyzed. The bonding failure was verified by experiments, which is consistent with the simulation result. The results show that: (1) The three-dimensional quantitative modeling reveals the process of bonding delamination and stress concentration. (2) The bonding-slip method (BSM) is adopted in the gold ball detaching process. The concept of three states, including deformation accumulation, cracking, and disengagement, was put forward to reveal the interface stress evolution trend according to the shear testing results. The results indicate that in the interface, the stress in the deformation accumulation state decreases from the tensile side (or compression side) to the center, and the stress in the cracking and disengagement states reduces gradually from the tensile side to the edge. When the interface is completely separated, the failed shear force concentrates on 42 g. The concept and theory proposed in this work can effectively reveal the failure mechanism of bonding interface and help to establish a new failure criterion.

Anomalous Nernst Effect Induced Terahertz Emission in a Single Ferromagnetic Film.

Despite its important role in understanding ultrafast spin dynamics and revealing novel spin/orbit effects, the mechanism of the terahertz (THz) emission from a single ferromagnetic nanofilm upon a femtosecond laser pump still remains elusive. Recent experiments have shown exotic symmetry, which is not expected from the routinely adopted mechanism of ultrafast demagnetization. Here, by developing a bidirectional pump-THz emission spectroscopy and associated symmetry analysis method, we set a benchmark for the experimental distinction of the THz emission induced by various mechanisms. Our results unambiguously unveil a new mechanism─anomalous Nernst effect (ANE) induced THz emission due to the ultrafast temperature gradient created by a femtosecond laser. Quantitative analysis shows that the THz emission exhibits interesting thickness dependence where different mechanisms dominate at different thickness ranges. Our work not only clarifies the origin of the ferromagnetic-based THz emission but also offers a fertile platform for investigating the ultrafast optomagnetism and THz spintronics.

AUF1-induced circular RNA hsa_circ_0010467 promotes platinum resistance of ovarian cancer through miR-637/LIF/STAT3 axis.

BACKGROUND: Increasing evidences has indicated that primary and acquired resistance of ovarian cancer (OC) to platinum is mediated by multiple molecular and cellular factors. Understanding these mechanisms could promote the therapeutic efficiency for patients with OC. METHODS: Here, we screened the expression pattern of circRNAs in samples derived from platinum-resistant and platinum-sensitive OC patients using RNA-sequencing (RNA-seq). The expression of hsa_circ_0010467 was validated by Sanger sequencing, RT-qPCR, and fluorescence in situ hybridization (FISH) assays. Overexpression and knockdown experiments were performed to explore the function of hsa_circ_0010467. The effects of hsa_circ_0010467 on enhancing platinum treatment were validated in OC cells, mouse model and patient-derived organoid (PDO). RNA pull-down, RNA immunoprecipitation (RIP), and dual-luciferase reporter assays were performed to investigate the interaction between hsa_circ_0010467 and proteins. RESULTS: Increased expression of hsa_circ_0010467 is observed in platinum-resistant OC cells, tissues and serum exosomes, which is positively correlated with advanced tumor stage and poor prognosis of OC patients. Hsa_circ_0010467 is found to maintain the platinum resistance via inducing tumor cell stemness, and silencing hsa_circ_0010467 substantially increases the efficacy of platinum treatment on inhibiting OC cell proliferation. Further investigation reveals that hsa_circ_0010467 acts as a miR-637 sponge to mediate the repressive effect of miR-637 on leukemia inhibitory factor (LIF) and activates the LIF/STAT3 signaling pathway. We further discover that AUF1 could promote the biogenesis of hsa_circ_0010467 in OC. CONCLUSION: Our study uncovers the mechanism that hsa_circ_0010467 mediates the platinum resistance of OC through AUF1/hsa_circ_0010467/miR-637/LIF/STAT3 axis, and provides potential targets for the treatment of platinum-resistant OC patients.